PHARMA, BIOTECH & LIFE SCIENCE WHAT’S INSIDE DISCOVERY 6 RESEARCH & DEVELOPMENT 12 PRECLINICAL 18 CLINICAL TRIALS 27 DIAGNOSTICS 35 BUSINESS & GOVERNMENT POLICY 39 TOOLS & TECHNOLOGY A high-tech Angie’s List .......................................................8 A resource for cellular metabolism .................................14 Matching drug and trial options to patients ..................30 On the cutting edge.............................................................40 FINANCE/MARKETS EDITORIAL/COMMENTARY PRODUCTS & SERVICES Q&A 3 10 45 46 SPECIAL REPORT 22 Disease Modeling So life-like After decades of questionable results, are disease models turning a corner? 32 SHOW PREVIEW: 54th ASCB Annual Meeting, Philadelphia A new universality in cell biology Recognizing potential in RSV Johnson & Johnson deals out $1.75B for respiratory disease company Alios BY KELSEY KAUSTINEN NEW BRUNSWICK, N.J.—Pharma giant John- son & Johnson isn’t interested in closing 2014 quietly, marking the last quarter of the year instead with the $1.75-billion acquisition of privately held Alios BioPharma Inc. The South San Francisco, Calif.-based clinicalstage biopharmaceutical firm is focused on the development of antiviral therapies for respiratory diseases, so the deal nabs Johnson & Johnson a portfolio of drug candidates in a variety of indications, including influenza, rhinovirus and respiratory syncytial virus (RSV). Both companies’ boards of directors unanimously approved the transaction. “We are so pleased to be joining the Janssen Pharmaceutical companies of Johnson & Johnson, who have an impressive track record of bringing breakthrough drugs for viral diseases to market,” Dr. Lawrence M. Blatt, president and CEO of Alios BioPharma, said in a news release. “Our portfolio of novel medications targets a diverse range of viral infections, including respiratory syncytial virus, which complements ongoing efforts by Janssen to develop innovative treatments for important and life-threatening infections.” The transaction, which is subject to customary closing conditions including the Hart-Scott-Rodino Act, is expected to close Johnson & Johnson will pay $1.75 billion to acquire privately held Alios BioPharma Inc., based in the Bay Area of California. J&J particularly has its eye on a promising candidate for treating respiratory syncytial virus, though the deal brings with it other antiviral pipeline products as well. in the fourth quarter of this year. “We are excited that this acquisition will enable us to explore treatment options for a number of viral infections, including RSV, the last of the major pediatric diseases with no available preventive therapy,” commented Dr. William N. Hait, global head of research and development at Janssen. “AL-8176 complements our existing early-stage portfolio for RSV, which aims to prevent and treat this disease, the leading cause of acute lower respiratory infection in children under the age of five.” AL-8176 is a nucleoside analog under development as an oral antiviral therapy against RSV. The compound inhibits RSV’s replication by acting on the viral polymerase, ALIOS CONTINUED ON PAGE 31 CREDIT: ENDO INTERNATIONAL Engineering, physics, computational modeling and quantitative methods are all part of this year’s ASCB special sessions NOVEMBER 2014 : VOLUME 10 : NUMBER 11 Endo International intends to leverage its resources to optimize and drive increased adoption of three key drugs—Xiaflex, Testopel and Testim—that are part of the portfolio of Auxilium, which Endo is in the process of acquiring. A new UC San Diego-led resource funded by the NIH will make it easier for pharmaceutical companies to share data for drug design. Pictured here is UC San Diego’s Atkinson Hall. Expanding the pipeline Mining pharma’s data Endo to acquire Auxilium Pharmaceuticals in a cashand-stock transaction for approximately $2.6 billion BY JEFFREY BOULEY DUBLIN, Ireland—Seeking in part to gain a broader offering of urology and orthopedic products that are natural complements to its current men’s health and pain products, Irish company Endo International plc announced in early October a definitive agreement with Auxilium Pharmaceuticals Inc. to acquire the Chesterbrook, Pa.-based company for $2.6 billion. Under the terms of the deal, Endo will acquire all of the outstanding shares of common stock of Auxilium for a per-share consideration of $33.25 in a cash-andstock transaction. The boards of directors of both companies have unanimously approved the transaction, including the repayment and assumption of debt. The ENDO CONTINUED ON PAGE 42 Pharmaceutical companies to share data for drug design via new UC San Diego-led resource BY LLOYD DUNLAP SAN DIEGO—Pharmaceutical companies will collaborate with researchers at the University of California, San Diego to provide previously unreleased proprietary data for drug discovery through a new $3.7-million effort. The project, led by UC San Diego princi- pal investigators Drs. Rommie Amaro, Victoria Feher and Michael K. Gilson, includes a major subcontract to Rutgers University, directed by Dr. Stephen K. Burley of the Research Collaboratory for Structural Bioinformatics Protein Data Bank. DATA CONTINUED ON PAGE 8 Modeling neurodegenerative disease Stem cells help develop cellular models for understanding Parkinson’s disease From modeling diseases to discovering therapies, stem cells have the potential to change the way we think about medicine. Our researchers have partnered with The Parkinson’s Institute to build a path to more physiologically relevant cellular models for Parkinson’s disease using donor cells to generate induced pluripotent stem cells. Read about the journey the researchers have started, the novel tools they have utilized, and the models they are producing to help advance Parkinson’s disease research. Access the free white papers at lifetechnologies.com/pdmodels For Research Use Only. Not for use in diagnostic procedures. В© 2014 Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified. CO011681 0914 PG1331-PJ4439-CO011681-EXP-RUSH-BrandUpdate-ParkinsonsPrintAd1-Americas-10.625x13.875.indd 1 9/9/14 2:31 PM FINANCE For more information, visit www.DDN-News.com NOVEMBER 2014 | | DDNEWS 3 Selecta nets more than $20M in equity funding WATERTOWN, Mass.—Selecta Bio- sciences Inc., a clinical-stage biotechnology company developing a novel class of targeted antigen-specific immune therapies, announced Oct. 15 that it has secured equity funding of more than $20 million from a combination of new and existing investors. “With strong financial support from both our current and new investors, we are now well positioned to rapidly advance our immune tolerance pipeline, including the lead program SEL-212, the first non-immunogenic treatment for refractory and tophaceous gout,” said Dr. Werner Cautreels, president and CEO at Selecta. “Severe gout is a highly debilitating disease and just one of the potential therapeutic applications of our proprietary Synthetic Vaccine Particle (SVP) platform. With a well-established development path and favorable proforma economics, SEL-212 is a great opportunity. SEL-212 is just the beginning for us, as we have identified many biopharmaceuticals, including existing and new classes of biologics such as gene therapy, where the effects of antidrug antibodies (ADAs) are deleterious.” Selecta reports that it has established strong research and develop- ment and manufacturing expertise to enable the company to readily adapt its proprietary SVP platform to other applications developed internally or in collaboration with partners. In addition to its lead program for severe gout (SEL-212), Selecta is advancing immune tolerance programs to prevent ADAs against Factor VIII (SEL-201), anti-TNF alpha antibodies and vectors used for gene therapy, as well as candidates for allergies and autoimmune diseases. Including the funding just secured, Selecta has obtained a total of $78.6 million in private equity funding to date from such investors as Polaris Venture Partners, Flagship Ventures, OrbiMed Advisors, NanoDimension, Rusnano, I2BF, Eminent Venture Capital and Leukon Investments. Selecta’s immunomodulatory SVPs can induce antigen-specific immune tolerance, enabling them to be applied in a variety of therapeutic areas with large unmet medical need. The company is focused on three key near-term applications: inhibition of immunogenicity for biologic therapies, treatment of allergies and treatment of autoimmune diseases. в– Rigontec raises €9.45M in first closing of Series A round BONN, Germany—Mid-October saw Rigontec GmbH, a privately held biopharmaceutical company developing RNA-based immunotherapeutics for the treatment of cancer and viral diseases, announce the first closing of its Series A financing round, raising €9.45 million, or about $12 million. The round was co-led by Wellington Partners and Boehringer Ingelheim Venture Fund, and it included NRW Bank and High-Tech GrГјnderfonds. Rigontec is developing synthetic ligands of a novel receptor of the innate immune system, retinoic acid inducible gene I (RIG-I), which recognizes viral RNA. RNA motifs that activate RIG-I promote the destruction of diseased cells and the induction of a lasting immune memory, thereby treating and preventing recurrence of disease. Rigontec’s lead compound ImOl100, a proprietary first-in-class product targeting RIG-I, is currently being evaluated for development in several cancer types, including melanoma and prostate cancer. ImOl100 is a chemically synthesized mimic of the natural ligand of RIG-I with improved safety and drug-like properties. In various preclinical models, ImOl100 has demonstrated substantial tumor regression and systemic antitumor activity, including long-term protection against tumor rechallenge. Rigontec’s technology also allows the design of pipeline candidates with additional gene silencing and inhibitory activities, further broadening the applicability of this new class of drugs in the area of oncology and viral infections. в– YOU USED TO KNOW US AS TACONIC FARMS, TACONIC EUROPE, AND TACONIC ARTEMIS We are now Taconic Biosciences Taconic Biosciences helps research organizations worldwide to find answers faster, taking research further by providing better, more predictive rodent models and services. Genetically Engineered Models & Services Genetic, Tissue & Cell Humanization Integrated Custom Model Generation & Breeding Genotyping & Molecular Analysis V I S I T O U R N E W W E B S I TE TO TA K E YO U R STU DY F U RTH ER . TACO NIC.COM | US 1 8 8 8 8 22-6642 | EU 45 70 23 04 05 MARKETS 4 DDNEWS | | NOVEMBER 2014 For more information, visit www.DDN-News.com Pharmaceutical and biotech market indices F Amex Pharmaceutical Index or the month of september, the Dow Jones Industrial Average fell 0.32 percent, the S&P 500 dropped 1.55 percent and the NASDAQ Composite Index sank 1.9 percent. Despite the weak month, the Burrill Select Index is up 20.03 percent for the year, strongly outpacing all of the major indices. 460 461 465 15/Nov 06/Dec 03/Jan 492 495 14/Feb 14/Mar 481 11/Apr 505 512 522 09/May 13/Jun 11/Jul 506 15/Aug 524 533 29/Aug 30/Sep 1151 1144 29/Aug 30/Sep SOURCE: YAHOO FINANCE Burrill Select Burrill Mid-Cap Biotech and Small-Cap Biotech 503 513 533 586 497 257 122 135 15/Nov 06/Dec 576 14/Feb 552 553 567 1105 610 903 945 946 06/Dec 03/Jan 1090 941 963 1036 1076 1116 300 207 145 03/Jan 505 621 14/Mar 11/Apr MID-CA P 184 09/May 215 13/Jun 197 11/Jul 220 225 218 15/Aug 29/Aug 30/Sep 15/Nov 14/Feb 14/Mar 11/Apr 09/May 13/Jun 11/Jul 15/Aug S MALL-CAP SOURCE: BURRILL & CO. SOURCE: BURRILL & CO. U.S. Treasury efforts to fend off inversions could quell M&As BY BURRILL MEDIA SAN FRANCISCO—Seeking to discourage com- panies from acquiring or merging with offshore companies in so-called inversions in order to avoid U.S. taxation, the U.S. Treasury Department in September announced new rules that eliminate the ability of U.S. companies to use earnings of their foreign subsidiaries to fund acquisitions without paying U.S. taxes on that capital. The rules also make it more difficult for companies to invert by strengthening the requirement that the former owners of the U.S. entity own less than 80 percent of the new combined entity. The rules apply to deals that have not closed as of Sept. 22, 2014. The result of these rules, not surprisingly, may be to suppress that rate of mergers and acquisitions (M&As), given that inversions have, so far, been a substantial driver of M&A activity in the life sciences in 2014. In fact, of the $286.2 billion in life-sciences M&A transactions announced so far this year, 44 percent involved inversions. That includes AbbVie’s $54.7-billion acquisition of Shire—which AbbVie now plans to abort—and Mylan’s purchase of Abbott Lab’s European-branded generics division for $5.3 billion. “The actions by the Treasury Department will diminish the attractiveness of inversions, but will fall short of putting an end to them. They will need to be justified by more than their tax benefits alone,” says G. Steven Burrill, CEO of Burrill Media. “It will take legislative action to put a halt to these transactions. When the new session of Congress begins, the controversy over inversions represents an opportunity for comprehensive tax reform and the opportunity to address sub- stantive tax issues of concern to the industry from the effects of tax policy on investment to its ability to incentivize R&D spending.” While inversions may be cooling, at least in the short run, initial public offerings (IPOs) are still taking place at a fairly heated pace. As Burrill notes, the “brisk pace of life- sciences initial public offerings continued in September with a total of seven IPOs completed on global markets, six of which occurred on U.S. exchanges. The activity raised the total number P U B L I Illumina reports record financial results for Q3 2014 C SAN DIEGO—Illumina Inc. recently announced its financial results for the third quarter of fiscal year 2014, noting that revenue was $481 million, a 35-percent increase compared to $357 million in Q3 2013, and that GAAP net income for the quarter was $93 million, or 63 cents per diluted share, compared to $31 million, or 22 cents per diluted share, for the same period last year. Non-GAAP net income for the quarter was $114 million, or 77 cents per diluted share, compared to $63 million, or 45 cents per diluted share in 2013. “Illumina experienced tremendous momentum in the third quarter, with strong shipments in HiSeq X, NextSeq and MiSeq, as well as the associated consumables, resulting in record financial results,” stated Jay Flatley, CEO. “With the most extensive sequencing portfolio available, we are well positioned for continued long-term growth as we develop and address the large and untapped market opportunities ahead of us.” The gross margin for the quarter was 69.5 percent completed globally in 2014 as of the end of September 2014, raising a total of $7.8 billion. That compares to 46 IPOs globally that raised nearly $6.2 billion in the same period last year. In September, four of the six IPOs on U.S. exchanges involved companies based overseas, indicating that companies are finding an easier time raising capital in the U.S. These included Affirmed Therapeutics (Germany), ReWalk Robotics (Israel), ProQR Therapeutics (Netherlands) and Foamix (Israel). в– of U.S. IPOs to 82 for the first nine months of the year for a total of $6.3 billion. That compared to 39 IPOs on U.S. exchanges during the first nine months of 2013, in which companies raised a total of $6 billion.” The 82 IPOs so far in 2014 are already the most to be completed in a single year. Though these new issues are up an average of 8.3 percent, 40 are above their initial offering price while 42 are below. Overall, a total of 102 IPOs have been C O M P A N compared to 58.8 percent in the prior year period; the prior year period included impairment charges of $25.2 million related to the discontinuation of a non-core product line. Excluding the effect of non-cash charges associated with stock compensation, amortization of acquired intangible assets, legal contingencies and impairments, non-GAAP gross margin was 73.2 percent compared to 70.2 percent in the prior year period. Trinity Biotech announces third-quarter results DUBLIN, Ireland—Trinity Biotech plc, a leading devel- oper and manufacturer of diagnostic products for the point-of-care and clinical laboratory markets, recently announced results for the quarter ended Sept. 30, 2014. In addition, it announced that it was temporarily suspending its FDA trials for its Meritas Troponin test. Total revenues for Q3 were $27.2 million, which compares to $24.1 million in Q3 2013, an increase of 12.6 percent. Gross profit for Q3 of this year amounted to $13 million, representing a gross margin of 47.9 percent, which is lower than the 49.7 percent achieved in the same period last Y N E W S year. Research and development expenses have increased to $1.1 million from $900,000 when compared to last year. Operating profit has decreased from $4.8 million to $4.6 million for the quarter. However, if U.K.-related closure costs and Meritas sales and marketing expenses are excluded, operating profit would have increased from $4.8 million in Q3 2013 to $5 million this quarter. ADOCIA reports Q3 financials LYON, France—ADOCIA, a biotechnology company specializing in the development of medicines from already-approved therapeutic proteins, announced its revenues for the third quarter of 2014, which were €100,000 (roughly $127,100), generated from research contracts on the formulation of monoclonal antibodies. For the same period last year, revenues were €4.7 million (nearly $6 million), principally as the result of the amortization of the upfront payment regarding the licensing contract signed with Eli Lilly. 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A recent study discovered that chemical modifications to DNA in the ANK1 gene have a strong association with measures of neuropathology in the brain, and individuals with more Alzheimer’s disease-related neuropathology had more DNA modifications to the ANK1 gene, particularly in the entorhinal cortex and other cortical regions that are traditionally affected. “It’s intriguing that we find changes specifically in the regions of the brain involved in Alzheimer’s disease. Future studies will focus on isolating different cell types from the brain to see whether these changes are neuron-specific,” said first author Dr. Katie Lunnon of the University of Exeter Medical School. CHDI extends collaboration with Evotec HAMBURG, Germany—Evotec AG has announced that its collaboration with CHDI Foundation Inc., established in 2006, has been extended and restated. As a result, CHDI will fund up to 52 full-time scientists at Evotec over the next three years. The partnership is focused on discovering new treatments for Huntington’s disease, and this extension expands the agreement to include the use of Evotec’s highthroughput screening and proteomics platforms. “Evotec represents one of our largest and longest-standing relationships and continues to be an important strategic partner in our search for effective treatments for Huntington’s disease,” Dr. Robert Pacifici, CHDI’s chief scientific officer, commented. “Their integrated drug discovery capabilities are helping us to discover novel targets and to advance drug candidates towards the clinic, and we look forward to continuing to work with Evotec over the coming years.” IN THIS SECTION Alzheimer’s disease A high-tech Angie’s List............................ 8 ANK1 gene modifications linked to Alzheimer’s disease ................... 6 Antibiotics/Microbiome Micriobiome to the rescue ....................... 6 Data sharing Mining pharma’s data (DATA from cover)..................................... 8 HIV/AIDS Computational combat ............................. 6 Huntington’s disease CHDI extends collaboration with Evotec.. 6 Oncology Creating realistic systems ........................ 6 Microbiome to the rescue Vaginal bacteria reveals untapped medical potential of the human microbiome BY ZACK ANCHORS SAN FRANCISCO—One of the most common bacterial organisms found in the vagina has helped scientists at the University of California, San Francisco (USCF) reveal the extent to which the human microbe could serve as a rich source for antibiotic compounds. The researchers found that Lactobacillus gasseri, a common species in the microbe community of the vagina, produces a compound, lactocillin, which closely resembles an antibiotic compound that the pharmaceutical company Novartis is currently testing in a Phase 2 clinical trial. The discovery, along with other key finding of UCSF’s study, suggests there could be many other small molecules produced by microbes in or on the human body that possess therapeutic potential. Dr. Mohamed Donia, who drafted the new study as a postdoctoral fellow at UCSF, tells DDNews that the ability of organisms like Lactobacillus gasseri to produce antibiotic compounds turns the typical drug development UNIVERSITY OF CALIFORNIA, SAN FRANCISCO ANK1 gene modifications linked to Alzheimer’s disease Researchers at the University of California, San Francisco have discovered that the human microbiome could serve as a rich source of potential therapeutics. Pictured here is the UCSF Mission Bay campus. process on its head. “We’re used to developing drugs by discovering natural products or using synthetic chemistry, and then spending years modifying these compounds to achieve the best biological activity and the least toxicity,” says Donia, who is currently an assistant professor of molecular biology at Princeton UCSF CONTINUED ON PAGE 7 Computational Creating combat realistic systems Researchers combine molecular, quantum mechanics to screen for HIV compounds Models are designed to show growth of tumor cells and effectiveness of drugs outside of the body BY KELSEY KAUSTINEN ODENSE, Denmark— The HIV virus remains a difficult one to treat due to its ability to constantly mutate and to protect vulnerable binding sites. In light of this tendency, drugs that have proven effective in the past can lose their potency, leading to a constant need for new drugs targeting new facets of the virus. Given the complexity of the virus, however, identifying compounds with the potential to target it effectively is a timeconsuming process—one that researchers from the University of Southern Denmark have been able to speed up through a new screening model. The researchers in question included postdoc Vasanthanathan Poongavanam, from the Department of Physics, Chemistry and UNIVERSITY OF SOUTHERN DENMARK BR IEFS BY ILENE SCHNEIDER CHARLOTTESVILLE, Va.—“Researchers can take primary cells Pharmacy at the University of Southern Denmark, and Jacob Kongsted, an associate professor from specific human organs, but they die in the Petri dish, and trying to get a drug response is unrealistic,” explains Dr. Brian Wamhoff, vice president of research and development and cofounder of HemoShear, adding, “Drug discovery with cells on the bench is not meaningful in a human context. Tumor cells grow faster in a Petri dish than they do in humans, and other parameters are not the same as they are in the human body. Experimenting on mice is not the same as using the same drugs on humans.” HemoShear, Wamhoff says, can create human responsiveness on the bench by taking multiple cell types that require each other in vivo, bringing them together in the right context and exposing them to physiological parameters that they experience in the human body. “The cells stay alive, wake up and respond, leading to better drug discovery,” he explains. Funded by a contract with the National Cancer Institute (NCI), HemoShear is developing a series of tumor models that recreate a wide variety of cancers for discovery of new drugs. HIV CONTINUED ON PAGE 8 MODEL CONTINUED ON PAGE 9 Postdoc Vasanthanathan Poongavanam, from the Department of Physics, Chemistry and Pharmacy at the University of Southern Denmark (pictured here), and Associate Professor Jacob Kongsted have combined molecular and quantum mechanics in a new, rapid screening model for HIV compounds. DISCOVERY For more information, visit www.DDN-News.com UCSF CONTINUED FROM PAGE 6 University. “This particular compound has bypassed that whole process, and there could be many molecules in other parts of the human microbiota with the same potential.” The UCSF study, which was published in Cell in September, found that lactocillan serves to kill common vaginal bacterial pathogens while sparing other bacteria known to dwell harmlessly in the vagina. “This bacteria actually produced the right drug in the right place, with the exact biological activity that is needed, and probably at the time,” says Donia. While many medicines are derived from microbes and plants, few efforts have been made to use host and interact with other bacteria,” says Donia. Researchers created a machinelearning algorithm that enabled a computer to identify known genes that produce small molecules with potential as drugs. When they used this algorithm to systematically analyze genes in the human microbiome, they identified 3,000 BGCs at different body sites. “We were surprised to find so many BGCs producing every small molecule type, and we were also surprised to find that so many of them were very common within a population of healthy humans,” says Donia. One of the compounds that researchers identified and then studied in greater detail was the molecule produced within the vaginal microbe community, lactocillin, which belongs to a class of antibiotics called thiopeptides. The approach taken by the UCSF researchers differed in significant ways from that of other studies car- NOVEMBER 2014 | | DDNEWS 7 ried out under the umbrella of the Human Microbiome Project. “Most studies have been focused on continuing to sequence and document just which microbes are part of the microbiome,” says Donia. “We took a functional approach and tried to find out what these microbes are actually doing.” The most common method of identifying bacteria residing in humans involves genus-level analysis, but UCSF researchers found that this method is not detailed enough to predict which drug-like molecules bacteria will produce. Individual species, and different strains within each species, produce different molecules. “We need to learn what these molecules are and what they are doing,” said Dr. Michael Fischbach, an assistant professor of bioengineering at UCSF and senior author of the study. “This could represent a pool of molecules with many tantalizing candidates for drug therapy.” в– EDITCONNECT: E111404 Translating Genomes | Personalizing Medicine FREE CRISPR Reagents “We’re used to developing drugs by discovering natural products or using synthetic chemistry, and then spending years modifying these compounds to achieve the best biological activity and the least toxicity,” says Dr. Mohamed Donia, formerly a postdoctoral fellow at the University of California, San Francisco and now an assistant professor of molecular biology at Princeton University. “This particular compound has bypassed that whole process, and there could be many molecules in other parts of the human microbiota with the same potential.” bacteria within the human body as a source for new drug molecules. But recent efforts to better understand the human mirobiome has created new opportunities to explore this therapeutic potential. Scientists have made significant progress toward mapping the bacterial ecosystems found in the gut, skin, nasal passages, mouth, vagina and other parts of the human body through research funded by the NIH’s Human Microbiome Project. However, much less is known about the small molecules that govern interactions between microbes and their human hosts. A primary purpose of the UCSF study was to identify the biosynthetic gene clusters (BGCs) that contain the genetic blueprints for creating such molecules. “Small molecules are the common language that almost every living cell can understand, so we wanted to interrogate what small molecules are being produced by these bacteria and find out how they interact with their Ending Soon! TM Join the Program Before it’s Over! 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Visit www.horizondiscovery.com/GENASSIST to learn more about GENASSISTв„ў and Horizon’s many other products and services HD_AD_DDN_Portrait(Oct2014).indd 1 10/13/2014 9:57:48 AM DISCOVERY 8 DDNEWS | | NOVEMBER 2014 A high-tech Angie’s List Platform links researchers with drug discovery expertise BY LLOYD DUNLAP JERSEY CITY, N.J.—The Alzheimer’s Drug Discovery Foundation (ADDF) and OnDeckBiotech have announced the launch of ADDF ACCESS, a new and improved openaccess platform to connect scientists with a virtual network of contract research organizations (CROs), drug development experts and educational resources. By leveraging OnDeckBiotech’s digital technology, the enhanced ADDF ACCESS platform will streamline links between researchers and CROs specializing in diseases of the central nervous system (CNS) to expedite drug discovery research and development. ADDF ACCESS users will see improved functionalities across the ADDF ACCESS platform, including direct communication with CROs and consultants, a suite of project management tools and educational resources focused on drug development for CNS diseases. The new ADDF ACCESS platform powered by OnDeckBiotech went live in early September right after the ADDF’s 15th International Conference on Alzheimer’s Drug Discovery, held Sept. 8-9, in Jersey City, N.J. “This is an exciting opportunity to leverage the OnDeck technology and a dedicated development team to improve the functionality of ADDF ACCESS,” said Dr. Howard Fillit, executive director and chief science officer of ADDF, in a statement announcing the collaboration. “The new platform will streamline the process of identifying and contracting with CROs that have pharmaceutical development expertise for challenging CNS diseases. This type of expertise is critical to the success of translational CNS research programs in academia and small biotechnology companies.” “It’s not uncommon for a study director to spend weeks searching for and evaluating vendors experienced with a particular model. These costly delays are an unnecessary distraction for scientific teams, and any misstep can compromise an otherwise promising program,” said Cliff Culver, CEO and founder of OnDeckBiotech. “We have seen significant savings of time and reduced administrative cost for both sponsors and vendors on the platform, and we are confident these improvements have a positive impact on research efficiency.” Culver notes that his company and ADDF were “working on similar things independently of each other.” ADDF realized that vendors were having trouble sourcing quality CROs, and the partnership with OnDeck was the result. OnDeck provides a cloud-based platform, which has now been customized for the Alzheimer’s community, to improve functionality, with enhanced search TOOLS & TECHNOLOGY DATA CONTINUED FROM PAGE 1 The data provide atomic details of drug mechanisms and will be used to improve computer-aided drug-design methods with the aim of accelerating drug discovery. “One of the challenges in medical research is the paucity of realworld data available to academic researchers and other interested parties to develop new and improved methods for computeraided drug discovery,” says Amaro, associate professor of chemistry and biochemistry at UC San Diego. “Pharmaceutical companies generate lots of data in-house as they conduct drug research, but often have difficulty sharing these datasets, due to legal and technical barriers.” “This project is all about helping companies release the high-quality data they have generated, which has incredible value to researchers working to improve methods of computer-aided drug discovery,” she adds. “Companies want to help, because everyone stands to benefit from the ability to develop new medications more quickly and inexpensively.” The new Drug Design Data Resource (D3R) will span UC San capabilities to help researchers identify companies that provide specific, relevant services. The service includes detailed profiles of featured CROs, including information on platform technologies relevant to CNS indications, opportunities to rate and review CROs and directly communicate with consultants and key personnel at participating CROs. Project management tools enable users to easily distribute requests for proposals (RFPs) to multiple vendors and ensure robust, competitive bids, including an RFP template, contracting templates and relationship history-tracking data. Educational material to support CRO selection and program design, including recommendations for selecting and managing CRO contracts, and access to webinars from the ADDF’s Annual Drug Discovery for Neurodegeneration Conference are all part of the package. By facilitating quality connections between scientists and toptier drug discovery experts, ADDF ACCESS removes an enormous hurdle to undertaking drug discovery and development in academia and small biotechnology companies, Culver notes. In addition, it’s provided as a free service to users. Vendors pay for the privilege of being listed and profit when new business is directed their way. ■“One of the challenges in medical research is the paucity of real-world data available to academic researchers and other interested parties to develop new and improved methods for computeraided drug discovery,” says Dr. Rommie Amaro, an associate professor at UC San Diego. Diego’s Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Chemistry and Biochemistry, Center for Research in Biological Systems, Center for Drug Discovery Innovation (CDDI) and the San Diego Supercomputer Center. The D3R is being administered through the Center for Research in Biological Systems, which is based at the UC San Diego Qualcomm Institute. D3R researchers will act as “data brokers,” collaborating with scien- EDITCONNECT: E111407 tists and attorneys in the pharmaceutical industry to identify, evaluate, release and enhance useful industrial datasets. The data will then be made available to the drug discovery research community in a manner designed to maximize value, longevity and impact. A dataset will ideally be comprised of approximately 50 or more compound structures provided in smiles (simplified molecular-input line-entry system) or sdf format, Feher notes, along with the associated Kd, Ka, Ki or IC50 assay values, and at least five target co-crystal structures in pdb format. “There are likely to be cases where crystal structures will be further refined by Dr. Stephen Burley’s group at Rutgers,” Feher adds, “in which case, crystallographic structure factors for electron density mapping may also be provided by the company.” The UC San Diego team members are developing a webpage, drugdiscoverydata.org, that will provide a portal to search and download the datasets collected and connect to related resources such as PDB, PubChem, BindingDB, MOAD and ChEMBL. This webpage will also provide information, participation instructions and For more information, visit www.DDN-News.com HIV CONTINUED FROM PAGE 6 in the same department. “HIV is a retrovirus that contains enzymes which make it able to copy itself with the help of host genetic material and thus reproduce,” Poongavanam explains. “If you can block these enzymes’ ability to replicate itself, the virus cannot reproduce.” The researchers’ new method is detailed in a pair of papers: “Binding free energy based structural dynamics analysis of HIV-1 RT RNase H-inhibitor complexes,” which appeared in Integrative Biology, and “Inhibitor Ranking through QM Based Chelation Calculations for Virtual Screening of HIV-1 RNase H Inhibition,” which appeared in PLOS ONE. So far, Poongavanam and Kongsted have used the new methods to screen half a million compounds, reveraling 25 compounds of interest that were tested in a conventional laboratory experiment, showing 14 of them were capable of inhibiting the HIV virus’ ability to reproduce. The promising candidates are now being explored by Italian researchers at the University of Cagliari to see if they could be advanced as HIV drugs. “Our approaches are not new, but we use a combination of existing approaches for this problem in a new way,” Poongavanam explains. “Methods that use molecular mechanics principles are often used to screen millions of chemical compounds in drug discovery because these methods challenge dataset downloads. Multiple industrial partners are currently being recruited to the project. Gilson, a professor of pharmacy and co-director of the CDDI, notes that the D3R will work closely with pharmaceutical companies to publicly release data for use by researchers developing new software to speed the discovery of new medicines for a variety of diseases. “Negotiations have begun, and we have found several companies [which] are very enthusiastic about the project,” Feher states. “Three companies expressed their support when we initiated our grant submission, and we are looking to them for our initial datasets. Members of the computational community, whether in pharmaceutical companies or academia, recognize the value in having these datasets publicly available.” “The drug companies, for example, might provide the structure of a protein and 50 molecules created during a drug discovery project, as well as how well those drugs and drug candidates bind to their protein targets,” adds Gilson. “Researchers worldwide will use these data as benchmarks to test their methods and improve their accuracy.” are fast. But in our study, we used quantum mechanics