Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Introductory Remarks

Transcription

1 Endocrinologic and Metabolic Drugs Advisory Committee Meeting Introductory Remarks December 12, 2013 Jean-Marc Guettier, MDCM Division of Metabolism and Endocrinology Products Office of Drug Evaluation II Office of New Drugs Center for Drug Evaluation and Research Guettier EMDAC December 12th

2 Objectives Summarize Key Aspects of the First Review Cycle Summarize the 2012 Regulatory Decision Introduce Discussion Points and Voting Questions Guettier EMDAC December 12th

3 Key Dates in First Review Cycle December 2010 Dapagliflozin application is submitted November 2011 Major Amendment is submitted July 2011 Dapagliflozin application presented to EMDAC January 2012 FDA issues a Complete Response Letter Guettier EMDAC December 12th

4 July 2011 Advisory Committee Data from 14 Phase 2b and 3 trials were reviewed Dapagliflozin exposure: ~4300 patient years Comparator exposure: ~1900 patient years Topics Covered General Efficacy and safety findings in overall program Areas of focus Efficacy findings in in patients with moderate to severe renal impairment Liver safety findings Breast cancer case imbalance in female participants Bladder cancer case imbalance in male participants Guettier EMDAC December 12th

5 July 2011 Advisory Committee Voting Question Does the efficacy and safety data provide substantial evidence to support approval of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes? Yes votes = 6 ; No votes = 9 Guettier EMDAC December 12th

6 November 2011 Major Amendment FDA asks for updated analyses to Determine impact of additional exposure on malignancy signal Determine impact of additional exposure on liver safety signal Assess the estimate of CV-risk with additional data Data from 19 Phase 2b and 3 trials were available Dapagliflozin exposure: ~5700 patient years (32% increase) Comparator exposure: ~3100 patient years (67% increase) Guettier EMDAC December 12th

7 November 2011 Major Amendment Impact of additional exposure on malignancy risk signal Incidence Rate Ratio (95% CI) 2011 AC Meeting 2011 Major Amendment Bladder Cancer * 5.1 (0.70, 222.6) 5.4 (0.84, 122.2) Breast Cancer φ 4.0 (0.56, 177.1) 1.9 (0.5, 8.9) * Male specific incidence rate used φ Female specific incidence rate used Guettier EMDAC December 12th

8 November 2011 Major Amendment Impact of additional exposure on liver risk signal No between group imbalance in marked aminotransferase increase Number of Cases/~PYE to dapagliflozin 2011 AC Meeting 2011 Major Amendment ALT 3x ULN and T. Bili 2 x ULN 5/~4300 7/~5700 Probable DILI or > 1/~4300 1/~5700 Guettier EMDAC December 12th

9 Probable DILI Case: 2011 Data 1. Significant hepatocellular injury (ALT > 1800) accompanied with liver function abnormalities (T. Bili > 4X ULN) 2. Temporal pattern of injury consistent with drug induced liver injury (normal baseline ALT, ALT gradually rises from 3 mos. on) 3. Ischemic, infectious, obstructive and other toxins excluded 4. Biopsy consistent with severe inflammation of relatively short duration and pattern consistent with viral, drug or autoimmune hepatitis 5. Improvement noted with de-challenge and at a later time with immunosuppression 6. Negative serology for auto-immune hepatitis 7. Age of onset not typical of auto-immune hepatitis Guettier EMDAC December 12th

10 November 2011 Major Amendment Do data support a unique clinically meaningful benefit of dapagliflozin over currently available anti-diabetic drugs that would warrant acceptance of more uncertainty related to the identified serious risks? The hypothesis that dapagliflozin could confer potential CV benefit was entertained by both the applicant and FDA reviewers This theory was supported in part by the following preliminary data The observation that Dapagliflozin exerts an effects on several CV-risk markers Blood pressure Weight Glucose The observed favorable estimated hazard ratio for MACE+ in the pre-specified meta-analysis of CV-risk MACE = Major Adverse Cardiovascular Events Guettier EMDAC December 12th

11 November 2011 Major Amendment Impact of additional exposure on CV-risk Hazard Ratio (95% CI) 2011 AC Meeting 2011 Major Amendment MACE (0.38, 1.18) 0.82 (0.58, 1.15) MACE+ = CV-death, non-fatal MI, non-fatal stroke and hospitalization for unstable angina Guettier EMDAC December 12th

12 November 2011 Major Amendment Interest in CV-assessment findings from subgroup made up of Trials 18 and 19 Similar in design Largest sample size and longest duration of exposure Contributed > 40% of the CV events to the updated analysis Patient characteristics were particularly useful to inform CVrisk All had documented, established, CVD at baseline Enriched for co-morbid conditions highly prevalent in diabetes population (i.e., dyslipidemia, renal dysfunction, hypertension, obesity) Higher proportion of elderly Longest duration of diabetes Guettier EMDAC December 12th

13 November 2011 Major Amendment Subgroup analyses for CV-risk Hazard Ratio (95% CI) 17 Phase 2b/3 Trials (Not CVD Enriched) Trials (CVD Enriched) MACE (0.42, 1.04) 1.07 (0.64, 1.77) MACE n/a 1.27 (0.69, 2.31) MACE+ = CV-death, non-fatal MI, non-fatal stroke and hospitalization for unstable angina MACE = CV-death, non-fatal MI and non-fatal stroke Guettier EMDAC December 12th

14 January 2012: Complete Response Benefits Novel mechanism of action Established glucose lowering benefit only in patients with mild or normal renal function Lack of established glucose lowering benefit in patients with moderate renal impairment (~ 20% of patient with diabetes*) No clear evidence that effects on CV-risk markers translates to clinically meaningful CV-benefit in relevant patient population Identified Potential Serious Risks Bladder and breast malignancy Liver toxicity *Source: United States Renal Data System; 2013 Atlas of CKD and ESRD Guettier EMDAC December 12th

15 January 2012: Complete Response Path Forward Additional patient year of exposure with at minimum complete 52-week data for trials 18 and 19 Updated analyses related to bladder cancer Updated analyses related to liver safety Updated CV-risk assessment including analysis based on MACE events Encouraged to continue plans to perform a cardiovascular outcomes trial (CVOT) Guettier EMDAC December 12th

16 Key Dates in First Review Cycle December 2010 Application is submitted November 2011 Major Amendment is submitted July 2012 Applicant files a Formal Dispute Resolution Request (FDRR) July 2011 Dapagliflozin application presented to EMDAC January 2012 FDA issues Complete Response letter September 2012 Dispute appeal is denied Guettier EMDAC December 12th

17 Path Forward Following Denied Dispute Appeal Path forward outlined in the Complete Response Letter is upheld Second AC should be convened to re-visit risk-benefit Discuss updated data on liver toxicity, breast, and bladder cancer CV risk analyses used to arrive at decision in this program Pre-planned analysis versus additional analyses Role of enriched population (when to include and weigh) Preclinical toxicology study to address issue of bladder tumor promotion should be carried out The model should reflect human experience and address whether changes in urinary composition caused by dapagliflozin use can result in bladder tumor promotion Guettier EMDAC December 12th

18 Today s Meeting The applicant filed the dapagliflozin application for a second time in July 2013 Today the applicant and FDA will present updates to Liver toxicity risk Breast cancer risk Bladder cancer risk CV-risk The committee will be asked to weigh in on the following issues Guettier EMDAC December 12th

