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Getting drugs to reach the market becomes harder and harder... Getting drugs to reach the market becomes harder and harder... Presentation Transcript

  • Getting drugs to reach the market becomes harder and harder... Antidiabetic drugsNicolas Bernard Pauline Flipo Mélanie Tilte Florent Zoonekynd
  • Diabetes worldwide Raised fasting blood glucose, 2008 Fasting blood glucose ≥ 7,0 mmol/L or medication for raised blood glucose Prevalence (%)WHO 2
  • T2DM complications Eye complications Skin complications Nephropathy Glaucoma Bacterial & fungal Cataracts infections Hypertension Retinopathy Diabetic dermopathy Hearing loss Foot complications Gastroparesis Cardiovascular Neuropathy diseases Hyperosmolar Calluses hyperglycemic Foot ulcers Myocardial nonketotic Poor circulation infarction syndrome Amputation Stroke Peripheral arterial Neuropathy Ketoacidosis diseaseAmerican Diabetes Association 3
  • What was the situation in theearly 2000s ?Avandia®: Rosiglitazone 4
  • Situation in 1999 ACARBOSE SULFONYLUREAS• Slow Carbohydrate • Directly ↑ Insulindigestion secretion• GI incomfort • ↑ Body Weight INSULIN • Subcutaneous injection • ↓ Hepatic glucose METFORMIN output MEGLITINIDES• ↓ Insulin resistance • Directly ↑ Insulin• ↓ Hepatic glucose secretionoutput • ↑ Body Weight• ≈ Weight neutral 5
  • Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com 6
  • A new perspective: Thiazolidinediones New mechanism of action THIAZOLIDINEDIONES • PPARγ Agonists • ↑ Insulin action • ↑ AdipogenesisTZDs and diabetes: testing the waters, Katie Ris Nature Medicine 11, 822 - 824 (2005) . 7
  • Rosiglitazone’s efficacy Studies Design Primary endpoint: HbA1c monotherapy +metforminA comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with T2DM, St John Sutton M and AllEffect of Metformin and Rosiglitazone Combination Therapy in Patients With T2DM. Fonseca V, Rosenstock J 8
  • FDA Approval ADA : « These drugs offer new options to health care professionals who treat people with type 2 diabetes and represent important advances in drug therapy » May 1999 FDA Approval Precautions on patients at risk of heart failureRosiglitazone, What went wrong? BMJ | 11 SEPTEMBER 2010 | VOLUME 341 9
  • Mechanism of action Increase in Plasma Volume Edema Patients with NYHA class III or IV status excluded from clinical trials. ↑ Body Weight Lipid AlterationRosiglitazone in the Treatment of Type 2 Diabetes Mellitus: A Critical Review, Jennifer M. Malinowski & Scott Bolesta 10
  • Situation in 1999 (UKPDS) «[…] The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.» (EASD) «Rosiglitazone works in a novel way to reduce insulin resistance » July 2000 Market Authorisation in Europe Warning on heart failure Post-marketing trial with CV safety as primary endpointTurner RC, Cull CA, Frighi V, Holman RR, for the UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, orinsulini n patients with T2DM.JAMA. 1999;281:2005-2012. 11
  • Several Warnings Safety Signals about CV eventsApproval 2007 Black Box Warning : Avandia may cause 1999 heart attack 12
  • New Reglementation CV guidelines 2008 Approval 2007 Black Box Warning : Avandia may cause 1999 heart attackhttp://www.qcclick.com/infarctus-myocarde.html 13
  • Situation in 1999 METFORMINMEGLITINIDES SULFONYLUREAS ACARBOSE INSULIN 14
  • Situation in 2008 METFORMIN MEGLITINIDES SULFONYLUREASGLIPTINS (DPP-4 GLP-1 receptor inhibitors) agonistTHIAZOLIDINEDIONE ACARBOSE INSULIN 15
  • Avandia®’s endSuspension of the MA in 2010 CV guidelines Europe 2008Approval Safety Concern : CV risk 1999 Restricted-access Program in USA 11 years 16