in addition to molecular mechanics methods in order to put more effort in accuracy of the prediction.” “These methods are very different in principle, but combining these methods solves many mysteries in understanding complex molecular recognition,” he continues. “Quantum mechanics is primarily used to study in detail how a compound binds to a protein at the atomic level; therefore, this method is very accurate, but slow. On the other hand, molecular mechanics-based methods are primarily used to understand large, complex structures at the molecular scale, and they are fast. In our study, we used a вЂ�hybrid’ in order to achieve more accuracy and speed. This approach is very powerful, and indeed became internationally recognized after the Nobel Prize (2013) was awarded to Prof. Martin Karplus, Prof. Michael Levitt and Prof. Arieh Warshel, who are considered pioneers in this growing field.” Poongavanam adds that “These approaches could be applicable to other diseases, but it needs to be tested thoroughly, as we have only validated the models for this enzyme.” He expects to see approaches such as this, utilizing computer-based predictions and screening models, become more prevalent, noting that they are areas of interest for pharmaceutical and biotech companies. в– EDITCONNECT: E111405 Feher, a project scientist in the UC San Diego Department of Chemistry and Biochemistry and lead for discovery resources at the CDDI, says these types of real-world challenges represent a powerful way to test and improve computational methods and thereby speed drug discovery and reduce costs. “Unfortunately drug discovery is still to a large extent trial and error,” says Feher, who spent a decade working in the pharma industry before coming to UC San Diego. “What computational chemists globally are trying to do is to make faster, more accurate, more predictive programs to speed up the process. Part of our mission is to engage the community in these challenges to test newly developed predictive algorithms.” Adds Gilson: “There’s a sense that, although computational drug discovery is already useful, it hasn’t fulfilled its potential, and that the calculations are not as accurate as they could be. We want to help the research community objectively identify the strengths and weaknesses of existing methods, so the results can be fed back into a process of continuous improvement and thus advance the field.” в– EDITCONNECT: E111403 DISCOVERY For more information, visit www.DDN-News.com MODEL CONTINUED FROM PAGE 6 The company recently announced that it has completed the first phase of development of a novel cancer drug discovery platform that replicates human tumor biology and responds to clinically relevant drug concentrations. Using its new platform, HemoShear was able to successfully replicate human therapeutic response to cisplatin, a drug approved to treat non-small cell lung cancer (NSCLC), at a therapeutically relevant concentration. Similarly, HemoShear evaluated two other drugs currently in clinical studies and confirmed a therapeutic response. When evaluated in traditional cell culture systems and mouse studies, the same dose of cisplatin does not show a response. HemoShear’s findings reinforce the need to test cancer drug candidates under more human-relevant tumor conditions. “Nearly 95 percent of all cancer drugs entering clinical trials fail because of toxicity or lack of efficacy,” Wamhoff says. “A major contributor to this dismal failure rate can be attributed to the inability of traditional models to uncover the underlying disease biology and predict efficacy and safety of cancer drug candidates. With our novel approach to recreating the tumor microenvironment, we have demonstrated a major step toward understanding human response to cancer drug treatments.” Wamhoff adds, “There are a lot of 3D tumor systems available, but ours can separate cell types to see how a drug targets each one. It’s a depth of biology not available on other systems.” HemoShear started in 2008 with the goal of validating human responses to 200 drugs in order to enter drug discovery collaborations with select pharmaceutical and biotechnology companies to identify novel therapeutic approaches. By bringing together cancer cells, stromal cells and vasculature under the right conditions, the company hopes to improve the success of drug candidates when they enter the clinic and bring them to patients faster. Two years ago the NCI approached HemoShear to create its tumor microenvironment. The company has received more than $10 million in Small Business Innovation Research funding from the government. HemoShear’s translational tissue systems apply physiological blood flow characteristics to human tissue to restore its in-vivo biology, using material from HemoShear’s biorepository and interpreting data with cutting-edge computational analytics. In Phase 1 of the NCI-funded program, HemoShear demonstrated that NSCLC tumor structure, biology and molecular signaling pathways are restored in the HemoShear platform. “Now the company is about a half-year away from more robustly establishing a model for NSCLC and developing one for pancreatic cancer, then one for prostate cancer and, eventually, one for any solid tumor,” says Dr. Dan Gioeli, director of tumor studies at HemoShear. “We also want to create a model to analyze the mechanism of liver cancer, the most common site for metastasis of lung and pancreatic cancer. We’re trying to understand the biology of metastasis, so we can develop drugs to target it. We want to determine how drugs affect metastasis, how metastasis affects the site and how drugs interdict those processes.” He concludes, “HemoShear’s goal is to enter drug discovery collaborations with select pharmaceutical and biotechnology companies to identify novel therapeutic approaches. We need to have the right partners, and we’re cautiously optimistic.” в– EDITCONNECT: E111406 “ The World’s Most Advanced Metabolic Analyzer ” The new XFp Analyzer is a compact and easy-to-use bench top instrument that is ideal for use in pairwise comparison assays, and with patient-derived samples. — Kacey Caradonna, Ph.D. Applications Scientist, Seahorse Bioscience The XFp Extracellular Flux Analyzer The XFp Analyzer is built on innovative and proven XF technology, and delivers the standard assays that are providing scientists with the necessary functional data that is enabling a greater understanding of cell metabolism. See what’s possible. Scan this QR code and learn more or visit www.seahorsebio.com/ddn NOVEMBER 2014 | | DDNEWS 9 “Now the company is about a half-year away from more robustly establishing a model for NSCLC and developing one for pancreatic cancer, then one for prostate cancer and, eventually, one for any solid tumor,” says Dr. Dan Gioeli, director of tumor studies at HemoShear. 10 DDNEWS | | NOVEMBER 2014 EDITORIAL For more information, visit www.DDN-News.com Clinical trials and tribulations S pay more. Or cancel. And so it is with clinical EVERAL MONTHS AGO, some folks trials and the push in recent years for pharma I follow online were raving about a and biotech companies to do clinical trials well new anime series available through outside one’s national borders. The lure has been a steaming video website dedicated lower costs and often easier patient recruitment. But the bill may be coming due, and to that genre, and I got the value proposition—though it sucked in. To get quicker, uninterprobably won’t be entirely elimirupted access to the episodes, I paid nated—will likely drop noticeably. for a membership. However, since By the way, I’m going to avoid the I’m not into anime overall as much popular term “overseas trials.” Ceras when I was younger, I canceled tainly, Central America is not overthat membership after a few maraseas from Canadian and U.S. pharthon sessions to plow through the mas. Asia is not overseas from Euroseries. pean pharmas. And India—both a I’ve done this kind of thing before. major player in pharma and a popular Enjoy the benefits of a free trial offer Jeffrey Bouley, DDNews Chief Editor clinical trial locale for pharmas based and cancel before the first payment is due. Pay for access to a site only long enough elsewhere—certainly isn’t overseas from itself. Ah, India. The real impetus for this month’s to get all the materials I need from it. Join a movie/music service to get my first dozen or editorial. Let me quote from an article in The Hindu, so DVDs and/or CDs for a penny plus shipping and handling, and then fulfill my membership titled “A steel frame for clinical trials,” that requirements as quickly and cheaply as possible caught my eye in October: “In recent months, to ensure that my discs overall still cost me less the quest for a safer, more transparent clinical trials regime has found new momentum. Fourthan going to a store… …wait, that last one probably dated me a bit. teen notifications in July 2014, governing variEgads, I’m getting old fast (though not quite old ous aspects pertaining to a clinical trial—ranging enough yet to enjoy AARP benefits and discounts). from placebo-controlled trials to compensation My point is that many of us like to enjoy these awards—have been notified. Further, the Central free or reduced-cost benefits, but in the vast Drugs Standard Control Organization (CDSCO) majority of cases, eventually we need to pay. Or has proposed a forward-looking IT-enabled inforBY JEFFREY BOULEY mation system that will ensure transparency and protect the interests of trial subjects.” And just a month earlier, on Hindu Business Online, this excerpt: “Pharmaceutical companies, research labs and others looking to conduct clinical trials will now have to justify the research. India is seen as a cheap destination for clinical trials and companies often test products meant for overseas markets here. A new order issued [by CDSCO] makes it compulsory for these entities to prove why the research needs to be conducted in India.” Interest in clamping down a bit on trials by outside nations inside India has been brewing for years. That might have been spurred sharply by the news in April that 254 Indian women from modest backgrounds died in the course of a 15-year U.S.funded clinical trial—a trial for a cervical cancer screening method in which the women who died were part of a control group denied screening, raising ethical concerns among Indians. Ethical concerns and missteps are not uncommon in the world of clinical trials. But they may be put in a more stark light if missteps or corner-cutting take place in parts of the world that offer “budget trial costs.” Without minimizing the need for ethicality, though, let me be blunt: The bill is coming due for those cheaper trial locales. Pharmas and biotechs should probably be thinking now about better ways to streamline costs and increase efficiencies. в– OUT OF ORDER: REGULATOR, GO TO HEAL A BY RANDALL C WILLIS S I ALLUDED IN MY last commen- tary, life has not been good for the last few months for Health Canada, the governmental department that, among other things, serves the healthcare functions covered in the United States by the FDA. And much of the difficulty has been prompted by one of Canada’s national newspapers, The Toronto Star. First, the Star did an exposГ© series highlighting the lack of transparency at Health Canada with regard to post-marketing adverse events, citing the lack of a centralized database that healthcare workers could access and no mechanism (or apparent will) to warn the population about problems as they arise. To support their position, the Star reporters cited information gleaned from an FDA site designed specifically for that purpose, information that was completely hidden in Canada. More recently, the Star published another series on the ineffectiveness of Health Canada in stopping pharmaceutical companies from importing contaminated drug compounds or excipients from other countries for use in Canadian patients. Again, as a comparator and offender-identification resource, the reporters turned to the FDA web site, which highlighted several cases where the U.S. organization fined drug manufacturers for shoddy practices and banned some products from the U.S. market. The Canadian government has slowly responded to the issues raised, but by late September, one commentator had had enough. “We should, in part, abolish Health Canada and harmonize our drug regulation with those foreign agencies that are more competent than our own government,” proclaimed University of Ottawa professor Amir Attaran in a Toronto Star commentary. can guidelines, literally referencing His demand is not unique, as he their counterpart and adjusting for quickly points out, citing the Eurolocal factors such as drug availability pean Medicines Agency and discusand treatment infrastructure. And sions within Africa, Asia and South in some cases, there is no Canadian America to regionally harmonize guidance and clinicians simply work drug and medical device regulations. with U.S.-produced guidance. So, is it time for Health Canada I can hear the Canadian mob to stick to its HHS-equivalent duties marching down the street. (Excuse and divest drug and medical device us, but we are here to flog you. Hope regulations to the FDA? it’s not a bad time. We can come back.) As I have joked with several AmerRandall C Willis “What about our national autonoican friends, we Canadians look just like you. If you give us too much anticoagulant, my?” they might cry. The science is the science; the medicine do we not bleed? Our regulatory approvals are based on the is the medicine. As in all other jurisdictions, same clinical trials data as yours, so why should the true autonomy comes in drug prices and drug companies have to double-up every time formulary coverage, which are handled regionthey submit an NDA? And because of the dra- ally, and there is nothing to suggest that this matically smaller potential patient populations would have to change in a merged North in Canada, a drug company may find itself American system. Ultimately, the question (at least north of the spending ungodly amounts of money applying for approval of a drug targeting 400 people or border) should come down to what’s in the best fewer. I have no numbers, but I wonder how interest of Canadians, and as I believe Attaran many drugs do not come across the border rightly points out: “The FDA is more transparbecause there is no economic model for profit. ent, better resourced and scientifically better Likewise, the practical reality is that neither equipped than Health Canada will ever be.” As for what would be in it for the FDA to country lives within a geographic bubble. What happens in one jurisdiction (with the possible accept such a merger: possibly nothing. But exception of Las Vegas) ultimately ripples then, I really don’t foresee the FDA’s practices needing to change, and other than expanding through the other one. If FDA officials learn of unforeseen post- its mailing lists to include Canadian addresses, marketing adverse events and decide to add a I don’t foresee any increased burdens, financial black box warning to a drug’s monograph, that or otherwise. And who knows, perhaps the FDA can follow same black box often becomes reflected in the Canadian monograph. I leave it to The Star to Health Canada’s lead on pharmaceutical mardetermine when and why the black box is added keting, which is dramatically more conservative than the United States’ relative Wild West in Canada. A merger of the two agencies (or engulfment) approach of forgiveness, not permission. In any event, if you don’t hear from me after would also reflect current Canadian clinical practices. Very often, in my experience, Canadi- this is published, it is probably because the pitchan practice guidelines are adaptations of Ameri- forked, hockey-sticked mob has had its way. в– www.DDN-News.com PUBLISHER Bruce Poorman [email protected] ASSOCIATE PUBLISHER Laurence Doyle [email protected] EDITORIAL Jeffrey Bouley, Chief Editor [email protected] Lloyd Dunlap, Managing Editor [email protected] Kelsey Kaustinen, Senior Editor [email protected] FEATURES EDITOR Randall C Willis CONTRIBUTING EDITORS Zack Anchors, Jim Cirigliano, Lori Lesko, Ilene Schneider ADVERTISING NORTHEAST Michael Stack 1127 Kristin Drive, Suite 100 Libertyville, IL 60048 847.922.1799 TEL [email protected] MIDWEST/MIDATLANTIC Ryan King 1900 N. 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FERRICK OF SEAHORSE I BIOSCIENCE & VICTOR DARLEY-USMAR OF THE UNIVERSITY OF ALABAMA AT BIRMINGHAM T IS NOW WIDELY ACCEPTED that com- plex diseases associated with aging involve dysfunctional metabolism. This growing healthcare problem includes obesity/diabetes, neurodegeneration, cancer and cardiovascular disease.1-3 The major driver of age-related, metabolic dysfunction is the availability of low-cost, highcalorie foods, in combination with a contemporary sedentary lifestyle. This modern-era health epidemic is creating a “perfect storm” of risk factors that is increasingly manifesting as multiple diseases within the human body and is straining, if not overwhelming, the capabilities and resources of healthcare systems worldwide. Defining Victor Darley-Usmar, metabolic health, Ph.D., professor of particularly the way pathology at cells use energy, or University of bioenergetics, has Alabama at become a necessity Birmingham for healthcare in the 21st century, and at the present time, there is no clinical test available to assess this critical parameter. At the crossroads of understanding cell physiology, disease pathology and etiology is cell metabolism, which is widely known to be a common feature of these costly, debilitating and lethal diseases. This association is in large part due to its central role in the life-sustaining and biosynthetic processes of the cell, specifically energy in the form of ATP, sensing and reacting to cellular stress and providing the building blocks that make up the cells, tissues and organs of the body. A new class of drugs The next decade will witness the release of a new class of drugs, known as “metabolotherapeutics,” which will target metabolic pathways and the individual metabolites that are required for the maintenance of normal health. Finally clinicians will be able to address the long-overlooked area of metabolic liabilities in complex diseases. Establishing metabolic phenotypes and their interdependency with specific signaling pathways has enabled researchers to reprogram them to affect disease states, and the result is a new generation of discoveries and metabolotherapeutic approaches across the entire spectrum of age-related diseases. Like many other classes of treatment, metabolo-therapies will probably be best utilized and result in better outcomes by employing a personalized, targeted therapeutic approach for each patient. Chronic diseases have a complex interplay of genetic and environmental factors and can take decades to cause harm. When they do, the resulting disease may take just as long to significantly disrupt a patient’s l i f e s t y l e a n d /o r threaten his or her life. Until now, the ability to determine a true indication of a patient’s metabolic health (the key David A. Ferrick, integrator of envi- Ph.D., chief scientific ronmental factors officer of Seahorse involved in disease Bioscience etiology and progression) has not been possible. This is a huge gap that needs to be addressed as we start to target the metabolic basis of diseases and as a result prescribe a new class of therapies that target metabolic pathways. We are, in fact, already behind, as many existing therapies are dose-limited due to the off-target effects on bioenergetics. Clinical tests aimed at bioenergetic status should play a critical role in the selection and monitoring of those metabolo-therapies that have the greatest efficacy and safety profile. Additionally, healthcare economics will more than likely favor approaches that identify the best therapeutics first and not the current “trial and error” process that often results in patients going through a gauntlet of therapies until one is found that works. The answer in our cells To develop an index of bioenergetic function, one has to look no further than the mitochondria. Mitochondria are the central organelle in cell metabolism that, along with producing the majority of energy for the cell, are also the biosynthetic hub for manufacturing cellular building blocks. Based on this metabolic role, mitochondria are fundamental in determining whether a cell will grow, mature or die. This explains why the study of cell metabolism has become so important in agerelated diseases. Valuable insight into mitochondrial function can be gained through measuring the rate of oxygen consumed by cells, as virtually all the oxygen is directed to the mitochondria. Oxygen metabolism is the key step that enables mitochondria to perform many tasks, and therefore, measurement of the oxygen consumption rate (OCR) can be used as a direct measure of mitochondrial activity. This realization provided the compelling rationale for exploring translational bioenergetics several decades ago. However, expansion into the clinical arena is only now possible due to breakthrough advances in oxygen sensor chemistry, assay throughput, workflow, ease-of-use and reliability of measuring OCR. Using a well-validated test of mitochondrial function, the Cell Mito Stress Test being an example, the OCR of a cell can be apportioned between the key factors that define bioenergetic health. The first factor is the basal condition that reflects the patient’s current status, based on when the blood sample was drawn and is used to calculate various changes from this “base” state. The second factor is the rate of energy production in the form of ATP, the energy currency of the cell. The third factor is the proportion of the mitochondrial OCR that, rather than being used to make ATP, instead “leaks” through the system as its energy is released as heat. This leak of mitochondrial energy can provide indications of metabolic efficiency. The fourth factor is the capacity of the mitochondria to respond to an energetic, or stress-induced, demand. This is achieved by determining the maximal OCR rate of the cells and is analogous to revving a car engine to its maximum rpm. The difference between basal and maximum OCR reveals the energetic capacity of the mitochondria and is perhaps the most sensitive and earliest indication of impairment and/or metabolic stress. And lastly, the amount of oxygen consumed outside of the mitochondria often correlates with negative aspects of cellular health, such as inflammation, that contribute to the progression of many age-related diseases. Canary in the coal mine In one test, a comprehensive measure of energetic health, or its disease-related deterioration, can now be made. The prognostic and diagnostic value of bioenergetic measurements in patients is still unknown, but recent findings support an emerging concept that circulating leukocytes and platelets can serve as the “canary in the coal mine” by acting as early sensors or predictive biomarkers of metabolic function under conditions of chronic stress and disease.4-8 These studies prompted researchers at the University of Alabama at Birmingham (UAB) to begin an integrated approach using cells isolated from human blood, to establish a quantitative assay of bioenergetic function that they expect will have the power to predict disease progression and response to treatment.9 The two main challenges to achieving this goal are: 1) the establishment of an index of bioenergetic activity that accounts for the complexity of metabolic function and can be appropriately weighted, based on the impairment(s) of a particular indication; and 2) the adaptation of a technology platform and an assay that can directly measure metabolic activity. To address these challenges, UAB established the Mitochondrial Medicine Laboratory to develop the clinical tests that can measure bioenergetics and partnered with Seahorse Bioscience to provide the technology platform and informatics. The goal of the Mitochondrial Medicine Lab is to develop a mitochondrial biomarker-based approach to assessing health, called the bioenergetic health index (BHI). To facilitate development of the BHI, Seahorse Bioscience addressed both the difficulty of obtaining functional metabolic measurements and the ability to interpret those results. This was accomplished by standardizing the direct measures of metabolic flux using a proprietary technology called extracellular flux. Early translational studies suggest that this platform may be amenable for defining metabolic status and that assays may be developed to pinpoint metabolic liabilities in diseases that can instruct which drug is most likely to be effective. An early finding by the group at UAB is that the mitochondrial parameters generated in the test of mitochondrial function are interactive. If integrated appropriately into a single value, they can serve as a sensitive indicator of the response of cells to environmental stress and chronic disease progression.9 This is accomplished in the BHI equation by quantifying positive aspects of bioenergetic function (reserve capacity and ATP-linked respiration) and contrasting these with potentially deleterious ones (non-mitochondrial oxygen consumption and proton leak). For example, the larger the value for reserve capacity, which raises BHI, the more effectively mitochondria can meet both the normal energy needs of the cell and the increased metabolic demand caused by stress and disease.10 Preliminary studies in several indications are in progress at the Mitochondrial Medicine Laboratory at UAB and other institutions around the world. The overall goal is to determine if BHI can be deployed as the first clinical test for assessing bioenergetic dysfunction. Can it be predictive early in disease progression before significant pathology and/or acutely prior to life-threatening conditions? If successful, the BHI test could become an important approach to integrating personalized medicine with state-of-theart translational bioenergetics. в– David Ferrick, Ph.D., is chief scientific officer at Seahorse Bioscience, a privately held Boston-area biotechnology company that designs and manufactures metabolic analyzers and assay kits for measuring cell metabolism in living cells. Victor Darley-Usmar, Ph.D., is the director of the Mitochondrial Medicine Laboratory at University of Alabama at Birmingham and has pioneered the application of the mitochondrial stress test to analysis of patient bioenergetic health. REFERENCES If you’d like to check out the 10 references for this commentary, just go to the online version of the commentary, which appears unabridged at: http://ddn-news.com/ news?newsarticle=8956 The opinions expressed in guest commentaries do not necessarily represent those of DDNews and/or its owners, editors or other staff. For more information, visit www.DDN-News.com 12 DDNEWS | | NOVEMBER 2014 RESEARCH & DEVELOPMENT LEIDEN, the Netherlands—MIMETAS has announced receipt of $1.6 million in funding to develop a kidney-on-a-chip for toxicological use and will collaborate in a consortium with Radboudumc and FHNW. This funding stems from the NephroTube CRACK IT Challenge, which is organized by the U.K.’s National Centre for the Replacement, Refinement and Reduction of Animals in Research and supports the development of a microfluidic renal model that can predict renal toxicity in preclinical development. The funds will allow the consortium to develop, analyze and validate a high-throughput kidney-on-a-chip model through the combination of MIMETAS’ OrganoPlate 3D-culturing technology and the human renal cell line ciPTEC. This model will aid in the detection of renal tubular injury seen in drug-induced nephrotoxicity and allow for fewer animal experiments. Ario boosts portfolio with TRPA1 acquisition CAMBRIDGE, U.K.—Ario Pharma Ltd. has announced the acquisition of a TRPA1 antagonist research program from PharmEste, a program that includes a series of small-molecule TRPA1 antagonists, patents and related data. Ario Pharma, which has its own TRPA1 chemistry portfolio as well, plans to initiate a TRPA1 lead optimization project with a focus on orally available TRPA1 antagonist small molecules for asthma. The TRPA1 target has shown potential in inflammatory diseases and plays a key role in the pathophysiology of asthma. “This asset acquisition significantly strengthens Ario Pharma’s chemistry portfolio in the TRPA1 field, and we plan to select one or more development candidates within the next 18 months,” said John Ford, CEO of Ario Pharma. “We are overcoming solubility and pharmacokinetic issues associated with historical TRPA1 modulators developed by other companies and are excited by the level of target validation of TRPA1 in respiratory, pain and other inflammatory diseases.” IN THIS SECTION Asthma Ario boosts portfolio with TRPA1 acquisition .......................... 12 Metabolomics A resource for cellular metabolism ........ 14 Non-coding RNA Centralizing research.............................. 12 Obesity/Liver disease Hickory dickory dock… .......................... 12 Renal toxicity MIMETAS to pursue kidney-on-a-chip model with $1.6M ...... 12 Stem cells Hitting the stem cell вЂ�reset’.................... 12 Hitting the stem cell вЂ�reset’ Scientists return human stem cells to earliest developmental state BY LLOYD DUNLAP CAMBRIDGE, U.K.—Scientists have managed to “reset” human pluripotent stem cells to their earliest developmental state, equivalent to cells found in an embryo before it implants in the womb (seven to nine days old). These “pristine” cells could be the true starting point for human development, but have until now been impossible to recreate in the lab. The findings, published in Cell, are expected to lead to a better understanding of human development and could eventually enable the production of more reproducible starting materials for a wide range of applications, including cell therapies. In the article, authors Dr. Yasuhiro Takashima, Prof. Austin Smith, et. al., note that, “Our findings suggest that authentic ground-state pluripotent stem cells may be attainable in CREDIT: CHRISTIAN RICHARDT MIMETAS to pursue kidneyon-a-chip model with $1.6M Researchers at the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute at the University of Cambridge (the university’s Clare College and King’s College Chapel pictured here) report that they have found a way to return stem cells to their earliest developmental state. human, lending support to the notion of a generic naive state of pluripotency in mammals. In human, the naive-state transcription factor circuitry appears in large part to be conserved but requires greater reinforcement to be stably propagated. Disposition to collapse reflects the transient nature of naive pluripotency in the embryo (Nichols and Smith, CREDIT: MIKE PEEL BRIEFS “The growth in non-coding RNA sequence and functional information is phenomenal and shows no signs of slowing. There has never been a greater demand for a universal resource for these data. The collaboration of RNAcentral consortium members to produce this resource represents an enormous step forward for the RNA field,” says Sam Griffiths-Jones of the University of Manchester (pictured here). tral, reportedly the first unified resource for all types of non-coding RNA data, was launched in September by the RNAcentral Consortium. RNAcentral brings together information from a federation of Hickory dickory dock… Using a novel biological aging clock and tissue samples, UCLA researchers find that obesity accelerates aging of the liver BY LORI LESKO LOS ANGELES—Armed with a recently developed biomarker of expert databases and provides tools for easy browsing. The RNAcentral consortium currently includes 24 RNA database resources. The initial release of RNAcentral contains about 8 million sequences. Using funding from RNA CONTINUED ON PAGE 15 UCLA CONTINUED ON PAGE 16 RNAcentral launched in September to provide unified resource for noncoding RNA data CAMBRIDGE , U.K.— RNAcen- STEM CONTINUED ON PAGE 17 aging known as an epigenetic clock, University of California, Los Angeles (UCLA) researchers and German investigators have discovered that obesity accelerates aging of the liver and increases odds of liver cancer. This finding was published Oct. 13 in the early online edition of Proceedings of the National Academy of Sciences. Although it had long been suspected that obesity ages a person faster, it wasn’t possible to prove the theory until first author Steve Horvath, a UCLA professor of human genetics and biostatistics, developed an epigenetic clock last year. A team headed by Horvath and Prof. Jochen Hampe of the University of Dresden in Germany were then able to show that carrying excessive weight can negatively impact select human tissues. “This is the first study that evaluated the effect of body weight on the biological ages of a variety of human tissues,” Horvath said in a news release. “Given the obesity epidemic in the Western world, the results of this study are highly relevant for public health.” The idea for the study actually began in 2003 when Horvath downloaded a freely available liver DNA methylation data set from Gene Expression Omnibus, an online repository of data. “I found a very strong correlation between body mass index (BMI) and epigenetic age acceleration in liver tissue,” Horvath tells DDNews. “I immediately contacted Prof. Jochen Hample Centralizing research BY ILENE SCHNEIDER 2009). The imperative for developmental progression may be intrinsically stronger in primates that, unlike rodents, have not evolved the facility for embryonic diapause (Nichols and Smith, 2012).” In conclusion, the authors state that, “Human genetic variation notwithstanding, IN PHARMA, time is Does the old saying apply to your work, or are there other answers? Business justification for every decision is the new normal in pharma. Maximizing efficiency and minimizing costs are part of daily life these days, and that’s no different in drug discovery and development. Yet how do you balance innovation, quality, and efficiency? How do you determine the ROI for trying something different? We understand your challenges and want to start a conversation in your community to acknowledge the tradeoffs you face every day. Join the conversation at bio-rad.com/info/Win 14-1741_PFD_NGC_Pharma_Print_Ad1_DDN_110114_FINAL.indd 1 10/10/14 10:24 AM C RESEARCH & DEVELOPMENT 14 DDNEWS | | NOVEMBER 2014 A resource for cellular metabolism Agilent teams with University of Toronto on metabolomics library BY ZACK ANCHORS SANTA CLARA, Calif.