19 Dapagliflozin Question 1 (Discussion Topic): Cardiovascular Risk Evaluation DISCUSS: Based on the information provided in the briefing package and the presentations at today s meeting, please address the following with regard to the cardiovascular risk assessment for dapagliflozin. a. Comment on which data (i.e., overall population, enriched population) best inform the cardiovascular risk associated with dapagliflozin use and discuss the weight you place on the evidence provided by the subgroup of patients specifically recruited on the basis of established cardiovascular disease in Trials 18 and 19. b. Discuss whether you believe the updated cardiovascular risk data derived from Trials 18 and 19 are consistent with the overall findings reported for the pool of 21 clinical trials. c. Discuss the clinical importance you place on the observed changes in blood pressure, weight, glycemic control and lipid parameters in informing overall cardiovascular risk of dapagliflozin. d. Discuss additional concerns, if any, you may have with regard to dapagliflozin and cardiovascular risk. 19

20 Dapagliflozin Question 2 (Discussion Topic): Malignancy DISCUSS: Based on the information provided in the briefing package and the presentations at today s meeting, discuss your level of concern with regard to the observed association between dapagliflozin use and occurrence of cancer identified in the application. Specifically, comment on whether you believe use of dapagliflozin is associated with an increased risk of bladder cancer and explain your rationale. 20

21 Dapagliflozin Question 3 (Discussion Topic): Liver Toxicity DISCUSS: Based on the information provided in the briefing package and the presentations at today s meeting, discuss your level of concern with regard to dapagliflozin use and drug-induced liver injury. Specifically comment on whether you believe use of dapagliflozin is associated with an increased risk of drug-induced liver injury and explain your rationale. 21

22 Dapagliflozin Question 4: (Voting Question): Cardiovascular Risk VOTE: In accordance with FDA s Guidance for Industry titled Diabetes Mellitus Evaluating Cardiovascular Risk in New Anti-diabetic Therapies to Treat Type 2 Diabetes, has the Applicant provided sufficient evidence that dapagliflozin, relative to comparators, has an acceptable cardiovascular risk profile? a. If you voted Yes to question #4, please provide your rationale. b. If you voted No to question #4, please provide your rationale. 22

23 Dapagliflozin Question 5 (Voting Question): Overall Risk:Benefit VOTE: Based on the information included in the briefing materials and presentations today, do the benefits of dapagliflozin use outweigh identified risks and support marketing of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus? a. If you voted Yes to question #5, please provide your rationale and whether you recommend any additional studies post-approval. b. If you voted No to question #5, please provide your rationale and discuss what additional data are necessary to support approval. 23

24 Dapagliflozin Statistical Assessment of CV Safety Endocrinologic and Metabolic Drugs Advisory Committee Advisory Committee Meeting, December 12, 2013 Eugenio Andraca-Carrera, PhD Division of Biometrics 7 Office of Biostatistics Office of Translational Sciences Center for Drug Evaluation and Research U.S. Food and Drug Administration Andraca - Carrera Statistical Assessment of CV Safety 1

25 Outline Trial Database 2011 AC Meeting 2011 Major Amendment 2013 Meta-Analysis Statistical Methods Results Summary Andraca - Carrera Statistical Assessment of CV Safety 2

26 2011 AC Database Pre-specified primary composite endpoint of adjudicated events: CV death, MI, stroke, and hospitalization for unstable angina Subjects Dapagliflozin Comparators Patient-Years Dapagliflozin Comparators Events Dapagliflozin Comparators AC 2011 (14 trials) Major Amendment 2013 Meta- Analysis Estimated Hazard Ratio (98% CI): 0.67 (0.38, 1.18) Andraca - Carrera Statistical Assessment of CV Safety 3

27 2011 AC Meta-Analysis of CV Safety * estimate values are out of range. Zero event trials (MB and MB102032) excluded from analysis Andraca - Carrera Statistical Assessment of CV Safety 4

28 Outline Trial Database 2011 AC Meeting 2011 Major Amendment 2013 Meta-Analysis Statistical Methods Results Summary Andraca - Carrera Statistical Assessment of CV Safety 5

29 2011 Major Amend. Database Pre-specified primary composite endpoint of adjudicated events: CV death, MI, stroke, and hospitalization for unstable angina Subjects AC 2011 (14 trials) 2011 Major Amendment** (19 trials) Dapagliflozin Comparators Patient-Years Dapagliflozin Comparators Events Dapagliflozin Comparators Estimated Hazard Ratio (95% CI): 0.82 (0.58, 1.15) 2013 Meta- Analysis **Data cutoff date: 15-July-2011 Andraca - Carrera Statistical Assessment of CV Safety 6

30 Design of Trials 18 and 19 Planned Duration: 24 weeks short term + 28 weeks and 52 weeks extensions (104 weeks total) Planned Sample Size: 900+ subjects per trial 1:1 randomization to dapagliflozin 10 mg and placebo Populations Trial 18: T2DM and prior CVD** and hypertension Trial 19: T2DM and prior CVD** **Prior CV disease = history of MI, congestive heart failure (CHF), hospitalization for unstable angina, stable angina, percutaneous coronary intervention, coronary artery bypass graft, coronary artery disease, cerebrovascular accident, carotid artery Andraca - Carrera Statistical Assessment of CV Safety 7

31 Findings of Trials 18 and 19 The 2011 Major Amendment analysis of trials 18 and 19 included at least 31 weeks and at most 76 weeks per subject (full planned duration is 104 weeks). Total Dapagliflozin Placebo Events events / PY HR (95% CI) Primary composite / / (0.64, 1.77) MACE / / (0.69, 2.31) ¹CV death, MI, stroke, hospitalization for unstable angina ²CV death, MI, stroke Andraca - Carrera Statistical Assessment of CV Safety 8

32 Outline Trial Database 2011 AC Meeting 2011 Major Amendment 2013 Meta-Analysis Statistical Methods Results Summary Andraca - Carrera Statistical Assessment of CV Safety 9

33 2013 MA Database Pre-specified primary composite endpoint of adjudicated events: CV death, MI, stroke, and hospitalization for unstable angina Subjects AC 2011 (14 trials) 2011 Major Amendment** (19 trials) 2013 Meta- Analysis (21 trials) Dapagliflozin Comparators Patient-Years Dapagliflozin Comparators Events Dapagliflozin Comparators **Data cutoff date: 15-July-2011 Andraca - Carrera Statistical Assessment of CV Safety 10

34 Trial Weeks of Duration Dapagliflozin (N) Placebo (N) Active Control (N) MB MB D1692C MB MB (24) MB MB (78) MB (78) MB D1690C (24) D1690C (78) MB (28) + (52) D1690C (52) + (104) D1690C (24) + (56) MB MB D1692C D1690C (24) MB D1690C (28) +(52) D1690C (28) +(52)

35 Trial Weeks of Duration Dapagliflozin (N) Placebo (N) Active Control (N) MB MB D1692C MB MB (24) MB MB (78) MB (78) MB D1690C (24) D1690C (78) MB (28) + (52) D1690C (52) + (104) D1690C (24) + (56) MB MB D1692C D1690C (24) MB D1690C (28) +(52) D1690C (28) +(52)

36 Trial Weeks of Duration Dapagliflozin (N) Placebo (N) Active Control (N) MB MB D1692C MB MB (24) MB MB (78) MB (78) MB D1690C (24) D1690C (78) MB (28) + (52) D1690C (52) + (104) D1690C (24) + (56) MB MB D1692C D1690C (24) MB D1690C (28) +(52) D1690C (28) +(52)

