Protocol F1K-MC-EVDP Efficacy and Safety of Drotrecogin Alfa (Activated) in Adult Patients with Septic Shock PROWESS SHOCK

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1 Protocol F1K-MC-EVDP Efficacy and Safety of Drotrecogin Alfa (Activated) in Adult Patients with Septic Shock PROWESS SHOCK Jonathan Janes FRCP MFPM Medical Director- Acute Care Lilly Research Centre Erl Wood Manor, UK Critical Care Canada Forum 2011 Toronto

2 Disclosures: I am an employee and shareholder of Eli Lilly and Company.

3 Xigris Studies Xigris Studies (> 11,000 patients) EVAA Phase II N= 131 PROWESS Phase III N=1690 ENHANCE Open label N= 2378 ADDRESS Lower risk of death N= 2640 RESOLVE Paediatric study N= 477 XPRESS Heparin study N= 1935 RESPOND Phase II study N= 433 Potential role of PC as a biomarker to guide Xigris therapy PROWESS SHOCK N= 1696

4 Ranges estimated from relative risk Clinical Trial and Registries Hospital/ ICU mortality Xigris Control, Adjusted Control, or Predicted Mortality Lilly Clinical PROWESS-Overall 29% 35% Study PROWESS- 3 OD 36% 44% Observational Poland (N=302) 39% 56% Studies Italy (GiViTI; N=668) 46% 55% United Kingdom 1 (ICNARC; N=1292) 45% 49% 58%* United Kingdom 2 (N=351) 47% 60% Belgium (N=436) 52% 64% Global 1 (N=882) 50% 57% -61%* Spain (N=87) 37% 57% United States 1 (N=1576) 41% 47% United States 2 (N=108) 35% 54% Global 2 (N=unknown) OR: % CI: France (N=1049) 47% 68%

5 Xigris Approvals & EU Annual Licence Reassessments November 2001 Approval from FDA August 2002 Approval from EMEA st Annual Licence Reassessment ENHANCE update nd Annual Licence Reassessment PROWESS Long-Term Follow-Up, ENHANCE, ADDRESS rd Annual Licence Reassessment ADDRESS Long-Term Follow-Up, RESOLVE th Annual Licence Reassessment XPRESS, Agreement to conduct PROWESS- Shock year renewal th Annual Licence Reassessment Final PROWESS-SHOCK protocol Reviewed th Annual Licence Reassessment SPC updates th Annual Licence Reassessment No SPC changes th Annual Licence Reassessment No SPC changes th Annual Licence Reassessment PROWESS-SHOCK Results

6 The small difference in the 28-day mortality of the overall population (26.4% in the Xigris arm versus 24.2% in the placebo arm; n=1680 patients) is not statistically significant. The risk of severe bleeding events, which is the main risk with this product, was 1.2% in the Xigris arm and 1.0% in the placebo arm, suggesting there was no increased harm.

7 Why did PROWESS SHOCK Results differ from PROWESS? PROWESS SHOCK was not designed to re-test PROWESS, but rather to test a high disease severity subset reflecting both the labeled indication and how DAA was being used in clinical practice Advances in standard of care were protocolised The following may have been contributing factors PROWESS PROWESS SHOCK CV Dysfunction 1 hr hypotension or 1 hr of vasopressors (any dose) Minimum 4 hr, minimum dose of vasopressors Resuscitation 500 ml fluid in 30 min 30 ml/kg within +/- 4 hr of vasopressors Other organ dysfunction 1 or more Shock + hypoperfusion Infection Coordinating centre Known or suspected infection Reviewed sepsis histories within 24 hr Evidence of infection receiving IV antimicrobials Approved every patient Placebo mortality 35% ( 2OD, Vasopressor) 24.2%

8 Why did Lilly Withdraw Xigris? Patents enrolled in PROWESS SHOCK largely reflected what would have been considered an indicated population The study failed to demonstrate that Xigris improved patient survival and thus calls into question the benefit-risk profile of Xigris and its continued use

9 Regulatory Guidance on Acceptance of a Single Study for Efficacy In some instances, clinical evidence consisting of a single, large-scale, adequate and well controlled study or one pivotal trial and additional clinical evidence may be deemed "substantial" [Jan 31,2003]

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11 EMA Guidance There is no formal requirement to include two or more pivotal studies in the phase 3 program In most cases several studies are the most or only feasible way to confirm usefulness In the exceptional event of a submission with only one pivotal study this has to be particularly compelling with regard to: Internal and external validity Clinical relevance Statistical significance Data quality Internal consistency

12 GuidanceComplianceRegulatoryInformation/Guidances/

13 FDA Guidance on Acceptance of a Single Study for Efficacy Limited to situations where a clinically meaningful effect is observed: Mortality Permanent morbidity Prevention of a disease with a potentially serious outcome Confirmation of the results in a second trial would be practically or ethically impossible

14 FDA Guidance on Acceptance of a Single Study for Efficacy (1) Large, multicenter clinical trial No single study site provided an unusually large fraction of patients No single investigator or site was responsible for the favorable effect seen (2) Consistency across study subsets Positive effects should be observed across clinically meaningful subsets of patients (age, gender, race, severity of illness) (3) Statistically very persuasive findings In a multicenter study, a very low p-value indicates that the result is highly inconsistent with the null hypothesis of no treatment effect.

15 FDA Guidance on Acceptance of a Single Study for Efficacy (4) Multiple endpoints involving different events In some cases, a single study will include multiple primary and secondary endpoints, each of which demonstrates a beneficial, but different, event as with reduction in MI and reduction in need for urgent intervention. (5) Multiple studies in a single study A large study can be viewed as two or more studies by subdividing it and showing that effectiveness is seen in the subdivisions.

16 Agennix Update on Talactoferrin: 2010 End-of-Phase II meeting with the U.S. Food & Drug Administration (FDA) to discuss future development plans for talactoferrin in severe sepsis The FDA strongly recommended that Agennix conduct two adequate and wellcontrolled Phase III studies to support a potential Biologic License Application (BLA) submission.

17 Other questions? If 2 trials are required in the future should these be run in sequence or parallel? In parallel similar to 1 large trial divided into 2 parts In sequence, the timeline and cost of Phase 3 may be prohibitive What is the value of registry data? Suggested a beneficial effect with Xigris yet RCT negative Suggested a harmful effect of steroids yet commonly used Is our ability to adjust/predict mortality adequate? Implications for other efficacy trials as clinical practice evolves? Are there instances where we might need to repeat clinical trials to assure continued efficacy of an intervention? Regulatory agencies monitor for new or worsening safety signals, not loss of efficacy

18 Thank You