— Scientists at the Univer- sity of Toronto’s main biomedical research laboratory will soon have a sophisticated new resource to support their studies of cellular metabolism. Agilent Technologies has announced that it is entering a collaboration with the university that will result in the creation of a comprehensive metabolomics multiple-reaction monitoring (MRM) library at the Donnelly Centre for Cellular and Biomolecular Research. The partnership will give scientists access to technologies that will allow them to accelerate the quantification of hundreds of metabolically important compounds for cell biology and disease research. “Routine metabolite quantification plays an essential role in helping scientists understand how diseases modify metabolic pathways,” Steve Fischer, market director for Agilent’s Life Science Research Division, tells DDNews. “The development of a routine, targeted metabolite MRM method and MRM library will make available a targeted metabolomics solution that will be used by many researchers worldwide.” Metabolomics is an field of research that aims to compare the relative differences between biological samples based on their metabolite profiles. It can provide researchers an instantaneous snapshot of the entire physiology of an organism. The system at the heart of the partnership involves Agilent’s Infinity 1290 UHPLC and 6460 triple quadrupole mass spectrometry technologies. “This highperformance, workhorse system will allow scientists at the Donnelly Centre to analyze thousands of biological samples a month to support targeted, high-throughput metabolomics studies,” says Fischer. This mass spectrometry process will be conducted after a researcher has already completed a biological hypothesis of which metabolic pathways are implicated in a disease process. The system will help confirm and quantify specific metabolites on a large, statistically valid sample set. Agilent will work with Drs. Amy Caudy and Agilent (the headquarters of which are pictured here) uses collaborations as a key component of its strategy to maintain strong ties with current and prospective customers, notes Steve Fischer, market director for Agilent’s Life Science Research Division. CREDIT: AGILENT TECHNOLOGIES CREDIT: AGILENT TECHNOLOGIES TOOLS & TECHNOLOGY The system at the heart1of4/30/2014 the partnership INDIGO_DDN_Ad_2014.04.29.pdf 1:16:10 PM between Agilent and University of Toronto involves Agilent’s Infinity 1290 UHPLC and 6460 triple quadrupole mass spectrometry technologies. Adam Rosebrock at the Donnelly Centre to create the MRM library and methodology. The MRM library will be a database that contains compound information and fragmentation spectra of MRM transitions and their optimal collision energy and other method information, such as retention time. This database will allow users the flexibility to select which metabolites they wish to analyze using Agilent’s mass spectrometry system. The collaboration originated when Caudy and Rosebrock purchased instruments from Agilent in 2010 for metabolomics shortly after arriving at the University of Toronto. Agilent remained in touch with the researchers, and after several years the researchers saw an opportunity for a collaborative relationship. “We are impressed with Agilent’s mass spectrometry instruments and software solutions, and we look forward to working together to M MY Y INDIGO Biosciences has the largest portfolio of human and nonhuman nuclear receptors available. INDIGO gives you the accurate results and fast turnaround you need. Our on-demand screening services and easy-to-analyze data reports bring the industry experts to your team. Or, bring the power of INDIGO into your lab with INDIGO Nuclear Receptor Assay Kits. When you need the ideal research partner for nuclear receptor screening, the name to know is INDIGO. INDIGO Biosciences is the only contract research organization focused exclusively on nuclear receptor research, offering a full range of nuclear receptor screening services, including both human and nonhuman nuclear receptor assays, functional assays and custom assay development. With INDIGO at your service, you can expect fast, accurate results, every time. MY K enable use of LC-MS metabolomics by a larger scientific audience,” according to Rosebrock, a principal investigator whose lab focuses on understanding the biochemistry underlying cell growth and division. Agilent is a measurement company that designs and manufactures a wide range of instruments used in chemical analysis, life sciences, diagnostics, electronics and communications. The company offers several instruments for the study of metabolomics. These tools enable users to conduct research in a diverse range of areas, including toxicology, environmental analysis, agriculture, biofuel development and nutrition. Metabolomics results can also be used to supplement gene expression or proteomics studies. Fischer tells DDNews he expects the new metabolomics MRM library to be completed AGILENT CONTINUED ON PAGE 17 For the largest selection of nuclear receptors, there’s only one name you need to know. M Y For more information, visit www.DDN-News.com Visit our website for a complete list of products and services. www.indigobiosciences.com [email protected] 814.234.1919 W P E . For more information, visit www.DDN-News.com RNA CONTINUED FROM PAGE 12 the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), partner institutes throughout the world were able to come together and build what they see as a practical solution to a shared problem. Since the 1950s, scientists have thought of RNA as an intermediate molecule that provides a link between stable DNA and proteins. However, in recent decades it has become clear that RNA plays a much wider range of roles in living organisms. Researchers have discovered a lot about different types of RNA, but until now these data have not been put in one place. “During the last decade, there has been a great increase in the number of noncoding RNA genes identified, including new classes such as microRNAs and piRNAs,” explains Alex Bateman, head of Protein Sequence Resources at EMBL-EBI (the European Bioinformatics Institute). “There is also a large amount of experimental characterization of these RNA components. Despite this growth in information, it is still difficult for researchers to access RNA data, because key data resources for noncoding RNAs have not yet been created. The most pressing omission is the lack of a comprehensive RNA sequence database, much like UniProt, which provides a comprehensive set of protein knowledge.” Before RNAcentral, finding the RNAs encoded by a specific genome required gathering information from several independent resources, for example miRBase for microRNAs and HAVANA for lncRNAs. “There is plenty of published data on noncoding RNAs, but each subtype is maintained separately,” according to Bateman. “This is the first time we have a central place where you can find it all: piRNAs, ribosomal RNAs, everything. A lot of that information has typically been locked up in supplementary materials, or referred to only by a non-standard gene name. RNAcentral is a big step towards making RNA sequence as easy to access for research as protein sequence.” RNAcentral 1.0 gives researchers access to data from 10 different expert databases and provides stable accession numbers that can be used consistently in the literature, other molecular databases and search engines. The RNAcentral website features a faceted search that enables users to explore different RNA sequences according to source, species and molecular function. Further expert databases will be included in future releases. The RNAcentral consortium has its roots in a workshop held on the Wellcome Genome Campus in 2010. At that time members of the RNA community came together to discuss the lack of centralized access to RNA data. “It is really satisfying to see this project come to fruition,” said Sam Griffiths-Jones of the University of Manchester. “The growth in non-coding RNA sequence and functional information is phenomenal and shows no signs of slowing. There has never been a greater demand for a universal resource for these data. The collaboration of RNAcentral consortium members to produce this resource represents an enormous step forward for the RNA field.” According to BBSRC Chief Executive Prof. Jackie Hunter, “Fundamental research into noncoding RNAs has many potential applications, including disease diagnostics, new therapies and biotechnology. With the abundance of data now available due to next-generation DNA sequencing, there is an urgent need for informatics tools to decipher it. RNAcentral is a vital resource that will aggregate and inte- RESEARCH & DEVELOPMENT grate information to unify the data landscape and improve the discoverability and use of data by researchers worldwide.” The resource uses EMBL-EBI infrastructure, notably data-submission and cross-reference services provided by the European Nucleotide Archive. It takes advantage of the nightly, global synchronisation of data from the International Nucleotide Sequence Database Collaboration. Future versions of RNAcentral will include additional data types and information about RNA structure, modifications, molecular interactions and function. A paper describing RNAcentral tools and features in detail has been accepted for publication in the journal Nucleic Acids Research. RNAcentral partners are EMBL-EBI, the University of Manchester, the Wellcome Trust Sanger Institute, the University of California Santa Cruz, the University of Texas, Auburn University, Sandia National Laboratory, the University of Oxford, the Garvan Institute of Medical Research, the International Institute of Molecular and Cell Biology Warsaw and Adam Mickiewicz University, Rockefeller University, the Chinese Academy of Sciences, the Peking Union Medical College and Taicang NOVEMBER 2014 | | DDNEWS 15 Institute of Life Sciences Information, Michigan State University, National Chiao Tung University, Stanford University, the University of Thessaly, the Institute of Bioinformatics and Systems Biology of the Department of Biological Science and Technology at National Chiao Tung University and the National Center for Biotechnology Information. “This resource will facilitate the next generation of RNA research and help drive further discoveries, including those that improve food production and human and animal health,” Bateman concluded. в– EDITCONNECT: E111409 Harness the Power of Metabolomics Achieve better models, candidates & markers with metabolomics. Innovative diagnostics and research solutions for discovery, clinic and bioprocess. Learn more at www.metabolon.com/pharma. www.metabolon.com 16 DDNEWS | | NOVEMBER 2014 UCLA CONTINUED FROM PAGE 12 in Germany, who was the senior author of this data set. He was happy to collaborate with me and generated additional validation data sets for this project. I also felt that it would be necessary to determine whether a similar effect could be observed in human adipose tissue, which is why I collaborated with several researchers from the Twins UK study: Tim Spector, Jordana Bell and Panos Deloukas.” RESEARCH & DEVELOPMENT “About a year ago, I published an article (at genomebiology.com) that describes a novel biomarker of aging that allows one to measure the age of the vast majority of human tissues, organs and cell types,” he adds. “Recent data have convinced me that the epigenetic clock measures at least some aspects of biological age. Many people have asked me whether caloric restriction or certain diets keep us young. We do not yet know whether the epigenetic age of liver tissue relates to all causes of mortality or even to the onset of various age-related diseases. It is, of course, a plausible hypothesis that the age of the liver should have prognostic and diagnostic utility, but we will need prospective cohort studies to rigorously test these hypotheses.” Also, it is well known that obese people are more susceptible to certain types of cancer, Horvath notes. “But we don’t quite understand why that is the case,” he adds. “Our study points to an intriguing explanation. Since age is a major risk fac- For more information, visit www.DDN-News.com tor of many cancers, it would make sense that livers that are older than expected are also at an increased risk of malignant transformation.” Horvath’s team also studied whether weight loss reverses the epigenetic age of liver tissue. “Unfortunately, we could not observe a beneficial effect within nine months of bariatric surgery,” says Horvath. “But it is unclear whether a rejuvenating effect due to weight loss can be observed after a longer follow-up. I don’t think our study points to new drugs and therapies for controlling obesity, per se. But it might lead to drugs that control the adverse effects of obesity.” “What is new in our study is the very strong effect observed in liver tissue: There, we find a strong correlation of 0.42 between BMI and epigenetic age acceleration,” he says. “At this point, only the epigenetic clock can be used to measure the ages of most human tissues and cell types, but there are several alternative epigenetic biomarkers of aging that can be applied to blood tissue.” According to the Proceedings of the National Academy of Sciences article, Horvath’s theory includes an aging clock which uses a previously unknown time-keeping mechanism in the body to accurately gauge the age of diverse human organs, tissues and cell types. Horvath used this epigenetic clock to measure the biological age of several tissues in mouse model subjects. The aging clock proved accurate in matching biological to chronological age in lean subjects. But liver tissues from obese subjects tended to have a higher biological age than expected. In this latest study, Horvath looked at almost 1,200 human tissue samples, including 140 liver samples, to study the relationship between epigenetic age acceleration and body weight. While obesity doesn’t affect the epigenetic age of fat, muscle or blood tissue, he and his collaborators found that on average, the epigenetic age of the liver increased by 3.3 years for every excess 10 body mass index units. Horvath will continue pursuing the research with Hampe, “a leading expert on the epigenomic underpinnings of non-alcoholic fatty liver disease and related complications,” he says. “At this point, it is too early to consider a potential marketing partner. I am looking for collaborators who would be interested in testing whether the epigenetic age of liver tissue is prognostic of adverse health outcomes for liver cancer. I am also looking for collaborators who are interested in developing drugs that prevent accelerated aging effects.” в– Consistently Brilliant Microscopy & Remarkable Data DO While obesity doesn’t affect the epigenetic age of fat, muscle or blood tissue, UCLA research indicates that the epigenetic age of the liver may increase by 3.3 years for every excess 10 body mass index units. WHAT YOU NEVER THOUGHT POSSIBLE Cytationв„ў 5 is the compact, automated cell imaging and multi-mode reader that easily and quickly captures and analyzes brilliant images and transforms them into meaningful results. Simplicity, precision and flexibility—all in one powerful bench top solution. Find out what is possible, visit www.cellimager.com EDITCONNECT: E111410 www.biotek.com Cytation5 ad DO Possible-DDN.indd 1 10/9/14 9:35 AM For more information, visit www.DDN-News.com STEM CONTINUED FROM PAGE 12 epigenome status may influence consistency of both undifferentiated phenotype and differentiation behavior. Low genomic H3K9me3 and genome-wide DNA hypomethylation point to epigenome erasure in reset cells, as in early embryos. It will be of great interest to determine the precise functional impact of such epigenetic cleansing.” Human pluripotent stem cells, which have the potential to become any of the cells and tissues in the body, can be made in the lab either from cells extracted from a very earlystage embryo or from adult cells that have been induced into a pluripotent state. However, scientists have struggled to generate human pluripotent stem cells that are truly pristine (or naive). Instead, researchers have only been able to derive cells which have advanced slightly further down the developmental pathway. These bear some of the early hallmarks of differentiation into distinct cell types—they’re not a truly “blank slate.” This may explain why existing human pluripotent stem cell lines often exhibit a bias toward producing certain tissue types in the laboratory. In this latest work, the team led by the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute at the University of Cambridge has managed to induce a ground state by rewiring the genetic circuitry in human embryonic and induced pluripotent stem cells. Their “reset cells” share many of the characteristics of authentic naive embryonic stem cells isolated from mice, suggesting that they represent the earliest stage of development. “Capturing embryonic stem cells is like stopping the developmental clock at the precise moment before they begin to turn into distinct cells and tissues,” explains MRC Prof. Austin Smith, co-author of the paper. “Scientists have perfected a reliable way of doing this with mouse cells, but human cells have proved more difficult to arrest and show subtle differences between the individual cells. It’s as if the developmental clock has not stopped at the same time and some cells are a few minutes ahead of others.” The researchers overcame this problem by introducing two genes—NANOG and KLF2— causing the network of genes that control the cell to reboot and induce the naive pluripotent state. Importantly, the introduced genes only need to be present for a short time. Then, like other stem cells, reset cells can self-renew indefinitely to produce large numbers, are stable and can differentiate into other cell types, including nerve and heart cells. By studying the reset cells, scientists will be able to learn more about how normal embryo development progresses and also how it can go wrong, leading to miscarriage and developmental disorders. The naive state of the reset stem cells may also make it easier and more reliable to grow and manipulate them in the laboratory and may allow them to serve as a blank canvas for creating specialized cells and tissues for use in regenerative medicine. “Our findings suggest that it is possible to rewind the clock to achieve true ground state pluripotency in human cells,” Smith adds. “These cells may represent the real starting point for formation of tissues in the human embryo. We hope that in time they will allow us to unlock the fundamental biology of early development, which is impossible to study directly in people.” Dr. Rob Buckle, head of regenerative medicine at the MRC, added: “Achieving a true RESEARCH & DEVELOPMENT ground state in human pluripotent stem cells is seen as a significant milestone in regenerative medicine. With further refinement, this method for creating вЂ�blank’ pluripotent cells could provide a more reliable and renewable raw material for a range of cellular therapies, diagnostics and drug safety screening tools. This is likely to be a highly attractive prospect to industry and regulators.” The paper published in Cell is entitled “Resetting transcription factor control circuitry towards ground state pluripotency in human.” в– NOVEMBER 2014 | | DDNEWS 17 AGILENT CONTINUED FROM PAGE 14 in the fall of 2015. It will be added to Agilent’s existing collection of MRM libraries, which address a variety of applications, including pesticides, veterinary drugs, forensics and toxicology. Agilent uses collaborations as a key component of its strategy to maintain strong ties with current and prospective customers. “Through customer collaborations, Agilent learns about the customer problem in great detail so that we can satisfy that customer’s challenge and offer the solution to the many customers that have similar problems,” says Fischer. “This relationship is one of many that Agilent has with customers. “Agilent is already a leader in untargeted, discovery mass spectometry based metabolomics, and the development of a routine, targeted metabolite MRM method and MRM library will establish Agilent as a leader in targeted MS-based metabolomics.” в– EDITCONNECT: E111411 EDITCONNECT: E111408 siRNA X2 DNA A Transfection Breakthrough NEW!TransIT-X2В® Dynamic Delivery System Achieve superior transfections with an advanced non-liposomal, polymeric system that efficiently delivers DNA and/or RNA out of the endosome and into the cytoplasm, overcoming a critical barrier to nucleic acid delivery. The TransIT-X2В® Dynamic Delivery System gives researchers: X2 Efficiency–superior broad spectrum transfection X2 Delivery–independent or simultaneous delivery of plasmid DNA and siRNA X2 Technology–novel, non-liposomal, polymeric technology Functional Co-delivery of Plasmid DNA and siRNA. TransIT-X2В® Dynamic Delivery System was used to simultaneously transfect Cyв„ў5-labeled plasmid DNA (blue) encoding nuclear YFP (yellow) and Cyв„ў3-labeled siRNA (red) into HeLa cells. Actin cytoskeleton is stained green. Visit www.mirusbio.com for full experimental details. www.mirusbio.com ADVANCE YOUR TRANSFECTIONS. Request a FREE SAMPLE of TransIT-X2В® Dynamic Delivery System. Visit www.mirusbio.com, call 888.530.0801 (U.S. only) or +1.608.441.2852 (outside the U.S.) Providing gene delivery expertise since 1995 В©2014 All rights reserved Mirus Bio LLC. TransIT-X2 is a registered trademark of Mirus Bio LLC. Mirus-Bio-TransIT-X2-DDN-Jun2014.indd 1 5/28/2014 1:03:31 PM For more information, visit www.DDN-News.com 18 DDNEWS | | NOVEMBER 2014 PRECLINICAL BR IEFS Exemplar Genetics reports on TP53 porcine model SIOUX CENTER, Iowa—Exemplar Genetics’ geneti- cally modified pig model of cancer was featured in a recent issue of The Journal of Clinical Investigation, in an article that detailed that this model expresses a TP53 mutation orthologous to one commonly found in humans. Computed tomography, MRI data and molecular genetic analysis have shown that the TP53 porcine represents a large-animal tumor model that replicates the human condition. Data suggest that this model is appropriate for the development of clinically relevant, noninvasive imaging approaches. “The new porcine model of cancer opens the door to developing more effective imaging approaches and therapies for tumor detection and treatment,” said Dr. John Swart, president of Exemplar Genetics. “The translational value to humans is significant in that earlier detection and treatment can greatly improve cancer mortality rates.” Fruits of their efforts Preclinical trials show experimental drug from seeds of Australian Blushwood tree fruit destroys cancer tumors BY LORI LESKO YOUNGABURRA, Australia— Scientists at QIMR Berghofer Medical Research Institute have developed an experimental drug produced from the seeds of the fruit of the Blushwood tree—found in a far north Queensland rainforest—that has cured solid cancer tumors in preclinical trials. The drug, called EBC-46, has been found to be effective in treating pets with cancer, according to Dr. Glen Boyle, lead author of the study published Oct. 1 in the journal PLOS One. The Australian research team reported that just one injection of EBC-46 led to rapid breakdown of tumors in a range of human tumor models, suggesting the drug could be GAITHERSBURG, Md.—Novavax Inc. recently shared IN THIS SECTION IN THIS SECTION Antibiotics Cutting Head off the avenues of ESKAPE........ 18 Shionogi antibiotic joins Text ........................................................... 0 fight against MDR pathogens ................ 200 Text ........................................................... Cardiovascular Head An agreement ................................. 200 TextACS ........................................................... Hepatitis Text ........................................................... 0 OnCore marks milestones in hep B mission ..................................... 18 Oncology Exemplar Genetics reports on TP53 porcine model ........................... 18 Fruits of their efforts .............................. 18 Vaccines Novavax RSV vaccine found effective in baboons ............................... 18 BY KELSEY KAUSTINEN NEW HAVEN, Conn.—Melinta Therapeutics has released an update on its ESKAPE Pathogen Program, presenting two posters at the Interscience Conference on Antimicrobial Agents and Chemotherapy on its RX-P873 molecule that demonstrated its activity against a range of Gram-negative bacteria, including multidrug resistant strains and those designated on the U.S. Center for Disease Control and Prevention’s (CDC) list of urgent threats. The ESKAPE pathogens consist of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species and Escherichia coli. These resistant bacteria are the most difficult to treat, and 66 per- DOYLESTOWN, Pa.— OnCore Bio- cent of all hospital infections are the result of these pathogens. Drug-resistant bacteria have, in recent years, been named one of the leading health concerns in the United States. According to the CDC, approximately 2 million people in the United States develop infections caused by resistant bacteria, and more than 23,000 people die each year from RX-P873 CONTINUED ON PAGE 21 ONCORE CONTINUED ON PAGE 20 SEEDS CONTINUED ON PAGE 19 Cutting off the avenues of ESKAPE Novel antibiotics from Melinta show in-vitro potential against resistant bacteria BY ZACK ANCHORS pharma has made a series of important steps toward its goal of developing a cure for chronic hepatitis B. During the last couple months, the biopharma firm has gained an exclusive worldwide license to a series of second-generation cyclophilin inhibitors for the treatment of hepatitis B and acquired a pharmaceutical company with two novel drug discovery programs that could prove crucial in the development of a treatment for the disease. OnCore was founded in 2012 by a team of former executives from Pharmasset (acquired by Gilead Sciences in 2011) who were involved in developing the drug Sovaldi, a hepatitis C therapy that was approved by the FDA last December. The new company’s mission is to discover and develop an all-oral cure for hepatitis B. Hepatitis B is a serious infection of the liver that is transmitted by exposure to infectious body fluids. It can lead to chronic liver disease, which increases a patient’s risk of death from liver cirrhosis and liver cancer. The World Health Organization estimates that more than 780,000 people die every year due to infection. The therapies that are currently available to treat the disease work by suppressing the hepatitis B virus (HBV), but do not lead to a cure in the vast majority of patients. Identifying a functional or complete cure remains a significant area of unmet medical need. OnCore’s strategy to develop a treatment for hepatitis B involves developing an all-oral treatment that targets covalently closed circular DNA (cccDNA) in HBV-infected hepatocytes. cccDNA is a unique DNA structure that develops in the cell nucleus of some viruses as they propagate. The company believes this strategy of targeting cccDNA has the potential to result in a functional cure that lowers the risk of death from liver disease to the same level experienced by a person with a naturally resolved infection. The company is working to develop a treatment that combines agents against cccDNA with other novel direct-acting antiviral mechanisms that engage immune response. “EcoLogic is based on our understanding of how the rainforest functions from an ecological point of view,” says Dr. Victoria Gordon of her company’s discovery technology. “Our discovery success rate (at the early discovery stage) is greater than 10 times more successful than any of our competitors. For anticancer, we concentrated on how plants and mammals interact and formulated collection strategies primarily around herbivory responses in both groups,” Novavax RSV vaccine found effective in baboons preclinical data regarding its respiratory syncytial virus (RSV) vaccine in baboons. The study found that immunizing pregnant baboons in the third trimester with Novavax’ RSV F-protein nanoparticle vaccine caused them to generate anti-F IgG antibodies that were transferred to their newborn babies, and infants born to these immunized mothers demonstrated protection from RSV challenge comparable to that seen from palivizumab therapy. Dr. Greg Glenn, senior vice president of research and development at Novavax, noted that “This study adds to substantial evidence and validation supporting our RSV maternal immunization strategy as we move towards the initiation of our first study in pregnant women in the next few months.” effective in treating human patients as well. “We were able to achieve very strong results injecting EBC-46 directly into melanoma models, as well as cancers of the head, neck and colon,” Boyle said. “In most cases the single injection treatment caused the loss of viability of cancer cells within four hours, and ultimately destroyed the tumors.” EBC-46 works in part by triggering a cellular response which effectively cuts off the blood supply to the tumor and kills it. “In preclinical trials we injected it into our models and within five minutes, you see a purpling of the area that looks like a bruise,” Boyle said. OnCore marks milestones in hep B mission From Melinta’s three novel classes of antibiotics, more than 2,500 molecules have been produced, and Melinta is completing preclinical work to advance the most promising leads into Phase 1 clinical studies. PRECLINICAL For more information, visit www.DDN-News.com CONTINUED FROM PAGE 18 “About 24 hours later, the tumor area goes black, a couple of days later you see a scab and at around the 1.5 week mark, the scab falls off, leaving clean skin with no tumor,” he said. “The speed certainly surprised me.” In more than 70 percent of preclinical cases, the response and cure was long-term and enduring, with very little relapse over a period of 12 months, he said. EBC-46 was actually discovered by the Queensland biotechnology company EcoBiotics. It is EcoBiotics’ subsidiary, QBiotics, that is developing the drug as a human and veterinary pharmaceutical. The experimental drug has been used by veterinarians to successfully destroy or shrink tumors in companion animals, including dogs, cats and horses. QBiotics is currently undertaking formal veterinary clinical trials with EBC46 in Australia and the United States, Boyle said. A final regulatory approval is still required for a human Phase 1 clinical trial. “At this point, EBC-46 will only be trialed in the short-term for tumors which can be accessed by direct injection or topical application,” Boyle said. “There is no evidence to suggest EBC-46 would be effective against metastatic cancers.” Ethical approval was recently granted for Phase 1 human clinical trials, but even if those proved successful, it is unlikely the drug would replace conventional chemotherapy treatment for cancer, he said. “Chemotherapy is still used because it is very effective for a lot of people,” Boyle said. “But EBC-46 could perhaps be used in people who, for some reason, chemotherapy doesn’t work, or for elderly patients whose body can’t sustain another round of chemotherapy treatment.” The preclinical trials at QIMR Berghofer have been largely funded by QBiotics with additional support from Australia’s National Health and Medical Research Council. Dr. Victoria Gordon, CEO and managing director of EcoBiotics, and her husband, fellow scientist Dr. Paul Reddell, discovered the drug and spent years developing EBC-46 and demonstrating its effectiveness in animals, including treating hundreds of horses, dogs and cats. “Paul and I discovered EBC46 via our biodiscovery technology we call EcoLogic,” Gordon tells DDNews. “EcoLogic is based on our understanding of how the rainforest functions from an ecological point of view. Using our knowledge of plant ecological attributes and plantanimal-microbe-insect interactions, we develop collection strategies for plant material we believe will have particular bioactivity such as anticancer, antibiotics, antifungal, antiinflammatory, etc. Our discovery success rate (at the early discovery stage) is greater than 10 times more successful than any of our competi- tors. For anticancer, we concentrated on how plants and mammals interact and formulated collection strategies primarily around herbivory responses in both groups.” “Our company group (EcoBiotics as the parent entity and QBiotics as the subsidiary) has been contracting the QIMR for the past 14 years to work on research directed by our research managers,” she adds. EBC-46 was discovered through EcoBiotics’ discovery technology EcoLogic about eight years ago, according to Gordon. Prof. Peter Parsons and Boyle have been working on the early-stage preclinical development of the drug as directed and paid for by QBiotics, which has spent about AU$30 million so far and owns the patents on EBC-46 (which have now been granted in all major regions), she said, adding that Boyle’s particular focus in the development efforts thus far has been on the mechanism of action of the drug. The company team (including directly employed as well as con- tracted participants) has worked on formal preclinical development of the drug (including toxicology studies, pharmacokinetic and pharmacodymanic studies), domestication and grow-out of the source plant (Blushwood), R&D as well as GMP manufacture of the active pharmaceutical ingredient and the drug product, veterinary clinical development and now human clinical development, Gordon says. EcoBiotics was founded by Gordon and Reddell in 2000, based on Isotype Control PD-L1 Events SEEDS NOVEMBER 2014 | | DDNEWS 19 Green = PD-L1 PD-L1 Red = Keratin the biodiscovery technology they developed and call EcoLogic. “We have built the company up over the years and now have laboratories and offices in Far North Queensland and offices in Brisbane,” Gordon says. “We placed EBC-46 into a subsidiary company for development (QBiotics) so that we could focus the capital-raising strategy on drug development rather than drug discovery, which are two quite disparate areas.” в– EDITCONNECT: E111412 20 DDNEWS | | NOVEMBER 2014 PRECLINICAL For more information, visit www.DDN-News.com AN ACS AGREEMENT MedImmune will in-license Shionogi’s biologic program for acute coronary syndrome CONTINUED FROM PAGE 18 MedImmune, the global biologics research and development arm of AstraZeneca, recently in-licensed a biologic program from Shionogi for the potential treatment of acute coronary syndrome. CREDIT: MEDIMMUNE BY KELSEY KAUSTINEN GAITHERSBURG, Md.— A global license agreement was announced in early October between MedImmune, AstraZeneca’s global biologics research and development arm, and Osaka, Japan-based Shionogi & Co. Ltd., under which MedImmune will in-license Shionogi’s novel preclinical biologic program for the treatment of acute coronary syndrome (ACS). Though AstraZeneca has had an ongoing relationship with Shionogi, having licensed the cholesterol drug Crestor—which AstraZeneca and Shionogi co-market—from Shionogi in 1998, this is some of the first work between MedImmune and Shionogi. “Cardiovascular and metabolic disease (CVMD) is a core therapeutic area for MedImmune, and Shionogi’s biologic program will be a valuable and strategic complement to our existing cardiovascular program,” Cristina Rondinone, vice president and head of the MedImmune CVMD Innovative Medicines Unit, said in a news release. “We are committed to sourcing the best scientific research across the globe. We were pleased to identify this early-stage program and will work to advance its research and development as quickly as possible to hopefully bring an important new medicine to ACS patients.” The American Heart Association describes ACS as “an umbrella term for situations where the blood supplied to the heart muscle is suddenly blocked.” Heart attacks and unstable angina are both examples of ACS. Per the terms of the deal, MedImmune will acquire exclusive rights to Shionogi’s cardiovascular biologic program and will assume responsibility for all future research, development and manufacturing. AstraZeneca will assume responsibility for any future commercialization, and Shionogi will have an option to co-market in Japan. No financial details were disclosed for this agreement. “Shionogi and AstraZeneca have been working together to bring Crestor to patients ONCORE for nearly two decades. Such a positive relationship created the foundation for this agreement with MedImmune,” Dr. Kohji Hanasaki, senior vice president of Shionogi’s Pharmaceutical Research Division, commented in a statement. “Shionogi is now pursuing research and development in the therapeutic areas to which we should devote resources in the new medium-term business plan. We think that this biologic program gets the best chance of success by joining our promising research with MedImmune’s proven capabilities for advancing biologic research as well as AstraZeneca’s commercial capabilities in marketing cardiovascular therapies.” Contrary to the approach of most cholesterol medications, this biologic program seeks to target high-density lipoprotein (HDL) levels, or good cholesterol, rather than trying to lower low-density lipoprotein (LDL) levels. The program acts on a biological mechanism that plays a physiological role in the metabolism of HDL. In the body, HDL works to move cholesterol out of blood vessels and plaques, and higher HDL levels have the potential to decrease individuals’ residual risk of cardiovascular disease. “Maybe action against LDL is not enough for some patients,” Rondinone explains. “You will need to raise HDL for those patients who have really low HDL and actually cannot take cholesterol from the tissues and eliminate that bad cholesterol. So this approach, and some of the approaches that we are having at MedImmune, is mainly to strive to modify the metabolism of the good HDL and try to make the HDL functional.” “We have internal assets, but also we are looking at innovation in every place: in companies, in academic institutions, in collaborations. So when we believe that there is some interesting target program, we are willing to collaborate,” Rondinone tells DDNews. “Collaborations such as the one we have entered with Shionogi actually support the drive to deliver new medicines to patients and are shaping the way we treat this condition.” In other recent partnering news, MedImmune, together with AstraZeneca, announced four new collaborations with the University of Cambridge in mid-October, building on the organizations’ existing strategic partnership. The four agreements include a three-year collaboration centered on neurodegenerative diseases, a material transfer agreement granting access to select AstraZeneca compounds, a Ph.D. program and an entrepreneur-in-residence program. в– EDITCONNECT: E111415 OSAKA, Japan—Shionogi & Co. Ltd. thinks it may have a new soldier in the war against multidrug-resistant (MDR) pathogens, in the form of S-649266, a new parenteral siderophore cephalosporin antibiotic discovered by the company. According to recent preclinical studies, S-649266 exhibits marked potency against Gram-negative bacteria, including MDR pathogens, and has demonstrated active penetration into bacteria and stability to beta-lactamases that hydrolyze carbapenem antibiotics. S-649266 has unique structural features that exploit the way Gram-negative bacteria acquire iron necessary for growth. S-649266 binds to free iron and is actively transported across the outer membrane with the iron. This “Trojan horse” strategy allows S-649266 to enter the periplasmic space where it binds to penicillin-binding proteins and disrupts cell wall synthesis. “Multidrug-resistant bacteria continue to increase, and with these difficult-to-treat infections come increased morbidity, mortality and costs not just in dollars but in an overall societal cost due to the impact of these problematic infections,” said Richard P. Wenzel, professor of medicine at Virginia Commonwealth University and former president of the International Society for Infectious Diseases, in a news release about the preclinical findings. “S-649266 has many of the criteria needed to be of value in this ongoing fight; we await clinical results with anticipation.” Among some of the findings reported in the past few months, data indicated that compared with other cephalosporins and carbapenems, S-649266 showed robust invitro activity against Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae, including MDR strains. Against carbapenemase producers, S-649266 was said to be more active than meropenem