CV SAFETY & OUTCOME TRIALS OF ORAL ANTIDIABETICS

CV SAFETY & OUTCOME TRIALS OF ORAL ANTIDIABETICS

CV SAFETY & OUTCOME TRIALS OF ORAL ANTIDIABETICS ADVERSE CV EVENTS LED THE FDA TO REQUIRE DEMONSTRATION OF CV SAFETY FOR NEW GLUCOSELOWERING DRUGS 1961 2005 UGDP study: tolbutamide discontinued due to increased CV mortality vs other treatment groups1 Sponsor withdrew Muraglitazar found to potentially increase CV application1 risk during FDA assessment2 2007 Rosiglitazone associated with increased risk for MI and CV-related death3 2008 ACCORD study: intensive glucose lowering was associated with increased all-cause mortality4 Withdrawn in the EU1 Use restricted in US1* HR 1.22 (95% CI: 1.011.46); p = 0.04 2008 2012 *In 2013, FDA panel voted to reduce safety restrictions on rosiglitazone7 New FDA requirements5 New EMA requirements6 New diabetes drugs should demonstrate CV safety with meta-analysis and a CVOT 2 1. Nissen. Ann Intern Med 2012;157:6712. 2. Nissen et al. JAMA 2005;294:25816. 3. Nissen et al. N Engl J Med 2007;356:245771. 4. ACCORD Study Group. N Engl J Med 2008;358:254559. 5. FDA Guidance for Industry. 6. EMA Guidelines. 7. FDA Safety Information. REGULATORY REQUIREMENTS FOR DRUG-SPECIFIC CV OUTCOME DATA IN T2DM FDA 2008 Guidance for Industry1 To establish the safety of a new antidiabetes drug to treat T2D, sponsors should demonstrate that the therapy will not result in an unacceptable increase in CV risk. Important CV events should be

analysed High-risk population to be included Long-term data required ( 2 years) Prospective adjudication of CV events by an independent committee Phase II and III trials designed and conducted to permit meta-analysis to be performed at completion EMA 2012 Guideline2 A fully powered CV safety assessment, e.g., based on a dedicated CV outcome study, should be submitted before marketing authorisation whenever a safety concern is intrinsic in the molecule/ MOA or has emerged from pre-clinical/clinical registration studies. Two approaches are recommended: Meta-analysis of safety events Specific long-term controlled outcome study with at least 1824 months follow-up 3 1. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ ucm071627.pdf. 2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. FDA GUIDANCE FOR CV OUTCOME DATA: METAANALYSIS LIMITS AND OUTCOME TRIAL REQUIREMENTS Upper bound of 2-sided 95% CI Postmarketing CV trial(s) generally not necessary if < 1.3 0.5 1.0 If overall risk benefit analysis supports approval, post-marketing CV trial(s) needed to prove < 1.3 1.3

Inadequate data to support approval 2.0 1.8 RR of incidence of CV events with investigational agent vs control http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm071627.pdf. 4 EVOLUTION OF T2D AGENTS DPP4 inhibitors Older T2D agents 1950 1960 Lente class of insulins produced SUs first used Metformi Metformin n introduced introduce d in the UK 1970 1980 1990 Recombinant human insulin produced 2nd generation SUs available SGLT2 inhibitors

Newer T2D agents 2000 2010 2012 GLP1 receptor agonists Glimepiride: 3rd generation SU 2013 Insulin degludec Insulin glargine available2 Three new classes introduced: -glucosidase inhibitors, meglitinides and TZDs Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:31520. 2. Lantus SPC. 5 METFORMIN Metformin is indicated for the treatment of T2D, and generally recommended as first-line therapy 1,2 Evidence for effect on CV risk cited in international prescribing information differs for US vs EU US prescribing information3 States that there are no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin (or any other anti-diabetes drug) EU prescribing information1 Cites UKPDS analysis from 342 overweight patients treated with metformin after failure of diet alone1