37 Outline Trial Database Statistical Methods Results Summary Andraca - Carrera Statistical Assessment of CV Safety 14

38 Pre-specified Analysis Objective Rule out risk margin of 1.8 (assessed using a nominal 95% CI) Analysis populations Primary: All randomized subjects in the 21 trials* (N = 5936 dapagliflozin, N = 3403 comparators) Secondary: trials 18 and 19 alone (N = 942 dapagliflozin, N = 945 placebo) Comparison Dapagliflozin vs. All Comparators (placebo, metformin, glipizide, HCTZ ) *except dapagliflozin 1 mg, and uncontrolled subjects in MB Andraca - Carrera Statistical Assessment of CV Safety 15

39 Composite Endpoints Primary composite endpoint Cardiovascular death Non-fatal myocardial infarction Non-fatal stroke Hospitalization for unstable angina Secondary composite endpoint: primary composite + unplanned coronary revascularization + hospitalization for heart failure MACE : CV Death, MI, stroke Adjudication was conducted prospectively in 19 of the 21 trials Andraca - Carrera Statistical Assessment of CV Safety 16

40 Pre-Specified Analysis Methods Primary analysis: Time-to-event (Hazard Ratio) Cox proportional hazards model stratified by trial Sensitivity analyses: Mantel-Haenszel incidence rate ratio Random effects incidence rate ratio (consistent with primary analysis, not shown here) Andraca - Carrera Statistical Assessment of CV Safety 17

41 Post-hoc Analysis Time to event during the first 30 days after randomization in the meta-analysis Andraca - Carrera Statistical Assessment of CV Safety 18

42 Outline Trial Database Statistical Methods Results Overall Meta-Analysis Trials 18 and 19 Post-hoc Analysis Summary Andraca - Carrera Statistical Assessment of CV Safety 19

43 Primary Endpoint Events by Treatment and Trial Trial events / N Dapagliflozin Comparators D1690C / 482 (4.6%) 26 / 483 (5.4%) D1690C / 460 (4.6%) 18 / 462 (3.9%) D1690C / 406 (2.0%) 10 / 408 (2.5%) D1690C / 610 (1.8%) 6 / 197 (3.0%) MB / 168 (4.2%) 8 / 84 (9.5%) MB / 409 (1.2%) 6 / 137 (4.4%) D1690C / 450 (1.3%) 1 / 146 (0.7%) MB / 410 (1.5%) 0 / 75 (0.0%) MB / 397 (0.5%) 1 / 201 (0.5%) MB / 430 (0.5%) 1 / 208 (0.5%) MB / 261 (0.8%) 1 / 132 (0.8%) D1690C / 225 (0.4%) 1 / 226 (0.4%) D1690C / 91 (1.1%) 1 / 91 (1.1%) Other 8 trials 3 / 858 (0.3%) 1 / 443 (0.2%) Total

44 Primary Endpoint Events by Treatment and Trial Trial events / N Dapagliflozin Comparators D1690C / 482 (4.6%) 26 / 483 (5.4%) D1690C / 460 (4.6%) 18 / 462 (3.9%) D1690C / 406 (2.0%) 10 / 408 (2.5%) D1690C / 610 (1.8%) 6 / 197 (3.0%) MB / 168 (4.2%) 8 / 84 (9.5%) MB / 409 (1.2%) 6 / 137 (4.4%) D1690C / 450 (1.3%) 1 / 146 (0.7%) MB / 410 (1.5%) 0 / 75 (0.0%) MB / 397 (0.5%) 1 / 201 (0.5%) MB / 430 (0.5%) 1 / 208 (0.5%) MB / 261 (0.8%) 1 / 132 (0.8%) D1690C / 225 (0.4%) 1 / 226 (0.4%) D1690C / 91 (1.1%) 1 / 91 (1.1%) Other 8 trials 3 / 858 (0.3%) 1 / 443 (0.2%) Total

45 Primary Analysis Results* Dapagliflozin Comparators N = 5936 N = 3403 Hazard Ratio PY = 6594 PY = 3831 (95% CI) Primary endpoint¹ (0.59, 1.09) ¹CV death, MI, Stroke, hospitalization for unstable angina * All 21 Phase 2/3 trials Andraca - Carrera Statistical Assessment of CV Safety 22

46 Primary Analysis Results* Dapagliflozin Comparators N = 5936 N = 3403 Hazard Ratio PY = 6594 PY = 3831 (95% CI) Primary endpoint¹ (0.59, 1.09) Secondary endpoint² (0.59, 1.00) ¹CV death, MI, Stroke, hospitalization for unstable angina ²Primary endpoint + unplanned coronary revascularization + hospitalization for HF * All 21 Phase 2/3 trials Andraca - Carrera Statistical Assessment of CV Safety 23

47 Primary Analysis Results* Dapagliflozin Comparators N = 5936 N = 3403 Hazard Ratio PY = 6594 PY = 3831 (95% CI) Primary endpoint¹ (0.59, 1.09) Secondary endpoint² (0.59, 1.00) MACE (0.55, 1.11) ¹CV death, MI, Stroke, hospitalization for unstable angina ²Primary endpoint + unplanned coronary revascularization + hospitalization for HF * All 21 Phase 2/3 trials Andraca - Carrera Statistical Assessment of CV Safety 24

48 Individual Components of the Primary Composite Endpoint in the Meta-Analysis 25

49 Outline Trial Database Statistical Methods Results Overall Meta-Analysis Trials 18 and 19 Post-hoc Analysis Summary Andraca - Carrera Statistical Assessment of CV Safety 26

50 Baseline CV Risk Factors History of CVD (%) History of Hypertension (%) History of Dyslipidemia (%) History of Congestive HF (%) Smokers (current or former) (%) SBP 140 mmhg Diabetes Duration 10 years Baseline egfr (ml/min) < Trials 18 and 19 (N = 1887 ) 99.5% 96.2% 84.2% 14.3% 59.6% 37.6% 58.0% 17.4% 59.3% 23.3% Other trials (N = 7452) 17.9% 60.8% 49.9% 1.8% 40.5% 24.6% 20.4% 10.2% 50.4% 39.3% Andraca - Carrera Statistical Assessment of CV Safety 27

51 Trials 18 and 19 Results Dapagliflozin Placebo N = 942 N = 945 Hazard Ratio PY = 1118 PY = 1119 (95% CI) Events (rate per 1000 PY) Primary endpoint¹ 43 (38.5) 44 (39.3) 0.98 (0.64, 1.49) ¹CV death, MI, Stroke, hospitalization for unstable angina Andraca - Carrera Statistical Assessment of CV Safety 28

52 Trials 18 and 19 Results Dapagliflozin Placebo N = 942 N = 945 Hazard Ratio PY = 1118 PY = 1119 (95% CI) Events (rate per 1000 PY) Primary endpoint¹ 43 (38.5) 44 (39.3) 0.98 (0.64, 1.49) Secondary endpoint² 56 (50.1) 63 (56.3) 0.89 (0.62, 1.27) ¹CV death, MI, Stroke, hospitalization for unstable angina ²Primary endpoint + unplanned coronary revascularization + hospitalization for HF Andraca - Carrera Statistical Assessment of CV Safety 29

53 Trials 18 and 19 Results Dapagliflozin Placebo N = 942 N = 945 PY = 1118 PY = 1119 Events (rate per 1000 PY) Hazard Ratio (95% CI) Primary endpoint¹ 43 (38.5) 44 (39.3) 0.98 (0.64, 1.49) Secondary endpoint² 56 (50.1) 63 (56.3) 0.89 (0.62, 1.27) MACE 32 (28.6) 29 (25.9) 1.11 (0.67, 1.83) ¹CV death, MI, Stroke, hospitalization for unstable angina ²Primary endpoint + unplanned coronary revascularization + hospitalization for HF Andraca - Carrera Statistical Assessment of CV Safety 30

