10/27/2011. Challenges in Anti-diabetic Global Drug Development A Shift from Surrogate to Outcome Trials. Disclaimer

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1 Challenges in Anti-diabetic Global Drug Development A Shift from Surrogate to Outcome Trials Eckhard Leifke, MD PhD Senior Medical Director Takeda Global Research Development Center, Inc. Presentation reflects personal view and does not represent Takeda s opinion Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. ( DIA ), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. Drug Information Association 2 New FDA guidance had immediate impact on drug development in type 2 diabetes Programs started prior to new FDA guidance Programs started after new FDA guidance A Post approval CV trial B Pre/Post approval CV trial Phase 3 Efficacy trials Phase 3 Efficacy trials NDA *delay NDA NDA Saxagliptin BMS/AstraZeneca Liraglutide Novo Nordisk Linagliptin Program Boehringer Dapagliflozin BMS- Astra Zeneca * Bromocriptin - VeroScience * Alogliptin Takeda (MACE number was not sufficient to exclude 1.8 at time of initial filing) SGLT-2 inh BI1773 Boehringer-Lilly Canagliflozin J&J Lixisenatide Sanofi-Aventis Marcinak et al JCPT accepted 1

2 Effect of glucose lowering on cardiovascular outcomes and death in type 2 diabetes mellitus (post-ukpds-era) 33 4 participants from 5 RCTs to assess the effect of an intensive glucose-lowering regimen on death and CV outcomes compared with a standard regimen over 3-5 years of treatment: 17% reduction in non-fatal myocardial infarction ( 83, 95% CI INTERPRETATION: Overall, intensive compared 75 93), with standard glycaemic control significantly reduces coronary events without 15% reduction an increased events of risk coronary of heart disease ( 85, 77 93). death. However, the optimum mechanism, speed, and extent of HbA(1c) reduction might be different in differing populations. no significant effect on stroke ( 93, ) or all-cause mortality (1 2, ). Ray et al. Lancet 29 Potential Benefit on Survival Needs Time to Be Observed Accommodation of a potential benefit of A1 c lowering on cardiovascular outcome within usual development timelines is challenging Holman et al. NEJM Year Follow up of intensive Glucose control in Type 2 Diabetes High risk patients not sufficiently included in clinical program Estimated annual event rate of MACE is low in diabetes programs Observational studies Framingham (196) Framingham Offspring (198) Freemantle (2) UKPDS 33 (1998) Regulatory submissions Randomized Control lled Trials UKPDS 34a (1998) UKPDS 34b (1998) COSMIC (25) PROactive (25) ADVANCE (28) ACCORD (28) Steno-2 (28) VADT (29) Exenatide (25) Sitagliptin (26) Saxagliptin (29) Annual event rate (%) Marcinak et JCPT accepted 2

3 traditional risk engines overestimate CV risks of trials in type 2 diabetics Standard of care applied in studies improves outcome of high risk patients 12 (per 1-pts yr) 1 According to Ye et al ADA 21 t rate observed even 8 6 BARI-2D PROACTIVE 4 VADT 2 ACCORD ADOPT ADVANCE RECORD (per 1-pts yr) UKPDS model -predicted annual event rate Total number of patients needed to address FDA requirements with a conventional Ph3 program s at NDA (app) Total number of patients vildagliptin sitagliptin saxagliptin liraglutide Sample size with a.5 % annual event rate (app 13 MACE events) to exclude upper bound of 1.8 if point estimate of HZ is slighlty below or close to 1. Luck? BMS interview at the GTCbio Annual Diabetes Summit, with William Washburn, PhD (Senior Research Fellow, Bristol-Myers Squibb) Q: Can you mention anything about how BMS handled the CV outcome studies? A: We conducted a meta-analysis. The FDA rule change occurred after we had embarked on phase 3. Rather than start over and recruit thousands of new subjects, we gambled that the meta-analysis coming from our phase 2 and 3 trials would support our filing. We were fortunate that it did, in our opinion, meet the criteria - whereas, J&J and BI learned of the change in time to initiate trials that would address cardiovascular safety. 3

