Getting drugs to reach the market becomes harder and harder

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<ul><li> 1. Getting drugs to reach the market becomes harder and harder... Antidiabetic drugsNicolas Bernard Pauline Flipo Mlanie Tilte Florent Zoonekynd </li> <li> 2. Diabetes worldwide Raised fasting blood glucose, 2008 Fasting blood glucose 7,0 mmol/L or medication for raised blood glucose Prevalence (%)WHO 2 </li> <li> 3. T2DM complications Eye complications Skin complications Nephropathy Glaucoma Bacterial &amp; 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 </li> <li> 4. What was the situation in theearly 2000s ?Avandia: Rosiglitazone 4 </li> <li> 5. 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 </li> <li> 6. Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, 6 </li> <li> 7. A new perspective: Thiazolidinediones New mechanism of action THIAZOLIDINEDIONES PPAR Agonists Insulin action AdipogenesisTZDs and diabetes: testing the waters, Katie Ris Nature Medicine 11, 822 - 824 (2005) . 7 </li> <li> 8. Rosiglitazones 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 </li> <li> 9. 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 </li> <li> 10. 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 &amp; Scott Bolesta 10 </li> <li> 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 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 </li> <li> 12. Several Warnings Safety Signals about CV eventsApproval 2007 Black Box Warning : Avandia may cause 1999 heart attack 12 </li> <li> 13. New Reglementation CV guidelines 2008 Approval 2007 Black Box Warning : Avandia may cause 1999 heart attack 13 </li> <li> 14. Situation in 1999 METFORMINMEGLITINIDES SULFONYLUREAS ACARBOSE INSULIN 14 </li> <li> 15. Situation in 2008 METFORMIN MEGLITINIDES SULFONYLUREASGLIPTINS (DPP-4 GLP-1 receptor inhibitors) agonistTHIAZOLIDINEDIONE ACARBOSE INSULIN 15 </li> <li> 16. Avandias endSuspension of the MA in 2010 CV guidelines Europe 2008Approval Safety Concern : CV risk 1999 Restricted-access Program in USA 11 years 16 </li> <li> 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 </li> <li> 18. Adapted from testimony by David Graham at the July 13, 2010, EMDAC meeting 18 </li> <li> 19. But 2002 Ten-year epidemiological study about Actos 2007 Interim results: increased risk of bladder cancer for use &gt; 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 </li> <li> 20. Lets be prudent...Victoza: Liraglutide 20 </li> <li> 21. Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, 21 </li> <li> 22. Victoza : Liraglutide once a day Liraglutide : GLP-1 analog Lipid chain =&gt; Prolonged duration of actionMay 23rd, 2008 : NDA filed with the FDA and EMA 22 </li> <li> 23. Victoza timeline August 20th: Liragutide improves glucose control and lowers body weight2007 2008 May 23rd: NDA filed with the FDA and Europe 23 </li> <li> 24. Clinical efficacy (glimepiride) 24Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009 </li> <li> 25. Clinical efficacy (glimepiride) HbA1c, FPG Still primary endpoints Before CV guideline...</li></ul>