  • An other thiazolidinedione?Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus, A Meta-analysis of Randomized Trials, 2007 17
  • Adapted from testimony by David Graham at the July 13, 2010, EMDAC meeting 18
  • But… 2002 Ten-year epidemiological study about Actos® 2007 Interim results: increased risk of bladder cancer for use > 12 months (+ 40%) BlackBoxWarning 2011 Meta-analysis using data from the French National Health Insurance Plan : HR = 1.22 (95% CI 1.03 to 1.43) Withdrawal in FranceSupplement approvals letter from FDA to Takeda about bladder cancer risk, July, 8 2011 19
  • Let’s be prudent...Victoza®: Liraglutide 20
  • Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com 21
  • Victoza® : Liraglutide once a day Liraglutide : GLP-1 analog Lipid chain => Prolonged duration of actionMay 23rd, 2008 : NDA filed with the FDA and EMA 22
  • Victoza® timeline August 20th: Liragutide improves glucose control and lowers body weight2007 2008 May 23rd: NDA filed with the FDA and Europe 23
  • Clinical efficacy (glimepiride) 24Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Clinical efficacy (glimepiride) HbA1c, FPG Still primary endpoints Before CV guideline 25Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Clinical efficacy (glimepiride) 26Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Clinical efficacy (glimepiride) Correction of a risk factor 27Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Victoza® timeline August 20th: Liragutide improves glucose control and lowers body weight April 2nd: FDA Advisory Committee Meeting December 17th: CV guidance2007 2008 2009 May 23rd: NDA filed with the FDA and Europe 28
  • Cardiovascular Safety -Qualitatively similar to total comparator -No relation dose/CV events -Upper bound of the 95% CI exceeded 1.3 Not designed for meta-analysis, or evaluation of Data of previous CV events clinical trials No patients with significant CV disease →Few major cardiovascular eventshttp://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-FDA.pdf 29
  • Thyroid cancers Thyroid C-cell Male rats : mid- and high-dose groups adenomas Female rats : all dose groups Thyroid C-cell Male rats : all dose groups carcinomas Female rats : mid- and high-dose groups A NOAEL for occurrence of C-cell tumors was not identifield in rats 30Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • GLP-1 Receptor(A) Saturation binding with fluorescence labeled GLP-1. (B) Saturation binding with iodinated GLP-1. (C) Western blotting.(D)Semi-quantitative PCR. Rat C-cell lines: CA-77 and MTC-23. Human C-cell line: TT. Rat beta-cell line: INS-1E 31Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Thyroid adverse events 32Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • All Thyroid adverse events Total Liraglutide Placebo Active Comparator % N % N % N 4257 907 1474 All Thyroid Adverse 1,9 80 1,4 13 1,4 21 Events 33Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Thyroid adverse events 34Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Goitres Total Liraglutide Placebo Active Comparator % N % N % N 4257 907 1474 All Thyroid 1,9 80 1,4 13 1,4 21 Adverse Events Goitres 0,4 17 0,1 1 0,1 2 35Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Pancreatitis 9 Cases 8 with Liraglutide 7 acute 2 chronic All pancreatitis events were reported in the intermediate and long-term trials Predisposing etiological factors Alcohol abuse Biliary tract disease or gall stones Abdominal surgery or family history of pancreatitis Recent abdominal trauma Weight loss 36Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Pancreatitis 37Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Risk Management Plan Post-approval safety surveillance -Focus on thyroid neoplasms, pancreatitis and CV events -3 to 5 years -Reporting to regulatory authorities at 6-months Post-approval CV trials -Submitted to FDA and EMA -Beginning: End of 2009 – beginning of 2010 38Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