Metformin significantly reduced any diabetes-related complication, mortality and risk of MI vs diet alone after 10.7 years 1. http://www.medicines.org.uk/emc/medicine/23244/SPC. 2. American Diabetes Association. Diabetes Care 2015;38(suppl. 1):S1S94. 3. http://www.drugs.com/pro/metformin.html 6 UKPDS 34 PROVIDES SOME EVIDENCE FOR BENEFICIAL CV EFFECTS OF METFORMIN IN OVERWEIGHT PATIENTS Proportion of patients with events (%) Risk of MI is 39% lower with metformin vs conventional therapy in obese patients1,2 Significant reduction in MI maintained over 10 years follow-up3 Myocardial infarction 30 Conventional (n = 411; events = 73) 10 Metformin vs conventional p = 0.01 HR (95% CI) 20 Intensive (n = 951; events = 139) Metformin (n = 342; events = 89) Overall values at study end in 1997 Annual values during 10-year post-trial monitoring period 1.4 RR 0.611 RR 0.67 p = 0.01 p = 0.005 1.2 1.0 0.8 0.6 0.4 1997

1999 2001 2003 2005 2007 Conventional therapy 73 83 92 106 118 126 Metformin 39 45 55 64 68 81 0.0 0 3 6 9 12 15 Time from randomisation (years) No. of events: 7 1. UKPDS 34. Lancet 1998;352:85465. 2. http://www.medicines.org.uk/emc/medicine/23244/SPC. 3. Holman et al. N Engl J Med 2008;359:157789. UKPDS 34: CV EFFECTS OF METFORMIN ADDED TO SU

Metformin added to SU vs SU alone was associated with increased risk of diabetes-related death and all-cause mortality Relative risk (95% CI) Median follow up 6.6 years RR p-value Any diabetes related endpoint 1.04 0.78 Diabetes-related deaths* 1.96 0.039 All-cause mortality* 1.60 0.041 Myocardial infarction* 1.09 0.73 Stroke* 1.21 0.61 Microvascular* 0.84 0.62 0.5 1.0 Favours added metformin 5 Favours

SU alone CV safety of Metformin remains questionable *Interpret with caution in view of small event numbers. UKPDS 34. Lancet 1998;352:85465. 8 SULFONYLUREAS META-ANALYSIS OF SU CV SAFETY TRIALS ( 6 MONTHS) FOUND NO CONSISTENT ASSOCIATION WITH MACE RISK MH-OR (95% CI) First author (year) Birkeland 1996 Chou 2008 Perriello 2006 Gerstein 2010 UKPDS 33 1998 Hanefeld 2007 Seino 2010 Charbonnel 2005 Matthews 2005 Rubin 2008 Home 2009 Arechavaleta 2011 va der Laar 2004 Mazzone 2006 Riddle 1998 Giles 2010 Tolman 2009 Kahn 2006 Goke 2010 Garber 2009 Nissen 2008 Ristic 2007 Ferrannini 2009 Bakris 2006 Gallwitz 2012 Jain 2006 Johnston 1998 Nauck 2011 Seck 2010 Overall Total # patients* 0.01 0.1 1 Favours SUs 10

100 36 452 283 672 3041 587 400 630 1250 1805 2222 1035 96 458 145 300 2097 4351 858 495 543 262 2789 374 1551 502 272 801 1172 29,783 Favours comparators Overall MACE risk estimate for SU vs comparators was not increased: MH-OR 1.08 (95% CI: 0.861.36); p = 0.52 *SU + comparator groups combined. Monami et al. Diabetes Obes Metab 2013;15:93853. Total # events* 1 3 9 55 610 4 4 14