and cefepime. In addition, S-649266 was reportedly shown to be 10 to 1,000 times more stable to carbapenemase than ceftazidime, cefepime and meropenem. “Opinion leaders we’ve been working with in the U.S., Europe and Japan believe the efficient use of the iron uptake system may allow S-649266 to be an effective approach to treat Gram-negative bacterial infections that CREDIT: HIROMITSU MORIMOTO Shionogi antibiotic joins fight against MDR pathogens Shionogi has high hopes that S-649266 will be effective in treating Gram-negative bacterial infections unable to be treated by available antibiotics. are not able to be treated by available antibiotics,” said Dr. Tsutae Den Nagata, chief medical officer for Shionogi. “S-649266 is the most advanced product in our anti-infective development portfolio. We are looking forward to the next stage of its development.” в– OnCore anticipates that combination therapy will be required to completely eradicate HBV from patients’ livers. OnCore gained rights to cyclophilin inhibitors that are central to this strategy through a licensing agreement with NeuroVive Pharmaceutical AB, a Swedish mitochondrial medicine company. The license agreement has a total value of up to $150 million, excluding royalty payments. OnCore will pay NeuroVive an initial upfront payment, development and sales milestones and royalties based on future sales. NeuroVive’s cyclophilin inhibitors, known as sangamides, are based on a new and unique polyketide chemistry platform. The lead drug candidate in the company’s cyclophilin program, NVP018, has undergone extensive preclinical development. OnCore anticipates that NVP018 will be evaluated in clinical trials in 2015. “NVP018 is a promising antiviral drug candidate and has tremendous clinical potential for oral use as a novel treatment for patients with chronic hepatitis B infection,” said Michael Sofia, OnCore’s chief scientific officer. “We believe that a curative therapy for HBV will likely contain an immunomodulatory agent, such as NPV018, combined with multiple antiviral agents with differing mechanisms of action.” Jan Nilsson, NeruoVive CEO, said the OnCore management team’s experience developing a treatment for hepatitis C made the company an appealing partner. “OnCore stood out in negotiations, which included several leading pharmaceutical companies, because of its exclusive focus on hepatitis B and its plan to bring the drug candidate to market as quickly and efficiently as possible,” he said. OnCore’s acquisition of Enantigen Therapeutics, a privately held pharmaceutical company, is also intended to support its goal of developing a hepatitis B cure. The acquisition will allow OnCore to assume development of Enantigen’s two novel discovery programs, one targeting inhibition of surface antigen secretion and one targeting capsid assembly inhibition. “We are very proud of the discovery work that we have done in hepatitis B,” said Entanigen President and CEO Xiaodong Xu. “We believe that OnCore is in the best position to rapidly advance our programs into human clinical trials, and we look forward to joining the OnCore research team to help realize their vision.” “Our plan is to combine Enantigen’s drug candidates with our existing alloral portfolio of HBV compounds and advance multiple combination regimens into human clinical trials,” said OnCore CEO Patrick Higgins. “Enantigen programs, together with our lead cyclophilin inhibitor, NPV018, and our cccDNA formation and capsid assembly inhibition programs, give OnCore the most comprehensive platform of assets consolidated to target a cure for hepatitis B.” в– EDITCONNECT: E111414 For more information, visit www.DDN-News.com RX-P873 CONTINUED FROM PAGE 18 antibiotic-resistant infections. Melinta’s ESKAPE Pathogen Program combines the company’s crystallography and computational chemistry experience to generate new classes of antibiotics and new molecules to treat extensively drug resistant and multidrug resistant bacteria. As noted on the company’s website, “Melinta researchers generated three unique molecular scaffolds with high binding affinity, low off-target effect and broad-spectrum antibiotic properties. Compounds based on one of these molecular scaffolds—the pyrrolocytosines— have shown in-vitro activity and preclinical efficacy against multidrug resistant Gramnegative and Gram-positive strains of bacteria known to cause complicated urinary tract infections, skin and lung infections, as well as sepsis.” From Melinta’s three novel classes of antibiotics, more than 2,500 molecules have been produced, and Melinta is completing preclinical work to advance the most promising leads into Phase 1 clinical studies. RX-P873 falls within the pyrrolocytosine class of compounds. It was specifically tested against Gram-negative species of bacteria, “Melinta’s discovery team employs a highly disciplined structure-based design approach that we believe can deliver both next-generation antibiotics and completely new classes, which can be fine-tuned to address current and emerging threats.” Dr. Erin Duffy, chief scientific officer of Melinta including 10 from the Enterobacteriaceae family, as well as Pseudomonas aeruginosa and Acinetobacter baumannii. The compound demonstrated potent activity against the Enterobacteriaceae family, as it inhibited more than 97 percent of isolates. RX-P873 was also shown to be highly active against P. aeruginosa, including strains that are resistant to ceftazidime or meropenem, and was the most active agent tested against A. baumannii; in that area, it displayed greater activity than colistin. “Melinta’s discovery team employs a highly disciplined structure-based design approach that we believe can deliver both next-generation antibiotics and completely new classes, which can be fine-tuned to address current and emerging threats,” Dr. Erin Duffy, chief scientific officer of Melinta, said in a news release. “As seen in the above studies, RX-P873 shows high and consistent in-vitro potency across a variety of Gramnegative pathogens, including those commonly associated with complicated urinary tract infections, complicated intra-abdominal infections and lung infections. We are encouraged by these early-stage results and PRECLINICAL look forward to completing our preclinical efforts and advancing molecules from the ESKAPE Pathogen Program into the clinic.” Melinta also recently shared news on one of its late-stage antibiotics, delafloxacin, a novel fluoroquinolone compound in Phase 3 development for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and uncomplicated gonorrhea. The U.S. Food and Drug Administration has designated delafloxacin as a qualified infectious disease product for ABSSSI, uncomplicated gonorrhea and community-acquired bacterial pneumonia. NOVEMBER 2014 | | DDNEWS 21 On Sept. 6, Melinta announced, along with Hartford Hospital, that in-vitro results from a recent study highlighted delafloxacin’s activity in low-pH environments, which are indicative of infection sites. When tested in samples from patients suspected to have urinary tract infections (UTI), delafloxacin demonstrated activity against E. coli and K. pneumoniae, both of which are associated with complicated UTIs. Two days later, the company shared results from in-vitro studies supporting delafloxacin’s potential in targeting Neisseria gonorrhoeae, the organism that causes gonorrhea. This pathogen has developed resistance to all classes of antimicrobials that have previously been recommended to treat gonorrhea, Melinta noted in a press release. In comparison, delafloxacin demonstrated activity against all 50 of the ciprofloxacin-resistant isolates tested in a study with University of Washington collaborators. In a separate in-vitro study, the compound proved to be more rapidly bactericidal against ciprofloxacin-susceptible and -resistant N. gonorrhoeae strains than ceftriaxone, the recommended first-line treatment for gonorrhea. в– EDITCONNECT: E111413 Are your stem cells notice repeat trace publish able? All achievable with high content imaging Make your breakthrough in stem cell research and transform data into unique biological insights with Molecular Devices. Robust instrumentation allows for consistent, live-cell imaging at high quality. Intelligent and flexible analysis helps track rare events with higher statistical significance over conventional microscopy. Unsurpassed service and support march alongside your vision to help achieve your goals. ImageXpressВ® Micro XLS System with transmitted light and environmental control options Together through life sciences. For research use only. Not for use in diagnostic procedures. В©2014 Molecular Devices, LLC. The trademarks mentioned herein are the property of Molecular Devices, LLC or their respective owners. Download eBook at moleculardevices.com/stemcell For more information, visit www.DDN-News.com 22 DDNEWS | | NOVEMBER 2014 SPECIAL REPORT So life-like D I S E AS E M O D E L I N G After decades of questionable results, are disease models turning a corner? I BY RANDALL C WILLIS T’S YOUR SON’S BIG DAY, his birthday, and he is sur- rounded by friends, cake, balloons and a ton of wrapping paper. But he’s been bouncing off the wall waiting for his gift from you. With a big smile, you give him a beautifully wrapped box. Are you human or a mouse? It is undoubtedly true that the biggest expense in developing a new drug and getting it to market is accommodating the failure of a molecule to translate preclinical success to the clinical setting. For any number of reasons, something is often lost between the efficacy and safety of a compound in an animal or cell culture model of a disease and in patients who actually have the disease. “We have found more ways to cure heart disease in mice than you can imagine,” says Brian Wamhoff, co-founder and vice president of research and development for HemoShear, a company working on more physiologically relevant in-vitro models of human disease. Wamhoff’s comment echoes the sentiment expressed years ago by oncology specialist Judah Folkman, who suggested that medical research has become very good at curing cancer in mice. “You can create models of fatty liver disease in a mouse,” says Wamhoff. “It looks like it; it “You can create models of fatty liver disease in a mouse. It looks like it; it smells like it. But how that mouse develops fatty liver disease is completely different than how a human does it.” Brian Wamhoff, vice president of research and development for HemoShear CREDIT: NATIONAL INSTITUTES OF HEALTH “I know how much you love airplanes,” you wink as he rips into the package like a hyena on carrion. Desperately, he claws at the top of the box and reaches inside to withdraw…a single sheet of blank printer paper. You beam with pride. He stares confused. His friends stare at their shoes. “I couldn’t get you an actual plane,” you explain. “But if you fold this just thus and so, it’s a pretty good approximation.” A decade later, the same boy struggles at his lab bench to develop a new drug compound, when suddenly another scientist runs into the lab, all excited and carrying a small case. “You have it?” the boy smiles, his friend nodding like a hypercaffeinated bobblehead. The boy rips off the cover and reaches inside to withdraw…a culture flask of pinkish cells. “I couldn’t get you an actual prostate,” the friend explains. “But if you shake this just thus and so, it’s a pretty good approximation.” Cells from a human organoid (here from a healthy prostate) can be xenografted into mice as controls for cancer research. smells like it. But how that mouse develops fatty liver disease is completely different than how a human does it.” “So you develop a drug to treat fatty liver disease in a mouse with a target that may or may not exist in a human, and then you go into a human and wonder why didn’t this work or worse, why is it causing liver injury now?” he adds, giving voice to the frustration felt across the pharma industry. As Wamhoff suggests, part of the problem may be that in many animal models, a disease is just that: a model. It gives all the outward appearance of being, say, rheumatoid arthritis (RA). The joint inflammation may show the same pathophysiology as human RA, but the question becomes if it is really the same condition at the molecular level, be that gene expression or metabolic pathway perturbation. And even if the disease is the same, does the compound react with the rest of the model animal’s physiology as it does in a human? Is the animal more or less tolerant of the test compound? Or are there unforeseen off-target effects to which the animal is less prone or completely immune? Highlighting the ubiquity of the frustration of insufficient animal models, Wamhoff points to comments made by Elias Zerhouni, former director of the U.S. National Institutes of Health (NIH) and current president of global research and development at Sanofi, in June 2013. “We have moved away from studying human disease in humans,” Zerhouni lamented to the NIH’s Scientific Review Management Board meeting. “We all drank the Kool-Aid on that one, me included.” “The problem is that it hasn’t worked, and it’s time we stopped dancing around the prob- SPECIAL REPORT lem,” he continued, suggesting researchers have become too reliant on questionable animal data. “We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans.” And that shift away from studying human disease in humans has potentially been expensive. “It takes about seven years to get into the clinic and anywhere between $50 million and $150 million depending on what you’re developing,” Wamhoff suggests. “If the target and the disease biology you’re starting with from day one are wrong, you lose seven years.” Thus the interest in moving back to more human-based studies, and the opportunity for companies like HemoShear. “What our partners are telling us now is that we want to start with more meaningful targets and more meaningful human disease biology,” Wamhoff continues. “It may still take seven years, but after those seven years, we’re going into the patient for the first time with more understanding of the human disease than we’ve ever had before.” The recent research of Robert W. Davis and colleagues in the Inflammation and Host Response to Injury, Large-Scale Collaborative Research Program may point to molecular reasons why the translation of results from mouse to human may be so difficult. Publishing their results in PNAS in early 2013, the researchers examined gene-expression profiles in both humans and mouse models of trauma, burn and endotoxin assault. They found that the genomic responses across the different inflammatory stresses were highly similar within the human populations but that these patterns were not reproducible in the mouse models of the same stresses, suggesting a disconnect that could easily translate to different responses to potential treatments. To some extent, they suggested, the differences could be explained in evolutionary terms, with different immune systems maturing from different environmental stressors. “Relative to the human response, mice are highly resilient to inflammatory challenge,” the authors wrote. “For example, the lethal dose of endotoxin is 5 to 25 mg/kg for most strains of mice, whereas a dose that is 1,000,000-fold less (30 ng/kg) has been reported to cause shock in humans.” By no means, however, are the researchers advocating for the elimination of mouse models, but rather for the application of more stringent model parameters. “Because virtually every drug and drug candidate functions at the molecular level, one practical approach forward is to raise the bar by requiring molecular detail in the animal model studies indicating whether the model mimics or fails to mimic the molecular behavior of key genes, key pathways or the genome-wide level thought to be important for the relevant human disease,” they suggested. “The quality of the animal model could then be determined by how well it reproduces the human disease on a molecular basis rather than simply phenotype.” One of the complaints about this study, however, was that the researchers only examined one strain of mice, and several commentators suggested that the findings might be less clear if a broader range of test animals had been studied. To some extent, this belief was borne out in a similar study by Michigan State University’s Daniel Hollern and Eran Andrechek, published earlier this year in Breast Cancer Research. NOVEMBER 2014 | | DDNEWS 23 CREDIT: HEMOSHEAR For more information, visit www.DDN-News.com HemoShear believes the best organ models involve not just the right cells, but also physiological forces found in vivo, such as hemodynamics. (Left to right are Brian Wamhoff, vice president of research and development; Vincent Aurentz, chief business officer; James Powers, CEO; Brett Blackman, chief scientific officer; and Nicole Hastings, vice president of operations.) Using extensive databases of mouse mammary tumor samples used to model human breast cancers, the researchers compared gene expression and pathway activation patterns both within and across mouse models (e.g., Myc, Neu, p53, BRCA). Even within models, they found significant heterogeneity at both the gene expression level and the pathway activation level, with some genes or pathways elevated in sample subgroups within each model. They then compared their mouse analysis with similar analyses in human breast cancer tissues and found a large number of mouse mammary tumor models had similar gene expression profiles to human breast cancers. Interestingly, however, they found that no single group of human breast cancer was modeled by a single mouse model at the pathway level. Thus, the researchers concluded that mouse mammary tumors could be effective models of human breast cancer, but cautioned that “great care should be taken to appropriately choose the mouse model to use and that a genomic and histological characterization of tumors should be completed following experimentation.” So what about cell culture models using human cells? Closer with stem cells? Cell culture models bring researchers closer to the organism of interest—in this case, humans—but even here problems can arise, because primary human cell cultures can be difficult to grow and maintain. Immortalized cells, meanwhile, are easier to grow but may be so significantly modified at the molecular level from their normal progenitors that the results of compound screening efforts may be suspect. The advent of stem cell technologies, however, has opened a door to not only studying normal cells—healthy or diseased—but also studying the cells of individuals with the disease of interest. “What you can do today is get or make a stem cell from that person, turn it into a liver and now technically in that dish you have a liver cell that has the same genetic mutations as the liver cell in that child,” Wamhoff says. Furthermore, as highlighted time and again at the International Society for Stem Cell Research (ISSCR) conference back in June, gene editing tools such as CRISPR and TALENS mean that researchers can go into these disease-affected cell lines and “fix” the errant genes to create healthy controls that have essentially the same genetic makeup as the donating patient. This affords scientists the opportunity to then test for the impact on the compound on these cultures and clearly distinguish between disease-specific effects and potential off-target effects. Such efforts may be particularly useful when examining conditions where cell biopsy can be difficult and/or dangerous, such as in neurological conditions. The Salk Institute’s Fred Gage and colleagues presented some of their efforts to model autism spectrum disorder (ASD) by generating neural progenitor cells and mature neurons from affected and age/gendermatched control cell lines. While the results are quite preliminary, the researchers noted altered cell cycle and levels of excitatory and inhibitory markers of neural cells during early stages of cell differentiation, providing a possible window into autism pathology. Also working in ASD, researchers at CHOC Children’s Research Institute described their efforts to build a repository of more than 200 cells lines from ASD patients and unaffected volunteers that can be differentiated into neurons and glia. The goal is to provide a resource to evaluate and compare data from different cells lines to better understand the causes and pathophysiology of ASD, whether to develop new therapeutics or better diagnostics. But even here there may be a problem, for it seems that newly minted stem cells may possess all of the tools of their newfound trade, but that doesn’t make them identical to the cells they’re mimicking. “It turns out that they are very naГЇve,” Wamhoff explains. “They’re immature at best, almost fetal-like. So they’re lacking all of the properties that the adult cell in the disease state has.” In a review published in Acta Pharmacologica Sinica, Harbin Medical University’s Xiao-hong Xu and GSK China’s Zhong Zhong concur, placing their focus on neurological diseases. “Many neurodegenerative diseases are late-onset diseases, and their key phenotypes may not manifest easily within a short period of time in culture,” they wrote, further suggesting that many of these conditions also involve interactions between cell types and/ or responses to environmental stressors. “Therefore, it may be necessary to expose cells to the relevant biological, chemical or environmental stressors to reveal the underlying disease phenotypes when modeling lateonset, non-cell-autonomous and complex multifactorial diseases using iPSCs,” they concluded. At ISSCR, Daniela Cornacchia and colleagues from Sloan-Kettering Institute for Cancer Research and Weill Cornell Medical College described their efforts to do just that, by looking for factors that could induce aging in iPSCs. Earlier efforts by the same group had shown that they could reinduce age markers erased during cellular reprogramming through ectopic expression of progerin, the mutant protein involved in the premature aging disease progeria. In the current studies, they set about to identify age-related transcriptional and epigenetic markers by comparing primary cells from young and old donors, as well as the iPSCs arising from those cells. “Differential factors identified by our studies are employed to yield an improved вЂ�aging cocktail,’ aimed at testing our primary hypothesis that induced in-vitro aging allows the development of more faithful models of late-onset degenerative disorders including [Parkinson’s disease],” they wrote. A potential challenge to this approach, however, is that you are introducing artificial factors to the cellular mix, albeit factors based on biological reasoning. Wamhoff, in contrast, takes a more reductionist view, advocating the idea of going back to the original physiology. “You need to take those cells and put them back in their physiological context,” he continues. “You need to find their neighbors and bring them back in. You need to restore blood LIFE-LIKE CONTINUED ON PAGE 24 LIFE-LIKE CONTINUED FROM PAGE 23 flow, restore contraction. “And when you do that, the really naГЇve rare disease liver cell you created from a stem cell can now become like an adult rare disease liver cell, and now you can go after a therapy.” Spheroids and organoids As noted in the feature Life moves on (July 2014 issue of DDNews), there has been significant movement toward the development of 3D cell cultures as a mechanism to gain some of the biologically critical information lost when cells are plated 2D. In a review published in Stem Cells in 2013, Robert Hynds and Adam Giangreco of University College London noted that complex intracellular communication and organization networks normally found in tissues can be difficult to identify or may be absent in 2D cultures. “This is because in vivo, cells exist within a complex network that provides important signalling and biomechanical components,” they wrote, echoing Wamhoff’s thoughts. “Overall, 3D cultures recapitulate invivo cell-cell and cell-matrix interactions more successfully than 2D plastic substrate cultures. Thus, 3D culture models allow for the emergence of more physiologically relevant cell phenotypes.” Increasing awareness of this phenomenon has led to rapid growth in the market for cells, tools and reagents for 3D cell culture. Companies like InSphero and Scivax USA produce spheroid cell lines for a variety of tissue types, while other companies such as 3D Biomatrix, AMS Biotechnology, Essen BioScience and Thermo Fisher provide reagents, instruments and assays for labs to develop and test their own cell lines. At the same time, suggested Anna Herland and colleagues from the Karolinska Institutet, despite spheroids providing some improvement in disease models over 2D cultures, there is still room for further improvement. “Due to the self-assembling nature of spheroid cultures, they are difficult to control, and the cell microenvironment differs significantly depending on the distance to the spheroid surfaces,” they wrote in a paper published this year in Biomaterials. They and other researchers took the idea of 3D culturing one step further by generating cultures that more closely resembled the organs they were trying to mimic, moving from a relatively homogeneous clump of cells to create a more clinically relevant microenvironment. With a nod to their morphology, these bodies were called organoids. Earlier this year, Yan Li and colleagues at Emory University and Florida State University described various efforts to use iPSCs to develop organoids, publishing their thoughts in Organogenesis. How’d they do that? flow on hepatocyte morphology, function and metabolic activity, researchers at HemoShear cultured rat hepatocytes for two weeks in either a nonflow collagen sandwich or in a perfused Transwell device that simulated controlled hemodynamics. They then monitored the hepatocytes using a combination of methods, including confocal microscopy and transmission electron microscopy, a cytochrome P450 activity assay and an MTT assay for toxicity in the presence of dexamethasone. The also examined the impact of hemodynamic flow by looking at the expression of various metabolic genes at both the RNA expression level using RTPCR and protein level using western blotting. In all cases, the morphology, function and metabolism of the hepatocytes more closely resembled that found in vivo in the cells cultured under hemodynamic flow conditions. CREDIT: HEMOSHEAR T O TEST THE IMPACT OF hemodynamic HemoShear researchers can perform upward of 120 simultaneous experiments in their vascular and hepatic platforms. “Taken together, these results highlight the importance of interfacing in-vitro biology with in-vivo physiological parameters,” the authors concluded. “Specifically, the retention of in-vivo-like hepatocyte phenotype and metabolic function coupled with drug responses at more physiological concentrations requires the restoration of in-vivo physiological transport parameters in vitro.” в– For more information, visit www.DDN-News.com Scientists at Harvard’s Wyss Institute have created a microfluidic chip that not only mimics the morphology of the human lung, but also its ability to “breathe.” “Most organoids are formed through the process involving intrinsic tissue mechanics and the programmed internal interactions, known as self-organization,” they explained, breaking that process into steps involving relative cell positioning, control of cell status and morphogenesis. Through these processes, the cells adapt within the context of one another to more closely resemble the morphology and various cell types of the target organ, whether liver, intestine, heart, lung or pancreas, among others. The goal, according to Hynds and Giangreco, is to then use these more complex systems much as we currently use 2D cell culture models of human disease. “Multiwell plate-based organoid assays would then be channeled into compound toxicity and efficacy screening systems such as gene expression microarray, protein mass-spectrometry and multiplex ELISA platforms,” they suggested. “High-throughput and high-content analysis would be achieved using automated cell manipulation and readout systems.” But even organoids have their limitations. Beyond a certain size, diffusion becomes a limiting factor for any test because of a lack of circulation, whether of nutrients or test compounds. To some extent, this issue can be moderated through improvements in bioreactor technology, but as Wamhoff indicated earlier, there is more to life than simply having the right cell combinations and being able to feed them. Organ recitals “It was not just a matter of bringing two cells together in a laboratory, because people had done that before and that wasn’t working,” he says. “There is something else missing.” That something else was physiology and the physical forces that act on those cells within the human body. “In a blood vessel, the cell that lines the blood vessel wall senses blood flow as soon as the heart starts to beat in development,” he continues. “The cell responds to blood flow and that blood flow dictates the function of that cell. And that cell talks to its neighbor and dictates the function of it.” Thus, to create a more accurate model of human health or human disease, it is critical to reintroduce the dynamics of physiology back into the cell culture system, and while technically challenging, this has been done in a number of ways. At the Wyss Institute at Harvard, for example, Founding Director Don Ingber and colleagues have taken a microfluidics approach to essentially create organs-on-chips. Organappropriate cells line the channels where they can be exposed to each other and to fluids or gases. But just as importantly, the chips—about the size of a memory stick—have been designed to allow physical processes such as flexing to be incorporated. In a video, Ingber introduces the lung-on-a-chip model: “It has human airway cells from the air sac on a membrane that’s porous. On the other side of the membrane are human capillary blood vessel cells. There’s air on one side. There’s flowing medium with human blood cells in it like blood on the capillary side. And the whole thing stretches and relaxes, just like our lung does when we breathe.” The breathing action is the result of changes in air pressure in two channels that line the main physiological channel. As the vacuum increases in these passages, it stretches the tissue, which then relaxes as the vacuum is diminished. “We mimic various types of physiological responses to drugs, toxins or various types of materials that we encounter on a daily basis,” adds Technology Development Fellow Dan Huh. In proof-of-concept experiments, the researchers were able to introduce bacteria to the airway and watch as white cells in the blood stream responded by moving through the membrane and attacking the bacteria. They monitored cell migration using high-content imaging. The group was also able to mimic IL-2-induced edema that can occur in cancer patients receiving the cytokine. At IL-2 levels commonly given to cancer patients, small amounts of fluid translated from the blood stream side to the airway when the system was static. When the system mimicked lung expansion and contraction, however, the fluid completely filled the airway chamber and blood clots were noted in the airway. Since their first publication in 2010, the organization has developed more than 10 organ models, including chips for liver, gut, kidney and bone marrow, and in late July, they announced the launch of the company Organs-on-Chips to commercialize the technology. Aside from the chips themselves, however, the group has also developed an instrument to automate the various chips and fluidically link the organs-on-chips together to better mimic whole-body physiology, human-body-on-chips. HemoShear took a somewhat different approach (see the sidebar in this section titled “How’d they do that?”). “We set out to create, first, a healthy human blood vessel in a laboratory,” Wamhoff explains. “And we did that by superimposing on the vascular system human physiological parameters that were deduced from a human high-resolution MRI.” To do this, they co-cultured endothelial cells and smooth muscle cells in a 75-mm Transwell plate and then added a cone and plate drive to simulation hemodynamics, as well as in-flow and out-flow tubing to move culture fluids across both cellular surfaces. As he goes on to explain, this work couldn’t have been done 15 to 20 years ago, as the technology CREDIT: WYSS INSTITUTE HARVARD SPECIAL REPORT 24 DDNEWS | | NOVEMBER 2014 For more information, visit www.DDN-News.com to understand how the mechanical forces were somehow sensed and then recreate them on the bench really didn’t exist until the early 2000s, when molecular physiologist Wamhoff and company co-founder and biomechanical engineer Brett Blackman first met at the University of Virginia. The combination of technologies was a total game-changer to Wamhoff. “When you take a cell and you put it in a dish, you can squirt a drug on it and get the response that you think you’re looking for,” he explains. “It turns out that the concentration of that drug is usually so high that you can never achieve that concentration in a human. So how do you make a decision off of that?” “Once we let the cells talk to each other and gave them the physiological forces back, they now started responding to drugs at in-vivo concentrations.” But as with drug discovery, success on the bench does not always translate into broader commercial success. Thus, it was critical for HemoShear to validate both their vascular and liver models. As Wamhoff explains, potential pharma partners weren’t about to sign on to collaborate with HemoShear if they couldn’t validate their system, because any IND filings arising from the research would slam up against FDA questions. “It took us well over five years and a lot of drugs and burning a lot of cash to validate it,” he says. The company has screened more than 200 drug compounds, most of them FDA-approved therapeutics, to validate that they can reproduce the known in-vivo effect at clinical concentrations. “We can show efficacy, safety or harm, and we’ve had a pretty good track record,” he adds. As a more recent show of success, the company announced in October the successful completion of the first phase of a project with the National Cancer Insitute to recreate the cancer tumor microenvironment. “We had tumor vasculature, the tumor cells and the stromal support cells, and the hypothesis would be that if you bring all of that together in the right physiological context, you’d see drug responses at clinical therapeutic concentrations,” explains Wamhoff. As proof-of-concept, the company created a non-small cell lung cancer tumor platform and then probed their construct with cisplatin, a drug commonly used to treat various cancers. Unlike what had been seen in mouse or other in-vitro models, HemoShear was able to demonstrate that they could effectively reduce tumor growth at clinically relevant IC50 levels. The next step in the agreement is to generate models for other tumor types and then validate those models against other FDA-approved drugs and combination therapies. Aside from filling in for traditional preclinical mouse models and tissue culture, Wamhoff also sees opportunities for the HemoShear system in areas such as drug repositioning (scanning other disease models), identification of off-target effects and potentially testing drugs in broader patient populations. The last opportunity may become significant, as many drugs are approved based on data from focused patient populations, e.g., Caucasian adults aged 25 to 55. SPECIAL REPORT But what about the impact of those drugs in the aged, children or people of different ethnic backgrounds or environmental exposures? The company has already performed experiments where they examined differences in the gastrointestinal bleeding profiles of Caucasian women 70 years or older vs. Caucasian women less than 70 years old to understand the underlying cause of the bleeding. But for all of their technical achievements, these new disease WHY R NOVEMBER 2014 | | DDNEWS 25 models run second to animal and traditional cell culture models in one significant way: throughput. Wamhoff is the first to admit that the HemoShear platform is low- to medium-throughput, although he balances that against the type of information arising from his system and the company’s arsenal of upward of 120 simultaneous experiments being more than enough for a company HemoShear’s size. That being said, he acknowledges that the pharma industry has built ISK IT Your research, funding, and global recognition are too important. Start with authenticated cell lines from ATCC and get the most reliable data from your experiments. Visit www.atcc.org/trust for more information В© 2014 American Type Culture Collection. The ATCC trademark and trade name, and any other trademarks listed in this publication are trademarks owned by the American Type Culture Collection unless indicated otherwise. ? billion-dollar infrastructures around high-throughput screening, infrastructures that these companies are not going to mothball simply because new technologies have arrived. Thus, he suggests, HemoShear and the nanofluidic device companies are going to have to evolve their systems to figure out how to plug into the high-throughput world. Wamhoff calls that the biggest challenge in the near future. в– EDITCONNECT: E111429 \st -’lГ¤r- s\ Stellaris RNA FISH Pr Probes e (G ree n) in S K-BR - 3 Ce l l s e в„ў t Ac i n H E R 2 (R ed) an e dB ta- DIRECT DETECTION iss ue IN SITU LOCALIZATION rT SINGLE SIN SI NGLE MO MOLECULE QUANTIFICATION ce in Posi re t i ve B a st Ca n Ce lls HER2 c- M yc in H E K- 2 93 Get a clear focus on mRNA biomarkers for cancer, developmental biology and pathology! Stellaris RNA FISH requires minimal prep work and produces strong signal-to-noise ratios for compelling and intuitive images which clearly illustrate the quantity and location of RNA in situ. 1 FIX 2 10 min fixation, >1 hour permeabilization permeabilization HYBRIDIZE 5 min setup, > 4 hr incubation 3 WASH 4 1 hour wash Localize & detect RNA in situ IMAGE Standard fluorescence microscope micr oscope Probes Pr obes bind to target target RNA in series Watch a Video about Stellaris RNA FISH Access the online video by scanning this QR code with your smartphone. В© 2012 Biosearch Technologies, Inc. Products and technologies appearing in this ad may have trademark or patent restrictions associated with them. Please see www.biosearchtech.com/legal for full legal disclosure. This product is sold under license from the University of Medicine and Dentistry of New Jersey and may be used under its patent rights for Research Use Only. For more information, visit www.DDN-News.com NOVEMBER 2014 | | DDNEWS 27 CLINICAL TRIALS BRIEFS Acceleron advances ACE-083 into the clinic CAMBRIDGE, Mass.