Advancing Research to Treatments:
Unmet Needs In Glioblastoma
Skip Irving
Partner and Managing Director
Health Advances, LLC
BOSTON
SAN FRANCISCO
www.healthadvances.com
ZURICH
May 8, 2013
Unmet Need
Senator Kennedy’s tragic death brought greater visibility to the tremendous
need for improved brain tumor treatment options.
§  76 years old at diagnosis
§  May 17, 2008: Seizure at his
home in Hyannis, MA
§  Medflight from Cape Cod
Hospital to Mass General
Hospital in Boston
§  Diagnosed with
Glioblastoma Multiforme
§  August 25, 2009: Died15
months after diagnosis
Senator Ted Kennedy - 2008 Democratic National
Convention in Denver, Colorado August 25, 2008. –
REUTERS
Unmet Needs in Glioblastoma
CONFIDENTIAL — May 8, 2013
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Unmet Need
By annual incidence, glioblastomas are the most common type of malignant
brain tumor.
US Distribution of Brain and CNS
Tumor Incidence By Histology
2005-2009
100%
Percentage
75%
Other Gliomas
NonMalignant
Oligoastrocytic Tumors
Pilocytic Astrocytomas
50%
Anaplastic Astrocytomas
Oligodendrogliomas
Other Malignant
25%
Ependymal Tumors
Diffuse Astrocytomas
Gliomas
Glioblastomas
0%
Brain Tumors
Gliomas
Source: CBTRUS, American Brain Tumor Association website.
Unmet Needs in Glioblastoma
CONFIDENTIAL — May 8, 2013
Glioblastomas
Most malignant, most
aggressive and
shortest survival
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Unmet Need
Glioblastomas progress rapidly without therapy.
Relative Survival Rates for Primary
Malignant Gliomas
Clinical history is less
than three months in
majority of patients;
Prognosis worse for
elderly patients
Relative Survival Rates
120%
100%
80%
Mixed Glioma
60%
Oligodendroglioma
Anaplastic Astrocytoma
40%
Glioblastoma
20%
Ependymoma
Astrocytoma, NOS
0%
0
12
24
36
60
Months After Diagnosis
96
Note: Relative survival rates for primary malignant gliomas are from SEER, 1973-2004.
Source: DataMonitor, CBTRUS, SG Cowen, Medscape.
Unmet Needs in Glioblastoma
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120
Therapeutic Options
The best current standard of care extends overall survival to about 14 to 16
months.
Median Overall Survival Time of Glioblastoma Patients by Therapy
24
Months
18
12
6
0
Surgery
Only
+ Radiotherapy
(RT)
+ RT +
Carmustine
Implant
Treatment Regimen
+ RT +
Carmustine
+ RT +
+ RT +
Temozolomide Temozolomide +
Bevacizumab*
* Data for bevacizumab represents newly-diagnosed glioblastoma and is from a phase II clinical trial with no placebo control.
Source: UpToDate; Gil-Salu, J., Neurocirugia, 2004; Walker, M., J. Neurosurgery, 1978; Westphal, M., Neuro-Oncology, 2003; Stupp, R., NEJM, 2005; Athanassiou, H., JCO, 2005;
Stewart, L., Lancet, 2002; Lai, A., JCO, 2011.
Unmet Needs in Glioblastoma
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Treatment Paradigms
Temozolomide with radiation is the first line treatment of choice.
Biopsy
MRI and/or CT
Suggestive of
Glioblastoma
Confirmation
of Glioblastoma
Surgical
Resection
GLIADEL WAFER
(polifeprosan 20 with carmustine implant
Radiotherapy
Nitrosoureas
First-Line
Therapies
Second-Line
Therapies
Clinical Trials
Unmet Needs in Glioblastoma
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Current Therapies
The basic patent on Temodar will expire in 2014.
