Guidance for Diabetes Drug Development

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Herbert Walton
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1 Diabetes and CV outcome trials: Selected Lessons Learned thus Far Darren K. McGuire, MD, MHSc Professor of Medicine University of Texas Southwestern Medical Center Guidance for Diabetes Drug Development ICH Guidelines: 1500 patients exposed x 6 months 100 x 1 year Approval based on as little as 250 patient-years of exposure 1

2 Number of Medication Classes Paradigm shift underpinning regulatory change Increasing incidence/prevalence of T2DM >10% of US adult population Growing awareness of CV impact of T2DM Proliferation of medications available Numerous examples of adverse drug effects On target Off target Half-Century of HTN & T2DM Medications in U.S zz zz peripheral α-1 blockers β-blockers central α-2 agonists angiotensin II receptor blockers ACE Inhibitors Ca 2+ channel blockers SGLT-2 inhibitors dopamine agonists renin inhibitors meglitinides thiazolidinediones bile acid sequestrants DPP-4 inhibitors amylin mimetics GLP-1 receptor agonists 4 3 adrenergic neuronal blockers diuretics Biguanides α-glucosidase inhibitors biguanides insulin 2 1 vasodilators sulfonylureas Courtesy of Silvio Inzucchi, MD, Yale University

3 Present FDA Regulatory Guidance for Drugs for Type 2 Diabetes sponsors should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk. Requires ~15,000 pt-yrs of exposure The sky is falling 3

4 # Subjects it was just an acorn that fell. 25 Trials Ongoing/Completed 8 classes of medications >200,000 planned participants 2008 FDA guidance Holman RR et al. Lancet 2014; 383: SAVOR-TIMI 53 Enrollment Final Enrollment n=16, st Patient Enrolled May 5, 2010 >300/week Last Patient Enrolled December 12, Courtesy of Ben Scirica, MD, TIMI Study Group 4

5 gastric emptying GLP-1 GIP The Incretin System: Key Regulator of Post-Prandial Glucose Metabolism insulin secretion DPP-4 Inhibitor glucagon secretion hepatic glucose production peripheral glucose uptake Courtesy, Silvio Inzucchi, MD Incretin Modulators on US Market Generic Trade Names DPP4 inhibitors sitagliptin Januvia saxagliptin Onglyza alogliptin Nesina linagliptin Tradjenta GLP1-Receptor Agonists exenatide Byetta liraglutide Victoza albiglutide Tanzeum exenatide ER Bydureon dulaglutide Trulicity 5

6 Percent with First Adverse Event Time to Onset of First Primary MACE in Prior Pooled Analysis 5 4 Saxagliptin Controlled Phase 2b/3 Pooled Population HR 0.44 (95% CI ) 41 total events Control All Saxa 0 BL Patients at Weeks Risk Control All Saxa Frederich R, et al. Postgraduate Medicine 2010;122(3). doi: /pgm Proposed Pleiotropic CV Effects of DPP4 Inhibition and GLP1-RA Myocardial infarct size 1,2 Endothelial function 3 Triglycerides 8 Inflammation and oxidative stress 4 Left ventricular function 6,7 Atherosclerotic plaque volume 5 1. Ye et al. Am J Physiol Heart Circ Physiol 2010;298:H Hocher et al. Int J Cardiol 2013;167: van Poppel et al. Diabetes Care 2011;34: Kröller-Schön et al. Cardiovasc Res 2012;96: Ta et al. J Cardiovasc Pharmacol 2011;58: Sauvé et al. Diabetes 2010;59: Read et al. Circ Cardiovasc Imaging 2010;3: Matikainen et al. Diabetologia 2006;49:

CV Death, MI or Ischemic CVA (%) SAVOR TIMI 53-Primary Endpoint 14 12 10 8 N = 16,492 1222 Primary MACE Events HR 1.00 95% CI 0.89-1.12 p<0.001 (non-inferiority) 2y KM Saxagliptin 7.3% 6 4 Placebo 7.

7 CV Death, MI or Ischemic CVA (%) SAVOR TIMI 53-Primary Endpoint N = 16, Primary MACE Events HR % CI p<0.001 (non-inferiority) 2y KM Saxagliptin 7.3% 6 4 Placebo 7.2% 2 Placebo Saxagliptin Months Scirica BM, et ai. N Engl J Med 2013; 369: Primary end point N = 5380 White WB, et. al. N Engl J Med. 2013; 369:1327 7

8 Primary Composite Cardiovascular Outcome* Per Protocol Analysis for Noninferiority * CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina Green JB et al. NEJM 2015;373: ELIXA: Lixisenatide vs. Placebo Effects on CV Outcomes Pfeffer MA et al. NEJM 2015; 373:

Rare but serious adverse drug reactions require large exposure

pt years) Nausea Vomiting Antibody formation Anaphylactoid

$Bone fracture GI Bleeds Fasiglifam (~2000 patient years)$ Rosenstock J et al. Diabetes Care 2013; 36: 498 504.