54 KM Plot of Primary Events in Trials 18 and 19 logrank test p-value =

55 Individual Components of the Primary Composite Endpoint in Trials 18 and 19 32

56 Outline Trial Database Statistical Methods Results Overall Meta-Analysis Trials 18 and 19 Post-hoc Analysis Summary Andraca - Carrera Statistical Assessment of CV Safety 33

57 Canagliflozin: First 30 days** CV Outcomes Trial (CANVAS) Primary endpoint: MACE+ = CV Death, MI, Stroke, HUA Events in the first 30 days 13 MACE+ in 2886 subjects on canagliflozin 1 MACE+ in 1441 subjects on placebo No evidence of increased risk over full follow-up: All trials: HR 0.91 (0.68, 1.21) CANVAS full follow-up: HR 1.00 (0.72, 1.39) **Data presented at 01/10/2013 AC meeting Andraca - Carrera Statistical Assessment of CV Safety 34

58 Dapagliflozin Program: Events within First 30 days Day of Trial Treatment Type of Event Gender Age event History of CV Disease D1690C00018 Dapagliflozin 2 CV death Female 77 Yes D1690C00006 Dapagliflozin 3 Stroke Female 43 No D1690C00018 Dapagliflozin 3 Stroke Male 58 Yes D1690C00018 Dapagliflozin 4 Hospitalization for UA Female 59 Yes MB Dapagliflozin 9 MI Female 55 No D1690C00006 Placebo 12 Stroke Female 64 Yes D1690C00004 Glipizide 13 MI Male 69 No MB Dapagliflozin 19 MI Male 68 Yes MB Dapagliflozin 22 Hospitalization for UA Male 55 No D1690C00019 Dapagliflozin 28 Stroke Male 70 Yes *Pooled sample size: N = 5936 on dapagliflozin and N =3403 on comparators 35

59 Dapagliflozin Program: Events within First 30 days Day of Trial Treatment Type of Event Gender Age event History of CV Disease D1690C00018 Dapagliflozin 2 CV death Female 77 Yes D1690C00006 Dapagliflozin 3 Stroke Female 43 No D1690C00018 Dapagliflozin 3 Stroke Male 58 Yes D1690C00018 Dapagliflozin 4 Hospitalization for UA Female 59 Yes MB Dapagliflozin 9 MI Female 55 No D1690C00006 Placebo 12 Stroke Female 64 Yes D1690C00004 Glipizide 13 MI Male 69 No D1690C00019 Placebo 15 Hospitalization for HF Male 56 Yes MB Dapagliflozin 19 MI Male 68 Yes MB Dapagliflozin 22 Hospitalization for UA Male 55 No D1690C00019 Dapagliflozin 28 Stroke Male D1690C00005 Glipizide 29 Hospitalization for HF Male *Pooled sample size: N= 5936 on dapagliflozin and N=3403 on comparators Yes Yes 36

60 Dapagliflozin: Post-hoc Analysis Within the first 30 days 8 primary events in 5936 subjects on dapagliflozin (0.13%) 2 primary events in 3403 subjects on comparators (0.06%) Estimated HR (95% CI) for primary event: 2.77 (0.57, 13.33) 2 additional secondary events in comparators (total 0.12%) Small numbers limit the interpretability of these findings Andraca - Carrera Statistical Assessment of CV Safety 37

61 Outline Trial Database Statistical Methods Results Summary Andraca - Carrera Statistical Assessment of CV Safety 38

62 Summary of Meta-Analyses 2011 AC Meeting Hazard Ratios (95% CI) 2011 Major Amendment 2013 MA Primary endpoint¹ 0.67 (0.39, 1.18)* 0.82 (0.58, 1.15) 0.81 (0.59, 1.09) MACE (0.54, 1.17) 0.78 (0.55, 1.11) ¹CV death, MI, Stroke, hospitalization for unstable angina *98% CI Andraca - Carrera Statistical Assessment of CV Safety 39

63 Summary of Analyses in Trials 18 and 19 Hazard Ratios (95% CI) 2011 AC Meeting 2011 Major Amendment 2013 MA Primary endpoint¹ (0.64, 1.77) 0.98 (0.64, 1.49) MACE (0.69, 2.31) 1.11 (0.67, 1.83) ¹CV death, MI, Stroke, hospitalization for unstable angina Andraca - Carrera Statistical Assessment of CV Safety 40

64 Summary No evidence of increased cardiovascular risk in the pre-specified meta-analysis Secondary analyses and analyses of individual components (CV Death, MI, stroke, HUA) were consistent with primary analysis Observed small imbalance of CV events with dapagliflozin within 30 days similar to canagliflozin experience Andraca - Carrera Statistical Assessment of CV Safety 41

65 Dapagliflozin: Clinical Efficacy and Noncardiovascular Safety Endocrinologic and Metabolic Drugs Advisory Committee Meeting December 12, 2013 Frank Pucino, PharmD, MPH Clinical Reviewer Division of Metabolism and Endocrinology Products Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration 1

66 Outline Efficacy Major Safety Issues Deaths and Serious Adverse Events (SAEs) Bladder cancer Hepatic safety Adverse Events of Interest Genital infections / urinary tract infections Renal impairment / volume depletion events / polyuria Bone safety Summary 2

67 Dapagliflozin: Mechanism of Action Dapagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor SGLT2 inhibition lowers the renal glucose threshold Increases urinary glucose excretion Glucose lowering effect of SGLT2 inhibition is dependent on plasma glucose concentration and renal function 3

68 Dapagliflozin: Proposed Indication and Dose Proposed Indication: Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes Proposed Dose: 5 mg or 10 mg taken once daily at any time of day regardless of meals 4

69 Key Clinical Pharmacology Findings PHARMACOKINETICS Absorption: T max : 2 hour F% : 77.8 Distribution Protein Binding: 91 % Metabolism Primarily by UGT1A9 T 1/2 : 12.9 hour Excretion 75% excreted renally 1.2% of dose as parent drug PHARMACODYNAMICS PK/PD was characterized at wide dose range (1 mcg to 500 mg) 10 mg is near the upper end of dose response curve for glycosuria INTRINSIC / EXTRINSIC FACTORS No dose adjustment based on Intrinsic factors (e.g., age, gender, hepatic function) No dose adjustment based on extrinsic factors (e.g., coadministered drugs, food) Source: Modified from Dr. Ritesh Jain s Clinical Pharmacology Review Abbreviations: F, bioavailability; PD, pharmacodynamics; PK, pharmacokinetics; T1/2, half life; Tmax, time to maximum concentration 5

70 Dose Selection for Phase 3 Program Phase 2 Study (MB102008): Dose range of 2.5 to 50 mg once daily studied over 12 weeks in treatment naïve patients with T2DM 2.5, 5, and 10 mg selected for Phase 3 Source: Modified from Dr. Ritesh Jain s Clinical Pharmacology Review Abbreviations: HbA1c, hemoglobin A1c 6

71 Outline Efficacy Major Safety Issues Deaths and SAEs Bladder cancer Hepatic safety Adverse Events of Interest Genital infections / urinary tract infections Renal impairment / volume depletion events / polyuria Bone safety Summary 7

72 Overview of Efficacy Applicant submitted data from 16 Phase 3 clinical trials of dapagliflozin (Dapa) 11 were previously reviewed at the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) Meeting (July 19, 2011) Trials grouped as Monotherapy, Combination Therapy, or Special Populations Summary of primary analyses of individual studies Integrated analyses including 12 placebo controlled studies Change from baseline to Week 24 in blood pressure, weight, glycemic control, and lipid parameters 8

