Master Eudipharm 2012 Introductory Module, Principles of Discovery of Medicine and Development Planning. Nathan Mewton, MD, PhD. September 26 th 2012

Transcription

1 Master Eudipharm 2012 Introductory Module, Principles of Discovery of Medicine and Development Planning * Nathan Mewton, MD, PhD. September 26 th 2012

2 *A little bit of History *Rabies a viral disease that causes acute encephalitis (inflammation of the brain) in warm-blooded animals. *The disease can be transmitted from one species to another, by a bite from an infected subject. *For a human, rabies is almost invariably fatal. *Rabies causes about 55,000 human deaths annually worldwide, mostly in Asia and Africa. *In 1800, thousands of people in Europe were dying from the disease.

3 *Pasteur and Roux s Translational Experience *Neurotropism of rabies virus in the literature. *Drying spinal cords of rabies infected rabbits for 10 days. *Subcutaneous injections of rabbit s dried spinal cord extract to dogs rabies exposition. *Joseph Meister, 9 years old, bitten 14 times by rabies dog. *13 inoculations of rabbit spinal cord extract patient saved. *Pasteur famous & rich.

4 * *Integrated application of innovative pharmacology tools, biomarkers, clinical methods, clinical technologies and study designs to improve: *Disease understanding, *Confidence in drug candidates, *Develop new drug candidates, *Understand therapeutic index in humans, *Increase clinical trial success, *Cost-effective decision making in exploratory development

5 New Drug Approvals are Lagging Ref: Arthur D. Little s views on key Pharma trends, March 31, 2010

6 Translational Medicine Basic Research Diseases In Vitro Experiments Animal Models Genomics Mechanisms Markers Drugs Interventions Clinical Research Human Research Participants Clinical Trials Phase I, II, III Quality Improvement Feasibility Strategy Effectiveness Safety Barriers Health Patient Populations Practice Workflows Policies CT Phase IV

7 Translational Medicine 2.Basic Research Lab Understand disease Create experimental models Test new drugs on these models. 3. Clinical Research Department Test new drugs on healthy volunteers and patients. Phase I III, clinical trial 4. On the field Side-effects Non-responders Interraction Cost 1.The Patient One main problem One problem solved, another one created

8 *One example: myocardial infarction and reperfusion injury

9 *Myocardial Infarction *= Heart Attack *results from the interruption of blood supply to a part of the heart, causing heart cells (myocardium) to die. *leading cause of death for both men and women worldwide in 2004 *ischemia = restriction in blood supply.

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11 *The Cure: Reperfusion ASAP *Reopening the occluded coronary artery as fast as possible with thrombolysis or percutaneous coronary intervention (PCI).

12 *A double edged cure *Reperfusion injury: brutal reperfusion of ischemic myocardium causes damage (edema, apoptosis, cytotoxic signals) that increase the final infarct size. Reperfusion injury adds up to 40% to the final infarct size.

13 *Experimental Model in 1974 EDEMA Fibrin deposits Capillary lumen CYTOTOXIC SIGNALS DISTAL EMBOLIZATION Red Blood Cell Kloner et al. J Clin Invest 1974 Endothelial rupture Cardiac capillary Endothelium White Blood Cell INFLAMMATIO N

14 *Back to the Lab to Find a Solution

15 *Experimental Model (pathophysiology). *Ischemia and reperfusion with control of different characteristics of ischemia and reperfusion stability. *Assess macroscopic and microscopic / cellular characteristics of reperfusion injury.

16 39 dogs with 60 minutes of coronary occlusion and different reperfusion techniques applied before or after occlusion. Ischemic postconditioning: brief repeated episodes of ischemia applied at the reopening of the occluded coronary artery. Assess the effect of postconditioning on final infarct size in comparsions to controls.

17 *Infarct Size Measurement TTC

18 *Results - Postconditioning reduces infarct size significantly (-40%) - Postconditioning reduces myocardiale edema in the ischemic myocardium. - Postconditioning reduces inflammation in the ischemic myocardium.

19 *Confirmative Experimental Trials *Understand the basic mechanisms. *Reproduce and push further the same results. Postconditioning inhibits opening of the mitochondrial permeability transition pore and provides a powerful antiischemic protection. PI3K regulates the opening of the mitochondrial permeability transition pore in rat hearts reperfused with low pressure or postconditioning The first minute of reperfusion in the rat model is critical to cardioprotection by postconditioning. Protection by Cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. Cyclosporin A given Griffiths prior to EJ, reperfusion Halestrap AP. inhibits J Mol Cell opening Cardiol 1993 of the mptp and reduces infarct size and reperfusion injury.

20 *Pharmacologic / Intervention Model (therapeutic). *Mechanical postconditioning reduces infarct size through different mechanisms (inhibition of mptp). *Cyclosporin A reduces infarct size in a similar way.

21 *Clinical Proof of Concept Study -Randomized, multicenter, open label, controlled study. -30 patients with first acute myocardial infarction: -Chest pain onset < 12 hours -Occluded coronary artery -Signed informed consent Primary Endpoint: area under the curve of myocardial biomarkers (troponin I, creatine kinase).

22 Postconditioning with Angioplasty Balloon during PCI

23 *Results Significant infarct size reduction by 36% in the postconditioning group ( IU vs IU, P<0.05)

24 MBG *Secondary Endpoints P=0,04 P=0,09 ST-segment elevation (mm) Suggest reperfusion injury reduction by ischemic postconditioning.

25 Pilot Trial on Cyclosporin IV given Prior to Reperfusion in AMI patients with occluded coronary artery. 58 patients included Primary endpoint: area under the curve of creatine kinase, infarct size determined by MRI. Results: significant reduction of infarct size by cyclosporin A.

26 *Pivotal Phase III Clinical Trial: the CIRCUS study. C I R C U S *Cyclosporin A at the acute phase of STEMI patients with occlusion of LAD. *Multicenter, randomized, international, double-blind, controlled study. *Primary endpoint: composite of cardiovascular death, hospitalization for heart failure, cardiac remodeling by echocardiography, assessed at 1 year. *972 patients planned. *Cyclosporin given intravenously immediately prior to reperfusion at 2.5 mg/kg dosage.

27 *Pivotal Phase III Clinical Trial: the CIRCUS study. *Follow-up at 1, 3, 6 and 12 months. Echocardiography at baseline and at 1 year. *42 participating centers in France, 3 in Belgium, to be started in Spain. *Study start: April 2011.

28 Nombre de patients *Pivotal Phase III Clinical Trial: the CIRCUS study. 450 Ongoing as we speak Courbe d'inclusion CIRCUS patients included so far 50 0 févr-11 avr-11 juin-11 août-11 oct-11 déc-11 févr-12 avr-12 juin-12 août-12

29 *Conclusion *Success in medicine and medical research relies on a good application of translational medicine. *Taken apart, each component usually leads to nothing but trivial knowledge, failure, and potential harmfulness. *Importance of communication between all components in order to produce solid research models. *Should be centered on the patient s problem.