15 46 312 4 2 4 2 26 61 72 13 13 24 5 34 11 38 11 4 3 4 1495 9 CV SAFETY OF SUS The UGDP study raised safety concerns with tolbutamide (excess of cardiac deaths vs placebo)1 UKPDS 33 demonstrated no deleterious effect of SUs on CV safety compared with insulin or conventional management2 In a meta-analysis of 115 trials, overall MACE risk estimate for SUs vs comparators was not increased (OR 1.08)3 CV safety of SUs cannot be considered established unless evaluated in long-term CVOTs4 10 1. Meinert et al. Diabetes 1970;19(suppl):789830. 2. UGDP. Diabetes 1970;19(suppl 2):747830. 3. UKPDS Group. Lancet 1998;352:83753. 4. Monami et al. Diabetes Obes Metab 2013;15:93853. THIAZOLIDINEDIONES IN 2007, SEPARATE META-ANALYSES SUGGESTED DIFFERING CV EFFECTS OF DRUGS WITHIN THE TZD CLASS Rosiglitazone meta-analysis1

Pioglitazone meta-analysis2 MI HR 0.81 (95% CI: 0.64 1.02) p = 0.08 MI OR 1.43 (95% CI: 1.031.98) p = 0.03 Death HR 0.92 (95% CI: 0.76 1.11) p = 0.38 CV death OR 1.64 (95% CI: 0.98 2.74) p = 0.06 1.0 0.5 Favours rosiglitazone 2.0 Favours control 1.0 0.5 Favours pioglitazone 2.0 Favours control No clinical trial directly compares the CV effects of pioglitazone and rosiglitazone 11 1. Nissen & Wolski. N Engl J Med 2007;356:245771. 2. Lincoff et al. JAMA 2007;298:11808. CV SAFETY OF TZDS TZDs cause or exacerbate congestive heart failure in some patients1

CV meta-analyses in 2007 suggested differing effects on CV outcomes Pioglitazone was associated with a significant 16% reduction in 3P-MACE (as a secondary endpoint) vs placebo in PROactive 2 Rosiglitazone open-label RECORD data showed no increase in CV death1 FDA reduced the safety restrictions on rosiglitazone imposed following 2007 meta-analysis3 but controversy over CV safety remains Within the PPAR family, there is no class effect and each agent must be considered unique. The FDA has mandated that each agent within this class be evaluated individually in a variety of ways including clinical outcome studies 4 12 1. AVANDIA US Prescribing information. 2. Dormandy et al. Lancet 2005;366:127989. 3. FDA Safety Information. 4. Rosenson et al. Am Heart J. 2012;164:67280. CVOTS (PLACEBO-CONTROLLED) TRIALS 3 POSSIBLE RESULTS CV outcome trials PRIMARY ENDPOINT 3P-MACE: CV death, nonfatal MI, nonfatal stroke 4P-MACE: CV death, nonfatal MI, nonfatal stroke, unstable angina requiring hospitalisation + - CV PROTECTION Superiority to placebo CV SAFETY Non-inferiority to placebo INCREASES CV RISK Inferiority to placebo All patients receive standard-of-care treatment in addition to the study drug or placebo 13 MACE: major adverse cardiac events GLP1 agonists SGLT2 inhibitor s Ongoin Ongoing

g CVOTs CVOTs DPP4 inhibitor s 14 CV SAFETY TRIALS WITHIN THE NEWER CLASSES SAVOR-TIMI 531 (n = 16,492) 1,222 3P-MACE EXAMINE2 (n = 5380) 621 3P-MACE 2013 OMNEON13 CAROLINA11 (n = 4000) (n = 6000) 4P-MACE 631 4P-MACE CARMELINA12 (n = 8300) 4P-MACE + renal TECOS4 (n = 14,724) 1300 4P-MACE 2014 2015 ELIXA3 (n = 6068) 844 4P-MACE GLP1 CVOTs EMPA-REG OUTCOME5 (n = 7034) 691 3P-MACE 2017 2018 EXSCEL14 (n = 14,000) 1591 3P-MACE SUSTAIN-67