—Acceleron Pharma Inc. has begun a Phase 1 trial of ACE-083, a novel muscle drug engineered to selectively increase muscle mass and strength in the muscles it is administered to by blocking proteins in the transforming growth factor-beta protein superfamily that modulate muscle growth. Acceleron is developing this investigational protein therapeutic for diseases in which improved muscle strength stands to provide a clinical benefit, such as certain forms of muscular dystrophy and inclusion body myositis. “[We] believe that ACE-083 has the potential to treat a wide array of diseases in which patients have lost muscle mass and strength in specific muscles or muscle groups,” Dr. John Knopf, CEO of Acceleron, said in a news release. Partners on lung cancer immunotherapy INGELHEIM, Germany & RIDGEFIELD, Conn.—Boehring- er Ingelheim and CureVac have jointly announced an exclusive global license and development collaboration centered on CureVac’s CV9202, a novel investigational therapeutic mRNA vaccine being developed for lung cancer. The therapeutic is a combination of mRNA molecules that code for six antigens that are overexpressed in lung cancer. CureVac will receive approximately $45 million, with the potential for up to about $556 million in milestone payments, as well as sales royalties. Boehringer Ingelheim will receive exclusive global rights to develop and commercialize CV9202, and will begin clinical investigation of the compound in at least two different lung cancer settings, in combination with afatinib in patients with advanced or metastatic epidermal growth factor receptormutated non-small cell lung cancer (NSCLC) and in combination with chemo-radiation therapy in patients with unresectable stage III NSCLC. Strong statement Easing Monoclonal antibody HIV drug succeeds in monotherapy clinical trial BY ILENE SCHNEIDER VANCOUVER, Wash.—According to the U.S. Centers for Disease Control and Prevention (CDC), some 1.14 million people aged 13 years and older are living with human immunodeficiency virus (HIV) infection. There are about 50,000 new HIV infections per year. Because HIV is such a big problem, the U.S. Food and Drug Administration (FDA) has given fast-track status to PRO 140, a drug candidate from CytoDyn Inc. PRO 140 belongs to a new class of HIV/ AIDS therapeutics—viral-entry inhibitors— that are intended to protect healthy cells from viral infection. PRO 140 is a humanized monoclonal antibody directed against CCR5, a molecular portal that HIV uses to enter cells. PRO 140 blocks the HIV coreceptor CCR5, and clinical trial results thus far indicate that it does not affect the normal function of the cell. CytoDyn, a biotechnology company focused on developing subcutaneously delivered humanized cellspecific monoclonal antibodies as entry inhibitors for the treatment and prevention “We believe this of HIV, recently drug could change announced the the paradigm of continuation of HIV treatment,” strong positive says CytoDyn CEO results for four and President Dr. weeks of monoNader Pourhassan of PRO 140. “The therapy with PRO patient gets a 140. Patients with holiday from taking HIV-1 are currentpills, and the drug ly participating in answers an unmet the company’s need by Phase 2b treatsuppressing the patient’s viral load.” ment substitution trial. The company has requested an “end of Phase 2b meeting” with the FDA to discuss Phase 3 plans. The Phase 2b clinical study was designed PRO 140 CONTINUED ON PAGE 29 Progress on dementia Intra-Cellular Therapies announces topline safety results from Phase 1/2 trial of lead dementia drug candidate BY LLOYD DUNLAP NEW YORK—Intra-Cellular Therapies Inc., IN THIS SECTION IN THIS SECTION Antivirals/M&A activity Recognizing potential in RSV Head (ALIOS from cover).................................. 31 Text ........................................................... 0 HIV/AIDS Text ........................................................... Strong statement.................................... 270 Head Muscle mass/strength Text ........................................................... 0 Acceleron advances ACE-083 Text the ........................................................... into clinic .......................................... 270 Neurology/CNS Easing the pain ....................................... 27 Hope for spinal injury? ........................... 28 Progress on dementia............................. 27 Oncology Matching drug and trial options to patients .......................... 30 Partners on lung cancer immunotherapy ........................... 27 a biopharmaceutical company focused on the development of therapeutics for central nervous system disorders, has announced topline results from ITI-007-200, a Phase 1/2 clinical trial designed to evaluate the safety, tolerability and pharmacokinetics of low doses of its lead drug candidate, ITI-007, in healthy geriatric subjects (trial part one) and in patients with dementia, including Alzheimer’s disease (trial part two). The data presented at the 2014 annual meeting of the American Neurological Association relate to part one of the trial. Additional data, including part two of the trial, will be presented at a future scientific conference. The initial results demonstrated that ITI007 is safe and well tolerated in healthy geriatric subjects and met the primary objectives of the study. Further, the results indicate a ITI-007 CONTINUED ON PAGE 28 Intra-Cellular Therapies recently released data for dementia drug ITI-007 that relate to part one of the trial, focused on healthy geriatric subjects, that indicates a wide safety window for use in the elderly. Data from part two of the trial, which focuses on patients with dementia, will be presented at a future scientific conference. the pain Improved treatment for spasticity on the horizon BY ZACK ANCHORS LEXINGTON, Mass.—The first clinical study of a new drug under development by Concert Pharmaceuticals holds promise for people who suffer from spasticity, a chronic condition that involves painful tensing and spasms of muscles. The biopharmaceutical company’s results from its Phase 1 study of CTP-354 suggest that the drug could present significant advantages over currently available treatments for spasticity. Concert is one of several companies working to find a new and more effective treatment for spasticity. GW Pharmaceuticals is planning to launch a Phase 3 trial for its cannabisbased treatment this fall. “All of the current treatments for spasticity have substantial limitations, both in terms of dosing regimen and efficacy,” Roger Tung, CEO of Concert, tells DDNews. “We think there’s great potential for a medicine that’s easier to comply with and that doesn’t have the sedative effects of the most commonly used treatments.” Roughly 12 million patients suffer from spasticity worldwide, according to a 2006 estimate by the American Association of Neurologic Surgeons. The condition can result from a wide range of disorders, including multiple sclerosis, spinal cord injury, cerebral palsy, amyotrophic lateral sclerosis, stroke and hereditary spastic paraplegia. Symptoms range from mild muscle tightness to more severe symptoms, including crippling and painful inability to move limbs that can result in disability and diminished quality of life. Concert’s recent study focused specifically on the treatment of patients suffering from spasticity as a result of spinal cord injury and multiple sclerosis. “We think there are about 250,000 patients in the U.S. that fit those two categories, and we think about half or so are not satisfied with their treatment or are not receiving adequate CTP-354 CONTINUED ON PAGE 30 CLINICAL TRIALS 28 DDNEWS | | NOVEMBER 2014 For more information, visit www.DDN-News.com Hope for spinal injury? ITI-007 CONTINUED FROM PAGE 27 StemCells Inc. takes step toward treating cervical spinal cord injury and possibly achieving a cure NEWARK, Calif.—StemCells Inc. has launched its Pathway Study, a Phase 2 proof of concept clinical trial using its proprietary HuCNSSC platform of human neural stem cells, for the treatment of cervical spinal cord injury (SCI). This is the company’s first study accessing the efficacy of neural stem cells for the treatment of paraplegics dependent on wheelchairs and breathing tubes. StemCells’ Pathway Study is reportedly the first clinical study designed to evaluate both the safety and efficacy of transplanting stem cells into patients with traumatic injury to the cervical spinal cord. “The expansion of this trial into patients with cervical injury is exciting because even a gain of one to two segments in cervical spinal cord injury patients can allow for additional function in the upper extremities,” Greg Schiffman, chief financial officer of StemCells, tells DDNews. The decision to pursue a therapy for SCI “was based on the large unmet medical need combined with the strength of the preclinical science supporting the use of our HuCNS-SC cells to treat victims of spinal cord injury,” Schiffman said. “We showed the cells could repair and replace damaged or lost cells such as the myelinating oligodendrocytes or new neurons.” Approximately 1.3 million people in the U.S. report being paralyzed due to an SCI, and there currently are no effective treatments available. Approximately 56 percent CREDIT: STEMCELLS INC. BY LORI LESKO StemCells’ Pathway Study is reportedly the first clinical study designed to evaluate both the safety and efficacy of transplanting stem cells into patients with traumatic injury to the cervical spinal cord. Illustrated here is an image of StemCells’ proprietary HuCNS-SC human neural stem cells. trial will follow the patients for one year from the time of enrollment. “StemCells Inc. has been evaluating our proprietary human neural stem cells (HuCNS-SC) for the treatment of spinal cord injury for over 10 years,” Schiffman says. “Our first preclinical work was published in the Proceedings of the National Academy of Sciences in 2005, demonstrating that our cells could promote locomotor recovery in spinal cord-injured mice.” “Our first clinical trial in spinal cord injury was initiated in 2011 for victims with thoracic injuries to their spinal cord,” Schiffman adds. “The thoracic cord is responsible for sensory function. Earlier “The expansion of this trial into patients with cervical injury is exciting because even a gain of one to two segments in cervical spinal cord injury patients can allow for additional function in the upper extremities.” Greg Schiffman, chief financial officer of StemCells Inc. of the spinal cord injuries occur in the cervical region. Overall, approximately 13 percent of SCI patients have no mobility, and 35 percent have limited mobility after the traumatic injury. The upcoming trial will be conducted as a randomized, controlled, single-blind study and efficacy will be primarily measured by assessing motor function according to the International Standards for Neurological Classification of Spinal Cord Injury. The primary efficacy outcome will focus on change in upper extremity strength as measured in the hands, arms and shoulders. The this year, the company completed enrollment and reported interim results from this trial on eight patients with at least six months of follow-up post transplantation. Half of the patients transplanted had significant post-transplant gains in sensory function. The interim results also continue to confirm the favorable safety profile of the cells and the surgical procedure.” “The key to its success so far has been the HuCNS-SC product candidate,” he continues. “We have conducted four clinical trials so far in disorders involving the brain, eye and spine. We have seen results consistent with our preclinical models in all of these studies. We believe that we have a platform in our HuCNS-SC human neural stem cells that has the ability to address a broad number of indications in the CNS, including spinal cord injuries. We see our HuCNS-SC platform as a next generation of cellular therapy and find that the vast majority of people seem to support the idea of using cells to treat serious disorders that have no other treatment options available.” Schiffman believes that the cell therapy field is at a point “where clinical data is being generated and I think we will see several breakthrough therapeutic approaches validated over the next three to five years. This is a time of excitement and promise for the field of regenerative medicine, and I look forward to a time where we have several breakthrough stem cellbased therapies approved to treat serious disorders where there are no treatments available today.” “The initiation of the Pathway Study represents a major milestone for StemCells Inc. as we pursue the development of a truly breakthrough therapy for spinal cord injury,” said Martin McGlynn, president and CEO of StemCells. “While we are thrilled by the prospect that patients with thoracic level injuries might be able to regain lost sensory function below the site of the injury, the possibility that patients with injuries to the cervical region of the cord might regain or improve lost motor function could be truly life-changing.” в– EDITCONNECT: E111419 dose-related pharmacokinetic profile in geriatric subjects consistent with previous studies in younger subjects. This study marks an important milestone in defining the low dose range of ITI-007 to be developed for the treatment of behavioral disturbances associated with dementia and related disorders. In these healthy geriatric subjects, ITI-007 was safe and well tolerated at doses up to and including 30 mg. Subjects did not exhibit extrapyramidal adverse events or clinically relevant changes in cardiovascular parameters. The tolerability and pharmacokinetic profile of ITI-007 in geriatric subjects indicate a wide safety window for ITI-007 in the elderly. Previous positron emission tomography studies demonstrated that a 10 mg dose of ITI-007 represented an approximate 10 percent occupancy of D2 receptors in the striatum. Doses of ITI-007 ranging from 1 to 10 mg resulted in improved sleep in patients with primary insomnia (clinical trial ITI-007004). Taken together, these data indicate that low doses of ITI-007 demonstrate proof of mechanism by engaging key brain targets and pharmacodynamic effects consistent with the mechanisms of action, and are safe and well tolerated in relevant patient populations. Based on previously reported data and the data from the geriatric study announced today, the company plans to further evaluate low doses of ITI-007 for the treatment of behavioral disturbances associated with dementia, including Alzheimer’s disease. To date, the FDA has not approved any drug to treat the behavioral symptoms of dementia, including Alzheimer’s disease. As symptoms progress and become more severe, physicians often resort to off-label use of antipsychotic medications in these patients. Current antipsychotic drugs are associated with a number of side effects, which can be problematic for elderly patients with dementia. In addition, antipsychotic drugs may exacerbate the cognitive disturbances associated with dementia. “Dementia is associated with behavioral symptoms including agitation, aggression and irritability. These symptoms often gradually increase in frequency and severity during the course of the disease, becoming distressing to patients and caregivers and contributing to early institutionalization,” said Dr. Sharon Mates, CEO and chairman of Intra-Cellular Therapies. “We believe the ITI007-200 results are consistent with the existing favorable safety and tolerability profile of the drug and its pharmacokinetic profile. The results allow the future testing of a range of low doses of ITI007 that offer the potential clinical benefits of optimal 5-HT2A antagonism and additional potential benefits offered by the gradual engagement of other receptors as the dose is increased. The outcome of ITI-007-200 represents an important step forward in the clinical development of ITI-007 for the treatment of behavioral disturbances associated with dementia and related disorders.” ITI-007 is Intra-Cellular Therapies’ lead product candidate, whose mechanism of action is believed to have the potential to yield a first-in-class antipsychotic therapy and, at lower doses, a firstin-class therapy for the behavioral disturbances associated with dementia. In preclinical and clinical trials to date, ITI-007 combines potent serotonin 5-HT2A receptor antagonism, dopamine receptor phosphoprotein modulation, glutamatergic modulation and serotonin reuptake inhibition into a single drug candidate. At dopamine D2 receptors, ITI-007 has been demonstrated to have dual properties and to act as both a postsynaptic antagonist and a presynaptic partial agonist. ITI007 has also been demonstrated to stimulate phosphorylation of glutamatergic NMDA NR2B, or GluN2B receptors in a mesolimbic specific manner. At the lowest dose studied to date (1 mg), ITI-007 has been demonstrated to act primarily as a potent 5-HT2A serotonin receptor antagonist. As the dose is increased, additional benefits are derived from the engagement of additional drug targets, including modest dopamine receptor modulation and modest inhibition of serotonin transporters. The company believes that combined interactions at these receptors may provide additional benefits above and beyond selective 5-HT2A antagonism for treating agitation, aggression and sleep disturbances in diseases that include dementia, Alzheimer’s disease and autism spectrum disorders, while avoiding many of the side effects associated with more robust dopamine receptor antagonism. As the dose of ITI-007 is further increased, leading to moderate dopamine receptor modulation, inhibition of serotonin transporters and indirect glutamate modulation, these actions complement the complete blockade of 5-HT2A serotonin receptors. In this dose range, ITI-007 may be useful in treating the symptoms associated with schizophrenia, bipolar disorder, major depressive disorder and other neuropsychiatric diseases. в– EDITCONNECT: E111417 CLINICAL TRIALS For more information, visit www.DDN-News.com PRO 140 CONTINUED FROM PAGE 27 to investigate the potential of allowing patients to enjoy treatment interruption from their current highly active antiretroviral therapy (HAART) regimen concurrent with a monotherapy consisting of weekly injections of PRO 140. The results from the treatment substitution trial to date have demonstrated 100-percent success in suppressing the viral load among patients who had weekly injections of PRO 140 for four weeks of monotherapy. There were zero virologic failures among 21 patients who have reached four weeks of monotherapy, and 36 patients out of 40 have received at least the first injection of PRO 140. Now CytoDyn is requesting FDA clearance to conduct a larger, similar Phase 3 licensing trial to demonstrate further the efficacy of PRO 140. As Dr. Nader Pourhassan, president and CEO of CytoDyn, explained, “Currently, there is no approved antibody therapy. We have the antibody … HIV patients will be able to stop taking pills and have a better quality of life while letting the body come back to itself. We believe we can suppress the infection for three months with the injections alone with low toxicity, low side effects and high patient acceptance.” Comparing these results with previous studies used as histori- “Currently, there is no approved antibody therapy. We have the antibody … HIV patients will be able to stop taking pills and have a better quality of life while letting the body come back to itself. We believe we can suppress the infection for three months with the injections alone with low toxicity, low side effects and high patient acceptance.” Dr. Nader Pourhassan, president and CEO of CytoDyn cal controls supports the current study’s successful outcome. In a 37-patient trial of treatment interruption from HAART, the use of multiple antiretroviral drugs in an attempt to control HIV infection, approximately 50 percent of patients experienced viral load breakout before four weeks, and approximately 100 percent showed viral load breakout at eight weeks. In another similar study, results indicated that 10 of 12 patients experienced viral load breakout after just two weeks of treatment interruption from HAART. According to Pourhassan, “We believe this is a very strong indication that PRO 140 is effective to allow four weeks of drug holiday with weekly injections. PRO 140’s safety has been well documented in previous studies, as well as our current study.” PRO 140 has been the subject of four Phase 1/1b and two Phase 2a clinical trials, each of which demonstrated its ability to significantly NOVEMBER 2014 | | DDNEWS 29 reduce HIV viral load in human test subjects. The PRO 140 antibody appears to be a powerful antiviral agent, leading to potentially fewer side effects and less frequent dosing requirements as compared to daily drug therapies currently in use. Pourhassan described the commercial potential of PRO 140 as “huge.” CytoDyn acquired it from Progenix in 2012. Progenix, which worked on PRO 140 for more than a decade, chose to focus its efforts on cancer drugs. CytoDyn has received about $20 million for clinical trials with the drug in the past and recently received $8.4 million from the U.S. National Institutes of Health for a testing program at Drexel University. “We believe this drug could change the paradigm of HIV treatment,” Pourhassan said. “The patient gets a holiday from taking pills, and the drug answers an unmet need by suppressing the patient’s viral load.” в– EDITCONNECT: E111416 Partnering toВ build your compound libraries With more than 10 million building blocks and screening compounds from 70+ vendors around the globe, AldrichВ Market Select is your solution for procuring building blocks and screening compound libraries. Features • Quote and order management • Custom formatting and packaging • International shipping and compliance • B2B procurement solutions • Consolidated invoices and supplier payments • Post-procurement follow-up support To start searching today, visit www.AldrichMarketSelect.com AldrichMarketSelect.com 82513 82513_Compound LIbraries DDN Nov.indd 1 10/15/14 9:19 AM For more information, visit www.DDN-News.com 30 DDNEWS | | NOVEMBER 2014 Matching drug and trial options to patients LEWISVILLE, Texas & CLEVELAND— Together, med fusion, an integrated molecular center of excellence and clinical trials service organization, and GenomOncology, an Ohio-based genomics technology and services provider, recently announced a partnership to optimize treatment strategies based on the patient’s disease state and tumor profile. The companies believe that GenomOnoclogy’s proprietary technology platform, the GO Clinical Workbench, and support services will complement med fusion’s expanded solid tumor disease-specific panels and deliver a comprehensive laboratory report detailing relevant drug and clinical trial options. An expansion of med fusion’s solid tumor menu is underway, including options for non-small cell lung cancer and colorectal cancer. The expanded oncology menu is powered in part by next-generation sequencing (NGS) technology that med fusion validated this summer in its CLIA- and CAP-accredited laboratory. GenomOncology’s GO Clinical Workbench reportedly streamlines the use of NGS data in conjunction with other ana- lytic modalities, simplifies the creation of a summary report and provides a fully traceable workflow and rulesbased decision support for the clinical interpretation of genomic data. “Cancer is a complex disease of the genome where each tumor has its own set of genetic alterations,” said Dr. Tom Lohmann, chief medical officer of med fusion. “Increased understanding of the underlying genetic changes that may be driving tumor growth or metastasis can enable precise treatment strategies tailored to the genetic profile of each patient’s cancer.” “Genomics-based precision medicine requires the clinical interpretation of genomic data—streamlined use of nextgeneration sequencing information in conjunction with other analytic modalities—as well as rules-based decision support,” added Manuel Glynias, president and CEO of GenomOncology. “The availability of an expert knowledge base like My Cancer Genome, exclusively integrated with the GO Clinical Workbench, provides a clinical report that educates physicians and gives them confidence as they make treatment decisions for patients.” в– TOOLS & TECHNOLOGY CTP-354 CONTINUED FROM PAGE 27 treatment,” says Tung. Several oral treatments are currently available to treat spasticity and are used widely, but each has significant drawbacks. Patients typically need to take doses of most of these drugs three to four times a day, which is considered by many to be an overly burdensome dosing regimen. “We understand from talking to physicians and patients that this dosing regimen is very inconvenient for both caregivers and patients,” says Tung. Another shortcoming of current treatments involve their sedative effects, which can impair cognition and cause patients to have difficulty staying awake, preventing individuals from participating in many everyday activities. Concert conducted a clinical trial that tested multiple dosing levels through a randomized, double-blind, placebo-controlled study of 30 healthy volunteers. The trial was designed to evaluate the safety, tolerability and pharmacokinetics of 10-day repeat dosing of three different amounts of CTP-354. Results showed that the molecule was generally well tolerated, with mild dizziness and drowsiness being the most common adverse effects. No sedation was observed. “We found that the compound was very well absorbed, with the amount present in blood stream proportional to the amount taken orally,” Tung tells DDNews. “The compound had a very long half-life—about 20 hours—which is in great contrast to the available drugs, which have half-lives of three to four hours.” The study also examined the effect of food on the drug’s effect in patients and found that CTP-354 provided similar exposure under both fed and fasted conditions, suggesting that it can be dosed without regard to meals. Concert presented the findings of its Phase 1 trial in July at the at the American Neurological Association’s annual meeting. CTP-354 is a novel, potentially first-inclass drug, but its development is built on a version of a drug initially developed by Merck. The compound L-838417, a subtypeselective GABAA receptor modulator, was discovered by Merck, which profiled the compound extensively in preclinical efficacy models and found potential efficacy against both inflammatory and neuropathic pain. But Merck ultimately abandoned the development of L-838417 because it also demonstrated substantial pharmacokinetic limitations. Concert was able to apply its expertise in precision deuterium chemistry to use the failed Merck compound to create CTP-354, which it then patented. Concert was able to achieve more favorable pharmacokinetics with the new molecule, even though it retained many of the same chemical qualities of L-838417. The company plans to move forward soon with multiple Phase 2 clinical trials of CTP354. “We remain on track to advance the program into Phase 2 testing later this year, initially targeting spasticity in patients with spinal cord injury followed by the start of a Phase 2 trial in multiple sclerosis patients in early 2015,” said Tung. Tung tells DDNews that he anticipates potential for CTP-354 beyond its use to treat spasticity if the upcoming trials continue to build an attractive profile for the drug. “We view spasticity as offering a very targeted population with a specific medical need, but there may be potential for CTP-354 to treat a range of other conditions,” he said. в– EDITCONNECT: E111418 CLINICAL TRIALS For more information, visit www.DDN-News.com CONTINUED FROM PAGE 1 and demonstrates a high barrier to the development of viral resistance. RSV is the most common cause of serious lower respiratory tract infections in infants, and though most healthy adults can recover from RSV infection fairly quickly, infection can also be severe for the elderly, immunocompromised or those with preexisting pulmonary issues. The U.S. Centers for Disease Control and Prevention note that “Almost all children will have had an RSV infection by their second birthday.” There is also a link between RSV infections and the later development of asthma in children. No effective treatments exist for RSV. On Oct. 13, Alios announced results from a Phase 2 challenge study of AL-8176, a randomized, double-blind, placebo-controlled study conducted in healthy adult volunteers who had been infected with RSV intranasally. Sixty-two healthy volunteers received either placebo or one of three dosing regimens of AL-8176: 375 mg administered orally twice daily, or 750 mg given as a single loading dose followed by twice-daily maintenance doses of 150 mg or 500 mg. In the study, AL-8176 reached its primary and secondary endpoints of reduction in viral load and improvement in symptom scores compared to placebo. The drug candidate was found to be well tolerated, with no discontinuations and no clinically significant laboratory abnormalities. All three dosage groups of AL-8176 demonstrated a rapid, significant reduction in RSV viral load following treatment, with a mean time to nondetectability of RSV load of 1.3 to 2.3 days for the AL-8176 treatment groups. At day 12, all subjects that received AL-8176 were RSV RNA undetectable, and remained so upon followup on days 16 and 28. “Alios BioPharma’s pipeline is closely aligned with our vision to continue to address important unmet medical needs through scientific innovation,” Dr. Johan Van Hoof, global head of infectious diseases and vaccines at Janssen, noted in a statement. “This acquisition will allow us to combine their innovative compounds with our vast experience in viral diseases to deliver novel medicines and treatment options for patients worldwide.” Correction The article “Cognitive computing in the clinic” in the October 2014 issue erroneously attributed several quotes and comments to Dr. Nicholas LaRusso of the Mayo Clinic that should have been attributed to Dr. Michael Weiner, director of healthcare strategic services at IBM. To see the corrected copy in the online version of the story, you can enter E101402 in the Edit-Connect Code window at http://ddn-news.com/15 “We are so pleased to be joining the Janssen Pharmaceutical companies of Johnson & Johnson, who have an impressive track record of bringing breakthrough drugs for viral diseases to market.” Dr. Lawrence M. Blatt, president and CEO of Alios BioPharma This could be a boost in Johnson & Johnson’s ability to compete with rival Gilead Sciences in another arena, as Gilead is also advancing an RSV drug candidate: GS-5806, an investigational oral Copyright Cisbio Bioassays. All rights reserved. All trademarks are property of Cisbio Bioassays. ALIOS NOVEMBER 2014 | | DDNEWS 31 RSV fusion inhibitor that saw positive results in a Phase 2a study earlier in the year. Michael Yee, an RBC Capital Markets analyst, noted that an RSV drug could potentially see annual sales of at DISCOVER AN EPIGENETICS ASSAY PORTFOLIO YOU’LL NEVER OUTGROW least $1 billion. The companies raced each other to be the first to get a hepatitis C compound approved last year, and while both got a horse to the track, so to speak—Gilead’s Sovaldi and Johnson & Johnson’s Olysio— Sovaldi has outperformed its competition, seeing better Phase 3 clinical trial results and becoming “the drug to most rapidly ever reach billion-dollar blockbuster status, with sales totaling more than $5 billion in the first six months of this year,” according to a Motley Fool article. Alios also has three hepatitis C compounds in its pipeline, in preclinical, IND and Phase 2 development. в– EDITCONNECT: E111401 EPIGENEOUSв„ў EPIGENETICS ASSAYS. From universal to specific assays, biochemical to cell-based, no one gives you a broader range of tools to research enzymatic targets in epigenetics than Cisbio. 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For more information on our complete line or to discuss your specific custom requirements, please email us at [email protected] or visit www.htrf.com/epigenetic-screening www.cisbio.com For more information, visit www.DDN-News.com 32 DDNEWS | | NOVEMBER 2014 American Society for Cell Biology 54TH ANNUAL MEETING Pennsylvania Convention Center Philadelphia December 6-10, 2014 в– in Philadelphia together with the International Federation for Cell Biology, an event that will have a very strong international focus under the leadership of one of ASCB’s greatest champions of international outreach, President Jennifer Lippincott-Schwartz. Of special interest this year, points out Executive Director Stefano Bertuzzi, is a special session co-organized by the International Affairs Committee and the Women in Cell Biology Committee that will explore the role and the challenges of women in science in different countries. “This is an event not to be missed by men or women,” Bertuzzi enthuses. In the recent past, ASCB has strengthened its relationship with several European organizations, such as EMBO, as well as the French Society of Cell Biology, at whose 2013 conference on imaging ASCB sponsored speaker Derek Toomre of Yale University, and the German Society for Cell Biology, at whose annual meeting ASCB sponsorship enabled 2013 Kaluza Prize Winner Tina Han to present the award-winning research she did at the University of Texas Southwestern Medical Center. These are small steps geared, Bertuzzi notes, toward promoting exchanges and engagement among organizations in the same field. ASCB was also a sponsor of the Seventh Congress of the Asia-Pacific Organization for Cell Biology (APOCB), which was held in Singapore in February 2014. The next APOCB meeting will be in India in 2018, and ASCB is planning a higher level of engagement with that event. “Finally, during the summer Yixian Zheng and I traveled to China,” says Bertuzzi, “where we met with top leaders in cell biology, biophysics and other basic sciences. The economies of East, Southeast and South Asia—including China, India, Japan, Malaysia, Singapore, South Korea and Taiwan—have been greatly expanding their investments in science, and in 2011 accounted for 34 percent of global research and development investments. These international activities and many others are the concrete implementation of ASCB’s interest in international collaboration.” Graduate School Fair PHILADELPHIA—ASCB is holding its annual Graduate School Fair from 12:30 p.m. to 2:30 p.m. on Saturday, Dec. 6, 2014, in the Grand Hall of the Pennsylvania Convention Center. ASCB invites you to represent your institution (whether U.S. or international) at the Graduate School Fair. The hall will be open at 9 a.m. on Saturday, Dec. 6, for setup. The tables will be arranged alphabetically by school. Participants will also have two chairs and free WiFi, though no electric or poster boards are available. Also, fair exhibitors may bring laptop presentations, giveaways, brochures, table coverings, etc. It is “quite an informal event,” the organizers emphasize. Cost is $100 per institution. Brand new for 2014— the ASCB Learning Center PHILADELPHIA—The exhibit floor as you know it is gone, ASCB states, announcing that “It’s time to interact in a whole new way. Be a part of the newest and most innovative interactive exhibitor community—The ASCB Learning Center,” which will be open from 9:30 a.m. to 4:30 p.m. Sunday, Dec. 7, through Tuesday, Dec. 9., and will be populated by approximately 1,200 exhibitors. Morning and afternoon refreshment breaks will be provided Sunday through Tuesday from 9:30 a.m. to 11:30 a.m. and noon to 4 p.m., with a cash bar available. A new universality in cell biology Engineering, physics, computational modeling and quantitative methods are all part of this year’s ASCB special sessions BY LLOYD DUNLAP PHILADELPHIA—It is not by chance that the American Society for Cell Biology’s 54th ASCB Annual Meeting is co-hosted this year by the International Federation of Cell Biology (IFCB). Indeed not. “You are a cell biologist, whether you think of yourself that way or not,” notes Wallace Marshall, chair of the Program Committee for the 2014 ASCB Annual Meeting. “Regardless of what field is stamped on your union card, if you care about cell biology, you need to go to the ASCB Annual Meeting, which this year is being held jointly with the International Federation for Cell Biology.” Cell biology and disease The field of cell biology is constantly evolving, Marshall notes, “and an important goal of the annual meeting is to track new developments. In recent years, there has been a growing appreciation of the role of cellular dysfunction in diseases. Studies at the interface of medicine and cell biology have shed important light on both fields, and so for the past several years the ASCB Annual Meeting has devoted special attention to highlighting the cell biological basis of disease and medicine.” “At this year’s ASCB/IFCB meeting, we will continue this trend in two ways,” Marshall observes. “First, we will have a special bench-to-bedside panel discussion on translation of cell biological discoveries to the understanding and treatment of disease. Second, we have included disease experts as organizers of many of the sessions, and these experts B. KRIST FOR VISIT PHILADELPHIA A new level of international engagement BETHESDA, Md.