73 Phase 3 Trials to Support Efficacy Monotherapy Study ID Population Dose (mg) Background Tx Comparator Weeks MB Drug naïve Dapa 2.5, 5, 10 None Placebo 24 + extension MB Drug naïve Dapa 1, 2.5, 5 None Placebo 24 Source: Modified from Dr. Wei Liu s Statistical Review Abbreviations: Tx, treatment 9

74 Phase 3 Trials to Support Efficacy Combination Therapy Study ID Population Dose (mg) Background Tx Comparator Weeks MB Inadequate control Dapa 2.5, 5, 10 Metformin Placebo 24 + extension D1690C00005 Inadequate control Dapa 2.5, 5, 10 Glimepiride Placebo 24 + extension MB Inadequate control Dapa 5, 10 Pioglitazone Placebo 24 + extension D1690C00006 Inadequate control Dapa 2.5, 5, 10 Insulin ± 2 OAD Placebo 24 + extension D1690C00004 Inadequate control Dapa Metformin Glipizide* 24 + extension D1690C00012 Inadequate control Dapa 10 Metformin Placebo 24 + extension D1690C00010 MB MB Drug naïve Inadequate control Drug naïve higher HbA1c Drug naïve higher HbA1c Dapa 10 Dapa 5 + Metformin Dapa 10 + Metformin Sitagliptin and/or Metformin None None Placebo 24 + extension DAPA 5 mg Metformin DAPA 10 mg Metformin Source: Modified from Dr. Wei Liu s Statistical Review 10

75 Phase 3 Trials to Support Efficacy Special Populations Study ID Population Dose (mg) Background Tx Comparator Weeks MB Moderate renal impairment Dapa 5, 10 Any except metformin Placebo 24 + extension MB Hypertension Dapa 10 Oral antidiabetic drugs and/or insulin MB Hypertension Dapa 10 Oral antidiabetic drugs and/or insulin D1690C00018 D1690C00019 Cardiovascular disease with hypertension Cardiovascular disease Dapa 10 Oral antidiabetic drugs and/or insulin Placebo 12 Placebo 12 Placebo 24 + extension Dapa 10 OAD and/or insulin Placebo 24 + extension Source: Modified from Dr. Wei Liu s Statistical Review 11

76 Primary Endpoint HbA1c change from baseline Primary endpoint in all but one study Change in body weight Primary endpoint in Trial D1690C00012 HbA1c change from baseline is a secondary endpoint Systolic blood pressure (SBP) Co primary endpoint in Trials MB and MB Item composite endpoint Reductions in HbA1c 0.5%, weight 3%, and SBP 3 mmhg at Week 24 Co primary endpoint in Trials D1690C00018 and D1690C

77 Primary Efficacy Placebo Controlled Studies (Placebo subtracted change from baseline to Week 24 in HbA1c) Study Dapagliflozin Dose MB Dapa Placebo (SE) 1 mg 2.5 mg 5 mg 10 mg Monotherapy 0.35 (.15) * 0.54 (0.15) ** 0.66 (.15) ** MB Dapa Placebo(SE) Source: Modified from Dr. Jonathan Norton s Statistical Review *p <0.05 vs. placebo; **p<0.001 vs. placebo) 0.69 (0.17) ** 0.74 (.17) ** 0.84 (0.17) ** N.A. 13

78 Primary Efficacy Placebo Controlled Studies Dapagliflozin or Placebo Added to Background Agent(s) (Placebo subtracted change from baseline to Week 24 in HbA1c) Study MB Dapa Placebo (SE) Dapagliflozin Dose 1 mg 2.5 mg 5 mg 10 mg Combination Therapy 0.38 (0.10) ** 0.41 (0.10) ** 0.54 (0.10) ** D1690C00005 Dapa Placebo (SE) N.A (0.09) ** 0.49 (0.09) ** 0.68 (0.09) ** MB Dapa Placebo (SE) N.A (0.12) ** 0.55 (0.12) ** D1690C00006 Dapa Placebo (SE) 0.45 (0.07) ** 0.52 (0.07) ** 0.60 (0.07) ** D1690C00010 Dapa Placebo (SE) 0.48 (0.07) ** Source: Modified from Drs. Jonathan Norton and Wei Liu s Statistical Reviews *p <0.05 vs. placebo; **p<0.001 vs. placebo); New submission 14

79 Primary Efficacy Dapagliflozin + Metformin vs. Individual Therapies (Placebo Subtracted change from baseline to Week 24 in HbA1c) MB Dapa 5 mg + Metformin Treatment Arm Dapa 5 mg Metformin Adj. Mean (SE) 2.05 (0.09) 1.19 (0.09) 1.35 (0.09) Diff. from Combination (SE) MB Dapa 10 mg + Metformin 0.86 (0.12)** 0.70 (0.12)** DAPA 10 mg Metformin Adj. Mean (SE) 2.01 (1.08) 1.44 (1.31) 1.42 (1.41) Diff. from Combination (SE) Source: Modified from Dr. Jonathan Norton s Statistical Review **p<0.001 vs. combination; New submission 0.53 (0.11)** 0.54 (0.11)** 15

80 Phase 3 Trials Previously Reviewed by the EMDAC Placebo controlled trial, D1690C00012 Primary endpoint: change in body weight at Week 24 Dapagliflozin 10 mg + metformin arm lost an additional 2.08 kg compared to the metformin only arm (p <0.0001) Glipizide controlled trial, D1690C00004 Dapagliflozin (N=400) and glipizide (N=401) Mean HbA1c change baseline to Week % for both groups (95% 0.11%, 0.11%) Dapagliflozin noninferior to glipizide 16

81 Trial D1690C00004 (Active Control vs. Glipizide) Adjusted Mean Change from Baseline Over time in HbA1c (%) (LOCF) for 52 Week Treatment Period, Full Analysis Set Source: Figure 3 in Sponsor s study d1690c00004 csr 52 week.pdf 17

82 Pharmacodynamics with Renal Impairment Normal Mild 42% Severe 90% Moderate 80% Source: Modified from Dr. Ritesh Jain s Clinical Pharmacology Review 18

83 Primary Efficacy Special Population (Dedicated Renal Study) Study endpoint, n Baseline LS Mean change DAPA Placebo p value (Weeks) Arm (SD) ± SE (95% CI) HbA1c Changes (%) from Baseline to Week 24 MB HbA1c Dapa 10 mg (0.97) 0.44 ± ( 0.40, 0.17) (24) Dapa 5 mg (1.04) 0.41 ± ( 0.37, 0.20) Placebo (1.29) 0.32 ± 0.17 Source: Modified from Dr. Wei Liu s Statistical Review *Responders, HbA1c <7% 19

84 Primary Efficacy Special Populations (Hypertension and Cardiovascular Disease) Study endpoint, n Baseline LS Mean DAPA Placebo p value Population Arm (SD) change (95% CI) (Weeks) ± SE HbA1c Changes (%) from Baseline to Week 24 MB HbA1c Dapa 10 mg (1.00) 0.56 ± ( 0.59, 0.33) < HTN Placebo (0.91) 0.10 ± 0.06 (12) MB HbA1c Dapa 10 mg (0.91) 0.63 ± ( 0.76, 0.46) < HTN Placebo (0.96) 0.02 ± 0.07 (12) D1690C00018 HbA1c Dapa 10 mg ± ± ( 0.56, 0.37) < CV Disease + HTN Placebo ± ± 0.04 (24) D1690C00019 HbA1c Dapa 10 mg ± ± ( 0.50, 0.30) < CV Disease Placebo ± ± 0.04 (24) Source: Modified from Dr. Wei Liu s Statistical Review Abbreviations: CV, cardiovascular; HTN, hypertension 20