(n = 3297) 3P-MACE LEADER6 (n = 9340) 611 3P-MACE DPP4 inhibitor CVOTs SGLT2 inhibitor CVOTs 2016 2021 2019 REWIND16 (n = 9622) 1067 3P-MACE DECLARE-TIMI 5815 ITCA CVOT9 (n = 17,150) (n = 4000) 1390 3P-MACE 4P-MACE CREDENCE17 CANVAS10 (n = 3700) (n = 4365) Renal + 5P-MACE 420 3P-MACE CANVAS-R8 (n = 5700) Albuminuria Ertugliflozin CVOT18 (n = 3900) 3P-MACE Timings represent estimated completion dates as per ClinicalTrials.gov Adapted from Johansen. World J Diabetes 2015 15 GLP1 agonists Ongoing CVOTs

SGLT2 inhibitor s DPP4 inhibitor s 16 CV OUTCOMES TRIALS WITH GLP1 AGONISTS ELIXA1,2 LEADER3 SUSTAIN-64 EXSCEL5 REWIND6 Lixisenatide / placebo Liraglutide/ placebo Semaglutid e/ placebo Exenatide ER*/ placebo Dulaglutide/ placebo Main inclusion criteria History of acute coronary syndrome Vascular disease, or risk factors, or CRF, or CHF Evidence of CV disease No CV

criteria specified Pre-existing vascular disease or 2 CV risk factors No. of patients 6068 9340 3297 14,000 9622 Primary outcome 4P-MACE 3P-MACE 3P-MACE 3P-MACE 3P-MACE Key secondary outcome (s) Expanded MACE Expanded MACE Expanded MACE All-cause mortality; HHF Microvascul ar composite

Target no. of events 844 > 611 Not specified Not specified Not specified Estimated follow-up 2.1 years median Up to ~5 years Up to ~3 years Up to ~7.5 years Up to ~6.5 years Estimated completion Completed (Safety proved) Nov 2015 Jan 2016 Apr 2018 Apr 2019 Intervention 17 *Once weekly. 1. NCT01147250. 2. Bentley-Lewis et al. Am Heart J 2015;0:1-8.e7. 3. Marso et al. Am Heart J 2013;166:82330.e5. 4. NCT01720446. 5. NCT01144338. 6. NCT01394952.

GLP1 agonists Ongoing CVOTs SGLT2 inhibitor s DPP4 inhibitor s 18 CV OUTCOME TRIALS WITH SGLT2 INHIBITORS EMPA-REG OUTCOME1 CANVAS2 CANVAS-R3 CREDENCE4 DECLARETIMI 585 Ertugliflozin CVOT6 Interventions Empagliflozin/ placebo Canagliflozin/ placebo Canagliflozin/ placebo Canagliflozin/ placebo Dapagliflozin/ placebo Ertugliflozin/ placebo Main inclusion criteria Est. vascular

complications Est. vascular complications or 2 CV risk factors Est. vascular complications or 2 CV risk factors Stage 2 or 3 CKD + macroalbuminu ria High risk for CV events Est. vascular complications No. of patients 7034 4339 5700 3627 17,150 3900 Primary outcome 3P-MACE 3P-MACE Progression of albuminuria ESKD, S-creatinine doubling, renal/CV death 3P-MACE

3P-MACE Key secondary outcome 4P-MACE Fasting insulin secretion, progression of albuminuria Regression of albuminuria, change in eGFR Target no. of events 691 420 TBD TBD 1390 TBD Estimated median FU ~3 years 67 years 3 years ~4 years 45 years 57 years Apr 2017 2017 2019 2019