4 How to address FDA CV requirements in a more predictive way than luck How to enrich the study population? Event driven approach Stand alone CV outcome trial in a high risk population Pooled data across efficacy studies and CV outcome trial Pooled data across all Ph3/2 (enriched with high risk patients) Choice of the right major adverse cardiovascular composite endpoint: (MACE) unstable angina and myocardial infarction represent two states on a continuum of the same underlying disease Outcome trials with at least 1 randomized and 1 yr duration included: IMAGINE, PEACE, CAMELOT, Irbesartan Diabetic Nephropathy Trial, QUIET, HOPE, SAVE, SOLVD, VADT, PROactive, ALERT (Extension), PROVE-IT Area of discordance Area of concordance Marcinak et al JCPT accepted Annual frequency of adverse CV outcome true hazard ratio impact trial duration Enrollment app15 per month Enrollment app 3 per month Marcinak et al JCPT accepted 4

5 Statistics and Plausibility What assumption regarding the hazard ratio (point estimate) on cardiovascular (MACE) risk reduction should guide phase 3 planning? DPP4- inhibitors Linagliptin z.34 (.15,.74). 34 events (driven by SU comparator study with 2 events).86 (.23, 3.26). (placebo controlled studies only) Saxagliptin 1 :.43 - (95% CI.23-.8) 4 events Sitagliptin 2 :.68 (95 % CI ) 64 events Vildagliptin 3 : 1.2 (95 % CI ) for 5 mg qd; 24 events.84 (95 % CI ) for 5mg bid 161 events Z SBA Summary for Linagliptin FDA June Frederich R et al Postgrad Med 21 May 122 (3) Williams-Herman et al. BMC Endocrine Disorders 21 3 Schweizer et al Dibetologica 29 (52) 915. Statins 4.78 [95% CI,.67 to.89] in primary prevention in type 2 diabetes 87 events.76 [CI,.59 to.93]) in secondary prevention 1484 events Candesartan 5.79, (95% CI ) in hypertensive patients with renal impairment 39 events Pioglitazone 6,7.82 (95% CI.7-.97) in type 2 diabetes patients 57 events 4 Vijan S et al. Ann Intern Med. 24 Apr 2;14(8): Shiga T et al Blood Press. 21 Dec;19(6): Dormandy et al Lancet 25 Oct Erdmann E et al J Diabetes 21 Sept trial simulations help to establish timelines timing of the CV trial and true hazard ratio of drug candidate impact phase 3 timelines 16 True HZ ratio = Number of Events True HZ ratio =.85 True HZ ratio =.75 CV Study All Phase III without CV Study CV Study+All Phase III CV (Starts 12 Months Later)+All Phase III 4 CV (Starts 24 Months Later)+All Phase III 2 CV (Starts 42 Months Later)+All Phase III Months Assumptions e.g. MACE Events (CV=2.%/Year, All Phase III=.5%/Year) Estimates on program size, time (IND to NDA) and costs ects in 1x Number of subje rs Year sample time costs size before FDA Guidance FDA Guidance addressed by conventional programs (MACE at.5% annual rate) FDA Guidance addressed by more targeted program approach (MACE > 3%, separate CV outcome trial in high risk population etc) Mio $ in 1 5

6 Conclusions Impact on cost and time for new anti-diabetic drug candidates can be mitigated through careful clinical program planning Intensify signal detection for potential cardiovascular harm during the pre-clinical and early clinical stages prior to phase 3 Adjudication of adverse cardiovascular (CV) events across Ph 2 and 3 has become a requirement CV outcome trials in a high risk population irrespective of presence or absence of pre-clinical/clinical signals or mechanism of action related plausibility becomes part of the pre approval program Inclusion of hospitalization for unstable angina with or without coronary revascularization in addition to core MACE in the primary composite endpoint 6