85 Primary Efficacy Special Populations (Hypertension and Cardiovascular Disease) Study Primary endpoint, n Baseline LS Mean change DAPA Placebo p value Population Arm (SD) ± SE (95% CI) (Weeks) Systolic Blood Pressure (mmhg) MB Seated SBP DAPA 10 mg (7.5) ± ( 4.78, 1.24) HTN Placebo (8.0) 7.34 ± 0.88 (12) MB Seated SBP DAPA 10 mg (7.9) ± ( 6.54, 2.02) HTN Placebo (6.7) 7.62 ± 1.07 (12) Proportion of Responders for a 3 item Composite Endpoint* D1690C00018 Responders DAPA 10 mg , 11.7% 9.9% (7.0%,12.9%) < CV Disease + HTN (24) Placebo 451 4, 0.9% D1690C00019 Responders DAPA 10 mg , 10.0% 7.0% (4.3%, 9.8%) < CV Disease Placebo 469 9, 1.9% (24) Source: Modified from Drs. Wei Liu and Jonathan Norton s Statistical Reviews * Reductions in HbA1c 0.5%, body weight 3%, and SBP 3 mmhg at Week 24 21

86 Summary of Primary Efficacy of Individual Trials Dapagliflozin was superior to placebo in all but one placebo controlled trial (i.e., MB102029; renal impairment), for the proposed 5 and 10 mg once daily doses In the active controlled trial, titrated doses of dapagliflozin and glipizide yielded similar results (i.e., statistically non inferior) at Week 52 Dapagliflozin was inferior to glipizide at several earlier time points 22

87 Integrated Analyses of Placebo Controlled Studies (Dapa 5 and 10 mg, Week 24) Dataset pooled from 12 Phase 3 studies excluding: MB (patients with renal impairment) Cohort 1 of Trial MB and group 2 of Trial MB102013, both of which were uncontrolled Two 12 week trials, MB and MB (patients with HTN) Initial Analyses combination studies Data of DAPA + metformin and placebo + metformin arms of Trials MB and MB were stratified by study Changes from baseline to Week 24 in HbA1c, fasting plasma glucose (FPG), low density lipoprotein cholesterol (LDL C), SBP, and weight and proportion of patients with HbA1c of <7% Analyses for descriptive purposes 23

88 Integrated Analysis of Glycemic Parameters Placebo Controlled Trials Endpoint n Placebo n Dapa 5 mg n Dapa 10 mg HbA1C (%) Baseline mean (SD) Adj. Mean Change from baseline±se Dapa P, adjusted LS Mean (95% CI) p value (1.03) 0.37 ± (1.13) 0.88 ± ( 0.58, 0.43) < (0.97) 0.90 ± ( 0.58, 0.47) < HbA1c <7%, (%) 325 (14%) 202 (20%) 418 (20%) FPG (mg/dl) Baseline mean (SD) Adj. Mean Change from baseline±se Dapa P, adjusted LS Mean (95% CI) p value (47.8) 4.23 ± 0.86 Source: Modified from Dr. Wei Liu s Statistical Review (51.9) ± ( 25.27, 18.98) < ± (46.7) ± ( 26.77, 22.25) <

89 Integrated Analyses of LDL C, Body Weight, and SBP (Placebo Controlled Trials) % 3.2% Weight (kg) SBP (mmhg) 0 Placebo Dapa 5 mg LDL C 1 (mg/dl) Dapa 10 mg Mean (95% CI) Placebo Subtracted Change from Baseline to Week 24 Mean (SE) Dose (mg) LDL C (mg/dl) Weight (kg) SBP (mmhg) Dapa (0.19, 4.74)* 1.40 ( 1.64, 1.16) 2.28 ( 3.25, 1.32) Dapa (1.65, 5.03) 1.82 ( 1.99, 1.65) 3.17 ( 4.05, 2.29) Source: Derived from Dr. Wei Liu s Statistical Review *p<0.05 P<

90 Integrated Analyses of Placebo Controlled Trials Reductions in HbA1c and FPG at Week 24 relative to placebo Small reductions in weight and systolic blood pressure at Week 24 relative to placebo Small increase in mean LDL C concentration Greater after 24 weeks compared to baseline in dapagliflozin treated patients LDL C concentrations in the placebo arm remained close to baseline concentrations 26

91 Summary of Efficacy and Statistical Issues Dapagliflozin lowers HbA1c at 5 and 10 mg once daily doses; effect size modest Reduction in FPG, and small reductions in seated SBP and body weight, were observed in the integrated analyses LDL C elevation observed 27

92 Outline Efficacy Major Safety Issues Deaths and SAEs Bladder cancer Hepatic safety Adverse Events of Interest Genital infections / urinary tract infections Renal impairment / volume depletion events / polyuria Bone safety Summary 28

93 Safety Database and Demographics All Phase 2b/3 Study Pool and Placebo Controlled Pools Patient Characteristics Placebo Controlled Pool (ST) Placebo Controlled Pool (ST+LT) All Phase 2b/3 Pool Dapa 10 mg Placebo Dapa 10 mg Placebo Dapa Total All Control (N=2360) (N=2295 (N=2026) (N=1956) (N=5936) (N=3403) Age (y), Mean ± SD (Range) Females (%) Race (%) White Black Asian Other Body Mass Index (kg/m 2 ) Duration of T2DM (y) Mean ± SD HbA1c (%) Mean ± SD 58.4 ± ± ± ± ± ± 10.3 (20 84) (21 86) (22 84) (22 86) (18 92) (20 86) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.0 Source: Modified from the Applicant s 30 Month Update, Part 2 (pages ; pages ) and Part 3 (pages and pages ) 29

94 Deaths, SAEs, and AEs All Phase 2b/3 Study Pool Event 30 Month Safety Update (NDA resubmission) Dapa N=5936 (%) All Comparators N=3403(%) 4 Month Safety Update (First review cycle) Dapa N=4310 (%) All Comparators N=1962 (%) Deaths 37 (0.6) 24 (0.7) 22 (0.5) 12 (0.6) At Least One SAE 602 (10.1) 408 (12.0) 363 (8.4) 184 (9.4) At Least One AE 3594 (60.5) 1979 (58.2) 1398 (62.1) 467 (59.5) Source: Modified from the Applicant s 4 Month Safety Update (pages 71 and 1722) and derived from the ADCV datasets 30

95 Causes of Death ( 2 Patients) All Phase 2b/3 Study Pool MedDRA Preferred Term Dapa Total N=5936 (%) All Phase 2b/3 Pool Control N=3403 (%) TOTAL PATIENTS WITH AN EVENT OF DEATH 37 (0.6) 24 (0.7) MYOCARDIAL INFARCTION 6 (0.10) 5 (0.15) SEPTIC SHOCK 3 (0.05) 0 SUDDEN DEATH 3 (0.05) 2 (0.06) ACUTE MYOCARDIAL INFARCTION 2 (0.03) 4 (0.12) CARDIAC FAILURE 2 (0.03) 1 (0.03) CARDIOGENIC SHOCK 2 (0.03) 0 CARDIO RESPIRATORY ARREST 2 (0.03) 0 MULTI ORGAN FAILURE 2 (0.03) 0 PULMONARY EMBOLISM 2 (0.03) 1 (0.03) RENAL FAILURE 2 (0.03) 1 (0.03) Source: Modified from the Applicant s 30 Month Update (pages 39 44) 31

