Your SlideShare is downloading. ×
De-Risking the Phase II to Phase III Advancement Decision: Sound Science, Critical Thinking and Weighing Time versus Cost
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Introducing the official SlideShare app

Stunning, full-screen experience for iPhone and Android

Text the download link to your phone

Standard text messaging rates apply

De-Risking the Phase II to Phase III Advancement Decision: Sound Science, Critical Thinking and Weighing Time versus Cost

382
views

Published on

Lisa presented an analysis of Phase II program metrics comparing those of drugs that failed late in development (Phase III or filing) versus those that ultimately gained U.S. licensure. Findings …

Lisa presented an analysis of Phase II program metrics comparing those of drugs that failed late in development (Phase III or filing) versus those that ultimately gained U.S. licensure. Findings indicate that late failures conducted fewer Phase II trials with lower median patient enrollment and advanced on weaker efficacy evidence.


0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
382
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
6
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • 523 compounds terminated in 967 disease indications152 compounds marketed in 225 disease indications
  • Vast majority terminate at Phase I or Phase II - for self-originated compounds in our database, 155 term’d @P1 and 222 term’d @P2
  • Mean phase III program enrollment for terminated cpds = 1,311Mean phase III program enrollment for approved cpds = 1,188
  • Transcript

    • 1. De-Risking the Phase II to Phase III Advancement Decision:Sound Science, Critical Thinking and Weighing Time versus Cost
      June 28, 2011
    • 2. Speakers & Topics
      Lisa Natanson
      Senior Analyst
      Deloitte Recap LLC
      David Stump
      Executive Vice President, R&D
      Human Genome Sciences, Inc.
      John Orwin
      Chief Executive Officer
      Affymax, Inc.
      Panel Session
      What Can We Learn From the Data About Late-Stage Drug Development Failures?
      BenlystaTM Case Study
      Killing the Vampire:
      Anti-IGF1R Phase III Go/No-Go Recommendation
      Q&A
      2
    • 3. What Can We Learn From the Data About Late-Stage Drug Development Failures?
      Lisa Natanson
      Senior Analyst, Deloitte Recap LLC
    • 4. Success
      Late-Stage Failure
      A terminated product that…
      • Fails at Phase III or Filing after years of development, providing no benefit to patients
      • 5. Provides no return on investment for companies and stockholders
      An approved product that…
      • Improves survival and quality of life for patients
      • 6. Provides return on investment for companies and stockholders
      4
    • 7. 5
    • 8. Data Source: 190 Leading Biotechnology Companies
      587
      Ongoing Compounds
      523 Terminated Compounds
      41%
      47%
      12%
      60% Small Molecules
      160 Fast Track Indications
      152 Marketed
      Compounds
      40% Large Molecules
      308 Orphan Indications
      DATA SOURCES: Securities and Exchange Commission filings, clinical trial registries, U.S. and E.U. regulatory agency briefing documents, refereed journal articles, scientific and medical meeting abstracts, corporate press releases and investor presentations, university and governmental medical research institute websites, as well as other public, primary data sources.
      6
      23 June 2011
    • 9. Compound Data Set (n=97)
      Approved
      Compounds
      152
      117
      --
      --
      74
      70
      64
      Terminated
      Compounds
      523
      450
      74
      56
      44
      39
      33
      Compound was developed by RBI company(1)
      Compound’s origin was In-House
      For Terminated Compounds:
      • Phase at Termination was Phase III or Filing
      • 10. Documented Reason for Termination was “Lack of Activity or Efficacy” or “Safety”
      Compound reached final clinical outcome between January 1, 2000 and May 31, 2011
      Vaccines, imaging agents, devices, and 505(b)(2) NDAs excluded
      Complete and verifiable data for all Phase II and Phase III trials conducted*
      * Missing data for 15% (6/39) of Terminated compounds and 9% (6/70) of Approved compounds.