—This year ASCB will be hosting its annual meeting в– Opened in June 1993, the Pennsylvania Convention Center in Philadelphia will play host to the 2014 annual meeting of the American Society for Cell Biology in December. will help stimulate thinking about disease connections across the full spectrum of cell biological topics.” “Another emerging trend in cell biology is the constantly increasing importance of quantitative concepts and approaches,” he adds. “The living cell is an emergent phenomenon, produced by the mutual interaction of huge numbers of molecules. The only way to begin to understand how such a complex system assembles and functions is to harness the same tools and conceptual approaches that have proven useful in engineering and physics.” In recent years, Marshall notes, the importance of computational modeling and quantitative methods has been emphasized in special sessions, such as ones on mathematical modeling. “But having one or two special sessions on quantitative thinking also creates a sense that this is a different way of approaching cell biology, perhaps as a supplement to вЂ�real’ cell biology,” he says. “Indeed, I attended one session on the role of modeling in which it was implied that models are something to be added onto the end of a cell biology paper to increase publishability, much as a piece of parsley may be added as a garnish to a steak dinner. In my humble opinion, this approach is completely backwards and misses the most important value of a model, that it can be used to help design the experiments from the outset of a project. “So this year, rather than isolating modeling and quantification in their own separate compartment, like toxic enzymes to be sequestered in the lysosome, we decided to let quantitative and physical sciences pervade the entire meeting by appointing quantitative cell biologists to co-chair many of the minisymposium sessions.” Marshall explains that to balance the tasks of increasing coverage of disease and quantitative biology, while retaining the traditional core topics of cell biology, they assembled a tripartite Program Committee, consisting of a “core” subcommittee (Mohan Balasubramanian, Magdalena Bezanilla, Orna Cohen-Fix, Ana Maria Cuervo, Beatriz Fontoura, Cynthia Jensen, Franck Perez, William Prinz, Lois Weisman, Mark Winey, Richard Youle and Xiaodong Wang); a “cell biology and disease” subcommittee (Helen Blau, Catherine Dulac, Tom Misteli, Gregory Pazour, Jody Rosenblatt and Marino Zerial); and a “physical and quantitative cell biology” subcommittee (Marileen Dogterom, Aki Kusumi, David Odde and Jitu Mayor). “Keeping all the conference calls between these groups organized was only possible through the tireless efforts of ASCB’s Meeting and Abstracts Manager Alison Harris,” he adds. “Three other participants deserve special mention. ASCB President Jennifer Lippincott-Schwartz and Executive Director “We are truly blessed in our field to have a single unifying event each year that brings us all together in one place. The tradition of a single, recurring meeting in cell biology that has now been running for 54 years helps to create a group identity. This is particularly important for cell biology, an inherently interdisciplinary field that has historically drawn on methods and concepts from a wide range of disciplines, including molecular biology, cytology, genetics, microscopy and physics.” Wallace Marshall, program chair for the 2014 ASCB Annual Meeting ASCB ANNUAL MEETING 2014 NOVEMBER 2014 | | DDNEWS 33 R. KENNEDY FOR VISIT PHILADELPHIA For more information, visit www.DDN-News.com In the warmer months, people love to hang out in Rittenhouse Square, where they can grab a seat on a coveted bench or a shady spot on the grass. Popular park activities include picnicking, reading, socializing, dog walking, Frisbee throwing and, of course, people-watching. Stefano Bertuzzi never failed to offer their own insights and perspectives, which we found invaluable as we grappled with difficult decisions about topics and organization. In addition, Cynthia Jensen of the IFCB has been one of the most active participants in all of our conference calls and has played an invaluable role in helping to organize this joint meeting.” Four reasons to attend ASCB 2014 “First of all,” the ASCB’s program chair emphasizes, “you need to go to the meeting because it is simply the most efficient way to learn about the latest thinking, methods and results in the field. Whether you are an established investigator or someone just starting out, you need to have access to this cuttingedge information.” “The ASCB Annual Meeting was the first scientific conference I ever attended,” Marshall continues. “I had been in graduate school only a couple of years, and as an electrical engineer who had become interested in living cells, I had the sense that many of my classmates had some outside source of information about cell biology that I didn’t have access to. Gradually it emerged that this magic source of information was the ASCB Annual Meeting. So that year I signed up for the meeting and showed up with my poster. It was like a window onto a whole wider world had been opened. Now I could see the people whose papers I had been reading, hear them discussing their latest results in their own words and even have the chance to talk about my own science with these same individuals when they came to my poster. I haven’t missed a single ASCB Annual Meeting since. I make sure to go every year because I can’t afford to miss it, and neither can you.” Second, he says, “We are truly blessed in our field to have a single unifying event each year that brings us all together in one place. The tradition of a single, recurring meeting in cell biology that has now been running for 54 years helps to create a group identity. This is particularly important for cell biology, an inherently interdisciplinary field that has historically drawn on methods and concepts from a wide range of disciplines, including molecular biology, cytology, genetics, microscopy and physics.” Third, he notes, ASCB has a strong tradition of providing mentoring and career support for its members, especially students and postdocs. Again this year, the meeting will include a Professional Development thread comprising a host of activities that can help attendees get jobs or enhance their careers. These activities include a grant writing workshop, scientific career panels, one-on-one CV review, sessions on international training and funding opportunities, career discussion and mentoring roundtables, and much more. “Finally, the ASCB as a society fights for science funding and helps all of us through its advocacy, outreach and career development activities,” Marshall points out. “The Annual Meeting provides a focal point for regrouping and discussing where these efforts are going. By attending the meeting you have access to workshops and special sessions in a range of important issues and topics. This is the best time and place to make your voice heard in guiding the future of the field and shaping its role in society.” “On the whole, I’d rather be in Philadelphia” The subhead above comes to us by way of late, great performer W.C. Fields when he was contemplating his eventual death; also, movies like “Rocky” depict Philadelphia as a gritty, tough city, but this image belies the architectural beauty, cultural diversity and rich history of one of America’s oldest cities. Within cell biology, Philadelphia has long been a research hub, and that continues to be the case today. In that respect, there are few more appropriate cities for the ASCB/IFCB meeting. But if you are attending, you might want to ensure getting there early, because Saturday starts the meeting with memberorganized special interest sessions. These intense sessions feature topics and speakers selected by the people who know cell biology best—the members of ASCB. That night at 6 p.m., keynote talks from Steven W. Squyres and Robert M. Hazen will offer a panoramic view of reality that spans the history of the cosmos to the origin of life. Special award talks from Keith Porter Lec- turer Michael Sheetz and E.B. Wilson Medalists Bill Brinkley, John Heuser and Peter Satir will cap the program on Sunday and Tuesday evenings. But while these special talks will be exciting and thought-provoking, another important reason to go to a meeting is to learn detailed information that can help you in your own research. And for this purpose you just can’t beat posters. Posters provide the best way to learn the most cutting-edge information from the people actually doing the work and to engage in a back-and-forth discussion that is usually not possible just before, during or after lectures, no matter how interactive the format of some of them. Posters are the heart of any serious meeting, and this has always been particularly true at ASCB. In recognition of the importance of posters, this year ASCB has carefully structured the meeting schedule to ensure that everyone has plenty of opportunity to view them and meet the presenters. The former concept of the exhibit hall has been transformed into the ASCB Learning Center, and from noon to 3 p.m., Sunday through Tuesday, all meeting activities will take place there. Poster presentations and ePoster talks are scheduled for that time slot. This will also provide an opportunity to interact with the exhibitors, who have been encouraged to provide attendees with a variety of learning experiences, not just “sales pitches.” Visit the exhibits and attend their tech tutorials and tech showcases to learn about the latest advances that help move cell biology forward. Between the posters and exhibits, Marshall insists, you really can learn a lot in the ASCB Learning Center. Each day the posters are augmented with symposia and minisymposia on a range of topics that span all of cell biology. Between the special talks, workshops, posters, symposia and minisymposia, think of the ASCB/IFCB meeting as an all-you-caneat buffet of cell biology for your mind to feast on—after all, Philly is famous for some signature eating options, like cheesesteaks and soft pretzels, among its many other features. But they probably won’t help your career along as well as the ASCB/IFCB fare will. в– EDITCONNECT: E111428 34 DDNEWS | | NOVEMBER 2014 ASCB ANNUAL MEETING 2014 For more information, visit www.DDN-News.com Keynote speakers will span the origin of life to the cosmos Carnegie Institution of Science and Deep Carbon Observatory Dr. Hazen is a research scientist at the Carnegie Institution of Washington’s Geophysical Laboratory and Clarence Robinson Professor of Earth Science at George Mason University. He received degrees in geology at the Massachusetts Institute of Technology in 1971 and a Ph.D. at Harvard University in earth science in 1975. After studies as NATO Postdoctoral Fellow at Cambridge University in England, he joined the Carnegie Institution’s research effort. Hazen is the author of more than 350 articles and 20 books on science, history and music. A Fellow of the American Association for the Advancement of Science, he has received the Mineralogical Society of America Award (1982), the American Chemical Society Ipatieff Prize (1986), the ASCAP Deems Taylor Award (1989), the Educational Press Association Award (1992), the Elizabeth Wood Science Writing Award (1998) and the Distinguished Public Service Medal of the Mineralogical Society of America (2009). Hazen’s recent research focuses on the role of minerals in the origin of life, including such processes as mineral-catalyzed organic synthesis and the selective adsorption of organic molecules on mineral surfaces. He has also developed a new approach to mineralogy, called “mineral evolution,” which explores the co-evolution of the geosphere and biosphere. In addition to his mineralogical research, he is principal investigator of the Deep Carbon Observatory, which is a 10-year international effort to achieve fundamental advances in understanding the chemical and biological roles of carbon in Earth’s interior. Some of Hazen’s books, such as The Music Men, Wealth Inexhaustible and Keepers of the Flame—all three co-authored with his wife, Margaret Hindle Hazen—explore ties between technology and culture. The Breakthrough, The New Alchemists, Why Aren’t Black Holes Black, The Diamond Makers and Genesis describe the forefront of scientific research. He has also written widely for popular audiences, including articles in Newsweek, Scientific American, Smithsonian Magazine, New Scientist and The New York Times Magazine. He appears frequently on radio and television programs on science, and he developed two popular video Visitors and locals use the Phlash to get to the city’s historic and cultural attractions easily and quickly. From May until Labor Day, the big purple bus transports people every day, every 15 minutes from 10 a.m. to 6 p.m., and then it runs on weekends until December 28. The Phlash is $2 per ride or $5 for an all-day pass, and its more than 20 stops are conveniently located near popular places—Independence Visitor Center, Independence National Historical Park, Philadelphia Museum of Art, Penn’s Landing, Reading Terminal Market, Pennsylvania Convention Center, Philadelphia Zoo and Please Touch Museum. courses: The Joy of Science and The Origins of Life, both produced by The Teaching Company. In addition to his scientific activities, Hazen is a professional trumpeter. He is presently a member of the National Philharmonic, the Washington Bach Consort and the National Gallery Orchestra. Steven W. Squyres James A. Weeks Professor of Physical Sciences Dr. Squyres’ research focuses on the robotic exploration of planetary surfaces, the history of water on Mars, geophysics and tectonics of icy satellites, tectonics of Venus, planetary gamma-ray and X-ray spectroscopy. Research for which he is best known includes study of the history and distribution of water on Mars and of the possible existence and habitability of a liquid water ocean on Europa. From 1978 to 1981 he was an associate of the Voyager imaging science team, participating in analysis of imaging data from the encounters with Jupiter and Saturn. He was a radar investigator on the Magellan mission to Venus, a member of the Mars Observer gamma-ray spectrometer flight investigation team and a co-investigator on the Russian Mars 96 mission. Squyres is currently the scientific principal investigator for the Mars Exploration Rover Project. He is also a co-investigator on the Mars Express mission and on the Mars Reconnaissance Orbiter’s High-Resolution Imaging Science Experiment. He is a member of the Gamma-Ray Spectrometer Flight Investigation Team for the Mars Odyssey mission and a member of the imaging team for the Cassini mission to Saturn. His scientific publications include “The Athena Mars rover science investigation,” “The Spirit rover’s Athena science investigation at Gusev Crater, Mars,” “In-situ evidence for an ancient aqueous environment at Meridiani Planum, Mars,” “The Opportunity rover’s Athena science investigation at Meridiani Planum, Mars,” “Sedimentary rocks at Meridiani Planum: Origin, diagenesis and implications for life on Mars,” “Rocks of the Columbia Hills,” “Two years at Meridiani Planum: Results from the Opportunity rover,” “Overview of the Opportunity Mars Exploration Rover mission to Meridiani Planum: Eagle Crater to Purgatory Ripple,” “Detection of silica-rich deposits on Mars” and “Exploration of Victoria Crater by the rover Opportunity.” в– M. FISCHETTI FOR VISIT PHILADELPHIA Robert M. Hazen J. FUSCO FOR VISIT PHILADELPHIA this year’s ASCB meeting, keynote speakers Robert M. Hazen and Steven W. Squyres bring career-long research specialties in the origins of life and exploration of space. “Mineral evolution, mineral ecology and the co-evolution of life and rocks” will be the subject of Hazen’s address, while “The habitability of Mars as revealed by the Mars Exploration Rovers Spirit and Opportunity” will be discussed by Cornell University’s Squyres. The keynote talks occur on the evening of the meeting’s opening day, Saturday, Dec. 6, at 6 p.m. The event will be followed by an opening night reception and the International Research and Training Exchange Fair. Philadelphia’s Love Park turns into a fun, alfresco and medieval shopping extravaganza when the German-style Christmas Village takes over each holiday season. More than 50 decorated booths showcase international seasonal gifts, traditional German Christmas ornaments, jewelry and highquality arts and crafts. Hot mulled wine, gingerbread and bratwursts add to the festive atmosphere. J. VARNEY FOR VISIT PHILADELPHIA U NDERSCORING THE MULTIDISCIPLINARY FOCUS OF Introduced to the region by German (“Pennsylvania Dutch”) settlers in the 18th century, pretzels—dough twisted into three loops, then baked, salted and served hard—quickly became a favorite local snack. Now, of course, there’s the famous Philly soft pretzel, purchased from street vendors or from bakery storefronts such as the Philly Soft Pretzel Factory. No matter what form the pretzel takes—braided, sticks, nuggets and bagels—it’s often accompanied by mustard. For more information, visit www.DDN-News.com NOVEMBER 2014 | | DDNEWS 35 DIAGNOSTICS SAN DIEGO—Illumina Inc. and four leading cancer centers have established the Actionable Genome Consortium (AGC), an initiative that will recommend openly published standards for widespread use of next-generation sequencing to aid in treatment decision for cancer patients. Specifically, the AGC will aim to define the principles and content of the “cancer actionable genome,” a comprehensive description of genomic alterations that define individuals’ tumors. The founding members include, other than Illumina, the Dana-Farber Cancer Institute, Fred Hutchinson Cancer Research Center, MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center. The AGC will publish a list of actionable events—including best practices regarding biopsy samples, performance standards for sequencing, guidelines for clinical reports and standards for genetic variants—and include a research arm for collaborative, cross-institutional projects regarding leading challenges in molecular oncology. Rockland receives SBIR grant LIMERICK, Pa.—The National Institutes of Health’s National Heart, Lung and Blood Institute has awarded Rockland Immunochemicals Inc. a Small Business Innovation Research grant worth $224,473 for the development of an antibodybased point-of-care device for diagnosing sickle cell disease (SCD). Early detection can mitigate the risk of life-threatening infections and increase survival, but there are currently no simple tests capable of differentiating patients with the sickle cell trait from sickle cell disease conditions. “Rockland’s antibody technology platform will help to overcome these barriers tremendously. We will create novel hemoglobin isoform-specific antibodies and configure a lateral flow point-ofcare assay,” said Dr. Carl Ascoli, Rockland’s chief science officer. “As a result of this project, the antibody-based lateral flow point-of-care device will allow rapid and inexpensive diagnosis of sickle cell disease in infants and young children in industrialized and low-income and low-resource settings.” IN THIS SECTION Diabetes Metabolon taps Metdia for European marketing of prediabetes tests .............. 35 Oncology Advanced Cell Diagnostics receives major NCI grant........................ 36 Proton therapy, oncology care ................ 35 Removing the вЂ�sword of Damocles’ ....... 35 Sequencing/Oncology Industry leaders launch Actionable Genome Consortium ............................... 35 Sickle cell disease Rockland receives SBIR grant ................ 35 Metabolon taps Metdia for European marketing of prediabetes tests The collaboration includes Metabolon’s Quantose IR and Quantose IGT tests BY KELSEY KAUSTINEN RESEARCH TRIANGLE PARK, N.C.—Metabo- lomics company Metabolon Inc. recently inked a partnership with Spanish biomedical company Metdia Biotech S.L. for the commercialization of Metabolon’s Quantose IR and Quantose IGT prediabetes tests in Europe. Under the collaboration, Metdia will market the tests to hospital and clinical laboratories in Spain, Portugal, France, Italy, the United Kingdom, Germany, Switzerland, Sweden, Norway, Denmark, Finland, the Netherlands, Belgium and Austria. Financial details for the partnership were not disclosed. “Licensing our Quantose IR and Quantose IGT technology to Metdia in Europe is an important next step in expanding the availability of these obesity-related diagnostic tests outside the U.S.,” Dr. John Ryals, president and CEO of Metabolon, commented in CREDIT: METABOLON INC. Industry leaders launch Actionable Genome Consortium Metabolon recently partnered with Spanish biomedical company Metdia Biotech for the marketing of its prediabetes tests in Europe. a statement. “We are confident in Metdia’s broad knowledge of the molecular diagnostics market in Europe. Earlier this year, Quantose IR became commercially available in Mexico through Patia Biopharma, a leading Latin American diabetes public health company. We are delighted to see our technology available to contribute to the health of millions of people in these two major markets.” Prediabetes, according to the American METABOLON CONTINUED ON PAGE 36 Removing the вЂ�sword of Damocles’ MetaSite Breast diagnostic test aims to remove threat hanging over heads of most breast cancer patients BY LORI LESKO MONTCLAIR, N.J.—Known for its innovative technologies in predicting systemic mestastasis in cancer cases, life-sciences company MetaStat Inc. has announced positive results from its MetaSite Breast test, published online in the Journal of the National Cancer Institute. The study successfully indicated the test could accurately predict the probability of which breast cancer patients need chemotherapy—and which patients do not. Systemic metastasis—cancer that spreads from a primary METASTAT CONTINUED ON PAGE 37 CREDIT: IBA BRIEFS IBA focuses, in part, on the development and supply of dosimetry solutions (pictured here) for quality assurance of medical equipment and increased patient safety. The company recently signed a global collaboration with Dutch company Royal Philips to provide advanced diagnostic and therapeutic solutions for the treatment of cancer. Proton therapy, oncology care Although only 35 to 40 percent of all breast cancers will ever metastasize, almost 85 percent of women with newly diagnosed breast cancer are treated with chemotherapy. MetaStat hopes to spare women from needless chemo with its MetaSite Breast diagnostic. IBA and Philips collaborate to personalize cancer diagnosis and treatment BY ILENE SCHNEIDER ANDOVER, Mass.—IBA (Ion Beam Applications S.A.), a provid- er of proton therapy and radiopharmacy solutions, and Dutch company Royal Philips, a diversified health and well-being company, signed a global collaboration to provide advanced diagnostic and therapeutic solutions for the treatment of IBA CONTINUED ON PAGE 37 36 DDNEWS | | NOVEMBER 2014 DIAGNOSTICS For more information, visit www.DDN-News.com Advanced Cell Diagnostics receives major NCI grant Award will fund development of proprietary in-situ RNA detection technology BY JIM CIRIGLIANO HAYWARD, Calif.—The U.S. National Can- cer Institute (NCI) has awarded a two-year, $1.4-million grant under its Small Business Innovation Research Phase II Program to Advanced Cell Diagnostics Inc. (ACD), a company with a focus on in-situ nucleic acid detection for life-sciences research and clinical diagnosis. The grant will allow ACD, along with its academic partner Cleveland Clinic, to work toward the development and validation of a diagnostic test based on the company’s proprietary RNAscope technology for discriminating various B-cell non-Hodgkin lymphomas (NHLs) from benign lympho- proliferative diseases. The test would be an important advance in diagnosing B-cell lymphomas due to the shortcomings of conventional methods of establishing clonality in the majority of NHLs. “Reliable in-situ detection of any RNA in routine clinical specimens has been an unmet need for over 40 years despite many efforts and improvements,” says Dr. Xiao-Jun Ma, chief scientific officer of ACD. “Traditional RNA in-situ hybridization (ISH) techniques are limited to the small fraction of highly expressed genes, leaving 95 percent of the expressed genes undetectable. ACD’s RNAscope technology addresses the need of detecting that 95 percent of the transcriptome.” RNAscope is said to be the first automated multiplex chromogenic and fluorescent insitu hybridization platform capable of detect- CREDIT: ACD “Developing and validating an RNAscopebased diagnostic test is similar to that of the more familiar PCR or IHC-based assays. In some ways, it is actually simpler due to the rapid assay development time (new probes can be had within two weeks) and the assurance of probe sensitivity and specificity.” Dr. Xiao-Jun Ma, chief scientific officer of ACD METABOLON CONTINUED FROM PAGE 35 Diabetes Association (ADA), is characterized by “blood glucose levels that are higher than normal but not yet high enough to be diagnosed as diabetes.” It is sometimes referred to as impaired glucose tolerance or impaired fasting glucose. Metabolon’s Quantose IR is a laboratorydeveloped test that reflects insulin resistance based on insulin and three non-glycemic biomarkers. It can determine an individual’s risk of progression to prediabetes earlier than traditional glycemic measures such as hemoglobin A1c. According to the ADA, the A1C test measures a patient’s average blood glucose over the past two to three months, with prediabetes diagnosed in the range of 5.7 to 6.4 percent and diabetes at 6.5 percent or higher. Quantose IGT reflects the degree of impaired glucose tolerance in a patient, which is a core metabolic defect in dysglycemia and a known risk factor for prediabetes. Quantose IGT can be used as an alternative to an oral glucose tolerance test or to determine patients who may be candidates for such a test. Eric Button, senior vice president of diagnostics at Metabolon, says this is the first time the companies have worked together. It is a sensible partnership, though, as Metdia is focused on providing disruptive technolo- ing and quantifying RNA biomarkers in situ at single-molecule sensitivity. A prime example of the potential of the RNAscope technology is in the detection of Ig kappa/lambda light chain mRNAs, which are expressed at extremely low levels in most B-cell lymphomas, falling into the undetectable 95 percent category for conventional techniques. Clinical laboratory detection of Ig light chain restriction (LCR) is a helpful tool in the differential diagnosis that includes lymphoid hyperplasia, atypical lymphoid hyperplasia, chronic inflammation and B-cell neoplasia. When fresh tissue is available for examination, LCR can be readily detected as an abnormal kappa/lambda surface immunoglobulin ratio using flow cytometry. However these samples are often unavailable in many clinical settings. Existing solutions, including chromogenic in-situ hybridization and immunohistochemistry (IHC), only address a small fraction of B-cell lymphomas, such as multiple myelomas and those lymphomas with plasmacytic differentiation. ACD’s assay reportedly will be applicable to essentially all B-cell lymphoma variants. “This breakthrough is achieved through a proprietary probe design and signal amplification strategy that allows robust signal generation for true target detection but not for nonspecific background,” says Ma. “This is in contrast to previous efforts focusing mainly on signal enhancement and little on the background problem.” “Developing and validating an RNAscopebased diagnostic test is similar to that of the more familiar PCR or IHC-based assays,” he notes. “In some ways, it is actually simpler due to the rapid assay development time (new probes can be had within two weeks) and the assurance of probe sensitivity and specificity.” “The biggest challenge may be that we need to be more vigilant about how samples are fixed and processed since we are detecting RNA, which is more labile than DNA and protein,” Ma says. “We have developed our technology to be compatible with established standards such as CAP/ASCO guidelines for clinical sample preparation. We also strongly recommend the inclusion of positive and negative control probes in the assay to assess RNA adequacy and sample quality. In our experience, most routinely processed clinical specimens, including archival materials that are more than 10 years old, are adequate for RNAscope staining.” Cleveland Clinic will provide their expertise in pathology and clinical medicine to guide the development and validation of the assay to help to ensure the final product is well-validated and suited for everyday clinical use by pathologists. Cleveland Clinic will also provide access to patient samples and corresponding reference data generated by standard of care testing. The Small Business Innovation Research grant is a highly competitive program that encourages domestic small businesses to engage in research and development that holds promise for commercialization. ACD had previously received a one-year Phase I grant and completed the project in 2013, which made it eligible to apply for Phase II funding. The Phase II award will be applied to expenses to cover personnel, materials and supplies and facilities related to the proposed research. “This award is a further validation of the clinical utility of RNAscope technology,” Dr. Yuling Luo, president and CEO of ACD, said in a news release announcing the receipt of the grant. “We are very pleased that NCI has recognized the diagnostic potential of RNAscope technology and are grateful for its continued support.” в– EDITCONNECT: E111423 “To stem the tide of the prediabetes/diabetes epidemic, we must get ahead of the development of these conditions and focus on prevention. That’s where Quantose IR comes in. The test is a tool that provides information to physicians, so they can identify at-risk patients and take steps to prevent the development of prediabetes and diabetes.” Eric Button, senior vice president of diagnostics at Metabolon gies and devices for the prevention, diagnosis and treatment monitoring of prediabetes and diabetes. “Diabetes is a significant global health concern, and the costs to society are high and growing rapidly,” Oscar RodrГguez, director of Metdia Biotech, said in a news release. “According to the International Diabetes Federation, more than 55 million adults in the European Region are coping with diabetes every day. Another 66 million have impaired glucose tolerance, a known risk factor for prediabetes. Tests using Metabolon’s Quantose technology provide cost-effective assessment tools that help physicians identify patients with prediabetes and monitor the impact of therapeutic interventions. If prediabetes is caught early, physicians can prescribe treat- ment that might prevent progression to type 2 diabetes.” Diabetes numbers in the United States aren’t any better. The U.S. Department of Health and Human Services estimated that approximately 86 million adults in the United States ages 20 and up had prediabetes in 2012, while the ADA reports that 29.1 million Americans (9.3 percent of the population) had diabetes. Button adds that “90 percent of people with prediabetes do not know they have it,” which is a serious concern, seeing as how the condition increases someone’s risk of not just type 2 diabetes, but also heart disease and stroke. Fortunately, if the condition is caught early, steps can be taken to avoid the development of diabetes; the ADA reports that an individual with prediabetes can lower their diabetes risk by 58 percent by losing 7 percent of their body weight and exercising moderately for 30 minutes a day, five days a week. The fact that early intervention can increase a person’s chances of avoiding a decline into diabetes provides significant support for tests like Metabolon’s. “To stem the tide of the prediabetes/diabetes epidemic, we must get ahead of the development of these conditions and focus on prevention,” Button tells DDNews. “That’s where Quantose IR comes in. The test is a tool that provides information to physicians, so they can identify at-risk patients and take steps to prevent the development of prediabetes and diabetes.” в– EDITCONNECT: E111420 DIAGNOSTICS For more information, visit www.DDN-News.com METASTAT CONTINUED FROM PAGE 35 tumor through the bloodstream to other areas of the body—is responsible for about 90 percent of all solid tumor cancer-related deaths, according to Dr. Oscar Bronsther, MetaStat CEO. Being able to predict the probability of systemic metastasis allows doctors to better customize cancer treatment decisions by identifying patients with a high-risk of systemic metastasis who need aggressive therapy, and sparing patients with a low-risk of systemic metastasis from the harmful side effects and expense of chemotherapy, Bronsther said. “Some 240,000 women are newly diagnosed with breast cancer every year in America,” Bronsther tells DDNews. “Virtually all will have their tumors surgically removed. That is the first step in their journey. What comes after that is answering the question of whether there is a need for chemotherapy, traditionally used to prevent cancer from spreading through the rest of the body.” “Because we lack a good (approved) cancer diagnostic, we lack the ability to effectively treat women with no progression or mestastasis at all,” he adds. “If we had a test right up front … that would tell a woman with breast cancer whether the risk of mestastasis was nearly zero. Then the sword of Damocles wouldn’t have to hang over her head for a decade.” If oncologists had access to MetaSite Breast, its diagnostic ability could dramatically improve lives and give the future back to most breast cancer survivors, Bronsther says, because only 35 to 40 percent of all breast cancers will ever metastasize. Unfortunately, at present “almost 85 percent of women with newly diagnosed breast cancer are treated with chemotherapy. Yet, only a fraction of these patients can actually benefit from chemotherapy, because only a fraction of these tumors have the biological potential to spread through the bloodstream,” he notes. A complete course of chemotherapy is extremely expensive and, more importantly, takes at least six months and is associated with significant morbidity and a small mortality, he says. Thus, “Having the ability to identify those patients whose tumors are unlikely to metastasize, we can therefore spare those patients the complications.” The journal paper, titled “Tumor Microenvironment of Metastasis and Risk of Distant Metastasis of Breast Cancer,” states how the MetaSite Breast test, a diagnostic assay that quantifies the number of “tumor microenvironments of metastasis” (TMEM) in tumor specimens, showed a strong and statistically significant association with the risk of distant spread—or metastasis—for the most common type of breast cancer. The test performed well at assessing metastasis risk for the study’s most populous cancer subgroup: women with estrogen receptorpositive (ER+)/ HER2/Neu-negative (HER2-) disease (i.e., their cancer cells possess estrogen receptors but lack HER2 protein). Women with ER+/HER2- disease account for approximately 60 percent of all cases of breast cancer, according to the study. When women with this common type of breast cancer were divided into three groups based on their TMEM scores, the risk of distant metastasis turned out to be 2.7 times higher for women with tumors in the highest-scoring TMEM or MetaSite group compared with women with tumors in the lowest-scoring group. The findings confirmed results from a smaller study of the test involving 30 pairs of biopsy specimens that was published in 2009. For comparison, TMEM predictions were compared on the same tumor samples to predictions from the IHC4 test, a diagnostic that assesses risk of recurrence by measuring levels of several proteins (ER,PR, HER2 and Ki-67) involved in tumor cell proliferation and response to hormone therapy in breast tumor tissue, the journal study reported. As for assessing metastatic risk in the study’s most common type of breast cancer (ER+/HER2-), “TMEM results were highly statistically significant, while IHC4 scores were borderline significant at best,” the study stated. “MetaStat believes this is due to its unique understanding of the mechanics and the function-based processes of tumor cell migration and entry into the bloodstream.” MetaStat is currently developing a commercially viable version of the MetaSite Breast test with automated systems to facilitate rapid repeatable implementation in a high-throughput clinical lab setting, Bronsther says. “We are thrilled to see additional positive validation of the MetaSite Breast test,” Bronsther stated in a news release. “We believe it confirms the path-breaking approach that our function-based diagnostics, based on the biology of the mena protein and its isoforms, provide an understanding in cancer metastasis.” “We believe our suite of breast cancer diagnostic tests, comprised of MetaSite Breast and MenaCalc, will offer women and their oncologists highly prognostic and actionable information,” Bronsther continued. “These diagnostic tests aim to empower patients with the information they seek to create the most personal and appropriate approach to their unique tumors.” MetaStat plans on commercializing its suite of breast cancer diagnostics in December 2015 or January 2016, based on CLIA and GLP certification. The company’s commercialization efforts will be headed by Heiner Dreissman, former president and CEO of Roche Molecular Systems. в– EDITCONNECT: E111421 NOVEMBER 2014 | | DDNEWS 37 IBA CONTINUED FROM PAGE 35 cancer. No finite timing has been set, and both IBA and Philips see this as an enduring collaboration. IBA’s proton therapy solutions are scalable and adaptable, offering universal full-scale proton therapy centers as well as next-generation compact, singleroom solutions. IBA also focuses on the development and supply of dosimetry solutions for quality assurance of medical equipment and increased patient safety as well as particle accelerators for medical and industrial applications. Royal Philips offers products in the areas of cardiac care, acute care and home healthcare, energy-efficient lighting solutions and new lighting applications, as well as grooming and oral healthcare products. According to Olivier Legrain, CEO of IBA, the two companies have been partners for some time, working together to improve the patient experience of proton therapy. As he explained, “This new collaboration was a natural next step for both IBA and Philips, allowing the two companies to exploit their leading positions in proton therapy and image guidance systems to provide advanced diagnostic and therapeutic solutions for the treatment of cancer. The collaboration aims to transform cancer care and will provide clinicians with more efficient, effective and personalized treatment for their patients, while also dramatically reducing the time to start of treatment and the cost of that treatment.” The collaboration covers sales, marketing and research and development of imaging and therapy solutions in oncology. By merging their respective expertise, IBA and Philips plan to innovate with an integrated vision for more efficient, personalized cancer care. The companies believe that leveraging highquality imaging and proton therapy offers Cambridge Healthtech Institute’s 14th Annual the potential to increase confidence in the diagnosis and treatment of cancer, reduce short- and long-term side-effects and potentially enhance the quality of life of the patient before, during and after treatment, while reducing costs. Additionally, the collaboration will enable both organizations to mutually leverage technologies and solutions: IBA will benefit from Philips’ diagnostic imaging products offered to oncology care centers, while Philips will leverage IBA proton therapy solutions within its offering for customers in select markets around the world. The commercial collaboration also includes an integrated offering for Molecular Imaging Centers, combining IBA’s expertise in PET radioisotope production centers with Philips’ imaging and diagnostics expertise. Gene Saragnese, executive vice president and CEO of imaging systems at Royal Philips, added, “Proton therapy is one of the most exciting technological advancements in the oncology field. We look forward to collaborating with IBA to enhance access to best-in-class technology for both Proton Centers and Molecular Imaging Centers, as well as to accelerate the development of our informed therapy guidance vision in ways that can change the future of care, and improve the quality of life for patients.” Legrain concludes, “This is an exciting and important step for IBA. A closer collaboration with a company of Philips’ caliber and global reach, where we are able to combine both companies’ expertise and excellence in oncology care, will accelerate innovation and provide more efficient and effective solutions in molecular imaging and treatment solutions. This collaboration is an important step toward adaptive treatment of cancer and a personalized treatment approach to enable the best possible result for cancer patients across the globe.” в– EDITCONNECT: E111422 January 19-23, 2015 San Diego, CA Town and Country Resort & Convention Center 20 Conferences, 300+ Speakers, 1,200+ Participants, 125+ Posters, 90+ Exhibitors, 1 Location Be a Part of It! Register Early for Advance Savings up to $200! Mention Keycode O30 and Save an Additional $100 For exhibit & sponsorship opportunities, contact: Companies A-K: Jason Gerardi 781-972-5452 [email protected] CHI-PepTalk.com Companies L-Z: Carol Dinerstein 781-972-5471 [email protected] Be in your element. 