  • Victoza® timeline August 20th: Liragutide improves glucose control and lowers body weight April 2nd: FDA Advisory Committee Meeting December 17th: CV guidance January 20th: Approval for Victoza® in Japan2007 2008 2009 2010 2011 January 25th: FDA approved Victoza® with REMS July 3rd: Marketing authorisation in Europe May 23rd: NDA filed with the FDA and Europe 39
  • Risk Evaluation & Mitigation Strategy Communication Plan - Reminder Dear HCP Letter for Primary Care Providers - Direct Mail Letter Timetable for the Submission of Assessments to the FDA On March 24th, at 1, 2, 3 and 7 years from the date of the initial REMS approvalhttp://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf 40
  • Risk Evaluation & Mitigation Strategy Thyroid nodules Patients should refer to an endocrinologist for futher Elevated serum calcitonin evaluationhttp://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf 41
  • Risk of Acute Pancreatitis Pancreatitis : VICTOZA® > comparators Observe patients carefully for signs and symptoms of pancreatitis Pancreatitis VICTOZA® : Confirmatory Appropriate suspected discontinue promptly tests management Pancreatitis VICTOZA® : not restarted confirmed Use with caution in patients with a history of pancreatitishttp://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf 42
  • A QT story...Bydureon® : Exenatideonce a week 43
  • Oral Pharmacological Agents for Type 2 Diabetes, Diabetes manager, pbworks.com 44
  • Bydureon® : exenatide once a week Exenatide : GLP-1 analog Twice a dayOnce weeklyOnce monthly In Phase II 45
  • Medisorb® Microspheres Technology Small molecules/Peptides encapsulated in Microspheres 1/10 mm CO2 + H20 Polylactide co-glycolide polymer (PLG)Medical Devices industry : bioabsorbable sutures- Versatile degradation kinetics- Established safety Shield from Extended release enzymatic attack- BiocompatibilityMahesh Chaubal. Polyactides/Glycolides – Excipients for Injectable Drug Delivery & Beyond, Drug Delivery Technology; 2002; 2(5), 34-36Alkermes Fact Sheet Medisorb® Microspheres Technology (2009)Rajan K. Verma, Sanjay Garg. Current Status of Drug Delivery Technologies and Future Directions, Pharmaceutical Technology On-Line; 2001; 25 (2), 1-14 46
  • Bydureon®/Byetta® : PK profileVanita R. Aroda, Mary Beth DeYoung. Clinical Implications of Exenatide as a Twice-Daily or Once-Weekly Therapy for Type 2 Diabetes. Postgrad Med;2011;123(5):228-38. 47
  • Bydureon®/Byetta® : PK profileVanita R. Aroda, Mary Beth DeYoung. Clinical Implications of Exenatide as a Twice-Daily or Once-Weekly Therapy for Type 2 Diabetes. Postgrad Med;2011;123(5):228-38. 48
  • Bydureon® : exenatide twice a week April : Byetta® approval in the US 2005 October : FDA/ICH guidance tQT studyBC October 2010 49
  • FDA/ICH Guidances for industry, october 2005 50
  • QT interval and hERG channel 51
  • Bydureon® : exenatide twice a week April : Byetta® approval in the US End-of-Phase II meeting : Simple process for Bydureon®’s QT profile July : DURATION-1 results 2005 2006 2007 2008 March : DURATION-1 – QT assessment (148 patients) October : FDA/ICH guidance tQT studyBC October 2010 52