96 Outline Efficacy Major Safety Issues Deaths and SAEs Bladder cancer Hepatic safety Adverse Events of Interest Genital infections / urinary tract infections Renal impairment / volume depletion events / polyuria Bone safety Summary 32

97 Bladder Cancer First Review Cycle Imbalance of bladder cancer cases 9 cases/5501 (0.16%) dapagliflozin treatment arm vs. 1/3184 (0.03%) controls Incidence Rate Ratio (IRR) = 5.38 (95% CI, 0.84 to ) Baseline characteristics between arms balanced for risk factors Examined for evidence of more frequent monitoring due to higher rates of urogenital AEs among dapagliflozin patients; increased frequency of monitoring not detected Applicant asked to submit additional clinical trial data with updated information on bladder cancer and new risk estimates 33

98 Bladder Cancer Current NDA Resubmission (30 Month Safety Update) 10 bladder cancer cases among 6045 dapagliflozintreated patients (0.17%) vs. 1/3512 (0.03%) patients in the comparator arm IRR = 6.11 (95% CI, 0.83 to ) 34

99 Study ID (Country) Dapa Age Dose (mg) (y) Bladder Cancer Cases Diagnosis Time in Trial (Day) Tumor Type/Stage */ Grade Tobacco Use Prior Pioglitazone Use Baseline Hematuria 1. D1692C (Japan) Papillary/T2/G2 50 pack-years No Positive, Occult 2. D1690C (Austria) TCC/Ta/G2 100 pack-years No Negative 3. MB (Canada) TCC/Ta/Low 25 pack-years No Positive: Occult (w/ureteric calculus) 4. MB (Argentina) TCC/T2/Mod No Yes Positive: Trace 5. D1690C (Germany) TCC/T1/G3 20 pack-years No Negative 6. D1690C (Hungary) TCC/NA/G2 No No Positive: Occult 7. D1690C (United States) TCC/NA/Low 53 pack-years No Negative 8. D1690C (United States) TCC/Noninvasive/Low 34 pack-years No Negative 9. D1690C (China) TCC/Noninvasive/NA No No Positive: Trace 10. D1693C (Slovakia)* TCC/G1 40 pack-years No Positive, Trace Source: Modified from Dr. Yang Min Ning s (DOP/OHOP) Consultation *Diagnosis after the database lock 35

100 Postmarketing Experience Division of Pharmacovigilance I evaluated postmarketing reports Searched for postmarketing reports of bladder cancer cases Dapagliflozin (approved in the European Union, Argentina, Australia, Brazil, Mexico, New Zealand) and canagliflozin (to assess a possible class effect) FDA Adverse Events Reporting System (FAERS) Vigibase Medical literature 36

101 Postmarketing Experience No 5 bladder cancer cases, all with canagliflozin (all post approval) n=4 urothelial carcinoma; n=1 nested variant of urothelial carcinoma (rare/aggressive) Smoking history for 4 of 5 cases Difficult to draw inference for causality cases noted in medical literature One 15 Day Safety Report (FDA Form 3500a) from an ongoing trial 67 y/o male (T2DM, previous smoker) presented with hematuria following 4 months of exposure to dapagliflozin 10 mg Grade 3 papillary urothelial bladder cancer (cystoscopy) 37

102 Non Clinical Summary: Original Submission No evidence of tumor initiation/promotion in 2 yr rodent studies with dapagliflozin Evaluation of tumor promotion in 2 yr rodent studies limited by lack of background neoplastic or pre neoplastic bladder lesions Numerical imbalance of bladder risk in clinical trials postulated to result from tumor promotion secondary to changes in the microenvironment of the bladder in vivo Recommended evaluating dapagliflozin in a rodent bladder tumor promotion model that best simulates clinical experience 38

103 Non Clinical Summary: Response to CR Letter Studies addressed dapagliflozin as a direct acting tumor promoter, independent from changes in bladder microenvironment and renal function results showed no tumor promotion Submitted studies did not evaluate dapagliflozin under conditions that simulate clinical experience: changes in bladder microenvironment and renal function from dapagliflozin and transitional tumors in the bladder 39

104 Non clinical Summary Non clinical studies demonstrate that dapagliflozin does not act directly as a carcinogen Possible bladder tumor promotion secondary to changes in the microenvironment of the bladder and renal function in response to dapagliflozin is incompletely assessed 40

105 Malignancies or Unspecified Tumors (Including Breast) For all malignancies, stratified IRR versus control (95% CI, 0.711, 1.506) IRR (95% CI, to 1.579) at time of Major Amendment IRRs for following tumor types numerically higher in dapagliflozin vs. comparator arms Musculoskeletal/Soft Tissue: 0.02% vs. 0% Pancreatic: 0.10% vs. 0.06%; IRR 1.84 (95% CI, 0.31 to 19.46) Prostate: 0.34% vs. 0.31%; IRR 1.6 (95% CI, 0.53 to 5.35) Breast: 0.45% vs. 0.21%; IRR 2.47 (95% CI, 0.64 to 14.10) 12/2693 females receiving dapagliflozin vs. 3/1439 female controls 41

106 Consultation with the Division of Oncology Products Increased incidence of breast cancer observed on the dapagliflozin relative to the comparator arms 30-MU: IRR = (95% CI, 0.636, ) Major Amendment (Nov. 2011): IRR = (95% CI, 0.461, ) EMDAC Meeting (July 2011): IRR = (95% CI 0.570, ) Potential confounders Lack of screening mammography; occurrence of the breast cancers within the 1 year of exposure; age; etc. Data with regard to breast cancer risk in association with this drug are inconclusive and insufficient 42

107 Outline Efficacy Major Safety Issues Deaths and SAEs Bladder cancer Hepatic safety Adverse Events of Interest Genital infections / urinary tract infections Renal impairment / volume depletion events / polyuria Bone safety Summary 43

108 Hepatic Safety First Review Cycle Case year old Indian male exposed to dapagliflozin 2.5 mg/day Elevations in transaminases starting on Day 85 Study medication stopped Day 192 Alanine aminotransferase (ALT) 1858 U/L (>37x upper laboratory reference range [ULRR]); TBL 4.2 mg/dl (>2.8x ULRR) on Day 200 Liver biopsy, Day 264, revealed portal inflammatory infiltrate without frank necrosis Started on immunosuppressants (prednisolone) on Day 349 Azathioprine added on Day 382; prednisolone discontinued Day 521 Originally adjudicated as probable drug induced liver injury (DILI) associated with dapagliflozin (Agency) / and possibly drug related by a blinded Hepatic Adjudicated Committee 44

109 Hepatic Safety The Applicant was informed that they would need to submit additional clinical trial data Increase the patient years of exposure Updated review of hepatic safety, including cases that meet the definition of Hy s law, with narratives of each case Incidence of transaminase elevations (3x, 5x, 10x, and 20x ULRR) These data are included in the NDA resubmission 45

110 Hepatic Safety Applicant used Standard MedDRA Queries (SMQ) for monitoring hepatic safety in the clinical program Liver abnormality events meeting prespecified criteria were reviewed by a blinded Hepatic Adjudication Committee 1. ALT >3x ULRR and TBL >1.5x ULRR within 14 days of the aspartate aminotransferase (AST) and/or ALT elevation 2. AST and/or ALT >5x ULRR 3. Liver related serious or non serious adverse event (SAE/AE) in subjects who prematurely discontinued study treatment due to any AE/SAE 4. Liver related SAE or AE in any subjects who died 46

