New York Product Development
Partnerships for Global Health:
The Global Alliance for TB
Drug Development
Gerald J. Siuta, Ph.D.
Consultant, Business Development
New York Biotechnology Association 17th Annual Meeting
New York City, NY
May 20, 2008
Global Tuberculosis Epidemic
• One-third of the world’s population is infected with
Mycobacterium tuberculosis (M.tb.)
– 2 billion people
• 8-9 million develop active disease annually
• 2 million deaths occur each year
– 1 person dies every 15 seconds
• 400,000 cases of MDR-TB each year
• Leading cause of death in HIV-positive people
– 12 Million people are TB/HIV co-infected
TB’s economic toll: $16 billion a year
Current TB Drug Therapy
• Active TB
– Standard therapy – 4 drugs (isoniazid, rifampin, pyrazinamide &
ethambutol) for 2 months, followed by isoniazid and rifampin for
4 months
• Latent TB
– Standard therapy – isoniazid for 9 months
• Multi-Drug Resistant TB (MDR-TB)
– Individualized, prolonged therapy, few available drugs, poorly
tolerated and difficult to administer
• TB/HIV Co-Infection
– Treatment as in active TB, but drug interactions with
antiretroviral agents make simultaneous therapy difficult
• Extensively Drug Resistant TB (XDR-TB)
– No treatment available
The Need for New TB Drugs
• Complex 6-9 months treatment with a
4 drug combination regimen
• No new anti-TB drug in over 40 years
• TB/HIV co-infections fueling each other
• MDR-TB is on the rise
• Unattractive market for private sector
• No capitalization of public sector research
History of the TB Alliance
• Cape Town Declaration – February 2000
– Hosts: Rockefeller Foundation and the Medical Research
Council of South Africa
– Over 120 organizations (health, science, philanthropy and
private industry)
• Results
– Support goals of Stop TB Initiative
– Create Scientific Blueprint
– Develop Pharmacoeconomic Analysis
Build a Global Alliance for
TB Drug Development
The TB Alliance
• Independent, international Product Development
Partnership founded in October 2000
• Non-profit organization
• Headquarters in New York City
– Offices in Brussels and Cape Town
• Entrepreneurial, virtual R&D approach
– Out-source R&D to public and private partners
• Pro-active fundraising
– Over US $200 million raised
• Support ~ 200 FTE worldwide and 35 FTE in-house
Our Mission
• Develop an entirely new therapeutic
regimen that will shorten or simplify the
treatment of tuberculosis
• Coordinate and act as catalyst for global
TB drug development activities
• Ensure Affordability, Adoption and Access
(AAA Strategy)
AAA Strategy
• Affordability
– Appropriate pricing in developing countries
• Adoption
– Ensure that new drugs are incorporated into
existing treatment programs
• Access
– Procurement and distribution to those patients
who need them most
Our Vision
10 Days
2 Months
6 Months
Profile of a New TB Drug
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Shorten treatment to less than 2 months
Novel mechanism of action (MDR/XDR-TB)
Orally active
Once daily or intermittent therapy
Compatible with HIV treatment
Low cost of goods
Financial Support
• Bill and Melinda Gates Foundation
• Rockefeller Foundation
• Netherlands Ministry for Development
Cooperation
• United States Agency for International
Development (USAID)
• Governments of Great Britain and Ireland
Types of Deals
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In-Licensing
IP Assignment
Sponsored R&D
Collaborative R&D
Freedom to Operate
Clinical Trials
TB Alliance Portfolio
TB ALLIANCE
PROGRAMS
Moxifloxacin
PA-824
Quinolones
Nitroimidazoles
Pleuromutilins
Mycobacterial Gyrase Inhibitors
InhA Inhibitors
Multifunctional Molecules
Riminophenazines
GSK Focused Screening
Phenotypic Screening
Malate Synthase Inhibitors
Protease Inhibitors
Energy Metabolism Inhibitors
CLINICAL DEVELOPMENT
DISCOVERY
Lead
Identification
Lead
Optimization
Preclinical
Phase I
Phase II
Phase III
Chiron/Novartis
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PA-824 – A novel nitroimidazole
Discovered by Pathogenesis, Inc.
Distinct mechanism of action
Potent activity against both active and
slow growing M.tb.