19 2021 Estimated completion Results 20152015 EASD 4P-MACE + HHF 4P-MACE + HHF + revascularisati on Adapted from Inzucchi et al. Diabetes Vasc Dis Res 2015;12:90100. 4P-MACE GLP1 agonists Ongoing CVOTs SGLT2 inhibitor s DPP4 inhibitor s 20 CV OUTCOMES TRIALS WITH DPP4 INHIBITORS Intervention Main inclusion criteria SAVOR-TIMI 531 Saxagliptin/ placebo EXAMINE2 TECOS3 Alogliptin/ placebo Sitagliptin/

placebo ACS within History of or 1590 days multiple risk before factors for randomisati CVD on CVD CAROLINA4 CARMELINA5 Linagliptin/ Linagliptin/ glimepiride placebo 2 specified High risk of traditional CV events CV risk (e.g. factors or albuminuria, manifest prior CVD) CVD 16,492 5380 14,671 6041 8300 Primary outcome 3P-MACE 3P-MACE 4P-MACE 4P-MACE 4P-MACE

Key secondary outcome Expanded MACE 4P-MACE 3P-MACE 3P-MACE 3P-MACE; renal composite 10406 650 1300 631 6257 No. of patients Target no. of events Estimated median follow-up (y) Estimated completion 21 2.1 1.5 3.0 67* 4*7 Completed Completed Completed 20188

2018 21 *Ongoing. 1. Scirica et al. N Engl J Med 2013;369:131726. 2. White et al. N Engl J Med 2013;369:132735. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Marx et al. Diabetes Vasc Dis Res 2015;12:16474. 5. NCT01897532. 6. Scirica et al. Am Heart J 2011;162:81825.e6. 7. Data on file (BI trial no. 1218.22 trial protocol). 8. NCT01243424. FOR THE PRIMARY OUTCOME, ALL COMPLETED CVOTS FALL WITHIN THE FDA MANDATED UPPER 95% CI LIMIT OF 1.3 Number of events (event rate, % per 100 personyears) DPP4 inhibitor trials SAVOR-TIMI 531 Placebo + usual care Comparator + usual care 609 (3.7%) 613 (3.7%) EXAMINE2 316 (11.8%) 305 (11.3%) TECOS3 851 (4.17%) 839 (4.06%) 406 (13.4 %) 399 (13.2%) GLP1 agonist trials ELIXA4 0.6 HR (95% CI) FDA mandated upper 95% CI for CV safety

* 0.8 Favours comparator 1.0 1.3 2.0 Favours placebo *Upper boundary of 1-sided repeated CI. Total event rate, %. 1. Scirica et al. N Engl J Med 2013;369:131726. 2. White et al. N Engl J Med 2013;369:132735. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation). 22 HOSPITALISATION FOR HEART FAILURE (HHF) DATA FOR ALL COMPLETED CVOTS Number of events (event rate, %) Placebo + usual care Comparator + usual care SAVOR-TIMI 53 (HHF)1 228 (2.8) 289 (3.5) EXAMINE (HHF analysis 1)2 79 (2.9) 85 (3.1) EXAMINE (HHF analysis 2)2

89 (3.3) 106 (3.9) TECOS (HHF)3 229 (3.1) 228 (3.1) TECOS (HHF + CV death)3 525 (7.2) 538 (7.3) ELIXA (HHF)4 127 (4.2) 122 (4.0) ELIXA (HHF + CV death)4 253 (8.3) 248 (8.2) 0.6 FDA mandated HR (95% CI) upper 95% CI for CV safety 0.8 Favours comparator 1.0 1.3 2.0 Favours placebo Analysis 1 = as component of expanded MACE. Analysis 2 = as component of post-hoc composite of CV death and HHF. 1. Scirica et al. N Engl J Med 2013;369:131726. 2. White et al. N Engl J Med 2013;369:132735. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation). 23

GLIPTINS - CVOTS DPP4 inhibitor CV safety endpoint SAVOR-TIMI 53 EXAMINE TECOS Saxagliptin Alogliptin Sitagliptin Achieved Achieved Achieved (non-inferior to (non-inferior to (non-inferior to placebo) placebo) placebo) CV benefit endpoint Not achieved Not achieved Not achieved HHF* Statistically significant increase in saxagliptin arm Nonstatistically significant increase in alogliptin arm No increase in HHF sitagliptin arm vs placebo 24 *HHF : hospitalization for heart failure Scirica BM et al. N Engl J Med 2013;369:1317-26. White WB et al. N Engl J Med 2013;369:1327-35. White WB. Zannad et al. Correspondence. NEJM. 370;5: 483-84 LINAGLIPTIN: NO INCREASED CARDIAC

