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  • May 8, 2013

    www.healthadvances.com

    Health Advances, LLC BOSTON SAN FRANCISCO ZURICH

    Skip Irving Partner and Managing Director

    Advancing Research to Treatments: Unmet Needs In Glioblastoma

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 2

    Unmet Need

    Senator Ted Kennedy - 2008 Democratic National Convention in Denver, Colorado August 25, 2008.

    REUTERS

    Senator Kennedys 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

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 3

    By annual incidence, glioblastomas are the most common type of malignant brain tumor.

    Gliomas

    Other Malignant

    Non- Malignant

    0%

    25%

    50%

    75%

    100%

    Brain Tumors Gliomas

    Perc

    enta

    ge

    Other Gliomas

    Oligoastrocytic Tumors

    Pilocytic Astrocytomas

    Anaplastic Astrocytomas

    Oligodendrogliomas

    Ependymal Tumors

    Diffuse Astrocytomas

    Glioblastomas

    US Distribution of Brain and CNS Tumor Incidence By Histology

    2005-2009

    Unmet Need

    Source: CBTRUS, American Brain Tumor Association website.

    Glioblastomas Most malignant, most

    aggressive and shortest survival

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 4

    Note: Relative survival rates for primary malignant gliomas are from SEER, 1973-2004. Source: DataMonitor, CBTRUS, SG Cowen, Medscape.

    Relative Survival Rates for Primary Malignant Gliomas

    Unmet Need

    Glioblastomas progress rapidly without therapy.

    0%

    20%

    40%

    60%

    80%

    100%

    120%

    0 12 24 36 60 96 120

    Rel

    ativ

    e Su

    rviv

    al R

    ates

    Months After Diagnosis

    Mixed Glioma

    Oligodendroglioma

    Anaplastic Astrocytoma

    Glioblastoma

    Ependymoma

    Astrocytoma, NOS

    Clinical history is less than three months in majority of patients; Prognosis worse for

    elderly patients

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 5

    The best current standard of care extends overall survival to about 14 to 16 months.

    Therapeutic Options

    * 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.

    Median Overall Survival Time of Glioblastoma Patients by Therapy

    0

    6

    12

    18

    24

    Surgery Only

    + Radiotherapy (RT)

    + RT + Carmustine

    + RT + Carmustine

    Implant

    + RT + Temozolomide

    + RT + Temozolomide + Bevacizumab*

    Mon

    ths

    Treatment Regimen

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 6

    Surgical Resection

    Treatment Paradigms Temozolomide with radiation is the first line treatment of choice.

    MRI and/or CT Suggestive of Glioblastoma

    Biopsy

    Confirmation of Glioblastoma

    Clinical Trials

    Second-Line Therapies

    Nitrosoureas

    First-Line Therapies

    Radiotherapy GLIADEL WAFER (polifeprosan 20 with carmustine implant

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 7

    Current Therapies The basic patent on Temodar will expire in 2014.

    Source: Compant 10ks, websites, Datamonitor, UpToDate, Analyst Reports.

    67% ~$920 25%

    ~$350

    8% ~$110

    Oral and IV Approved 2005 Generic launch in

    August 2013

    IV Approved for 2nd line

    glioblastoma in 2009 Evaluation as addition

    to 1rst line

    Implant Approved

    1996

    GLIADEL WAFER (polifeprosan 20 with carmustine implant

    Total Market: ~ $1.4B

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 8

    Drug Development Challenges Anticipating the path to market involves a series of connected questions.

    Proof-of-Concept Evidence

    Clinical Trial

    Endpoints

    Differentiated Clinical Utility

    Label Claims

    Revenue Potential

    Basic Research

    Pathway and

    Targets

    Translational Medicine

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 9

    Dramatic unmet needs will drive interest in any new therapy.

    Opportunities

    Development Challenges

    Challenges

    Blood-Brain Barrier Formulation and delivery?

    Tumor Heterogeneity Breadth of use?

    Lack of Screening Tools Risk factors? DX prior to malignancy?

    Low Incidence/Rapid Progression Market potential? Trial recruitment?

    High Unmet Need Incremental improvement Risk tolerant Rapid market uptake

    Small Population, Orphan Drug Potential

    Survival Drives Prevalence Increased population Extended duration of therapy

    Pricing Flexibility Extreme mortality Low generic impact

    Combination Therapy Multiple mechanisms

    Centers of Excellence Focused call points Specialty market strategy

    Paucity of Biomarkers Assessing prognosis? Patient segmentation? Differential treatment?

    And

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 10

    Development Challenges Better understanding of specific patients sub-segments can be valuable for clinical development and precision in selecting treatment options.

    Frequency 25% 75% 45% 55% 50% 50%

    Overall Survival 23 months

    1 15 months 22 months2 13 months2 15 months2 9 months2

    Negative for

    EGFRvIII

    Positive for

    EGFRvIII

    EGFRvIII

    Unmethyl-ated

    MGMT

    Methylated MGMT

    MGMT Gene

    Over 65 Under 65

    Age

    1 Data based on general patient populations treated with rindopepimut immunotherapy and temozolomide and lacking a placebo control. 2 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.

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 11

    Pipeline Activity An active early stage pipeline with a multiple different approaches.

    Number of Glioblastoma Therapies in Development

    By Category

    0

    20

    40

    60

    80

    Preclinical Phase I Phase II Phase III

    Num

    ber o

    f The

    rapi

    es

    Clinical Trial Phase*

    Other Therapies

    Immunotherapies

    Biologics

    Small Molecules

    * 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 CONFIDENTIAL May 8, 2013 12

    Todays Presentations Small molecule glycolysis inhibitor Drug-resistant cellular therapy

    Therapeutic vaccine Bi-specific antibody

    Pipeline Activity Presentations today reflect the diversity of therapeutic approaches being investigated.

    Small Molecule

    Chemotherapy

    Monoclonal Antibodies

    Other Approaches

    Gene therapy Lytic viruses Nucleic acid

    therapies Nanoparticles Stem cell therapy

    Immunotherapies Active immunization Adoptive therapies

    New Options for Glioblastoma

    Patients

  • Unmet Needs in Glioblastoma CONFIDENTIAL May 8, 2013 13

    Skip Irving Partner

    sirving@healthadvances.com

    Health Advances LLC 9 Riverside Road

    Weston, MA 02493

    781-647-3435 www.healthadvances.com

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