      (1) RBI = Recap BioPortfolio Index (n=190 companies)
      7
      23 June 2011
    • 11. Compound Data Set (n=97)
      January 1, 2000 - May 31, 2011
      Success
      Late-Stage Failure
      versus
      33 Compounds
      Terminated at Phase III or Filing
      64 Compounds
      Approved by FDA
      8
      23 June 2011
    • 12. Methodology for Comparing Phase II Programs
      Phase II program metrics reported contain only trials ongoing and/or completed prior to the Phase III trial start date or announced advancement decision. Phase II trials initiated and conducted after the pivotal trial(s) start date but prior to regulatory filings were not counted since they did not inform the advancement decision.
      Phase I/II trials were counted as Phase II trials and Phase II/III trials were counted as Phase III trials.
      9
    • 13. Median Metrics of Phase II Clinical Programs
      January 1, 2000 - May 31, 2011
      Data Source: Deloitte Recap LLC
      10
      23 June 2011
    • 14. Median Metrics of Phase II Clinical Programs
      January 1, 2000 - May 31, 2011
      Data Source: Deloitte Recap LLC
      11
      23 June 2011
    • 15. Median Metrics of Phase II Clinical Programs
      January 1, 2000 - May 31, 2011
      Data Source: Deloitte Recap LLC
      12
      23 June 2011
    • 16. Median Metrics of Phase II Clinical Programs
      January 1, 2000 - May 31, 2011
      39 Trials
      5,592 Patients
      126 Trials
      19,354 Patients
      Data Source: Deloitte Recap LLC
      13
      23 June 2011
    • 17. Median Metrics of Phase II Clinical Programs
      January 1, 2000 - May 31, 2011
      Data Source: Deloitte Recap LLC
      Successful programs invested more in Phase II trials.
      14
      23 June 2011
    • 18. Median Metrics of Phase II Clinical Programs
      January 1, 2000 - May 31, 2011
      Data Source: Deloitte Recap LLC
      IQR = Inter-Quartile Range (where 50% of the data reside).
      15
      23 June 2011
    • 19. Median Metrics of Phase III Clinical Programs
      January 1, 2000 - May 31, 2011
      Data Source: Deloitte Recap LLC
      Observation: The ratio of median patients enrolled from Phase II to Phase III was 1 to 12 versus a ratio for approved products of 1 to 4.
      IQR = Inter-Quartile Range (where 50% of the data reside).
      16
      23 June 2011
    • 20. Median Metrics of Phase III Clinical Programs
      January 1, 2000 - May 31, 2011
      Data Source: Deloitte Recap LLC
      Unsuccessful programs invested more in Phase III trials.
      IQR = Inter-Quartile Range (where 50% of the data reside).
      17
      23 June 2011
    • 21. Phase II Trial Conduct Patterns
      January 1, 2000 - May 31, 2011
      Data Source: Deloitte Recap LLC
      18
      23 June 2011
    • 22. Phase II Trial Conduct Patterns
      January 1, 2000 - May 31, 2011
      Data Source: Deloitte Recap LLC
      19
      23 June 2011
    • 23. Advancement Decisions Based on One Phase II Trial
      Does Quality of Efficacy Evidence Correlate with Risk?
      Question: Can we learn anything from looking at the Phase II trial results informing these advancement decisions?
      23 compounds advanced on data from a single trial.
      26 compounds advanced on data from a single trial.
