Top Banner
Getting drugs to reach the market becomes harder and harder... Antidiabet ic drugs Mélanie Tilte Pauline Flipo Florent Zoonekynd Nicolas Bernard
87

Getting drugs to the market becoms harder and harder (the diabetes exemple)

Jun 03, 2015

Download

Documents

MelanieTilte
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
  • 1. Getting drugs to reach themarket becomesharder and harder...Antidiabetic drugsNicolas Bernard Pauline Flipo Mlanie Tilte Florent Zoonekynd

2. Diabetes worldwideRaised fasting blood glucose, 2008Fasting blood glucose 7,0 mmol/L or medication for raised blood glucosePrevalence (%)WHO 2 3. T2DM complicationsEye complications Skin complications NephropathyGlaucomaBacterial & fungalCataracts infections Hypertension Retinopathy DiabeticdermopathyHearing loss Foot complicationsGastroparesis Cardiovascular Neuropathy diseasesHyperosmolarCalluseshyperglycemic Foot ulcers Myocardial nonketotic Poor circulationinfarction syndrome AmputationStroke Peripheral arterial Neuropathy KetoacidosisdiseaseAmerican Diabetes Association 3 4. What was the situation in theearly 2000s ?Avandia: Rosiglitazone4 5. Situation in 1999 ACARBOSE SULFONYLUREAS Slow Carbohydrate Directly Insulindigestion secretion GI incomfortINSULIN Body Weight Subcutaneousinjection Hepatic glucose METFORMIN output MEGLITINIDES Insulin resistance Directly Insulin Hepatic glucose secretionoutput Body Weight Weight neutral 5 6. Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com 6 7. A new perspective:ThiazolidinedionesNew mechanism of actionTHIAZOLIDINEDIONES PPAR Agonists Insulin action AdipogenesisTZDs and diabetes: testing the waters, Katie Ris Nature Medicine 11, 822 - 824 (2005) . 7 8. Rosiglitazones efficacyStudies DesignPrimary endpoint: HbA1cmonotherapy +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 9. FDA ApprovalADA : These drugs offer new options to health careprofessionals who treat people with type 2 diabetesand 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 3419 10. Mechanism of action EMA APPROVAL INITIAL REJECTION IN OCTOBER 1999 Increase in Plasma VolumeEdema 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 Bolesta10 11. 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 EuropeWarning 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 12. Several Warnings Safety Signals about CV eventsApproval2007Black Box Warning : Avandia may cause 1999 heart attack12 13. New ReglementationCV guidelines 2008Approval 2007Black Box Warning : Avandia may cause1999heart attackhttp://www.qcclick.com/infarctus-myocarde.html13 14. Situation in 1999METFORMIN MEGLITINIDES SULFONYLUREASACARBOSEClinical trials focusINSULIN on HbA1c 14 15. Situation in 2008METFORMIN MEGLITINIDESSULFONYLUREASGLIPTINS (DPP-4 GLP-1 receptor inhibitors) agonist THIAZOLIDINEDIONEACARBOSEClinical trials Independent endpointINSULINfocus on HbA1cto evaluate CV risk 15 16. Avandias endSuspension of the MA in 2010CV guidelinesEurope 2008ApprovalSafety Concern : CV risk1999 Restricted-access Program in USA11 years 16 17. An other thiazolidinedione?Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus, A Meta-analysis of Randomized Trials, 2007 17 18. Adapted from testimony by David Graham at the July 13, 2010, EMDAC meeting 18 19. But 2002 Ten-year epidemiological study about Actos 2007Interim results: increased risk of bladder cancer for use > 12 months (+ 40%) BlackBoxWarning 2011Meta-analysis using data from the French National HealthInsurance Plan : HR = 1.22 (95% CI 1.03 to 1.43) Withdrawalin FranceSupplement approvals letter from FDA to Takeda about bladder cancer risk, July, 8 2011 19 20. Lets be prudent...Victoza: Liraglutide20 21. Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com 21 22. Victoza : Liraglutide once a dayLiraglutide : GLP-1 analog Lipid chain =>Prolonged duration of actionMay 23rd, 2008 : NDA filed with the FDA and EMA 22 23. Victoza timelineAugust 20th: Liragutide improves glucose control and lowers body weight20072008 May 23rd: NDA filed with the FDA and Europe23 24. Clinical efficacy(glimepiride)24Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 25. Clinical efficacy(glimepiride) HbA1c, FPG Still primaryendpointsBefore CV guideline25Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 26. Clinical efficacy(glimepiride)26Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 27. Clinical efficacy(glimepiride)Correction of a risk factor27Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 28. Victoza timelineAugust 20th: Liragutide improves glucose control and lowers body weight April 2nd: FDA Advisory Committee MeetingDecember 17th: CV guidance20072008 2009 May 23rd: NDA filed with the FDA and Europe28 29. 