RISK 201 5 Pooled analysis of 19 Linagliptin trials ~9400 patients Arm No. of patients Incidence rate of CV events* Linagliptin 5847 13.4 Comparator (Total) 3612 18.9 Placebo Glimepiride Voglibose 2675 Hazard ratio (per 1000 patient years) 0.78 (95% CI: 0.55-1.12) (Non-significant) 775 162 25 *composite of CV death, non-fatal stroke, non-fatal myocardial infarction, and hospitalization for unstable angina pectoris Rosentock J et al. Cardiovascular Diabetology. 2015;14:57. doi:10.1186/s12933-015-0215-2 LINAGLIPTIN: DATA ON HHF Hospitalisation for heart failure (HHF)1 Hospitalisation for heart failure was added into the adjudication process after the initial

regulatory submission and has been assessed for the available studies Pooled-analysis with, adjudicated events 8 trials including 3314 patients No of patients, n No of pts with events, n (%) No of patients, n No of pts with events, n (%) Combined comparator Linaglipti n 1275 2039 9 (0.7) 12 (0.6) Placebo* Linaglipti n 1275 2039 5 (0.4) 9 (0.4) Given the small number of reported cases of CHF, this data should be interpreted with caution * The placebo-controlled dataset also includes 2,039 patients in the linagliptin group and 1,275 patients in the placebo group, as in one of the 8 studies all patients in the placebo group were switched to glimepiride. After switching to glimepiride, 5 patients on glimepiride and 3 patients on linagliptin were hospitalised for HF. Rosentock J et al. Cardiovascular Diabetology. 2015;14:57. doi:10.1186/s12933-015-0215-2 26 CAROLINA & CARMELINA: LINAGLIPTIN CV SAFETY STUDIES CAROLINA (CArdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes)

CARMELINA (CArdiovascular Safety & Renal Microvascular outcomE study with LINAgliptin) 27 QUESTIONS UNANSWERED EVEN WITH THE VARIOUS CVOTS Q1: Can we modify CV outcome by early intervention with gliptins in T2DM? Q2: Which is an ideal drug of choice after metformin considering CV safety? Will CAROLINA have the answer? 28 CAROLINA: KEY FEATURES Will define an ideal choice after metformin considering CV safety: a DPP4i or SU? 1,2 Largest study vs. active comparator with patient profile closer to UKPDS3,4 CV Outcome trial with a gliptin with longest follow-up.2 29 1. Abdelmoneim AS et al. Diabetes Obes Metab. 2015 Jun;17(6):523-32. 2. Marx N et al. Diab Vasc Dis Res. 2015 May;12(3):164-74. 3. Johansen O-E, et al. 49th Ann Mtg of the European Association for the Study of Diabetes (EASD), Barcelona, 23 - 27 Sep 2013, OP 3 4. Rosenstock et al. Diabetes & Vascular Disease Research 10(4) 289301.Barcelona, 23 - 27 Sep 2013, OP TYPE OF PATIENTS IN CV OUTCOME TRIALS: 3 DS Duration of trial Degree of CV risk Duration of diabetes UKPDS showed CV benefit with metformin ONLY when started early

H2H comparison Linagliptin vs Glimepiride Closest to UKPDS in terms of patient profile. Interim results: 2016 Sitagliptin/ Saxagliptin/ Alogliptin CV Neutral Saxagliptin showed increase in HF Hospitalization Linagliptin Linagliptin vs. Placebo Cardiac-Renal endpoints Results Awaited 2018 30 Johansen O-E, et al. 49th Ann Mtg of the European Association for the Study of Diabetes (EASD), Barcelona, 23 - 27 Sep 2013, OP 3 THANK YOU 31

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