  • July 2008 : DURATION 1 QT Data : No Relationship Between Baseline- adjusted Change in QTcF Interval and Exenatide Concentrations 148 patients ECG - 56 : mild renal impairment - At baseline - 10 : moderate renal impairment - At steady state71st Scientific Sessions of the American Diabetes Association. Amylin Investor Reception. Daniel M. Bradbury , President and Chief Executive Officer,Amylin Pharmaceuticals, Inc. June 26, 2011 53
  • 71st Scientific Sessions of the American Diabetes Association. Amylin Investor Reception. Daniel M. Bradbury , President and Chief Executive Officer,Amylin Pharmaceuticals, Inc. June 26, 2011 54
  • Bydureon® : exenatide twice a week April : Byetta® approval in the US End-of-Phase II meeting : Simple process for Bydureon®’s QT profile July : DURATION-1 results : “no clinically meaningful changes in QTc” – “acceptable” June : Byetta® tQT study’s results presented at ADA annual meeting 2005 2006 2007 2008 2009 May : Application submission March : DURATION-1 – QT assessment (148 patients) October : FDA/ICH guidance tQT studyBC October 2010 55
  • June 2009 : Byetta® QT study, ADA annual meeting Scatterplot of Changes from Predose in QTcF Interval Versus Plasma Exenatide Concentrations Following a Single 10 µg Dose71st Scientific Sessions of the American Diabetes Association. Amylin Investor Reception. Daniel M. Bradbury , President and Chief Executive Officer,Amylin Pharmaceuticals, Inc. June 26, 2011ADA 2009 56
  • Action of exenatide on hERG? Towards a hERG channel Tyr652 inhibitors pharmacophore Phe656 Intracellular Thr623 Ser624 interaction Mouse, Rat, Monkey models In vitro data No inhibition of hERG channel At concentrations 1.8 million times higher than human peak concentrationAndrea Cavalli et al. Towards a Pharmacophore for Drugs Inducing the Long QT Syndrome : Insights from a CoMFA Study of HERG K+ Channel Blockers.J. Med. Chem. 2002, 45. 3844-3853 57
  • Bydureon® : exenatide twice a week April : Byetta® approval in the US End-of-Phase II meeting : Simple process for Bydureon®’s QT profile July : DURATION-1 results : “no clinically meaningful changes in QTc” – “acceptable” June : Byetta® tQT study’s results presented at ADA annual meeting October : 2d CRL : tQT study for Bydureon® 2005 2006 2007 2008 2009 2010 April : answer March : CRL : manufacturing processes, REMS program, product labelling May : Application submission March : DURATION-1 – QT assessment (148 patients) October : FDA/ICH guidance tQT studyBC October 2010 58
  • FDA Experts’ opinion Impact of hypoglycemia and hyperglycemia on hERG channel Hypo/Hyperglycemia => Impairment of hERG K+ channel QT interval prolongation Torsades de pointeYiqiang Zhang et al. Impairment of human ether-à-go-go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia. The journal ofbiological chemistry, 2003;278(12):10417-10426. 59
  • FDA Experts’ opinion Impact of hypoglycemia and hyperglycemia on hERG channel Trials : hypoglycemia under exenatide Once a week => less control of its concentration Excreted via the kidney => ! renal impairment Need a tQT studyBC, October 2010 60
  • Bydureon® : exenatide twice a week April : Byetta® approval in the US End-of-Phase II meeting : Simple process for Bydureon®’s QT profile July : DURATION-1 results : “no clinically meaningful changes in QTc” – “acceptable” June : Byetta® tQT study’s results presented at ADA annual meeting October : 2d CRL : tQT study for Bydureon® July : answer 2005 2006 2007 2008 2009 2010 2011 April : answer March : CRL : manufacturing processes, REMS program, product labelling May : Application submission March : DURATION-1 – QT assessment (148 patients) October : FDA/ICH guidance tQT studyBC October 2010 61
  • And finally...January 27th, 2012 62
  • http://www.bydureon.com/content/pdfs/Highlighted__Information_Prescribers.pdf 63