• Possesses both bactericidal and sterilizing
activity
Chiron/Novartis
• Worldwide exclusive license for the
treatment of tuberculosis
• Defined scientific milestones
• Grant-back option
• Manufacturing rights
• No royalties in developing world
Development of PA-824
• Phase I clinical trials began June 3, 2005
– Preclinical development completed in 3 years
– Drug was well tolerated with no definitive
dose-limiting adverse events
• Phase II extended Early Bactericidal
Activity (EBA) study has begun in Cape
Town, South Africa
University of Auckland
• Synthesis of PA-824 analogs
• Identified many new pharmacophores,
several of which have demonstrated
potent activity against TB
• Optimization has led to nitroimidazole
analogs that have in vitro activity greater
than PA-824
GlaxoSmithKline
• Joint drug discovery program at GSK’s
Diseases of the Developing World facility
in Tres Cantos, Spain
• Five individual projects:
– Mycobacterial gyrase inhibitors
– InhA inhibitors
– Malate synthase inhibitors
– Pleuromutilins
– Focused screening
GlaxoSmithKline
• Project oversight by Joint Steering Committee
• TB Alliance helps to support 25 full-time
scientists at GSK working exclusively on the
TB drug program
• GSK absorbs all remaining overhead costs
• GSK contributes a matching number of staff
• Any resulting medicines will be made affordable
and accessible to those most in need
Korea Research Institute of
Chemical Technology (KRICT)
• Located in Daejeon, South Korea
• Synthesized more than 600 quinolones,
pyridones & quinolizines
• In vitro and in vivo biological testing at the
Yonsei University College of Medicine in
Seoul, South Korea
• Four lead compounds have been selected
for further preclinical evaluation
Cumbre Pharmaceuticals
• Joint program on the design, synthesis
and optimization of multifunctional
antibiotics
• The TB Alliance has exclusive rights to
these compounds for the treatment of
tuberculosis and other neglected diseases
• Cumbre retains rights to pursue the
compounds for use in other infectious
disease areas
Institute of Materia Medica
• Joint research partnership for the design,
synthesis and evaluation of a class of
compounds known as riminophenazines
– Class was discovered in the 1950s
• The collaboration will utilize IMM's
expertise and integrated capabilities in
chemistry, pharmacology and manufacture
The TB Alliance-Bayer
Moxifloxacin Deal
Moxifloxacin
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Fluoroquinolone antibiotic
Orally active
Once-a-day dosage
Approved in 104 countries for the
treatment of bacterial respiratory and skin
infections
Moxifloxacin for TB
• Novel mechanism of action: kills M.tb. by
inhibition of DNA gyrase
• In vivo studies showed moxifloxacin
reduced treatment time by two months
when substituted for isoniazid
• Safe to use with antiretroviral agents since
it is not metabolized by the cytochrome
P-450 enzyme system
October 18, 2005
TB Alliance and Bayer HealthCare
announced a partnership to
coordinate a global clinical trial
program to study the potential of
moxifloxacin to shorten the standard
six-month treatment of TB
The Partnership
• Clinically assess the efficacy and safety of
moxifloxacin as a front-line agent for the
treatment of TB
• If clinical trials are successful, register
moxifloxacin for a TB indication
• Committed to making the product
affordable and accessible to patients in the
developing world
Moxifloxacin Clinical Trials
• Evaluate whether substitution of moxifloxacin for
one of the standard TB drugs (isoniazid or
ethambutol) eliminates TB infection faster than
current standard therapy
• Trials to be run in Brazil, Canada, South Africa,
Spain, Tanzania, Uganda, the United States and
Zambia
• More than 3,000 TB patients will be enrolled
Bayer Commitments
• Donate moxifloxacin for each clinical
trial site
• Cover costs of regulatory filings
• Provide moxifloxacin at an affordable
price for patients with TB in the
developing world
TB Alliance Commitments
• Coordinate and help cover the costs of the
clinical trials
• Ensure coordination of information and
results towards the goal of registration
• Leverage substantial support from:
– U.S. Centers for Disease Control and
Prevention (CDC)
– Orphan Products Development Center of the
U.S. Food & Drug Administration
– European and Developing Countries Clinical
Trials Partnership (EDCTP)
Global Alliance for TB
Drug Development
www.tballiance.org