2015 Pi 5 PIT TCONIUM Make the smart choice Register now to attend Pittcon 2015, the world’s largest annual conference and exposition for laboratory science. March 8-12, 2015 New Orleans, LA Morial Convention Center • See product innovations from leading companies • Discover the latest scientific research in a wide range of disciplines • Network with colleagues from around the world Follow us for special announcements Learn why thousands of your colleagues say “Pittcon is a must-attend event.” Visit www.pittcon.org DDNews_PittconAd_NovIssue.indd 1 10/22/2014 3:10:21 PM For more information, visit www.DDN-News.com NOVEMBER 2014 | | DDNEWS 39 BUSINESS & GOVERNMENT POLICY BRIEFS Genisphere reaches collaboration goal HATFIELD, Pa.—Genisphere LLC recently achieved its goal for 2014 of 25 collaborations in targeted drug delivery, a number that includes collaborative research projects with 17 investigators in 11 institutions. The company is shifting its focus to the use of its 3DNA nanoparticles as a drug delivery platform, and it says it is currently the only commercial source of DNA-based nanocarriers. Its first research collaboration with MultiCell Technologies Inc. was announced last year to investigate the use of the 3DNA platform for targeted delivery of MultiCell’s MCT485 for primary hepatocellular carcinoma. “To date, proof-of-concept preclinical data have demonstrated specific targeting of tumors, selective killing of targeted cells, tumor shrinkage and no observed toxicity,” said Bob Getts, chief science officer at Genisphere. NeoStem licenses Rockefeller University patents NEW YORK—NeoStem Inc. and The Rockefeller University have begun an exclusive license agreement for patented technologies that expand NeoStem’s IP portfolio for its Targeted Cancer Immunotherapy Program. The patents that NeoStem has licensed are titled “Methods for use of Apoptotic Cells to Deliver Antigen to Dendritic Cells for Induction or Tolerization of T Cells.” “By licensing these patents that relate to NeoStem’s DC/TC (dendritic cell/tumor cell) technology ... NeoStem continues to look proactively for opportunities to expand and defend its technology platform as we simultaneously plan to initiate our Phase 3 Intus clinical study that will investigate our DC/TC technology in metastatic melanoma this year,” said Dr. Andrew L. Pecora, chief visionary officer at NeoStem. IN THIS SECTION Collaborations Genisphere reaches collaboration goal................................... 39 Licensing/Intellectual property NeoStem licenses Rockefeller University patents ............... 39 M&A activity A вЂ�win-win’ in women’s health............... 39 AbbVie aborts plan to acquire Shire ...... 39 Horizon Discovery acquires Sage Labs ................................ 42 Male health/M&A activity Expanding the pipeline (ENDO from cover) .................................. 42 Patent/Antitrust District courts implement Supreme Court’s Actavis decision...................................... 39 Tools and technology On the cutting edge ................................ 40 A вЂ�win-win’ in women’s health AMAG Pharmaceuticals to acquire Lumara Health, propelling company into women’s health of wooing, AbbVie and Shire came to a roughly $55-billion agreement. But then, in late September, the U.S. Department of Treasury proposed unilateral changes to the tax regulations designed to prevent or deter U.S. companies from re-domiciling in other countries—technically headquartering in SHIRE CONTINUED ON PAGE 41 PATENT CONTINUED ON PAGE 40 Makena, one of the women’s health products AMAG gains by acquiring Lumara, was granted seven-year Orphan Drug exclusivity in 2011 as the only FDA-approved product indicated to reduce the risk of preterm birth in women who are pregnant with one baby and who have delivered one preterm baby spontaneously in the past. spontaneously in the past. Preterm birth is defined as the delivery of a baby at less than AMAG CONTINUED ON PAGE 41 AbbVie aborts plan to acquire Shire After U.S. tax officials begin to put up roadblocks to inversion deals, deal falls apart NORTH CHICAGO, Ill.—The IRS has claimed its first victory with anti-inversion rules—or perhaps its first victim, depending on your perspective—in AbbVie with the scuttling of an intended acquisition by the company of Dublin, Ireland-based Shire plc. It was just in August that, after months L AST TERM, the Supreme Court in FTC v. Actavis overruled several Circuit Courts of Appeal by holding that so-called “reverse payment settlement agreements” (RPSAs) in Abbreviated New Drug Application (ANDA) litigation were not presumptively legal under antitrust law so long as the licensed rights were within the “scope of the patent” exclusivity. The Court opined that some agreements might be antitrust violations without regard to the extent Kevin Noonan, of patent protection partner, (or even without McDonnell regard to issues of Boehnen patent validity and Hulbert & enforceability)—for Berghoff LLP example, when “disproportionately large” reverse payments were involved. Ever since the Federal Trade Commission won this partial victory (having in the past contended that RPSAs were per se illegal), the FTC and private litigants have been trying to extend antitrust scrutiny beyond the bounds of the limits set by the court. The most common such attack has been on RPSAs having non-monetary components, such as so-called “authorized generics,” where the branded drug maker agrees not to introduce its own generic version into the marketplace, or where the branded drug maker agrees to permit a particular generic manufacturer to provide or purchase active pharmaceutical ingredients to be used in generic versions of the branded drug. These efforts have met with varying degrees of success, with some district courts permitting these arrangements to be subjected to antitrust scrutiny and others rejecting the extension of the court’s precedent. The most recent instance has been in a New Under the terms of the original acquisition agreement, Shire is entitled to a break fee of approximately $1.64 billion, payable by AbbVie, if AbbVie stockholders do not approve the adoption of the merger agreement at an AbbVie stockholder meeting or such a meeting does not occur by Dec. 14, 2014. BY JEFFREY BOULEY by Kevin Noonan District courts implement Supreme Court’s Actavis decision BY LLOYD DUNLAP WALTHAM, Mass.—AMAG Pharmaceuticals Inc. has entered into a definitive agreement to acquire Lumara Health Inc., a privately held pharmaceutical company specializing in women’s health, for $675 million ($600 million in cash and $75 million in stock) and additional contingent consideration of up to $350 million based on achievement of certain sales milestones. Lumara Health also announced recently that the company signed a separate agreement to divest certain other assets to a third party. Lumara Health markets the fast-growing product Makena (hydroxyprogesterone caproate injection), which was granted sevenyear Orphan Drug exclusivity in February 2011 and is the only U.S. Food and Drug Administration (FDA)-approved product indicated to reduce the risk of preterm birth in women who are pregnant with one baby and who have delivered one preterm baby Patent Docs BUSINESS & GOVERNMENT POLICY 40 DDNEWS | | NOVEMBER 2014 On the cutting edge A roundup of instrumentation, software and other tools and technology news T BY JEFFREY BOULEY HIS TIME in our month- ly Tools & Technology roundup, we have on tap massively parallel stem cells, rapid and reproducible antibody/ antigen expression, a stem cell growth matrix and mass spec imaging of 3D microtissues. However, as this is the November issue and not the December issue, we have no lords a’leaping, golden rings or partridges in pear trees. productivity, significantly cutting costs whilst accelerating the development of innovative therapies for serious medical conditions.” Dr. Yen Choo, Plasticell’s executive chairman and senior author of the scientific paper, added: “Optimizing laboratory methods to obtain affordable, industrialized cell manufacturing protocols is absolutely key to the development of cell therapies. The paper describes a study in which we used combinatorial screening to obtain a 250-fold reduction in cell bioprocessing costs, through a 50-fold increase in cell yield accompanied by a fivefold reduction in reagent costs via the use of cell culture media comprising small-molecule drugs.” TOOLS & TECHNOLOGY Can Plasticell’s massively parallel approach help transform regenerative medicine? STEVENAGE, U.K.—Stem cell bio- tech Plasticell Ltd. announced recently the publication of scientific research which it says demonstrates how the company’s innovative high-throughput Combinatorial Cell Culture (CombiCult) technology allows a single scientist to carry out 10,000 stem cell biology experiments in parallel. The scientific paper points to the potential of high-throughput technologies “Discovery of robust methods to differentiate stem cells remains a serious bottleneck for the industry. This is a major reason why only two pluripotent stem cell therapies have progressed to clinical trials despite the spending of many hundreds of millions of dollars on pluripotent stem cell translation.” Chris Mason of University College London such as CombiCult to accelerate painfully slow biomedical research, which has hampered the development of new therapies ever since human embryonic stem cells were developed in 1998. “Discovery of robust methods to differentiate stem cells remains a serious bottleneck for the industry. This is a major reason why only two pluripotent stem cell therapies have progressed to clinical trials despite the spending of many hundreds of millions of dollars on pluripotent stem cell translation,” said Chris Mason, professor of regenerative medicine bioprocessing at University College London, whose research group carried out external validation of the technology. “The unique CombiCult technology can dramatically increase research Sutro Biopharma to collaborate with UCSF SAN FRANCISCO—Sutro Biopharma, a biopharmaceutical company developing a new generation of protein therapeutics, including next-generation antibody drug conjugates and bispecific antibodies, announced Sept. 9 its collaboration with the laboratory of Dr. James Wells, professor and chair of the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF), as part of the Recombinant Antibody Network. Under the terms of the agreement, Sutro will provide its Xpress CF technology for the rapid and reproducible expression of antibodies and antigens by the Wells Lab for the comprehensive profiling of different target proteins and protein families in a high-throughput manner. “High-quality antibodies that perform well and exhibit high affinity and specificity are not only very important therapeutics for many diseases, they are also essential for basic research,” said Wells. “Technology that allows for parallel screening of many variants to generate quickly validated and renewable antibodies is an indispensable tool for researching the functions of specific proteins under normal or pathophysiological conditions.” Corning announces new agreement with BioLamina CORNING, N.Y.—On Sept. 11, Corning Inc. announced it had entered into an agreement with Swedish company BioLamina to manufacture and package the Recombinant Laminin-521 (rLaminin-521) pluripotent stem cell (PSC) and neu- ral stem cell (NSC) growth matrix. The collaboration will augment Corning Life Sciences’ portfolio of defined coating substrates and extend the availability of this product to research labs worldwide. Corning and BioLamina recognize a strong demand in the stemcell research market for chemically defined, xeno-free systems, and rLaminin-521 provides a defined, animal-free substrate that allows robust and scalable cell culture of PSCs and NSCs with greater cell purity—critical attributes for the emerging stem-cell processing market and a vital enabling component for future cell therapies using these types of cells, they say. “As cell-culture and cell-therapy technologies progress, it is increasingly important to offer today’s researchers more powerful and reliable culture systems,” said Dr. Kristian Tryggvason, CEO of BioLamina. Meanwhile, Dr. Lynsey Willetts, Ph.D., director of advanced cell culture at Corning Life Sciences, added, “By working with BioLamina, Corning now offers researchers who work with pluripotent and neural stem cells a more comprehensive and scalable cell culture solution—from research to production.” Protea and InSphero succeed with MS imaging of 3D microtissues MORGANTOWN, W.V.—The early days of October saw Protea Biosciences Group Inc. and Schileren, Switzerland-based InSphero AG jointly announce an update from their collaboration focused on mass spectrometry (MS) imaging of InSphero’s 3D InSight microtissues. In August 2014, Protea received microtissues from InSphero and hosted members of InSphero’s scientific team for onsite training on the handling and preparation of the microtissues. Protea has since developed workflows for processing the 3D microtissues for MS imaging and direct analysis. In addition, Protea has generated data from 3D microtissues grown from HCT-116 colon cancer cell line that showed the ability for MS imaging to detect and image numerous native proteins in 3D microtissues in a single experiment as well as putatively identify several proteins known to be present at elevated levels in colon cancer cells. “[Now] we look forward to developing new applications through the combination of our respective technologies and moving forward towards commercial offerings for our pharmaceutical and biotechnology customers,” stated Protea CEO Stephen Turner. в– EDITCONNECT: E111427 For more information, visit www.DDN-News.com PATENT CONTINUED FROM PAGE 39 Jersey action by a number of direct and indirect purchaser plaintiffs over Pfizer’s Lipitor drug (atorvastatin calcium); in this case, the district court granted the branded (Pfizer Inc., Pfizer Manufacturing Ireland and Warner-Lambert Co.) and generic (Ranbaxy Inc., Ranbaxy Pharmaceuticals Inc. and Ranbaxy Laboratories Ltd.) defendants’ motion to dismiss for failure to state a cause of action. The RPSA at issue was particularly complex, involving three separate ANDA litigations as well as more than two dozen other actions in foreign jurisdictions, and involving Pfizer drugs Accupril and Caduet as well as Lipitor. The settlement agreement was a “non-monetary” reverse payment, containing terms that absolved Ranbaxy from damages ordered in one of the terminated Accupril litigations. The agreement also delayed generic entry into the Lipitor market until Nov. 30, 2011; the parties agreed to the same market entry date for Caduet and Accupril. In addition, Ranbaxy paid Pfizer $1 million in damages for its earlier “at-risk” launch of generic Accupril. Finally, Pfizer agreed to be Ranbaxy’s active pharmaceutical ingredient supplier for Lipitor, and Ranbaxy changed its formulation from putatively noninfringing amorphous atorvastatin to putatively infringing crystalline atorvastatin calcium. The plaintiffs contended that the RPSA was a purposeful antitrust violation because it delayed entry of Ranbaxy’s generic atorvastatin calcium in part because Ranbaxy switched from the noninfringing amorphous form to the infringing crystalline form of atorvastatin calcium. In addition, the plaintiffs argued that Pfizer provided financial incentives for the RPSA by forgoing the lion’s share of its damages from Ranbaxy’s generic launch of Accupril. The district court identified “the heart of the issue” as being whether the agreement between the branded and generic drug companies was a RPSA and, if so, whether the agreement warranted antitrust scrutiny under the Actavis standards. The district court decided that plaintiffs had failed to put forth sufficient evidence that the agreement was an RPSA warranting antitrust scrutiny. The court agreed that a “payment” could be anything sufficient to discharge a debt or obligation and was not limited to cash payments, and the court further found no consistent or persuasive authority that the Actavis decision required a payment of money between the parties. However, the court found that there must be a way to “convert” whatever was exchanged between the parties into a monetary equivalent in order to apply the Supreme Court’s Actavis precedent. While the district court recognized that the Supreme Court’s “general concern” in Actavis was whether there were “genuine adverse effects on competition” (not limited to merely monetary arrangements), the court also recognized that the factual requirements needed to state a proper claim are more extensive for non-monetary consideration between the parties. Specifically, the court asserted that plaintiffs would need to establish a value for the non-monetary payments alleged in support of the complaint. Here, the complaint alleged no facts relating to the amount of the damages Ranbaxy was at risk for incurring in the Accupril II case, and merely assumed these damages to be on the order of the $200-million bond Pfizer posted in support of its injunction for Ranbaxy’s “at-risk” sales or the difference in gross sales ($525 million vs. $70 million). The court found neither of these assumptions to be plausible, citing as unmet considerations evidence of each party’s assessment of its own risk, including the probability of prevailing in the ANDA litigation, the profits expected when only the branded, or a combination of only the branded and the first ANDA filer were on the market, the amount of patent lifetime remaining in view of the agreed-to generic entry date and litigation costs for each party, as well as industry-specific damages measurements. This case illustrates the consequence of the Supreme Court’s jurisprudential decision to permit the contours of its Actavis decision to be “worked out” in district and appellate courts below. While a perfectly proper exercise of the court’s supervisory powers over the circuit courts, this way of changing the law has produced and will continue to produce uncertainties that can be expected to seriously harm competition and innovation, two of the supposed reasons why the court decided to reenter the patent law arena with such vigor. Rarely have the court’s decisions had the potential for such harm to the American economy and global competitiveness, particularly in a field where the U.S. has been a leader for a generation. в– EDITCONNECT: E111426 Kevin Noonan is a partner with the law firm McDonnell Boehnen Hulbert & Berghoff LLP and represents biotechnology and pharmaceutical companies on a myriad of issues. A former molecular biologist, he is also the founding author of the Patent Docs weblog, http://patentdocs. typepad.com/. For more information, visit www.DDN-News.com SHIRE CONTINUED FROM PAGE 39 those nations while often not actually moving any operations out of the U.S.—to reduce their tax burdens, a process known as inversion. That got AbbVie to rethinking the deal and its potential profitability, and on Oct. 14, the company announced that its board of directors would meet “to reconsider the recommendation made on July 18, 2014, that AbbVie stockholders adopt the merger agreement needed to complete the proposed combination of AbbVie and Shire” and “consider whether to withdraw or modify its recommendation.” Some market-watchers had speculated that the deal would simply be modified, as both companies, particularly AbbVie, had been emphasizing their excitement about the potential synergies rather than the tax benefits to AbbVie. The theory was that AbbVie had too much of its reputation invested in the deal and would take a hit to its credibility if it backed off the acquisition. Those analyses proved to be wrong when, just a day after the announcement that the board would reconsider the deal, AbbVie noted that Shire had waived a three-day notice period and the AbbVie board had made a “detailed consideration of the impact of the U.S. Department of Treasury’s unilateral changes to the tax rules” and recommended that shareholders reject the merger and acquisition (M&A) deal, as “The breadth and scope of the changes, including the unexpected nature of the exercise of administrative authority to impact longstanding tax principles, and to target specifically a subset of companies that would be treated differently than either other inverted companies or foreign domiciled entities, introduced an unacceptable level of uncertainty to the transaction. Additionally, the changes eliminated certain of the financial benefits of the transaction, most notably the ability to access current and future global cash flows in a tax-efficient manner as originally contemplated in the transaction. This fundamentally changed the implied value of Shire to AbbVie in a significant manner.” “Although the strategic rationale of combining our two companies remains strong, the agreed-upon valuation is no longer supported as a result of the changes to the tax rules, and we did not believe it was in the best interests of our stockholders to proceed,” said AbbVie Chairman and CEO Richard A. Gonzalez. Under the terms of the original acquisition deal, AbbVie will have to pay a break fee of approximately $1.64 billion. While that is the third-largest fee on record to break an M&A deal, the sting might not be too painful for AbbVie in the end, as analysts have noted the fee—like many other related costs of the M&A negotiations and now breakup—is tax-deductible. A contributed article by Robert W. Wood on the Forbes website estimates that AbbVie could realize at least $650 million in tax savings. в– EDITCONNECT: E111425 BUSINESS & GOVERNMENT POLICY AMAG CONTINUED FROM PAGE 39 37 weeks of pregnancy. Approximately one in every nine babies is born preterm, or 11.7 percent of births in the United States. Premature birth in the nation costs $26.2 billion annually, and average first-year medical costs are approximately 10 times greater for preterm infants than for full-term infants. “This is a truly transformative transaction that will propel AMAG into a profitable, highgrowth multiproduct specialty pharmaceutical company positioned for what we expect to be continued revenue and bottom-line growth, further business diversification and shareholder value creation,” says William Heiden, president and CEO of AMAG. Invoking what is often clichГ©, he refers to the deal as a “winwin,” but in this case there may be good reason for the characterization. Heiden and Lumara’s CEO Greg Divis have a 10-year-old relationship dating back to their days at SheringPlough. Divis notes that AMAG “shares our commitment,” and that Makena and AMAG’S Feraheme (ferumoxytol) are a good fit. “We believe the Lumara Health transaction will facilitate future product acquisitions in an attractive new therapeutic area and is an excellent strategic fit with our Feraheme market expansion plans,” Heiden adds. The acquisition of Lumara Health provides AMAG with a strategic commercial entry into the women’s health segment. Women’s health includes one of the largest pools of patients with iron deficiency anemia (IDA). Accordingly, if AMAG is successful at gaining FDA approval to expand the label of Feraheme beyond the current chronic kidney disease indication, the 75-person strong Lumara commercial sales force could become a meaningful contributor to the growth of Feraheme in the future. Of the 1.5 million patients with IDA, AMAG estimates that fewer than 10 percent are now treated with IV iron such as Feraheme. Thus, an expanded label for the product could produce a significant uptick in sales. NOVEMBER 2014 | | DDNEWS 41 Net sales of Makena over the 12 months ending August 31, 2014, were greater than $130 million, a 72-percent increase compared to the prior-year period. In addition, based on the three months ended August 31, 2014, Makena and Lumara Health’s maternal health business would be on pace to exceed annualized net sales of $180 million and EBITDA of $110 million. AMAG believes that positive market dynamics, including a favorable regulatory environment, and implementation of a new patient-centric business strategy contributed to the significant recent growth of Makena. Heiden continued, “Makena is a unique product with clear clinical benefits that serves an important medical need for at-risk pregnant mothers and their unborn children. The consequences of preterm birth are a significant public health issue, and we believe that Makena will be a tremendous addition to our portfolio and will be complementary to AMAG’s in-office injectables commercial expertise. We’re also looking forward to welcoming to AMAG the talented Makena commercial team, which has put Makena on a remarkably strong sales growth trajectory. We believe that our combined larger-scale, combined portfolio diversification, new resources and broader commercial expertise will allow AMAG to create new long-term growth opportunities and allow us to better serve patients.” Another arrow in the new company’s quiver is the Drug Quality and Security Act that placed new restrictions on compounding pharmacies. Heiden notes that 46 percent of the competition for Makena comes from compounders, and he expects AMAG to whittle away at this business. In addition, he points out that the physicians who specialize in women’s care frequently prescribe off-label drugs out of a perceived lack of a better alternative. “I strongly believe AMAG is the right partner to support the continued growth of Makena and our maternal health business,” said Lumara’s Divis. “This transaction is a great reflection of the outstanding work our team has done to build the maternal health franchise to what it is today, and I am pleased that this same team will continue to grow the brand within AMAG. It has been clear from the start of our discussions that AMAG shares our commitment to at-risk pregnant mothers, their babies and their healthcare providers.” The transaction is expected to result in projected combined 2015 product sales of $350 million and is expected to be immediately accretive to adjusted earnings per share, with cost synergies of at least $20 million per year. Following the closing of the transaction, AMAG expects to have approximately $100 million in cash and 25.2 million basic shares outstanding. AMAG intends to provide additional financial guidance for 2015 as promptly as practicable following completion of the transaction. Upon closing, Lumara Health’s commercial operations will function as a separate business unit within AMAG, reporting directly to Heiden. AMAG intends to name current Lumara Health executives who will be joining AMAG’s leadership team at or prior to closing. The transaction has been unanimously approved by both companies’ boards of directors. The transaction has also been approved by the stockholders of Lumara Health. It is expected to be completed in the fourth quarter of 2014, following termination or expiration of the waiting period under the HartScott-Rodino Antitrust Improvements Act of 1976 and completion of financing. In addition to the $675 million at closing, the terms of the agreement provide for contingent consideration of up to $350 million based on the achievement of various sales milestones for Makena, including sales achievement of $300 million, $400 million and $500 million in consecutive 12-month periods. AMAG believes that its tax attributes following the closing of the transaction represent an important corporate asset that can provide long-term shareholder benefits. в– EDITCONNECT: E111424 REGISTER NOW FOR ADVANCE DISCOUNT RATES! AT SLAS2015 Join more than 5,000 of the brightest, most innovative minds vested in scientific automation at SLAS2015 as they come together to learn, share and explore how to transform scientific research using technology. Scientists, engineers, researchers, business leaders and technology providers from industry, academia and government backgrounds will benefit from 132 peer-selected podium presentations comprising 33 unique scientific sessions, hundreds of posters, plentiful networking opportunities and access to the latest technologies from 300+ exhibitors from around the world. Participating at SLAS2015 is an invaluable investment that pays significant dividends toward your personal and organizational goals, as well as your professional success. , KEYNOTE PRESENTERS Francis Collins Director, U.S. National Institutes of Health (NIH) Donald E. Ingber Harvard University Laurie Garrett Renowned Author and Authority on Global Health Issues BUSINESS & GOVERNMENT POLICY 42 DDNEWS | | NOVEMBER 2014 For more information, visit www.DDN-News.com Horizon Discovery acquires Sage Labs CAMBRIDGE, U.K. & ST. LOUIS— There are a number of reasons for Horizon Discovery Group plc to want to acquire Sage Labs Inc. For one thing, it would enhance Horizon’s U.S. footprint and strengthens both its U.S. and European Union (EU) sales force, and it would strengthen Horizon’s intellectual property (IP) with regard to CRIS- PR technology as it gains exclusive rights for in-vivo zinc finger nuclease (ZFN) applications. And all this for the price of $48 million, according to Horizon’s lateSeptember announcement of a deal to acquire Sage. This deal “builds upon the acquisition of CombinatoRx in July and makes Horizon the world’s leading gene-editing Monochromator. Reinvented! CLARIOstarВ® - The multimode microplate reader with revolutionary LVF MonochromatorsTM Discover the most sensitive monochromator-based microplate reader. Any Wavelength. Any Bandwidth. Any Assay. www.bmglabtech.com company and the go-to company for the provision of integrated product, service and research solutions at all stages of translational genomics and personalized medicine research from sequence to treatment,” according to Horizon. Horizon will gain exclusive access to ZFN for in-vivo model generation and certain exclusive and non-exclusive CRISPR in-vivorelated IP to add to its extensive in-vitro IP in CRISPR, ZFN and rAAV, the latter of which is a ENDO CONTINUED FROM PAGE 1 transaction will include an election mechanism for Auxilium stockholders to elect cash and stock, all-stock or all-cash consideration, subject to proration in accordance with the terms of the definitive agreement. The pershare consideration represents a premium of 55 percent to Auxilium’s closing price on Sept. 16, 2014, the day Endo made public its proposal for Auxilium. Immediately prior to the entering into the merger agreement with Endo, Auxilium terminated its proposed merger agreement with QLT Inc., in accordance with the terms of the QLT merger agreement. According to Endo, the addition of Auxilium’s leading men’s health products and development portfolio should “significantly enhance Endo’s branded pharmaceutical business.” “We are pleased to have reached this agreement with Auxilium, which we believe will create value for both Endo and Auxilium shareholders, as well as for patients, customers and employees,” said Rajiv De Silva, president and CEO of Endo. “By adding Auxilium’s complementary commercial portfolio, we believe this transaction is aligned with our strategy of pursuing accretive, value-creating growth opportunities. We intend to leverage Auxilium’s leading presence in men’s health, as well as our R&D capabilities and financial resources, to accelerate the growth of Xiaflex and Auxilium’s other products. We look forward to working with the Auxilium team to achieve the growth and synergy potential of this compelling strategic combination.” Xiaflex seems to be a big selling point in the acquisition. It is a collagenase clostridium histolyticum (CCH) biologic compound currently approved in the United States, European Union, Canada and Australia for the treatment of adult Dupuytren’s contracture patients worldwide exclusive to Horizon. According to Horizon, it will focus on expanding Sage’s predominantly U.S. customer base by increasing its presence in Europe, Japan and beyond via access to Horizon’s business development and commercial infrastructure. The acquired business will continue to be known as Sage Labs Inc., and will operate as a wholly owned subsidiary of Horizon Discovery Group. The acquisition was expected to be complete by Oct. 2, though there with a palpable cord and in the United States for the treatment of adult men with Peyronie’s disease with a palpable plaque and penile curvature deformity. Xiafl ex is currently in a Phase 2a study for the treatment of edematous fibrosclerotic panniculopathy, commonly known as cellulite. Leerink Partners, an investment bank specializing in healthcare, forecasts pre- and post-deal five-year revenue compound annual growth rates of 3 percent and 8 percent, respectively. “Key to the improved growth outlook is Auxilium’s ability to launch Xiaflex in Peyronie’s disease, where diagnosis rates remain low but Xiaflex offers a first-line alternative to surgery,” writes Jason Gerberry of Leerink. “Based on a recent MEDACorp survey of urologic surgeons, specialists see Xiaflex as a firstline treatment and plan to prescribe the drug to one-third of their patients within 12 months post-launch.” Global research and consulting firm GlobalData values Auxilium’s pharmaceutical assets at approximately $2.5 billion, which it says is in line with Endo’s outlay. Largely driving the company’s valuation is Xiaflex with a net present value of $920 million, followed by Testopel at $570 million and Stendra at $558 million, says Adam Dion, GlobalData’s analyst covering healthcare industry dynamics. Dion also notes that Endo intends to leverage its resources to optimize and drive increased adoption of three key Auxilium drugs, which are Xiaflex, Testopel and Testim, the latter two both being hormone replacement agents. “Testopel and Testim generated combined sales of $271 million in 2013, and will supplement Endo’s hypogonadism therapy Fortesta,” he explains. However, GlobalData believes Endo’s purchase price might be slightly on the high side, “given that Auxilium was negotiating from a position of weakness.” was, as of press time, no confirmation on either company’s website that the deal had been finalized officially—however, Sage Labs was posting news dated Oct. 23 from Horizon on its website, which said that Horizon had “announced the launch of its patient-derived xenograft (PDX) models of breast cancer under its Sage Labs brand. The new panel is the largest available collection of highly characterized PDX models, and is licensed from Washington University.” ■“Auxilium’s top-line revenue was flat in 2013, and the company has been faced with slowing sales of Testim and witnessed a 50-percent year-on-year drop in sales from Xiaflex,” Dion notes. “The company responded by announcing that it would cut about 190 jobs, or 30 percent of its workforce, as part of a plan to save $75 million per year. Auxilium was also considering purchasing the Canadian eye drugmaker QLT in an effort to shave costs to a lower tax domicile, but recent changes to tax laws most likely thwarted those efforts.” Dion says that Endo’s motivation behind the deal centers on cash generation and cost-cutting, with the company expected to achieve annual cost synergies of about $175 million. “This synergy run-rate is expected to be immediately accretive in the first year after closing, and includes Auxilium’s reduction in annual operating expenses previously announced in September,” he explains. “After the transaction, Endo will have a stronger balance sheet, increased cash flow with improved financial flexibility to continue with its diversification strategy, transforming itself into a larger specialty pharma and medical device maker.” Zacks Investment Research remarked in an analyst note, “We believe it is a wise decision for Endo to acquire Auxilium Pharma. Endo has been struggling financially due to generic competition affecting its key painkillers Lidoderm and Opana ER. The Auxilium Pharma acquisition will not only help Endo to offset the impact of genericization with new products but will also help to diversify its portfolio.” For his part, Adrian Adams, CEO and president of Auxilium, noted in the news release about the acquisition deal that “We are proud of the work Auxilium has done to develop a portfolio of important products that are improving the lives of patients to create significant stockholder value.” в– EDITCONNECT: E111402 PEOPLE & PROMOTIONS For more information, visit www.DDN-News.com NOVEMBER 2014 | | DDNEWS 43 People & Promotions Perrigo Co. plc Clivetty Martinez, Ph.D. V.P. of Corporate Global Compliance & Chief Privacy Officer ALLEGAN, Mich.