  • A new strategyDapagliflozin 64
  • Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com 65
  • Discovery 1835 : Phlorizin (root bark of the apple tree) Inhibition of Sodium Glucose Cotransporter (SGLT) SGLT-1 : Enterocytes of the small intestine Proximal tubule of the nephron (10%) SGLT-2 : Proximal tubule of the nephron (90%)Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter. Meng W., Ellsworth B.A., Nirschl A.A., McCann P.J. 2008,J. Med. Chem., Vol. 51,pp.1145-1149 66
  • Mechanism ParadoxSGLT2 inhibition — a novel strategy for diabetes treatment. Chao E.C., Henry R.R. July 2010,Nature Reviews, Vol. 9,pp.551-559 67
  • Phlorizin : Non selective SGLT inhibitor – Not suitable drug candidate - Inhibits SGLT-1 → Absorption problems - Cleaved by β-glucosidase → Poor metabolic stability SAR → New entities Sergliflozin (GSK) Dapagliflozin (BMS/AZ)Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter. Meng W., Ellsworth B.A., Nirschl A.A., McCann P.J. 2008,J. Med. Chem., Vol. 51,pp.1145-1149 68
  • SGLT2 and SGLT1 inhibitory activity SGLT2 EC50 (nM) SGLT1 EC50 (nM) Selectivity vs SGLT1 (fold) Phlorizin 35.6+/-4.2 330+/-50 10 Sergliflozin 9.2+/-0.8 211+/-29 >90 Dapagliflozin 1.1+/-0.06 1390+/-7 1200Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter. Meng W., Ellsworth B.A., Nirschl A.A., McCann P.J. 2008,J. Med. Chem., Vol. 51,pp.1145-1149 69
  • Preclinical dataAcute in vivo activityDapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats . Han S., HaganD.L., Taylor J.R., Xin L., Meng W.,Biller S.A., Wetterau J.R., Washburn W.N., Whaley J.M.June 2008,Diabetes,Vol. 57,pp.1723-1729 70
  • Preclinical dataChronic in vivo efficacy • Lowering FPG maintained over a 2-week once-daily treatment regimen. • No bodyweight changes noted, no abnormal behavior observed. • No liver or renal toxicity measured.Dapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats . Han S., HaganD.L., Taylor J.R., Xin L., Meng W.,Biller S.A., Wetterau J.R., Washburn W.N., Whaley J.M.June 2008,Diabetes,Vol. 57,pp.1723-1729 71
  • Clinical data Patients with inadequate glycaemic control Dapagliflozin 2.5mg/day 137 with metformin Dapagliflozin 5mg/day 137 Dapagliflozin 10mg/day 135 Placebo/day 137 Total 546Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Bailey C., Gross J., Pieters A., Bastien A., List J.2010,Lancet,Num. 375,pp.2223-2233 72
  • Clinical data Patients with inadequate glycaemic control Dapagliflozin 2.5mg/day 137 with metformin Dapagliflozin 5mg/day 137 Dapagliflozin 10mg/day 135 Placebo/day 137 Total 546Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Bailey C., Gross J., Pieters A., Bastien A., List J.2010,Lancet,Num. 375,pp.2223-2233 73
  • Clinical data Patients with inadequate glycaemic control Dapagliflozin 2.5mg/day 137 with metformin Dapagliflozin 5mg/day 137 Dapagliflozin 10mg/day 135 Placebo/day 137 Total 546Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Bailey C., Gross J., Pieters A., Bastien A., List J.2010,Lancet,Num. 375,pp.2223-2233 74
  • Expectations BENEFITS RISKS • Hypoglycemia • Insulin-independent • Renal function • HbA1c lowering • Diuretic effect: • Reduction in: - Hypovolemia - Fasting Plasma Glucose - Hypotension - Weight - Dehydration • Reduction in Blood Pressure • Urinary tract infections, genital tract infections • Oral bioavailability: 84% • Serum free fraction: 3-4% • T1/2: 17.3hEndocrinologic and Metabolic Drugs Advisory Committee Meeting: Dapagliflozin BMS-512148 (BMS/AZ presentation)Drug report from Thomson Reuters: Dapagliflozin 75