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 ofData of previous CV eventsclinical trialsNo patients with significant CV disease Few major cardiovascular eventshttp://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-FDA.pdf29 30. Thyroid cancersThyroid C-cellMale rats : mid- and high-dose groupsadenomasFemale rats : all dose groupsThyroid C-cellMale rats : all dose groups carcinomas Female rats : mid- and high-dose groupsA NOAEL for occurrence of C-cell tumors was not identifield in rats30Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 31. 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 32. Thyroid adverse events32Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 33. All Thyroid adverse events Total LiraglutidePlacebo Active Comparator%N %N % N42579071474All Thyroid Adverse1,9 80 1,413 1,421Events33Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 34. Thyroid adverse events34Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 35. Goitres Total LiraglutidePlacebo Active Comparator%N %N % N42579071474All Thyroid 1,9 80 1,4 131,4 21Adverse Events Goitres0,4 17 0,1 1 0,1 235Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 36. Pancreatitis 9 Cases8 with Liraglutide7 acute2 chronic All pancreatitis events werereported in the intermediateand 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 loss36Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 37. Pancreatitis37Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 38. Risk Management PlanPost-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 201038Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 39. Victoza timelineAugust 20th: Liragutide improves glucose control and lowers body weightApril 2nd: FDA Advisory Committee MeetingDecember 17th: CV guidanceJanuary 20th: Approval for Victoza in Japan20072008 20092010 2011January 25th: FDA approved Victozawith REMS July 3rd: Marketing authorisation in Europe May 23rd: NDA filed with the FDA and Europe 39 40. Risk Evaluation & Mitigation Strategy Communication Plan - Reminder Dear HCP Letter for Primary Care Providers - Direct Mail LetterTimetable 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 41. Risk Evaluation & Mitigation StrategyThyroid nodulesPatients should refer to an endocrinologist for futherElevated serum calcitoninevaluationhttp://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf 41 42. Risk of Acute Pancreatitis Pancreatitis : VICTOZA > comparators Observe patients carefully for signs and symptoms of pancreatitis Pancreatitis VICTOZA : ConfirmatoryAppropriatesuspected discontinue promptly tests management PancreatitisVICTOZA : not restartedconfirmed Use with caution in patients with a history of pancreatitishttp://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf 42 43. A QT story...Bydureon : Exenatideonce a week43 44. Oral Pharmacological Agents for Type 2 Diabetes, Diabetes manager, pbworks.com 44 45. Bydureon : exenatide once a weekExenatide : GLP-1 analog Twice a dayOnce weeklyOnce monthly In Phase II 45 46. Medisorb Microspheres Technology Small molecules/Peptides encapsulated in Microspheres1/10 mmCO2 + H20Polylactide co-glycolide polymer (PLG)Medical Devices industry : bioabsorbable sutures- Versatile degradation kinetics- Established safetyShield fromExtended releaseenzymatic 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), 1-1446 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):228-38.47 48. 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 49. Bydureon : exenatide twice a weekApril : Byetta approval in the US 2005October : FDA/ICH guidancetQT studyBC October 201049 50. FDA/ICH Guidances for industry, october 2005 50 51. QT interval and hERG channel 51 52. Bydureon : exenatide twice a weekApril : Byetta approval in the USEnd-of-Phase II meeting : Simple process for Bydureons QT profileJuly : DURATION-1 results 20052006 20072008March : DURATION-1 QT assessment (148 patients) October : FDA/ICH guidance tQT studyBC October 201052 53. July 2008 : DURATION 1 QT Data : No Relationship Between Baseline- adjusted Change in QTcF Interval and Exenatide Concentrations148 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, 201153 54. 