— Pharmaceutical supplier Perrigo Co. announced Sept. 18 that it had hired Dr. Clivetty Martinez for the roles of vice president of corporate global compliance and chief privacy officer. Martinez will be responsible for overseeing the daily compliance program’s activities, driving awareness of Perrigo’s code of conduct and core values, identifying areas of compliance risk and guiding the efforts of the compliance teams at each Perrigo location worldwide. Martinez brings to Perrigo 14 years of global compliance experience in the healthcare and pharmaceutical industries. Myriad Genetics Inc. R. Bryan Riggsbee Executive V.P., Chief Financial Officer & Treasurer SALT LAKE CITY—Early October saw Myriad Genetics announce the appointment of R. Bryan Riggsbee as executive vice president, chief financial officer and treasurer. Riggsbee most recently served as the senior vice president of corporate finance at Laboratory Corp. of America Holdings, a $5.8-billion clinical laboratory company, where he oversaw the financial planning and analysis and treasury functions. Previously, he served in various finance positions at General Electric Co. Nurix Inc. Arthur T. Sands, M.D., Ph.D. Chief Executive Officer SAN FRANCISCO—Nurix, a company known for dis- covering and developing therapies that modulate the ubiquitin proteasome system, announced Sept. 18 the appointment of Dr. Arthur T. Sands as CEO, succeeding interim CEO Dr. Mark A. Goldsmith, a partner at Third Rock Ventures who will continue service to the company as chairman of its board of directors. Prior to joining Nurix, Sands co-founded Lexicon Pharmaceuticals and served as president, CEO and director there since 1995. At Lexicon, Sands pioneered the development of large-scale gene knockout technology for use in drug discovery and guided the evolution of Lexicon from a research-stage company to a drug development company, catalyzed by numerous alliances with Bristol-Myers Squibb, Takeda and Genentech, and generating more than $450 million in revenue. Dimension Therapeutics Annalisa Jenkins, MBBS, MRCP Chief Executive Officer CAMBRIDGE, Mass.—Dr. Annalisa Jenkins was recently named as the new CEO of Dimension Therapeutics, a gene therapy company focused on developing novel treatments for rare diseases, succeeding interim CEO Dr. Thomas Beck. Jenkins brings to Dimension nearly 20 years of experience in building and leading teams that advanced programs from scientific research through clinical development, regulatory approval and into healthcare systems globally. Prior to joining Dimension, she served as executive vice president and head of global research and development for Merck Serono, where she also led global medical affairs and quality. Prior to Merck Serono, Jenkins held several roles of increasing responsibility at Bristol-Myers Squibb, where she made significant contributions to the progression and approval of a number of key pipeline programs, including Eliquis, Orencia, Sprycel, Yervoy, Erbitux, Abilify and Plavix. Aptose Biosciences Inc. Stephen B. Howell, M.D. Chief Medical Officer SAN DIEGO and TORONTO— Aptose Biosciences, a clinical-stage company developing new therapeutics and molecular diagnostics that target the underlying mechanisms of cancer, recently announced that Dr. Stephen B. Howell will act in the capacity of chief medical officer. Howell is a renowned medical oncologist and leader in the development of novel drugs and drug delivery systems for the treatment of cancer and in the discovery of the molecular and genetic mechanisms underlying drug resistance. He holds the position of distinguished professor of medicine in the Division of Hematology-Oncology at the University of California San Diego Moores Cancer Center, where he also serves as the co-leader of the Solid Tumor Therapeutics Program and directs the Cancer Therapeutics Training Program. ICON plc Ira Spector, Ph.D. Executive V.P. of Analytics and Consulting a global provider of outsourced development services to the pharmaceutical, biotechnology and medical device industries, in September announced the appointment of Dr. Ira Spector as executive vice president of analytics and consulting. In this role, he will lead ICON’s global consulting and drug development services and will also be responsible for ICON’s business process improvement and analytics capabilities. Spector is an expert in clinical development and brings to ICON over 25 years of experience in managing global drug and medical device development programs. He joins ICON from Allergan Pharmaceuticals, where he was senior vice president of global development operations. ONLINE Here’s a tiny sampling of recent news stories on our main website and Cancer Research News site. Use the Editconnect number in the search windows on our homepages to reach the stories. Genentech, NewLink deal could be worth more than $1B Hemispherx Biopharma prevails in multimillion dollar federal lawsuit The companies will work to further develop NewLink’s IDO inhibitor NLG919 and discover next-generation IDO/TDO compounds All claims by Cato Capital were dismissed by a federal judge; company seeks $1-million award for fees and costs against losing party EDITCONNECT: E10211401 EDITCONNECT: E102213401 Yale announces three-year extension of Gilead collaboration AstraZeneca and University of Cambridge announce new collaborations Gilead will provide $30M in additional funding and gain a licensing option for resultant discoveries as the partners continue pursuing novel cancer therapies The agreements include a research collaboration, a Material Transfer Agreement, a doctoral training program and an entrepreneur-in-residence program EDITCONNECT: E10221400 EDITCONNECT: E10161401 Legal Notice U.S. Postal Service Statement of Ownership, Management, and Circulation 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Publication Title: DDNews Publication Number: 24-504 Filing Date: September 2014 Issue Frequency: Monthly Number of Issues Published Annually: 12 Annual Subscription Price: $0.00 Known Office of Publication: 19035 Old Detroit Rd., Suite 203, Rocky River, OH 44116-1750 General Business Office/Headquarters: 19035 Old Detroit Rd., Suite 203, Rocky River, OH 44116-1750 Publisher: Bruce Poorman, 19035 Old Detroit Rd., Rocky River, OH 44116 Editor: Jeffrey Bouley, 16 Prospect St., Saco, ME 04072 Managing Editor: Lloyd Dunlap, 112 Ascot Lane, #3023, Willowbrook, IL 60527 Owners: Old River Publications LLC 19035 Old Detroit Rd,. Rocky River, OH 44116 Bruce E. Poorman, 20566 Beaconsfield Blvd., Rocky River, OH 44116 Laurence J. 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Gorsline, Operations Manager PEOPLE AWARDS & PROMOTIONS & HONORS 44 DDNEWS | | NOVEMBER 2014 For more information, visit www.DDN-News.com Awards & Honors Inaugural Passion in Science Awards honor 15 вЂ�unsung heroes’ of the lab IPSWICH, Mass.—In commemoration of its 40th anniversary, New England Biolabs Inc. (NEB) recently announced its Passion in Science Awards, which recognize members of the scientific community who are committed to making a difference through their science, humanitarian service, environmental stewardship or artistic and creative spirit—a set of awards that were given out in late October as part of a two-day international summit NEB held in Ipswich. “We’ve always believed that science is more than a vocation—it embodies an ethos that inspires acts of compassion, brilliance and originality. We want to celebrate the many unsung heroes of the lab, not just for their discoveries, but for their passions that contribute to making the world a better place,” said James Ellard, CEO of NEB. The awards are given in four categories: the Inspiration in Science Award, which recognizes scientists whose passion for their field motivates them to push the frontiers of knowledge on a daily basis; the Environmental Stewardship Award, which recognizes scientists who are working to preserve our natural resources or reduce waste either in the lab or outside of it; the Humanitarian Duty Award, which recognizes scientists who are improving the welfare and happiness of others; and the Arts and Creativity Award, which recognizes scientists who demonstrate a love of the arts and may also explore their creative side in the laboratory. For DDNews readers, the five winners in the 2014 Inspiration in Science category of the Passion in Science Award are probably the most pertinent. One of them is Ite Laird-Offringa of the Norris Cancer Center at the University of Southern California, who was honored for fighting lung cancer. Said Laird-Offringa: “We are tackling lung cancer in many ways. We are studying the epigenetic changes underlying lung cancer development and progression, focusing on DNA methylation.” A recent finding promises to improve the sensitivity of detection of methylated DNA in patients’ blood, and Laird-Offringa and colleagues are partnering with NEB to further develop this technology. The Norris team is also studying the epigenomes of alveolar epithelial cells and the cancer-associated immune response in the most aggressive type of lung cancer, small cell lung cancer. There is also Jason Furrer of the University of Missouri, honored for inspiring by teaching, in large part because of his efforts to give opportunities for undergraduate students to participate in the research lab in which he works, and Laurie Doering of McMaster University in Ontario for research work on the role of astrocytes in autism. Kalai Mathee of Florida International University was honored for work on understanding why certain pathogens (primarily Pseudomonas aeruginosa) are so refractory to antibiotic treatment and why the P. aeruginosa organism leads to the demise of patients with cystic fibrosis. Whitney Hagins of Massachusetts Biotechnology Education was recognized for work supporting science and biotechnology education in Massachusetts through educational programs, work- force development and lifelong learning. In the Environmental Stewardship category, the winners of the Passion in Science Awards were Andrew Markley of the University of Wisconsin–Madison and Tonni Kurniawan of Xiamen University in China. In the Humanitarian Duty category, NEB honored Karl Booksh of the University of Delaware, Paul McDonald of the Virginia Tech Carilion Research Institute, Lori Baker of Baylor University and Peter Hotez of the Sabin Vaccine Institute. In the Arts and Creativity category, the winners were Shelly Xie of the University of Texas Southwestern Medical Center in Dallas, Tal Danino of the Massachusetts Institute of Technology, Alia Qatarneh of Harvard University and Louise Hughes of Oxford Brookes University in the United Kingdom. в– Agilent Thought Leader Fibrocell Science Award supports cancer stem receives 2014 cell research at Mount Sinai Marcum Innovator of the Year Award SANTA CLARA, Calif.—Agilent Technologies EXTON, Pa.— Recognized for pioneer- CREDIT: AGILENT TECHNOLOGIES Inc. announced Sept. 24 that Dr. Carlos Cordon-Cardo of the Mount Sinai Health System had received an Agilent Thought Leader Award in recognition of his groundbreaking work in molecular and translational pathology. CordonCardo is the Irene Heinz Given and John LaPorte Given Professor and chair of pathology at Mount Sinai. The Agilent award will support ongoing cancer research conducted by Cordon-Cardo and his team, who are using a combination of genomic and proteomic technologies from Agilent to characterize tumor-initiating cells with stem cell-like properties derived from solid tumors taken from subjects with various types of cancer. The goal of studying this subpopulation of cancer cells is to better understand their ability to resist drug treatments and metastasize. “Our goal is to bring in the outstanding measurement tools from Agilent to develop new diagnostic and predictive biomarkers,” said CordonCardo. “This, in turn, will provide each patient a better chance of cure by defining their disease and optimizing treatment while offering a superior quality of life. This collaboration offers Dr. Carlos Cordon-Cardo of the Mount Sinai Health System recently received an Agilent Thought Leader Award for his work in molecular and translational pathology. a unique opportunity to translate data into knowledge that maximizes personalized patient management, treatment efficacy and clinical outcomes.” “We are very pleased to support Dr. Cordon-Cardo’s pioneering work in cancer stem cell research at one of the largest departments of pathology in the United States,” said Jacob Thaysen, vice president and general manager of Agilent’s Diagnostics and Genomics group. “Molecular characterization of these cells, using Agilent technologies and solutions, could result in the development of new cancer diagnostics.” The Agilent Thought Leader Award promotes fundamental scientific advances by contributing financial support, products and expertise to the research of influential thought leaders in the life sciences, diagnostics and chemical analysis. в– ing cell-based therapies for orphan skin diseases, Fibrocell Science Inc. recently received a 2014 Marcum Innovator of the Year Award. These awards recognize entrepreneurship and innovation by companies in the greater Philadelphia region that are pioneering new advancements in the biotech/healthcare, technology, manufacturing and business services sectors. David Pernock, chairman and CEO of Fibrocell Science, accepted the award at a ceremony in Philadelphia on Oct. 22. “We are proud to be recognized for developing innovative cell-based therapies based on our proprietary fibroblast technology,” Pernock said. “These treatments have the potential to relieve the suffering of those with painful and debilitating skin and connective tissue diseases, such as recessive dystrophic epidermolysis bullosa, a rare genetic blistering disorder. We appreciate the recognition of our commitment to developing treatments for these patients, as well as our support of the Philadelphia business community.” Fibrocell Science is an autologous cell therapy company focused on developing first-in-class treatments for rare and serious skin and connective tissue diseases with high unmet medical needs. Fibrocell’s lead orphan drug program is in late-stage preclinical development for the treatment of recessive dystrophic epidermolysis bullosa. Working in collaboration with Intrexon Corp., a leader in synthetic biology, Fibrocell is genetically modifying autologous fibroblast cells to express target proteins that are inactive or missing from patients with rare genetic skin and connective tissue disorders. Fibrocell is also pursuing medical applications for azficel-T, the company’s proprietary autologous fibroblast technology, for restrictive burn scarring and vocal cord scarring. Both indications are currently in Phase 2 clinical trials. в– For more information, visit www.DDN-News.com PRODUCTS & SERVICES ADVERTISER ’S INDEX F E AT U R E D P R O D U C T Visualize, quantify, analyze and phenotype multiple types of immune cells simultaneously in solid tumors PerkinElmer Inc. PerkinElmer launches its Mantra Quantitative Pathology Imaging System for cancer immunology research. This is an easy-touse, compact, quantitative pathology imaging solution for quantifying biomarkers and protein expression in situ. It enables the development of multiplexed immune cell and protein expression profiling assays for cellular phenotyping in the tumor and tumor microenvironment of standard formalin-fixed, paraffin-embedded (FFPE) tissue sections. The Mantra workstation was developed for use with PerkinElmer’s comprehensive cancer immunology research workflow solution. It readily integrates with PerkinElmer’s Opal multiplexed immunohistochemistry reagents and inForm software’s new quantitative per-cell analysis for phenotyping immune cells in situ. PerkinElmer Inc. www.perkinelmer.com/cancer-immunology Lipofectamine MessengerMAX is your ticket in Thermo Fisher Scientific Lipofectamine MessengerMAX mRNA transfection reagent delivers up to five times the efficiency of DNA reagents in neurons and a broad spectrum of primary cells, enabling improved application outcomes and more biologically relevant research. That’s because our novel lipid nanoparticle technology is optimized to deliver the highest amount of mRNA possible without the nuclear entry step that is required with DNA. Thermo Fisher Scientific www.thermofisher.com SEE US AT ASCB BOOTH 219 You’ll be introduced to the practice of laboratory cell culture, covering topics such as laboratory setup, safety and aseptic technique. You’ll also discover basic methods for passaging, transfecting, freezing and thawing cultured cells. When ready, test your cell culture knowledge and you will be rewarded with an official certificate of completion of Gibco Cell Culture Basics. Thermo Fisher Scientific www.lifetechnologies.com/ cellculturebasics SEE US AT ASCB BOOTH 219 IDT launches modular NGS gene capture pools Integrated DNA Technologies Eppendorf’s new Mastercycler nexus X2 provides a multi-block solution for simultaneous PCR runs Eppendorf The new Mastercycler nexus X2 is ideal for researchers looking to carry out two PCR reactions simultaneously, without any compromise on the number of samples. The instrument comprises two asymmetric blocks, consisting of 64 and 32 wells, which can be programmed and run completely independently, enabling two separate PCR protocols to be run in parallel. Eppendorf www.eppendorf.com (800) 645-3050 Are you stem cell-able? Molecular Devices Make your breakthrough in stem cell research and transform data into unique biological insights with Molecular Devices. Robust instrumentation allows for consistent, live-cell imaging at high quality. Intelligent and flexible analysis helps track rare events with higher statistical significance over conventional microscopy. Unsurpassed service and support march alongside your vision to help achieve your goals. Download e-book at http://info. moleculardevices.com/acton/ form/2560/0653:d-0021/0/index.htm Molecular Devices Moleculardevices.com/stemcell These modular gene capture probes are the latest addition to IDT’s growing portfolio of high-quality, customizable next-generation sequencing (NGS) products. xGen Predesigned Gene Capture Pools and Plates are ideal for creating customized target capture panels for enrichment of 10 or more genes or for enhancing the performance of existing panels. Predesigned Gene Capture Pools and Plates are ideal for scientists who need to reduce the cost of their NGS experiments without sacrificing quality and specificity. xGen Predesigned Gene Capture Pools are available for the coding regions of any human RefSeq gene and are delivered premixed in tubes or in individual plate wells for selective mixing. Integrated DNA Technologies www.idtdna.com ATCC Cell and Molecular Biology .........................25 Biocision......................................................................30 Bio-Rad Laboratories, Inc. .................................13, 48 Biosearch Technologies, Inc. .................................26 BioTek Instruments, Inc. ..........................................16 BMG LABTECH GmbH...............................................42 Cell Signal Technology, Inc.....................................19 Cambridge Healthtech Institute .............................37 Cisbio US, Inc. ............................................................31 Eppendorf North America .......................................... 5 Horizon Discovery Ltd................................................. 7 INDIGO Biosciences .................................................14 Life Technologies – a Thermo Fisher Scientific brand ....................... 2 Metabolon, Inc. ..........................................................15 Mirus Bio LLC .............................................................17 Molecular Devices, LLC ...........................................21 nanoString Technologies .........................................47 Pittsburgh Conference..............................................38 Seahorse Bioscience ................................................. 9 Sigma-Aldrich ............................................................29 SLAS 2015 ....................................................................41 Taconic ........................................................................... 3 Bio-Rad introduces wet-lab validated real-time PCR assays for rat genome Gibco Cell Culture Basics certification: Now become certified by the leading authority in cell culture Thermo Fisher Scientific NOVEMBER 2014 | | DDNEWS 45 Bio-Rad Laboratories Inc. New UN-SCAN IT gel Version 7.1 gel analysis software Silk Scientific Inc. Analyzing gels just got easier with the UN-SCAN-IT gel Version 7.1 software. This new version contains many new features including a zoomable and scalable analysis screen. UN-SCAN-IT gel converts virtually any scanner, digital camera or other image input device into an accurate high-speed densitometer and digitizer system. Windows and Macintosh versions are available. Silk Scientific Inc. www.silkscientific.com/gels Bio-Rad’s PrimePCR Assays are fully wet-lab validated for specificity, efficiency and sensitivity, and they help researchers adhere to industry best practices known as MIQE. As part of this validation process, Bio-Rad scientists validate all PCR products using next-generation sequencing, verifying the percentage of on-target amplification. In addition, all of the validation raw data are available to the customer. Bio-Rad Laboratories Inc. www.bio-rad.com www.atcc.org www.biocision.com www.bio-rad.com www.biosearchtech.com www.biotek.com www.bmglabtech.com www.cellsignal.com www.healthtech.com www.htrf.com www.eppendorf.com www.horizondiscovery.com www.indigobiosciences.com www.lifetechnologies.com www.metabolon.com www.mirusbio.com www.moleculardevices.com www.nanostring.com www.pittcon.org www.seahorsebio.com www.sigma-aldrich.com www.slas2014.org www.taconic.com New kit for performing neurite outgrowth studies Essen BioScience Inc. The CellPlayer NeuroPrime Cell Kit is the first commercially available cryopreserved neuronal/astrocyte co-culture kit. It is designed for longterm, kinetic live-cell measurement of neurite dynamics. Each cell kit contains cryopreserved cell vials of rat forebrain neurons and rat astrocytes and a vial of the novel, neuron-specific labeling reagent, NeuroLight Red. A fully validated protocol for thawing, labeling and measuring neurite outgrowth in a 96-well format using IncuCyte ZOOM live-cell imaging system is also included. Essen BioScience Inc. www.essenbioscience.com New customer-driven format for quality-control standards portfolio ATCC ATCC announces the release of ATCC Minis to support qualitycontrol (QC) testing in pharmaceutical and industrial labs. Only ATCC Genuine Cultures are authenticated and supported by ATCC polyphasic testing to ensure both microbial identity and phenotypic characteristics. To meet the needs of QC biologists, ATCC developed ATCC Minis—with the same high-quality ATCC Genuine Cultures—provided as a six-pack of ready-to-use QC strains preserved in glass-free “mini” cryovials containing glycerol stock. Each tube has a 2D barcode to allow for easy storage and tracking, and offers a peeloff label for fast and reliable recordkeeping. ATCC www.atcc.org TriStar2 S, now with monochromator technology Berthold Technologies TriStar2 S with multiple measurement technologies employs the new patentpending optical concept ALL-4-ONE, for the first time enabling luminescence, fluorescence and absorbance measurements with highest respective sensitivity as known from dedicated instruments. Besides filters, the instrument is equipped with a unique 3D double monochromator with high blocking efficiency and high f-number (increased transmission) for filterless absorbance measurements and fluorescence excitation. Berthold Technologies www.Berthold.com/bio Phenomenex introduces first synthetic sorbent for simplified liquid extraction Phenomenex Inc. Novum Simplified Liquid Extraction (SLE) is a novel, synthetic alternative to traditional diatomaceous earth SLE (also known as supported liquid extraction) products and a simplified approach to traditional liquid-liquid extraction (LLE). As the first of its kind, the synthetic Novum SLE sorbent (patent pending) can be used with the same procedure as traditional SLE sorbents while delivering improved lotto-lot reproducibility. Supplies are readily available, compared to diatomaceous earth, which is a natural resource that must be mined. Phenomenex Inc. www.phenomenex.com 46 DDNEWS | | NOVEMBER 2014 Q&A: Gur Roshwald,Q&A M.D., OF CELSUS THERAPEUTICS For more information, visit www.DDN-News.com Celsus seeks to develop the antiinflammatory drugs of the future C BY LLOYD DUNLAP ELSUS THERAPEUTICS is a drug development company focusing on novel anti-inflammatory, first-in-class synthetic drugs called multifunctional anti-inflammatory drugs (MFAIDs). Celsus’ proprietary drug technology platform potentially offers an answer to an urgent unmet need: the lack of satisfactory alternatives to corticosteroids in the treatment of a multitude of inflammatory diseases. The company has assembled an experienced team that shares its vision and is committed to making it a success. Dr. Gur Roshwald joined Celsus as CEO early last year, and DDNews interviewed him about his new company’s progress toward its goals. DDNews: Dr. Roshwald, where did Celsus Therapeutics originate and how did it come to be U.S.-based? Celsus was spun out from technology developed at Hebrew University in Jerusalem and was incorporated in 2005 in the U.K. Celsus listed in the U.S. in 2013 with new management at the helm and is currently only traded on NASDAQ under the ticker symbol CLTX. As we advanced, the company required management with drug-development and public-market experience and access to greater institutional capital from well-established healthcare funds. We decided on listing in the U.S. where the biotech/specialty pharma market is active and well-funded. When the board of directors made the decision to go public, new, experienced management with deep healthcare and U.S. public company experience was brought on board. Gur Roshwald: produce large families of eicosanoids; many of them are involved in the development of numerous pathological conditions, especially in inflammation-related processes. These include prostaglandins, thromboxanes and leukotrienes. LysoPLs induce white cell activation and extravasation, induce cell activation (by lyso phosphatidylserine in particular), induce tissue damage, such as gastric ulceration, and act as growth factors (especially lyso phosphatidic acid) to induce proliferation of cancer cells and tumor metastasis. Furthermore, LysoPLs are also the precursors of platelet activating factor (PAF), possibly the most potent mediator of inflammatory processes. MFAIDs inhibit sPLA2 with a different chemistry than corticosteroids and are generally specific to inhibiting cell surface sPLA2 activity, thus providing the benefit of inhibition, but, due to the different chemistry, none of the steroid side effects. “The market potential for MRX-6 in skin inflammation is more than $350 million per year in peak U.S. sales, with sales in Europe and Asia bringing in a likely equal amount. Cystic fibrosis and osteoarthritis are both potential multibillion-dollar markets.” DDNews: Please describe your “First-in-class multifunctional anti-inflammatory program” and how and why it provides a potential alternative to corticosteroids. Celsus’ lead products are firstin-class, novel, nonsteroidal, synthetic antiinflammatory drugs termed multifunctional anti-inflammatory drugs (MFAIDs) that focus on one of the most sought-after pharmaceutical targets in inflammation research: the sPLA2 family. This extracellular family of enzymes is a universal early trigger in all of the inflammatory diseases studied that hydrolyze phospholipids on the cell membrane into two key inflammatory precursors: arachidonic acid (AA) and lysophospholipids (LysoPLs). AA is metabolized via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways to Roshwald: DDNews: You have characterized MFAIDS as a potential disruptive technology. How would you define disruptive technology? Roshwald: As Clayton Christensen describes, it is a process by which a product or service takes root initially in simple applications at the bottom of a market and then relentlessly moves up market, eventually displacing established products or services. A good example would be cell phones replacing landlines. For Celsus, it would be our products replacing corticosteroids for inflammation. DDNews: What is currently happening with each of your four pipeline therapeutics? Roshwald: Our most advanced product is MRX-6, a cream formulation currently in Phase 2 development for the treatment of atopic dermatitis (eczema). Our other pipeline products are in preclinical animal testing for inflammation in the eye, lung, joints and bowel. DDNews: What class of molecule is MRX-6? How are your four current drugs related (or different)? Roshwald: MRX-6 is made of a series of sPLA2 inhibitory lipids conjugated to a glycosaminoglycan (hyaluronic acid). The glycosaminoglycan (GAG) is anchored on the cell surface through proteins known as adherins (CD44, as an example), and provide antioxidant benefit, while the lipids conjugated to the GAG act as competitive inhibitors of sPLA2 at the cell surface. Our pipeline products are similar in that we use various lipids, conjugated in different ways to a set of potential sugars (GAGs). DDNews: Please describe your expectations for market potential and your patent position for each product. Roshwald: The market potential for MRX-6 in skin inflammation is more than $350 million per year in peak U.S. sales, with sales in Europe and Asia bringing in a likely equal amount. Cystic fibrosis and osteoarthritis are both potential multibillion-dollar markets. We have patent protection on our lead compounds and methods-of-use patents in the United States and major markets around the world, in addition to our pending applications. The other compounds in our pipeline are all new and have long-term composition of matter, formulation and method-of-use potential protection. DDNews: Finally, what are the reasons you are confident of success when Lilly, Wyeth and Anthera have failed? The key to successfully controlling this “universal inflammatory trigger,” or sPLA2, has been demonstrated by the past clinical failures of several pharmaceutical companies. It can be summarized as follows: 1. Inhibit the entire sPLA2 family, not just one or two of its isomers. 2. Do not interfere with the cPLA2 family, a related group of enzymes that are located inside the cell (unlike the sPLA2) and which have a vital homeostatic role (unlike sPLA2) that must not be interfered with. There are about 12 different isomers of sPLA2, and Lilly’s/Anthera’s compound inhibited the most ubiquitous—subtype IIA. Although they achieved good biomarker results, it is unclear if the compound failed due to an actual lack of benefit or simply because the indications pursued were too difficult (sepsis and post-MI inflammation). The lesson learned is to only pursue indications where we know steroids have demonstrated a benefit. In Wyeth’s case, the compound inhibited both sPLA2 and cPLA2, which was toxic. Celsus’ MFAIDs were designed and synthesized to overcome these two critical, and previously insurmountable, problems and represent not just a single molecule but an entire new genus of compounds, each different but with a similar mechanism of action. Roshwald: “Celsus’ lead products are first-in-class, novel, nonsteroidal, synthetic anti-inflammatory drugs termed multifunctional anti-inflammatory drugs (MFAIDs) that focus on one of the most soughtafter pharmaceutical targets in inflammation research: the sPLA2 family.” Gur Roshwald, M.D., of Celsus Therapeutics The glycosaminoglycan backbone is too big to enter the cell, thus not interfering with cPLA2, but very good at anchoring the compound on the target cell surface. The lipids are pan inhibitors of sPLA2. в– Gur Roshwald joined Celsus Therapeutics as CEO in March 2013. From April 2008 to February 2013, he was a vice president at Venrock, where he was an investment professional on the healthcare team investing in both private and public companies. From May 2004 to March 2008, he was a vice president and equity analyst at Piper Jaffray, publishing research on specialty pharmaceutical companies. Prior to Piper, Roshwald was in private practice in New York and board-certified in internal medicine. He received his M.D. from Albert Einstein College of Medicine and his MBA from the New York University Stern School of Business. EDITCONNECT: E111430 DDNEWS (USPS 024-504) is published monthly by Old River Publications LLC, 19035 Old Detroit Road, Suite 203, Rocky River, OH 44116; 440-331-6600. Periodical postage paid at Cleveland, Ohio and additional mailing offices. Publisher assumes no responsibility for unsolicited material or prices quoted in the magazine. Contributors are responsible for proprietary classified information. В©2014 by Old River Publications. All rights reserved. Reproduction, in whole or in part, without written permission of the publisher is expressly prohibited. Back issues, when available, cost $7 each within the past 12 months; $12 each prior to the past 12 months. Back orders must be paid in advance by check. 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