  • Patients with insulin treatment Vital signs and laboratory outcomes at week 12 Placebo + Insulin Dapagliflozin 10 mg + Insulin Dapagliflozin 20 mg + Insulin Number of patients 23 24 24 Systolic/diastolic blood pressure Slight increase - 7.2/- 1.2 mm Hg - 6.1/- 3.9 mm Hg Urinary glucose excretion - 1.5 mg/24 h 83.5 mg/24 h 85.2 mg/24 h 24h urinary volume + 255 mL + 365 mL + 444 mL FPG + 17.8 mg/dL + 2.4 mg/dL - 9.6 mg/dL Total daily dose of insulin + 1.7 UI - 1.4UI - 0.8UI Adverse events of special interest Placebo + Insulin Dapagliflozin 10 mg + Insulin Dapagliflozin 20 mg + Insulin Urinary tract infection - - 1 Genital tract infection 1 - 5 Events of hypoglycemia 3 (1 severe) 7 6A Study of Dapagliflozin in Patients with Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers . Wilding J., Norwood P., Tjoen C.,Bastien A., List J., Fiedorek F.,September 2009,Diabetes Care,Vol. 32,pp.1656-1662. 76
  • Urinary tract infections Placebo Dapagliflozin 2.5mg Dapagliflozin 5mg Dapagliflozin 10mg Dapagliflozin Total N= 1393 N=814 N=1145 N=1193 N=3291 Total subjects with an event 63 (4.5%) 34 (4.2%) 84 (7.3%) 77 (6.5%) 209 (6.4%) Females 52 (7.7%) 165 (10.0%) Males 11 (1.5%) 44 (2.7%) Not dose related Common adverse event One serious AE: pyelonephritis Included in proposed labelingFDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011 77
  • Genital tract infections Placebo Dapagliflozin 2.5mg Dapagliflozin 5mg Dapagliflozin 10mg Dapagliflozin Total N= 1393 N=814 N=1145 N=1193 N=3291 Total subjects with an event 29 (2.3%) 47 (5.8%) 80 (7%) 83 (7%) 223 (6.8%) Females 23 (3.4%) 165 (10.0%) Males 6 (0.8%) 58 (3.5%) Appears dose related None of these infections are serious Included in proposed labelingFDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011 78
  • FutureFDA Advisory Committee: July 19th, 2011 Vote: 9 against and 6 for Action date: October 26th, 2011Delayed action date: January 28th, 2012 79
  • Bladder cancers Cases Dapagliflo Control SEER zin (Surveillance, Epidemiology and End Result) program Total 4310 1962 Including: •Adjustment for smoking and BMI •Epidemiology of bladder cancer in Expected 2.05 1 the US population Downward-adjusted hazard ratio Effective 9 1 of 1.40 calculated for the diabetic population Limits •Concerns US population: only 20% of patients •Literature-based factor: subject to uncertainty •Incidence may be underestimatedFDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011 80
  • Further more... Age Sex Dapagliflozin Cancer Diagnosis day Smoking Baseline dose (mg) grade hematuria 75 M 2,5 2 43 Former 2+ 48 M 10 Low 74 Former - 67 M 5 (+ Pio) High 144 Never Trace 55 M 10 Low 169 Current Trace 63 M 5 (+ Ins) 2 393 (tumor 358) Current - 67 M 10 (+ Ins) 2 399 Never 3+ 60 M 5 (+ Met) Low 512 Former 2+ 66 M 10 (+ Ins) Low 581 Former - 76 M 2,5-10 (+ Met) High 727 Former - 67 M Placebo High 136 Current 3+FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011 81
  • Both sides arguments FDA BMS/AZ Trials not powered to distinguish the incidence of bladder cancer Bladder cancer Increased surveillance of urinary Dapagliflozin may be associated symptoms with dapagliflozin = with increased risk a bladder increased detection of cancer cancer Continued follow-up of all participants in the dapagliflozin clinical trials and further analysis should be done to evaluate the relative risk of cancer associated with dapagliflozin treatment.FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011 82
  • Future Action date: October 26th, 2011 Delayed action date: January 28th, 2012 Complete Response Letter: January 19th, 2012Additional clinical data for a better benefit-risk assessment 83
  • New requirementsUnexpected effects Pharmacological risksClinical data data benefitsReducing risk Improving benefit 84