      Data Source: Deloitte Recap LLC
      20
      23 June 2011
    • 24. Advancement Decisions Based on One Phase II Trial
      Efficacy Evidence and Risk
      Higher Risk Evidence
      61% (14/23)
      Data Source: Deloitte Recap LLC
      21
      23 June 2011
    • 25. Phase II Trial Result Categories
      Based on Design Rigor & Prospectively Defined Primary Endpoint
      Negative or Neutral Efficacy Signals
      Higher Risk Evidence
      22
    • 26. Advancement Decisions Based on One Phase II Trial
      Efficacy Evidence and Risk
      Lower Risk Evidence
      61% (14/23)
      39% (9/23)
      Data Source: Deloitte Recap LLC
      23
      23 June 2011
    • 27. Phase II Trial Result Categories
      Based on Design Rigor & Prospectively Defined Primary Endpoint
      Positive Efficacy Signals
      Lower Risk Evidence
      24
    • 28. Advancement Decisions Based on One Phase II Trial
      Efficacy Evidence and Risk
      Higher Risk Evidence
      Lower Risk Evidence
      61%
      39%
      Data Source: Deloitte Recap LLC
      25
      23 June 2011
    • 29. Advancement Decisions Based on One Phase II Trial
      Efficacy Evidence and Risk
      Higher Risk Evidence
      61%
      19% (5/26)
      Data Source: Deloitte Recap LLC
      26
      23 June 2011
    • 30. Advancement Decisions Based on One Phase II Trial
      Efficacy Evidence and Risk
      Lower Risk Evidence
      39%
      81% (21/26)
      Data Source: Deloitte Recap LLC
      27
      23 June 2011
    • 31. Advancement Decisions Based on One Phase II Trial
      Efficacy Evidence and Risk
      Higher Risk Evidence
      Lower Risk Evidence
      61%
      39%
      19%
      81%
      Data Source: Deloitte Recap LLC
      28
      23 June 2011
    • 32. Advancement Decisions Based on One Phase II Trial
      Efficacy Evidence and Risk
      Higher Risk Evidence
      Lower Risk Evidence
      To emulate successful drugs, Phase II advancement decisions made on the basis of Higher Risk evidence from a single trial should occur infrequently (about 1 in 5 decisions)
      61%
      39%
      19%
      81%
      Data Source: Deloitte Recap LLC
      29
      23 June 2011
    • 33. Changing Endpoints Between Phase II and Phase III
      Percent of Compounds that Switched Primary Efficacy Endpoint
      88%
      45%
      Terminated at Phase III
      or Filing
      (n=33)
      Approved By FDA
      (n=64)
      Data Source: Deloitte Recap LLC
      30
      23 June 2011
    • 34. Compound Characteristics: Therapeutic Areas
      TAs with Balance or Minor Imbalance Between Groups
      Data Source: Deloitte Recap LLC
      * Includes: Dental/Oral, Dermatologic, Genitourinary, Respiratory, Transplantation, Ophthalmic and Other.
      31
      23 June 2011
    • 35. Compound Characteristics: Therapeutic Areas
      TAs with Major Imbalance Between Groups
      Data Source: Deloitte Recap LLC
      Observation: When we removed all compounds (n=23) representing these three Therapeutic Areas from both data sets, results for Phase II and Phase III program conduct remained essentially unchanged.
      32
      23 June 2011
    • 36. Compound Characteristics: Miscellaneous
      Balance Between Groups of Other Relevant Factors
      Data Source: Deloitte Recap LLC
      * For approved drugs, 58% (37/64) received Priority Review and 42% (27/64) could be considered First-in-Class.
      33
      23 June 2011
    • 37. Phase II Risk Factors
      Program Characteristics of 33 Products That Terminated Late
      34
      23 June 2011
    • 38. Phase II Risk Mitigation
      Program Characteristics of 64 FDA-Approved Products
      35
      23 June 2011
    • 39. Derisking the Phase II to Phase III Advancement DecisionCase Study: Belimumab
      David C. Stump, MD
      Executive Vice President, R&D
      Human Genome Sciences, Inc.
      June 28, 2011
    • 40. Monocytes, activated by antigen, express membrane bound BLyS
      Antigens present in the periphery
      BLyS: Mechanism of Action
      BLyS is cleaved to active, soluble form
      B cell survival, differentiation, & antibody formation
      B cell
      37
    • 41. Rationale for BLyS Antagonists in SLE
      Mouse data links BLyS and autoimmune disease
      Transgenic models over-expressing BLyS have autoimmune/SLE-like phenotype
      Genetic models of autoimmune disease have elevated levels of circulating BLyS
      Soluble BLyS receptors administered in an animal model of SLE ameliorates disease progression and improves survival
      BLyS antagonists inhibit BLyS effects in mice
      Human BLyS administration results in increased spleen weight, B220+/ThB+splenic B cell numbers and serum IgA
      BLyS antagonists selectively inhibit these BLyS-induced effects
      38
    • 42. Autoimmune Patients Display Elevated Serum BLyS Concentrations
      39
    • 43. BLyS Observational SLE Study
      There is a strong association between SLE disease activity, the presence of anti-dsDNA and BLyS levels in SLE patients.