71st Scientific Sessions of the American Diabetes Association. Amylin Investor Reception. Daniel M. Bradbury , President and Chief Executive Officer,Amylin Pharmaceuticals, Inc. June 26, 201154 55. Bydureon : exenatide twice a weekApril : Byetta approval in the USEnd-of-Phase II meeting : Simple process for Bydureons QT profileJuly : DURATION-1 results : no clinically meaningful changes in QTc acceptable June : Byetta tQT studys results presented at ADA annual meeting 2005200620072008 2009 May : Application submissionMarch : DURATION-1 QT assessment (148 patients) October : FDA/ICH guidance tQT studyBC October 2010 55 56. June 2009 : Byetta QT study, ADA annual meetingScatterplot of Changes from Predose in QTcF Interval Versus Plasma ExenatideConcentrations Following a Single 10 g 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 200956 57. June 2009 : Byetta QT study, ADA annual meetingScatterplot of Changes from Predose in QTcF Interval Versus Plasma ExenatideConcentrations Following a Single 10 g 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 200957 58. Action of exenatide on hERG? Towards a hERG channel Tyr652inhibitors pharmacophorePhe656 IntracellularThr623Ser624interaction Mouse, Rat, Monkey models In vitro data No inhibition of hERG channelAt 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 58 59. Bydureon : exenatide twice a weekApril : Byetta approval in the USEnd-of-Phase II meeting : Simple process for Bydureons QT profileJuly : DURATION-1 results : no clinically meaningful changes in QTc acceptable June : Byetta tQT studys results presented at ADA annual meeting October : 2d CRL : tQT study for Bydureon 2005200620072008 20092010 April : answer March : CRL : manufacturing processes, REMS program, product labelling May : Application submissionMarch : DURATION-1 QT assessment (148 patients) October : FDA/ICH guidance tQT studyBC October 2010 59 60. 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--go-go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia. The journal ofbiological chemistry, 2003;278(12):10417-10426. 60 61. FDA Experts opinion Impact of hypoglycemia and hyperglycemia on hERG channelTrials : hypoglycemia under exenatideOnce a week => less control of its concentrationExcreted via the kidney => ! renal impairment Need a tQT studyBC, October 201061 62. Bydureon : exenatide twice a weekApril : Byetta approval in the USEnd-of-Phase II meeting : Simple process for Bydureons QT profileJuly : DURATION-1 results : no clinically meaningful changes in QTc acceptable June : Byetta tQT studys results presented at ADA annual meeting October : 2d CRL : tQT study for BydureonJuly : answer 2005200620072008 200920102011 April : answer March : CRL : manufacturing processes, REMS program, product labelling May : Application submissionMarch : DURATION-1 QT assessment (148 patients) October : FDA/ICH guidance tQT studyBC October 2010 62 63. And finally...January 27th, 201263 64. http://www.bydureon.com/content/pdfs/Highlighted__Information_Prescribers.pdf 64 65. A new strategyDapagliflozin 65 66. Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com 66 67. Discovery1835 : Phlorizin (root bark of the apple tree) Inhibition of Sodium Glucose Cotransporter (SGLT)SGLT-1 :Enterocytes of the small intestineProximal 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. 2008J. Med. Chem. Vol. 51pp.1145-114967 68. MechanismSGLT2 inhibition a novel strategy for diabetes treatment Chao E.C., Henry R.R. July 2010Nature Reviews Vol. 9pp.551-55968 69. MechanismParadoxSGLT2 inhibition a novel strategy for diabetes treatment Chao E.C., Henry R.R. July 2010Nature Reviews Vol. 9pp.551-55969 70. Phlorizin : Non selective SGLT inhibitor Not suitable drug candidate - Inhibits SGLT-1 Absorption problems - Cleaved by -glucosidase Poor metabolic stabilitySAR New entitiesSergliflozin (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. 2008J. Med. Chem. Vol. 51pp.1145-114970 71. SGLT2 and SGLT1 inhibitory activity SGLT2 EC50 (nM) SGLT1 EC50 (nM) Selectivity vs SGLT1 (fold) Phlorizin35.6+/-4.2 330+/-50 10 Sergliflozin 9.2+/-0.8211+/-29>90Dapagliflozin 1.1+/-0.06 1390+/-71200Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter Meng W., Ellsworth B.A., Nirschl A.A., McCann P.J. 2008J. Med. Chem. Vol. 51pp.1145-114971 72. 