De-Risking the Phase II to Phase III Advancement Decision:Sound Science, Critical Thinking and Weighing Time versus Cost<b...
Speakers & Topics<br />Lisa Natanson<br />Senior Analyst<br />Deloitte Recap LLC<br />David Stump<br />Executive Vice Pres...
What Can We Learn From the Data About Late-Stage Drug Development Failures?<br />Lisa Natanson<br />Senior Analyst, Deloit...
Success<br />Late-Stage Failure<br />A terminated product that…<br /><ul><li>Fails at Phase III or Filing after years of d...
Provides no return on investment for companies and stockholders</li></ul>An approved product that…<br /><ul><li>Improves s...
Provides return on investment for companies and stockholders</li></ul>4<br />
5<br />
Data Source: 190 Leading Biotechnology Companies<br />587<br />Ongoing Compounds<br />523 Terminated Compounds<br />41%<br...
Compound Data Set (n=97)<br />Approved<br />Compounds<br />152<br />117<br />--<br />--<br />74<br />70<br />64<br />Termi...
Documented Reason for Termination was                                      “Lack of Activity or Efficacy” or “Safety”</li>...
Compound Data Set (n=97)<br />January 1, 2000 - May 31, 2011<br />Success<br />Late-Stage Failure<br />versus<br />33 Comp...
Methodology for Comparing Phase II Programs<br />Phase II program metrics reported contain only trials ongoing and/or comp...
Median Metrics of Phase II Clinical Programs<br />January 1, 2000 - May 31, 2011<br />Data Source: Deloitte Recap LLC<br /...
Median Metrics of Phase II Clinical Programs<br />January 1, 2000 - May 31, 2011<br />Data Source: Deloitte Recap LLC<br /...
Median Metrics of Phase II Clinical Programs<br />January 1, 2000 - May 31, 2011<br />Data Source: Deloitte Recap LLC<br /...
Median Metrics of Phase II Clinical Programs<br />January 1, 2000 - May 31, 2011<br />39 Trials<br />5,592 Patients<br />1...
Median Metrics of Phase II Clinical Programs<br />January 1, 2000 - May 31, 2011<br />Data Source: Deloitte Recap LLC<br /...
Median Metrics of Phase II Clinical Programs<br />January 1, 2000 - May 31, 2011<br />Data Source: Deloitte Recap LLC<br /...
Median Metrics of Phase III Clinical Programs<br />January 1, 2000 - May 31, 2011<br />Data Source: Deloitte Recap LLC<br ...
Median Metrics of Phase III Clinical Programs<br />January 1, 2000 - May 31, 2011<br />Data Source: Deloitte Recap LLC<br ...
Phase II Trial Conduct Patterns<br />January 1, 2000 - May 31, 2011<br />Data Source: Deloitte Recap LLC<br />18<br />23 J...
Phase II Trial Conduct Patterns<br />January 1, 2000 - May 31, 2011<br />Data Source: Deloitte Recap LLC<br />19<br />23 J...
Advancement Decisions Based on One Phase II Trial<br />Does Quality of Efficacy Evidence Correlate with Risk?<br />Questio...
Advancement Decisions Based on One Phase II Trial<br />Efficacy Evidence and Risk<br />Higher Risk Evidence <br />61% (14/...
Phase II Trial Result Categories<br />Based on Design Rigor & Prospectively Defined Primary Endpoint<br />Negative or Neut...
Advancement Decisions Based on One Phase II Trial<br />Efficacy Evidence and Risk<br />Lower Risk Evidence <br />61% (14/2...
Phase II Trial Result Categories<br />Based on Design Rigor & Prospectively Defined Primary Endpoint<br />Positive Efficac...
Advancement Decisions Based on One Phase II Trial<br />Efficacy Evidence and Risk<br />Higher Risk Evidence <br />Lower Ri...
Advancement Decisions Based on One Phase II Trial<br />Efficacy Evidence and Risk<br />Higher Risk Evidence <br />61%<br /...
Advancement Decisions Based on One Phase II Trial<br />Efficacy Evidence and Risk<br />Lower Risk Evidence <br />39%<br />...
Advancement Decisions Based on One Phase II Trial<br />Efficacy Evidence and Risk<br />Higher Risk Evidence <br />Lower Ri...
Advancement Decisions Based on One Phase II Trial<br />Efficacy Evidence and Risk<br />Higher Risk Evidence <br />Lower Ri...
Changing Endpoints Between Phase II and Phase III<br />Percent of Compounds that Switched Primary Efficacy Endpoint<br />8...