      *Petri M et al. A&R 2008;58(8)2453-9.
      40
    • 44. By Binding to BLyS, Belimumab Inhibits B-cell Survival, May Induce Apoptosis
      Belimumab Binds BLyS
      Autoimmune Disease
      Autoreactive B-cell apoptosis
      Autoreactive B-cell survival
      = Belimumab
      = TACI, BCMA, BAFF-R
      = BLyS
      Do RKG et al. J Exp Med. 2000;192:953-964; Ammana et al. J Immunol. 2003;170:4593-4600.
      41
    • 45. Belimumab Clinical Studies in SLE*
      *Excludes Continuation Clinical Trials
      42
    • 46. Phase 2 SLE Trial Design
      43% (193/449) remained on treatment as of 28 Dec. 2010
      1,632 Cumulative Patient-years
      Efficacy assessments
      SELENA-SLEDAI (SS), SLE Flare Index (SFI), PGA, BILAG Classic 2000
      Every 4-8 weeks in first 52 weeks & extension; every 8-16 weeks in continuation
      Safety assessments
      Adverse events recorded every visit. Safety labs every 4 weeks in first 52 weeks;
      every 8 weeks in extension &continuation
      43
      *All treatments included standard of care PGA = Physician’s Global Assessment. BILAG = British Isles Lupus Assessment Group
    • 47. Lessons Learned from the Belimumab Phase 2 SLE Study
      Did not meet co-primary endpoints of:
      % reduction of SELENA SLEDAI score at week 24
      time to first SLE flare over 52 weeks
      Presumption of 65-70% annual flare rate too low in moderate-severe SLE patients
      Early reductions in B-cell subsets and improved PGA responses required time to translate into decreased SLE disease activity as measured by the SELENA-SLEDAI
      Serologically active (ANA≥1:80 and/or anti-dsDNA ≥30 IU/mL) patients at entry were more responsive to BLyS-specific inhibitor therapy
      Permitting changes in prednisone and immunosuppressive medications confounded SLE disease activity assessments
      44
    • 48. Lessons Learned from the Belimumab Phase 2 SLE Study
      Limitations and strengths of BILAG and SELENA SLEDAI (SS) disease activity scales were identified:
      Using the same scale to show improvement and worsening
      Population-based disease activity more difficult to interpret than individual responders
      Wanted unambiguous measure of stable improvement in disease activity
      SS is a better measure of sustained overall improvement
      BILAG highly variable measure of improvement
      BILAG B flares could easily be triggered
      BILAG is a better measure of organ specific worsening
      45
    • 49. Rationale for Novel Composite Endpoint in SLE
      FDA had recommended that results of clinical trials be analyzed to verify that improved SLE disease activity score translates into a clinical benefit for the patient1
      Improvement in disease activity should not be accompanied by worsening in other disease manifestations
      SELENA SLEDAI(SS) tracks complete elimination, but not partial changes. Has 24 items.
      Clinical response on SS defined as ≥4-point decrease2
      BILAGmeasures changes in disease activity in individual organ systems
      BILAG A or 2 BILAG B flares represent increased activity sufficient to require a therapeutic alteration (e.g., steroid or immunosuppressant); triggered by physician’s “intent to treat”
      PGAis semi-quantitative and sensitive to patient’s overall condition
      No worsening defined as <0.3-unit (≈10%) increase on visual analog scale
      1. FDA. Draft Guidance for Industry: Systemic Lupus Erythematosus — Developing Drugs for Treatment. Released March 16, 2005;