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 2008DiabetesVol. 57pp.1723-172972 73. 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 2008DiabetesVol. 57pp.1723-172973 74. Clinical dataPatients with inadequate glycaemic control Dapagliflozin 2.5mg/day 137with metformin Dapagliflozin 5mg/day 137 Dapagliflozin 10mg/day135 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.2010LancetNum. 375pp.2223-2233 74 75. Clinical dataPatients with inadequate glycaemic control Dapagliflozin 2.5mg/day 137with metformin Dapagliflozin 5mg/day 137 Dapagliflozin 10mg/day135 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.2010LancetNum. 375pp.2223-2233 75 76. Clinical dataPatients with inadequate glycaemic control Dapagliflozin 2.5mg/day 137with metformin Dapagliflozin 5mg/day 137 Dapagliflozin 10mg/day135 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.2010LancetNum. 375pp.2223-223376 77. Expectations BENEFITSRISKS 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 77 78. Patients with insulin treatmentVital signs and laboratory outcomes at week 12Placebo + InsulinDapagliflozin 10 mg + InsulinDapagliflozin 20 mg + InsulinNumber of patients2324 24 Systolic/diastolic blood pressureSlight increase- 7.2/- 1.2 mm Hg- 6.1/- 3.9 mm HgUrinary glucose excretion - 1.5 mg/24 h 83.5 mg/24 h 85.2 mg/24 h24h urinary volume+ 255 mL + 365 mL + 444 mLFPG+ 17.8 mg/dL+ 2.4 mg/dL- 9.6 mg/dLTotal daily dose of insulin+ 1.7 UI- 1.4UI- 0.8UIAdverse events of special interestPlacebo + InsulinDapagliflozin 10 mg + InsulinDapagliflozin 20 mg + Insulin Urinary tract infection-- 1 Genital tract infection 1 - 5Events of hypoglycemia3 (1 severe)76A 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 2009Diabetes CareVol. 32pp.1656-1662 78 79. Urinary tract infectionsPlaceboDapagliflozin 2.5mg Dapagliflozin 5mg Dapagliflozin 10mg Dapagliflozin Total N= 1393N=814N=1145 N=1193 N=3291Total 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%)Males11 (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, 201179 80. Genital tract infections PlaceboDapagliflozin 2.5mgDapagliflozin 5mg Dapagliflozin 10mg Dapagliflozin TotalN= 1393N=814 N=1145 N=1193 N=3291Total subjects with an event29 (2.3%) 47 (5.8%)80 (7%)83 (7%)223 (6.8%) Females23 (3.4%)165 (10.0%)Males6 (0.8%) 58 (3.5%)Appears dose relatedNone of these infections areseriousIncluded in proposed labelingFDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 201180 81. FutureFDA Advisory Committee: July 19th, 2011Vote: 9 against and 6 forAction date: October 26th, 2011Delayed action date: January 28th, 201281 82. Bladder cancersCases DapaglifloControl SEERzin (Surveillance, Epidemiologyand End Result) programTotal 43101962 Including: Adjustment for smoking and BMI Epidemiology of bladder cancer inExpected2.051the US population Downward-adjusted hazard ratioEffective 9 1of 1.40 calculated for the diabetic population LimitsConcerns US population: only 20% of patientsLiterature-based factor: subject to uncertaintyIncidence may be underestimatedFDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011 82 83. Further more... AgeSex DapagliflozinCancerDiagnosis day Smoking Baseline dose (mg) gradehematuria 75 M2,5 2 43 Former2+ 48 M 10 Low 74 Former - 67 M5 (+ Pio) High144 Never Trace 55 M 10 Low 169CurrentTrace 63 M5 (+ Ins) 2 393 (tumor 358)Current- 67 M 10 (+ Ins) 2 399 Never3+ 60 M 5 (+ Met)Low 512Former2+ 66 M 10 (+ Ins) Low 581Former - 76 M2,5-10 (+ Met)High727Former - 67 MPlacebo High136Current 3+FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 201183 84. Both sides argumentsFDABMS/AZTrials not powered to distinguishthe incidence of bladder cancerBladder cancer Increased surveillance of urinaryDapagliflozin may be associatedsymptoms with dapagliflozin =with increased risk a bladderincreased detection of cancercancer 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 84 85. FutureAction date: October 26th, 2011 Delayed action date: January 28th, 2012 Complete Response Letter: January 19th, 2012Additional clinical data for a better benefit-risk assessment85 86. New requirementsUnexpectedeffectsPharmacological risksClinical data data benefitsReducing riskImproving benefit86