Pharmacy & Therapeutics - March 2009 - (Page 155) MEETING HIGHLIGHTS FDA Advisory Committee Meeting on Prasugrel For Acute Coronary Syndromes Walter Alexander On February 3, 2009, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted affirmatively on a New Drug Application for prasugrel HCl 5 and 10 mg (proposed name, Effient). At a meeting in Silver Spring, Maryland, the panel voted unanimously (9–0) to approve the drug for the treatment of acute coronary syndromes (ACS) in patients with either • J. Anthony Ware, MD, Vice-President, Lilly Research Laboratories, Indianapolis, Ind. Prasugrel, which was approved in Europe on February 23, is considered the most important drug in Eli Lilly’s pipeline. Presenting for the drug’s sponsors (Daiichi Sankyo, Inc., and Lilly), Dr. Ware noted that the proposed indications were for (1) unstable angina (UA) or NSTEMI managed with percutaneous coronary intervention (PCI) and (2) STEMI managed with primary or delayed PCI. He explained that prasugrel has been shown to reduce the rate of a combined endpoint of cardiovascular (CV) death, nonfatal myocardial infarction (MI), or nonfatal stroke and to prevent stent thrombosis. The new thienopyridine’s faster, higher, and more consistent inhibition of platelet function, as compared with clopidogrel (Plavix, Bristol-Myers Squibb/ Sanofi-Aventis), is expected to produce important clinical benefits for patients with ACS. • Eugene Braunwald, MD, Distinguished Hersey Professor of Medicine, Harvard Medical School, and Chairman, TIMI Study Group, Brigham and Women’s Hospital, Boston, Mass. • Jeffrey S. Riesmeyer, MD, Senior Clinical Research Physician, Prasugrel Product Team Medical Fellow, Eli Lilly, Indianapolis, Ind. • Elliott Antman, MD, Professor of Medicine, Harvard Medical School, and Director, Samuel A. Levine Cardiac Unit, Brigham and Women’s Hospital, Boston, Mass. Dr. Braunwald, who was listed as an external consultant, said that there are 1.57 million hospital admissions for ACS annually in the U.S., indicating a significant unmet medical need. He noted the limitations of clopidogrel, the current standard, pointing to its modest antiplatelet effect, high variability in responses among patients, and delayed onset of action. He underscored that evidence from clinical trials strongly suggests that the lesser clopidogrel response leads to increased risks of MI and stent thrombosis. Discussing prasugrel’s pharmacology, Dr. Riesmeyer said unstable angina/non–ST-segment elevation myocardial infarction (UA/NSTEMI) or STEMI. The FDA is not constrained to follow the panel’s recommendations, but it usually does. If approved, prasugrel would be the first within its class to compete with clopidogrel (Plavix), which is scheduled to go off-patent in 2011 in the U.S. that the benefits of prasugrel, relative to clopidogrel, can be attributed to more effective platelet inhibition from the higher active metabolite concentrations achieved through prasugrel’s loading dose and higher response rates with prasugrel’s 10-mg maintenance dose. Dr. Antman gave the core of the sponsors’ presentation— the results of TRITON-TIMI 38 (Trials to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction). This study was a 12-month double-blind comparison of clopidogrel (with a 300-mg loading dose and a 75-mg maintenance dose) and prasugrel (with a 60-mg loading dose and a 10-mg maintenance dose). All patients received aspirin. TRITONTIMI 38 included 13,600 ACS patients with planned PCI. The findings show a balance of efficacy and safety, Dr. Antman said, with CV death, MI, and stroke rates (the combined primary endpoint) of 12% at 450 days for clopidogrel and 9.9% for prasugrel (P = 0.0004). The number needed to treat for that benefit was 46. The rate of TIMI Major Bleeding after non–coronary artery bypass grafting (CABG), however, was higher for prasugrel at 2.4%, compared with a rate of 1.8% for clopidogrel (P = 0.03). The number needed to harm was 167. TIMI Major Bleeding was defined as any intracranial hemorrhage or overt bleeding requiring intervention associated with a decrease in hemoglobin of 5 g/dL or more. Both the UA/NSTEMI and STEMI patients experienced significant benefits with prasugrel (UA/NSTEMI, P = 0.002; STEMI, P = 0.019). Benefits were found consistently as well at 30, 60 and 90 days. In a prospectively defined landmark analysis, the primary endpoint also favored the prasugrel loading dose significantly at three days (4.7% vs. 5.6% for clopidogrel; P = 0.01) and the maintenance dose at 450 days (5.6% vs. 6.9% for clopidogrel; P = 0.003). Although an assessment of net clinical benefit (death, MI, stroke, and TIMI Major Bleeding) favored prasugrel (12.2% vs. 13.9% for clopidogrel; P = 0.004), a post hoc evaluation found that the advantage disappeared in patients 75 years of age and older. Clopidogrel was slightly favored in patients weighing less Vol. 34 No. 3 • March 2009 • P&T® 155
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