      2. Gladman DD, et al. J Rheumatol. 2000;27:377-379.
      46
    • 50. Novel SLE Responder Index
      ≥ 4 point improvement in SELENA SLEDAI score
      AND
      No new BILAG A or 2 BILAG B organ domain flares
      AND
      No worsening in Physician’s Global Assessment
      (<0.3 point increase)
      47
    • 51. Difference in Phase 3 BLISS Trials Compared to the Phase 2 SLE Trial Design
      Created a novel evidence-based SLE responder index (SRI) as the primary endpoint at Week 52
      Only enrolled autoantibody positive (ANA≥1:80 and/or anti-dsDNA ≥30 IU/mL) at baseline as these patients were more responsive to belimumab therapy in Ph 2
      Ensures improvement is disease activity and is not accompanied by worsening in specific organ systems or in the patient’s condition overall
      Increased the sample size ~3-fold for 90% power
      Global input on trial design and background standard of care therapies allowed participation of patients from different regions of the world
      48
    • 52. Difference in Phase 3 BLISS Trials Compared to the Phase 2 SLE Trial Design
      Strict entry criteria to identify SLE patients with moderate to severe disease activity
      Increased minimum entry SS score from 4 to 6
      Stable standard of care medications 1-6 months before study initiation
      Controlled concomitant use of standard of care therapies during the trial that could impact SLE disease activity assessments
      Extensive training of SLE disease activity scales (SELENA SLEDAI and BILAG )
      Automatic edits programmed in eCRF for SLE disease activity scales and cross-checking
      49
    • 53. Austria
      Belgium
      Czech Republic
      France
      Germany
      Israel
      Italy
      The Netherlands
      Poland
      Romania/Romania
      Russia
      Slovakia
      Spain
      Sweden
      UK
      US
      Puerto Rico
      Canada
      Mexico
      Costa Rica
      Australia
      Hong Kong
      India
      Korea
      The Philippines
      Taiwan
      Argentina
      Brazil
      Chile
      Colombia
      Peru
      BLISS Phase 3 Clinical Trial Program
      BLISS-52
      BLISS-76
      1,684 patients from 223 centers in 31 countries
      865 (BLISS-52) and 819 (BLISS-76) patients
      50
    • 54. BLISS-52 Study Design
      • 865 subjects with active SLE
      • 55. SELENA-SLEDAI ≥ 6
      • 56. Serologically active (ANA ≥ 1:80 and/ or anti-dsDNA ≥ 30 IU/mL)
      • 57. Stable standard of care therapy >30 days
      • 58. No active severe lupus nephritis or CNS lupus
      • 59. Progressive restrictions on concurrent medications (weeks 16, 24 and 44)
      R
      A
      N
      D
      O
      M
      I
      Z
      E
      Placebo
      + Standard of Care
      Belimumab 1 mg/kg
      + Standard of Care
      Belimumab 10 mg/kg
      + Standard of Care
      51
    • 60. BLISS-52: Primary Response at Week 52
      52
    • 61. R
      A
      N
      D
      O
      M
      I
      Z
      E
      Placebo + Standard of Care
      Belimumab 1 mg/kg + Standard of Care
      Belimumab 10 mg/kg + Standard of Care
      BLISS-76 Study Design
      • 819 subjects with active SLE
      • 62. SELENA-SLEDAI ≥ 6
      • 63. Serologically active (ANA ≥ 1:80 and/ or anti-dsDNA ≥ 30 IU/mL)
      • 64. Stable standard of care therapy >30 days
      • 65. No active severe lupus nephritis or CNS lupus
      • 66. Progressive restrictions on concurrent medications (weeks 16, 24 and 44)
      53
    • 67. BLISS-76 Primary Efficacy Endpoint at Week 52
      Belimumab
      54
    • 68. Efficacy Conclusions: Primary Endpoint
      • Belimumab 10 mg/kg met primary endpoint in both trials
      • 69. Greater duration of response
      • 70. Robust in sensitivity analyses
      • 71. Greater benefit at higher thresholds (SRI ≥5)
      • 72. At Weeks 52 and 76
      • 73. Multivariate analyses
      • 74. No heterogeneity of effect by study, region or race
      • 75. Further study of black patients needed
      • 76. Identified potential predictors of greater response
      • 77. Higher SELENA SLEDAI, low complement, steroid use
      55
    • 78. Safety Summary
      Overall adverse event rates similar to placebo
      With wide range of standard therapies
      Numerically more deaths reported than placebo; rates and causes of death consistent with SLE
      Increased rate of infusion reactions
      Majority mild to moderate; manageable
      Serious infection rates similar to placebo
      No increase in malignancies
      56
    • 79. So What’s One to Do?