9 Rare but serious adverse drug reactions require large exposure Courtesy of Ben Scirica, MD, TIMI Study Group Rare but serious adverse drug reactions require large exposure Taspoglutide (~600 pt years) Nausea Vomiting Antibody formation Anaphylactoid reactions Aleglitazar (>14,000 patient years) HF Decline in egfr Bone fracture GI Bleeds Fasiglifam (~2000 patient years) Drug-associated liver injury (10-fold increase in elevated LFTs) Rosenstock J et al. Diabetes Care 2013; 36: Lincoff AM et al. JAMA 2014; 311:

10 H o s p i t a l i z a t i o n f o r H e a r t F a i l u r e ( % ) Gastrointestinal Bleeding Associated with Aleglitazar: ALECARDIO Trial Lincoff AM et al. JAMA 2014; 311: SAVOR TIMI 53-Hospitalization for Heart Failure 4% Time to the 1 st occurrence of any hospitalization for heart failure; 517 events Sa x a g l i p ti n Pl a c e b o HR 1.27 P= % 3% 2% 1% 0% HR 1.80 P= % 0.6% HR 1.46 P= % 1.3% 2.8% Landmark Analysis at 12m 1.7% vs. 1.5% - HR 1.09, p=0.51 Time-varying interaction p value = D a y s fr o m R a n d o m i za ti o n Scirica BM, et al. Circulation 2014; 130:

11 % SAVOR-TIMI 53, EXAMINE, and TECOS*: Hospitalization for Heart Failure Trial HR (95% CI) P-Value SAVOR-TIMI EXAMINE TECOS 1.27 ( ) ( ) 1.00 ( ) SAVOR-TIMI + EXAMINE + TECOS 1.14 ( ) McGuire DK, et al. ESC 2015 Test for heterogeneity for 3 trials: p=0.16, I 2 =44.9 Annualized Rates of CV Death/MI/Stroke in Recent Outcomes Trials SAVOR TIMI 53 TECOS ALECARDIO EXAMINE ELIXA* (+ USA) Scirica BM et al. N Engl J Med 2013;369: Green JB et al. N Engl J Med 2015;373: Lincoff AM et al. JAMA 2014; 311: White WB et al. N Engl J Med 2013;369: Pfeffer MA et al. N Engl J Med 2015; 373:

12 Kaplan-Meier Event Rate Kaplan-Meier Event Rate PROactive Primary Endpoint Pioglitazone (514 events) Placebo (572 events) HR 0.90 P CI N at risk: (228) Time From Randomization (mo) Death, MI, CVA, ACS, Leg Revascularization or Amputation, PCI, or CABG Dormandy JA, et al. Lancet 2005; 366: 1279 PROactive Prioritized Secondary Endpoint 0.15 Pioglitazone (301 events) Placebo (358 events) HR 0.84 P % CI N at risk: (256) Time From Randomization (mo) Death, MI, CVA Dormandy JA, et al. Lancet 2005; 366:

Am J Physiol Renal Physiol 2001; 280:F10 18; Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; Hummel CS, et al.

13 Normal renal glucose handling Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule Glucose Filtration ~180g/day Remaining glucose is reabsorbed by SGLT1 (10%) Minimal to no glucose excretion Wright EM. Am J Physiol Renal Physiol 2001; 280:F10 18; Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21 SGLT2 Antagonists on US Market Generic canagliflozin dapagliflozin empagliflozin Trade Name Invokana Farxiga Jardiance 13

14 Primary outcome: 3-point MACE HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* Zinman B et al. N Engl J Med 2015; 373: CV death HR 0.62 (95% CI 0.49, 0.77) p< Zinman B et al. N Engl J Med 2015; 373:

15 CV death Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p= Empagliflozin 25 mg HR 0.59 (95% CI 0.45, 0.77) p= Zinman B et al. N Engl J Med 2015; 373: Hospitalization for heart failure HR 0.65 (95% CI 0.50, 0.85) p= Zinman B et al. N Engl J Med 2015; 373:

IRIS Primary Outcome Cumulative Event-Free Survival Probability 100% 95% 90% 85% 80% 0 Pioglitazone Placebo HR 0.76 95% CI, 0.62 to 0.93 P=0.007 9.0%* 11.

16 IRIS Primary Outcome Cumulative Event-Free Survival Probability 100% 95% 90% 85% 80% 0 Pioglitazone Placebo HR % CI, 0.62 to 0.93 P= %* 11.8%* Months in Trial Kernan WN et al. N Engl J Med, published on-line Feb 17, 2016 DOI: /NEJMoa *cumulative event rates Hot of the Press 16

17 Conclusions Diabetes is common and increasing, with significant associated CV morbidity and mortality Role of glucose control in CVD risk mitigation remains uncertain What drugs/strategies; what intensity; what timing Side effects-both on- and off-target Imperative to at a minimum establish CV safety Evolution of regulatory guidance has dramatically altered the trial landscape of drug development for type 2 diabetes mellitus >200,000 patients enrolled/planned in CV outcomes trials 4 trials now reported demonstrating CV safety EMPA REG outcome has reported CV efficacy with empagliflozin 17

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