Compound Characteristics: Therapeutic Areas<br />TAs with Balance or Minor Imbalance Between Groups<br />Data Source: Delo...
Compound Characteristics: Therapeutic Areas<br />TAs with Major Imbalance Between Groups<br />Data Source: Deloitte Recap ...
Compound Characteristics: Miscellaneous<br />Balance Between Groups of Other Relevant Factors<br />Data Source: Deloitte R...
Phase II Risk Factors<br />Program Characteristics of 33 Products That Terminated Late<br />34<br />23 June 2011<br />
Phase II Risk Mitigation<br />Program Characteristics of 64 FDA-Approved Products<br />35<br />23 June 2011<br />
Derisking the Phase II to Phase III Advancement DecisionCase Study:  Belimumab<br />David C. Stump, MD<br />Executive Vice...
Monocytes, activated by antigen, express membrane bound BLyS<br />Antigens present in the periphery<br />BLyS: Mechanism o...
Rationale for BLyS Antagonists in SLE<br />Mouse data links BLyS and autoimmune disease<br />Transgenic models over-expres...
Autoimmune Patients Display Elevated Serum BLyS Concentrations<br />39<br />
BLyS Observational SLE Study<br />There is a strong association between SLE disease activity, the presence of anti-dsDNA a...
By Binding to BLyS, Belimumab Inhibits B-cell Survival, May Induce Apoptosis<br />Belimumab Binds BLyS<br />Autoimmune Dis...
Belimumab Clinical Studies in SLE*<br />*Excludes Continuation Clinical Trials<br />42<br />
Phase 2 SLE Trial Design<br />43% (193/449) remained on treatment as of 28 Dec. 2010<br />1,632 Cumulative Patient-years<b...
Lessons Learned from the Belimumab Phase 2 SLE Study<br />Did not meet co-primary endpoints of:<br />% reduction of SELENA...
Lessons Learned from the Belimumab Phase 2 SLE Study<br />Limitations and strengths of BILAG and SELENA SLEDAI (SS) diseas...
Rationale for Novel Composite Endpoint in SLE<br />FDA had recommended that results of clinical trials be analyzed to veri...
Novel SLE Responder Index<br /> ≥ 4 point improvement in SELENA SLEDAI score<br />				AND<br />	No new BILAG A or 2 BILAG ...
Difference in Phase 3 BLISS Trials Compared to the Phase 2 SLE Trial Design<br />Created a novel evidence-based SLE respon...
Difference in Phase 3 BLISS Trials Compared to the Phase 2 SLE Trial Design<br />Strict entry criteria to identify SLE pat...
Austria<br />Belgium<br />Czech Republic<br />France<br />Germany<br />Israel<br />Italy<br />The Netherlands<br />Poland<...
BLISS-52 Study Design<br /><ul><li>865 subjects with active SLE
SELENA-SLEDAI ≥ 6
Serologically active (ANA ≥ 1:80 and/ or anti-dsDNA ≥ 30 IU/mL)
Stable standard of care therapy >30 days
No active severe lupus nephritis or CNS lupus
Progressive restrictions on concurrent medications        (weeks 16, 24 and 44)</li></ul>R<br />A<br />N<br />D<br />O<br ...
BLISS-52: Primary Response at Week 52<br />52<br />
R<br />A<br />N<br />D<br />O<br />M<br />I<br />Z<br />E<br />Placebo                       + Standard of Care<br />Belim...
SELENA-SLEDAI ≥ 6
Serologically active (ANA ≥ 1:80 and/ or anti-dsDNA ≥ 30 IU/mL)
Stable standard of care therapy >30 days
No active severe lupus nephritis or CNS lupus
Progressive restrictions on concurrent medications        (weeks 16, 24 and 44)</li></ul>53<br />
BLISS-76 Primary Efficacy Endpoint at Week 52<br />Belimumab<br />54<br />
Efficacy Conclusions: Primary Endpoint <br /><ul><li>Belimumab 10 mg/kg met primary endpoint in both trials
Greater duration of response
Robust in sensitivity analyses
Greater benefit at higher thresholds (SRI ≥5)
At Weeks 52 and 76
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De-Risking the Phase II to Phase III Advancement Decision: Sound Science, Critical Thinking and Weighing Time versus Cost

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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.

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

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

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