      Thoroughly understand target biology and pathophysiology
      Define relationship of target to manifestations of disease
      Effective phase 2 strategy
      Do not skip it
      Consider it exploratory rather than pivotal
      Learn from it
      57
    • 80. So What’s One to Do?
      Effective phase 3 strategy
      Apply phase 2 learnings
      Understand and manage risks from BOTH noise of implementation and natural variability of disease
      Adequately power studies
      Do not fear going global
      58
    • 81. Derisking the Phase II to Phase III Advancement DecisionCase Study: Belimumab
      David C. Stump, MD
      Executive Vice President, R&D
      Human Genome Sciences, Inc.
      June 28, 2011
    • 82. Killing the Vampire
      Anti-IGF1R Phase III Go/No-Go Recommendation
      John Orwin
      Chief Executive Officer
      Affymax
    • 83. Anti-IGF1R Phase III Go / No Go Decision
      IGF1R was a target of high scientific and commercial interest market
      IGF1R highly expressed in several highly prevalent tumor types
      Appeared combinable with other targeted and cytotoxic therapies
      Genentech portfolio planning set a high bar
      1st in class or best in class
      Competition with other high value projects
      Highly sophisticated market planning models
      Patient-based, tumor-specific incidence and prevalence based models
      Captured order and angle of entry
      An undifferentiated, late to market product would not meet the hurdle – but how to convince the enthusiastic scientists?
      61
    • 84. IGF1R Antibody
      IGF1R TKI
      Insmed
      INSM-18
      Prostate
      MerckMK-0646CRC
      Exelixis
      XL-228
      Abbott
      A928605
      OSI OSI-906 (QPIP)
      Roche
      R1507
      Biogen/IDEC
      BIIB-022
      Amgen
      AMG 479
      Genentech
      10H5
      PfizerCP-751,871
      Imclone
      IMC-A12
      Competitive Landscape anti-IGF1R Class, April 25, 2007
      GSK
      GSK-665,602
      GSK-621,659
      BMS
      BMS-695,735
      BMS-544,417
      BMS-536,924
      Novartis
      NOV-AEW-541
      NOV-ADW-742
      Merck/PierreFabre
      h7C10/F50035
      ImmunoGen/Sanofi
      EM-164/AVE1642
      Schering-Plough
      19D12
      62
      Preclinical
      Phase I
      Phase II
      Phase III
      Launched
    • 85. Predicted anti-IGF1R Launches:10H5 Will Launch More than 2 Years After Leader
      NSCLC
      Launch
      Order
      2009
      2013
      2010
      2011
      2012
      2014
      GNE:
      4
      2L NSCLC FPI
      Launch
      LPO
      BLA
      Pfizer
      1
      2L NSCLC
      mBC, HRPC
      1L NSCLC
      Roche
      Sarc
      (no AA)
      *2L NSCLC
      Sarc (AA)
      Amgen
      mBC
      Sarc (AA)
      Sarc (no AA)
      Panc
      Schering Plough
      Sarc
      (no AA)
      Sarc (AA)
      2L
      CRC
      Merck
      3
      2L
      CRC
      2L NSCLC
      ImClone
      2
      2L NSCLC
      RR mBC, Sarc, HNC, 2L HCC
      2L CRC, Prostate
      *Assumed – not publicly disclosed
      Timelines based on generic PPC-approved assumptions for approval, and Ph II/III unless accelerated approval expected (AA)
      63
    • 86. Anti-IGF1R Class is a Commodity
      • Current data suggests that anti-IGF1R class is undifferentiated
      • 87. No clear path to demonstrate best in class for10H5
      • 88. No dosing nor safety advantage over competitors
      • 89. All mAbs predicted to have similar PTS to launch
      • 90. None have IP advantage
      • 91. Therefore, market order entry will dictate resulting market share
      • 92. First mover advantage is often retained in oncology markets without clear advantages of follow on products
      64
    • 93. Slide 65
      2/29/2008
      Pfizer Gains First-Mover Advantage in Undifferentiated Market