GLIADEL WAFER
(polifeprosan 20 with carmustine implant
§  Implant
§  Approved
1996
§  IV
2nd
§  Approved for
line
glioblastoma in 2009
8%
~$110
67%
~$920
25%
~$350
§  Approved 2005
§  Generic launch in
August 2013
§  Evaluation as addition
to 1rst line
Total Market: ~ $1.4B
Source: Compant 10ks, websites, Datamonitor, UpToDate, Analyst Reports.
Unmet Needs in Glioblastoma
CONFIDENTIAL — May 8, 2013
§  Oral and IV
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Drug Development Challenges
Anticipating the path to market involves a series of connected questions.
Basic
Research
Pathway
and
Targets
Translational Medicine
Proof-of-Concept
Evidence
Clinical
Trial
Endpoints
Differentiated
Clinical
Utility
Unmet Needs in Glioblastoma
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Label
Claims
Revenue
Potential
Development Challenges
Dramatic unmet needs will drive interest in any new therapy.
Challenges
And
Opportunities
High Unmet Need
Blood-Brain Barrier
§  Incremental improvement
§  Risk tolerant
§  Rapid market uptake
§  Formulation and delivery?
Tumor Heterogeneity
Small Population, Orphan Drug
Potential
§  Breadth of use?
Survival Drives Prevalence
Lack of Screening Tools
§  Increased population
§  Extended duration of therapy
§  Risk factors?
§  DX prior to malignancy?
Pricing Flexibility
Paucity of Biomarkers
§  Extreme mortality
§  Low generic impact
§  Assessing prognosis?
§  Patient segmentation?
§  Differential treatment?
Combination Therapy
§  Multiple mechanisms
Low Incidence/Rapid Progression
Centers of Excellence
§  Market potential?
§  Trial recruitment?
§  Focused call points
§  Specialty market strategy
Unmet Needs in Glioblastoma
CONFIDENTIAL — May 8, 2013
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Development Challenges
Better understanding of specific patients sub-segments can be valuable for
clinical development and precision in selecting treatment options.
MGMT
Gene
EGFRvIII
Positive
for
EGFRvIII
Negative
for
EGFRvIII
Methylated
MGMT
Unmethylated
MGMT
Under 65
Over 65
25%
75%
45%
55%
50%
50%
Frequency
Overall
Survival
Age
23 months1 15 months 22 months2 13 months2 15 months2 9 months2
Data based on general patient populations treated with rindopepimut immunotherapy and temozolomide and lacking a placebo control.
Data based on patient populations receiving radiotherapy and temozolomide.
Source: Babu, R., Core Evidence, 2012; Hegi, M., NEJM, 2005; Oszvald, A., Journal of Neurosurgery, 2012.
1
2
Unmet Needs in Glioblastoma
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Pipeline Activity
An active early stage pipeline with a multiple different approaches.
Number of Glioblastoma
Therapies in Development
By Category
Number of Therapies
80
Other Therapies
60
Immunotherapies
Biologics
40
Small Molecules
20
0
Preclinical
Phase I
Phase II
Clinical Trial Phase*
Phase III
* Clinical Trial Phase refers to the highest regulatory phase reached worldwide and excludes therapies already launched in another indication.
Source: Pipeline databases, company websites, clinicaltrial.gov.
Unmet Needs in Glioblastoma
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Pipeline Activity
Presentations today reflect the diversity of therapeutic approaches being
investigated.
Other
Approaches
§  Gene therapy
Immunotherapies
§  Lytic viruses
§  Active immunization
§  Nucleic acid
§  Adoptive therapies
therapies
§  Nanoparticles
§  Stem cell therapy
Monoclonal
Antibodies
Small
Molecule
Chemotherapy
New Options for
Glioblastoma
Patients
Today’s Presentations
§  Small molecule glycolysis inhibitor §  Therapeutic vaccine
§  Drug-resistant cellular therapy
§  Bi-specific antibody
Unmet Needs in Glioblastoma
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Skip Irving
Partner
[email protected]
Health Advances LLC
9 Riverside Road
Weston, MA 02493
781-647-3435
www.healthadvances.com
Unmet Needs in Glioblastoma
CONFIDENTIAL — May 8, 2013
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