111 Hepatic Adverse Events All Phase 2b/3 Pool Event Type Dapa 2.5 mg N=814 X (%) Dapa 5 mg N=1668 X (%) Dapa 10 mg N=3315 X (%) Dapa Total N=5936 X (%) All Control N=3402 X (%) AE of Hepatic Disorder 12 (1.5) 20 (1.2) 60 (1.8) 93 (1.6) 65 (1.9) SAE of Hepatic Disorder (0.2)* 7 (0.1) 1 (<0.1) AE of Hepatic Disorder Leading to Discontinuation 1 (0.1) 1 (0.1) 11 (0.3) 13 (0.2) 3 (0.1) Source: Modified from the Applicant s 30 Month Update, Part 3 (pages ) *Cirrhosis; esophageal varices hemorrhage; hepatic enzyme increased (n=2); hepatic neoplasm malignant; hepatitis; liver abscess 47

112 Marked Liver Laboratory Abnormalities (All Phase 2b/3 Pool) LFT Abnormality 30 MU Dapa Total N=5936 X/N (%) 30 MU All Control N=3403 X/N (%) Patients with Elevated LFTs 255/5895 (4.3) 152/3380 (4.5) AST >10X ULRR >20X ULRR 8/5895 (0.1) 4/5895 (0.1) 3/3379 (0.1) 0/3379 (0) ALT >10X ULRR >20X ULRR 7/5895 (0.1) 3/5895 (0.1) 5/3380 (0.1) 2/3380 (0.1) Total Bilirubin >2X ULRR >2X ULRR 22/5894 (0.4) 11/3379 (0.3) ALT/AST >3X ULRR and TBL >2X ULRR 7/5894 (0.1) 4/3379 (0.1) Source: Modified from the Applicant s 30 Month Update, Part 2 (pages ) 48

113 Hepatic Safety 81 cases met criteria for referral for adjudication N=17 adjudicated as possibly related to study medication 10 dapagliflozin treated patients (0.1%) vs. 6 controls (0.1%) vs. 1 open label single arm study (0.1%) N=14 cases AST or ALT >3x ULRR and TBL >2x ULRR within 14 days 10 dapagliflozin treated patients (0.1%) vs. 4 placebo (0.1%) 2 events adjudicated events as possibly related and 12 unlikely or excluded 4 of the cases identified since the Major Amendment 3 dapagliflozin vs. 1 comparator arm The causal relation ship was adjudicated as unlikely for all 3 cases 49

114 Hepatic Safety Case Almost Now 84 y/o 4 years of follow up Had been treated with corticosteroids (after transaminases had begun to decline); transaminases returned to near normal levels Now off dapagliflozin ~3 years Azathioprine continued ~2.6 years Two additional episodes of transaminase elevations, while on azathioprine but off dapagliflozin Applicant proposes reclassification of event as autoimmune hepatitis (recommendations of their hepatology consultants) 50

115 Hepatic Safety Case Time Course of Liver Tests Indian Man 84 (in UK) # test values, log10(xuln) ALTx ASTx TBLx ALPX bx retended f ollow -up 0.1 dapa prednisone azathioprine days since dapagliflozin started Source: Reproduced from Dr. John Senior s (OSE) Consultation Review 51

116 Hepatic Events Postmarketing Experience Division of Pharmacovigilance I consulted Evaluated postmarketing reports for all liver events with dapagliflozin and canagliflozin (assess for a class effect) One FAERS and Vigibase databases and medical literature case with dapagliflozin identified (none with canagliflozin) 83 y/o male receiving dapagliflozin 10 mg/day Concomitant medications: niacin, pravastatin, levofloxacin Previously adjudicated by the blinded Hepatic Adjudication Committee (HAC) and excluded from the HAC Summary Report No cases noted in medical literature 52

117 Hepatic Safety Summary The majority of cases of ALT >3x ULRR with TBL >2x ULRR had other diagnoses that were more likely than dapagliflozin to have caused the test abnormalities No imbalance in increases in minor ALT elevations of clinical consequence due to study drug have been observed The long term follow up for patient D1690C supports a diagnosis of autoimmune hepatitis, but an association with dapagliflozin cannot be excluded One postmarketing report from another country, with multiple other possible contributing factors 53

118 Outline Efficacy Major Safety Issues Bladder cancer Hepatic safety Adverse Events of Interest Genital infections / urinary tract infections Renal impairment / volume depletion events / polyuria Bone safety Summary 54

119 Common AEs ( 2% and More Frequent vs. Placebo) Adverse Event Dapagliflozin N=2360 (%) 30 MU Placebo N=2295 (%) Hypoglycemia Genital infection Urinary tract infection Back pain Polyuria Source: Modified from the Applicant s Proposed Product Labeling 55

120 Outline Efficacy Major Safety Issues Deaths and Serious Adverse Events Bladder cancer Hepatic safety Adverse Events of Interest Genital infections / urinary tract infections Renal impairment / volume depletion events / polyuria Bone safety Summary 56

121 Genital Infections in Placebo Controlled Trials (Short Term Pool) Treatment Arm Dapagliflozin Placebo 5.5% 0.6% 8.4% 3.4% Total Events Females Males Received Antimicrobials 5.3% (125/2360) 0.7% (12/2295) 1.2% Recurrent Infections 17% (22/130) 7% (1/15) 0.2% Dapagliflozin(N=2360) Placebo (N=2295) Source: Modified from the Applicant s 30 Month Update (pages ) Most Common Reported Terms ( 1%) Vulvovaginal mycotic infection (1.9%) Balanitis (1.8% ), Vaginal infection (1%) 57 57

122 Urinary Tract Infections in Placebo Controlled Trials (Short Term Pool) % 3.5% 8.5% 6.7% 1.8% 1.3% Dapagliflozin (N=2360) Placebo (N=2295) Source: Modified from the Total Events Females Males Applicant s 30 Month Update (pages ) Treatment Arm Withdrawal Due to UTI % (n/n) UTI SAEs % (n/n) Recurrent Infections %(n/n) Dapagliflozin Placebo 0.2% (5/2360) 0.1% (2/2295) 1% (1/110) 2.5% (2/81) 16.4% (18/110) 8.6% (7/81) 58

123 Outline Efficacy Major Safety Issues Deaths and SAEs Bladder cancer Hepatic safety Adverse Events of Interest Genital infections / urinary tract infections Renal impairment / volume depletion events / polyuria Bone safety Summary 59

124 Events of Renal Impairment/Failure in Placebo Controlled Trials (Short Term plus Long Term Pool) Treatment Arm Dapagliflozin Placebo 6.7% 4.2% Total Events (x/n) 136/ / % 65 y/o (x/n) 7.9% 87/620 52/ % 16.1% egfr 30 to <60 ml/min/1.73 m 2 (x/n) 71/251 40/ % 19.1% 65 y/o + egfr 30 to <60 ml/min/1.73 m 2 (x/n) 47/134 27/141 Dapagliflozin Placebo Source: Modified from the Applicant s 30 Month Update (pages ) MedDRA PTs 1% (Dapa Placebo): Creatinine renal clearance decreased (2.3% vs. 1.4%), renal impairment(1.9% vs. 1.1%) 60

125 2.5 Events of Volume Depletion in Placebo Controlled Trials (Short Term Pool) 2.5% 2 1.7% % 1 0.7% 0.8% 1.9% 1.5% 1.5% Treatment Arm Total Events (x/n) 65 y/o (x/n) egfr 30 to <60 ml/min/1.73 m 2 (x/n) Receiving Loop Diuretics Dapagliflozin Placebo Dapagliflozin Placebo 27/ / /665 6/771 5/265 4/268 6/236 4/267 Source: Modified from the Applicant s 30 Month Update (pages ) 61