      GNE captures 10% market share as 4th entrant in 2L NSCLC
      aIGF1R Net Usage in 2L NSCLC
      Key Drivers and Barriers of Class Penetration
      • Strong efficacy improvement over Tarceva expected
      • 94. High degree of combinability with chemo and other targeted agents due to clean safety profile
      • 95. Combination with anti-angiogenics less likely
      • 96. Large class due to 5+ aIGF1R agents in late stage development
      • 97. Greater use of biomarker tests lead to fragmented market
      65
    • 98. Strategies Explored to Maximize the Value of 10H5
      Maximize Speed to Market
      • Order of market entry is a critical driver of revenue assumptions
      Independent Value for 10H5
      Maximize Market Share
      • Line extensions may provide additive value
      Incremental Value to Portfolio
      Combo Augments Efficacy
      • Combinations with pipeline products may be innovative
      66
    • 99. Target launch window
      Attempt Earlier Launch to Gain Greater Market Share
      2009
      2013
      2010
      2011
      2012
      2014
      GNE:
      2L NSCLC Launch
      FPI
      Pfizer
      2L NSCLC
      mBC, HRPC
      1L NSCLC
      Roche
      Sarc
      (no AA)
      *2L NSCLC
      Sarc (AA)
      Amgen
      mBC
      Sarc (AA)
      Sarc (no AA)
      Panc
      Schering Plough
      Sarc
      (no AA)
      Sarc (AA)
      2L
      CRC
      Merck
      2L
      CRC
      2L NSCLC
      ImClone
      2L NSCLC
      RR mBC, Sarc, HNC, 2L HCC
      2L CRC, Prostate
      *Assumed – not publicly disclosed
      Timelines based on generic PPC-approved assumptions for approval, and Ph II/III unless accelerated approval expected (AA)
      67
    • 100. No Fast to Market Strategies Could Launch Within Target Timeframe
      Speed
      SCLC
      Science
      Melanoma (w/DTIC)
      2L HR
      PrCa
      NSCLC
      Portfolio/
      Pipeline
      HCC
      w/nex
      Sarcoma
      Pancreatic
      w/EGFR
      CRC
      RCC w/mTOR
      MBC
      1L HRPrC
      HNSCC w/EGFR
      HSPrC
      HCC
      (w/A+T)
      Ref OvCa
      Melanoma (w/Mek, Avastin)
      Neuroendocrine
      RCC w/VEGF
      OvCa
      w/pert, AVF
      Ewing’s
      Sarcoma
      No current IGF1R trials
      68
    • 101. Ph 1
      Ph 2
      Ph 3
      Large Markets Crowded by Anti-IGF1R Competitors
      • Unlikely that 10H5 will enter market early in big indications, thereby constraining market value
      69
    • 102. Anti-IGF1R Phase 3 Decision
      Commercial recommendation was not to advance 10H5
      Numerous approached explored to differentiate product but were unconvincing
      Different antibody
      Unique combinations with proprietary, earlier stage molecules
      Many fast-to-market development options were considered
      Rare, high unmet need tumor types
      Strategic value was considered – but was owning the product the only or best way to release the combination potential?
      The product was discontinued prior to phase 3 start
      The class later was largely abandoned when products failed in late stage phase 2 and phase 3 trials
      70
    • 103. Anti-IGF1R Lessons Learned
      Models are valuable when they are used to help inform decisions rather than support a given decision
      Decision rules are valuable but only if they are followed – discipline is required
      Commercial risk must be considered along with scientific and technical risk
      Great momentum exists for projects in motion
      Even for companies with a high hurdle and competing opportunity set
      Great care and tenacity are required when killing a vampire!
      71
    • 104. De-Risking the Phase II to Phase III Advancement Decision:Sound Science, Critical Thinking and Weighing Time versus Cost
      June 28, 2011
      Q&A