June 3, 2009
Margaret Hamburg, M.D.
Commissioner, Food and Drug Administration
10903 New Hampshire Ave
Silver Spring, MD 20993
Dear Dr. Hamburg,
The Division of Cardiovascular and Renal Products is currently reviewing New Drug Application 22-307, prasugrel hydrochloride for use in acute coronary syndrome(ACS). We have previously raised concerns about the efficacy and safety of prasugrel, as well as serious flaws in TRITON-TIMI 38, the Phase 3 study comparing prasugrel with clopidogrel (PLAVIX) in patients with ACS.,,,,, One of the authors of our letter (V.S.) is a paid U.S. patent application holder for prasugrel and worked on early clinical studies of prasugrel. We urgently request that the FDA halt its review of prasugrel for possible approval until a properly-designed Phase 3 study has been performed with a lower, safer dose of prasugrel and properly defined clinical outcomes.
1) WRONG DOSE OF PRASUGREL STUDIED IN TRITON-TIMI 38
Prasugrel and clopidogrel are both thienopyridine drugs that similarly inhibit adenosine diphosphate-induced platelet aggregation. However, based on conventional aggregation studies, the loading (60mg) and maintenance (10mg daily) doses of prasugrel used in TRITON-TIMI 38 were approximately 2.5 times more potent than the doses of clopidogrel used (300 and 75mg). Furthermore, in the Phase 2 JUMBO study, prasugrel at a dose of 10mg daily resulted in complete platelet inhibition in some patients, which is unseen with any currently marketed oral antiplatelet agents. Given concerns that this degree of platelet inhibition would translate into an excess risk of hemorrhage, one of the authors (V.S.) suggested to Lilly and TRITON-TIMI 38 investigators as early as May 2004 that a much lower dose of prasugrel, 3-4 mg daily, be tested in dose ranging studies before proceeding with a Phase 3 clinical trial.
TRITON-TIMI 38 did not test two uniquely different methods of platelet inhibition in the setting of ACS. Rather, it tested platelet inhibitors that act through a similar mechanism at two different potencies, with prasugrel being more potent and appearing much less safe than clopidogrel. Not surprisingly, this trial showed a dramatic increase in serious hemorrhage with prasugrel compared to clopidogrel, a drug that is already associated with increased bleeding, as well as an unexpected increase in new cancers.
2) SAFETY CONCERNS: HEMORRHAGE AND CANCER
In TRITON-TIMI 38, prasugrel increased the risk of life-threatening hemorrhage by half compared with clopidogrel, and the risk of fatal hemorrhage fourfold. The bleeding risk in patients undergoing coronary artery bypass graft surgery was “particularly malignant,” in the words of an FDA reviewer – major bleeding events occurred in 11.3% of patients on prasugrel compared to just 3.6% of patients on clopidogrel. However, because TRITON-TIMI 38 excluded patients with the greatest risk of hemorrhage, the actual risk in the general population of patients with ACS is likely to be much greater.
In addition, an excess of new cancers, especially highly metastatic solid tumors, was detected in the prasugrel group. While prasugrel does not appear to be a carcinogen, it may act as a cancer promoter through its excessive antiplatelet activity, diminishing the natural capacity of platelets to halt the spread of locally-confined or “silent” tumors.
While the purported efficacy of prasugrel is heavily weighted to early events, with most occurring during the first week of treatment, the risk of hemorrhage and cancer increases with greater duration of therapy. This is problematic, as dual antiplatelet therapy is recommended for one year after percutaneous coronary intervention (PCI) with drug eluting stents, and many patients continue dual antiplatelet therapy indefinitely.
3) CLAIMS OF EFFICACY FROM TRITON-TIMI 38 ARE SUSPECT
The efficacy of prasugrel over clopidogrel in TRITON-TIMI 38 has been overstated in several ways in published analyses., First, the 300mg loading dose of clopidogrel was suboptimal. At this dose, loading is recommended at least six hours prior to PCI, yet in TRITON-TIMI 38 over half of patients were loaded after PCI. This delay favors prasugrel, which has a faster onset of platelet inhibition than clopidogrel, and subgroup analysis shows that the benefit of prasugrel over clopidogrel was marginal in patients who were loaded prior to PCI. Therefore, this trial did not offer a “fair” comparison of prasugrel and clopidogrel, both because of the dose selection and the timing of the loading dose.
Second, most of the reduction in the primary endpoint with prasugrel was driven by nonfatal myocardial infarction (MI), the definition of which changed several times during development of the drug. In TRITON-TIMI 38, the primary endpoint included asymptomatic elevations in cardiac enzymes, which are of questionable clinical significant but comprised over half of all nonfatal MIs.
Third, most MIs were adjudicated by a central committee rather than by site investigators. Analysis by the FDA reveals that site-adjudicated events were more predictive of death than centrally adjudicated events, and that mortality was similar in patients with asymptomatic cardiac enzyme elevations and patients without MI. If only events reported by site investigators were counted, the difference between prasugrel and clopidogrel was no longer statistically significant. Also arguing against the clinical relevance of these enzyme leaks, the number of heart failure deaths was similar in the prasugrel and clopidogrel groups.
The available evidence suggests that prasugrel at a daily dose of 10mg is unsafe, resulting in excess hemorrhage and perhaps cancer. The efficacy of the drug is also in question. While prasugrel may turn out to be a useful new antiplatelet agent at a lower dose, it does not fulfill an “unmet need” as defined by the FDA – there is substantial doubt of the superiority of prasugrel over available effective antiplatelet therapies in meaningful clinical outcomes, and certainly no improvement in mortality. Therefore, priority review of this drug is unwarranted. Further, current data are insufficient to demonstrate its safety and efficacy for use in ACS, and we urge the FDA to immediately halt review of this drug until a new Phase 3 study can be conducted with an appropriate lower dose of prasugrel and properly defined outcomes.
Victor Serebruany, M.D., Ph.D.
Johns Hopkins University
James Floyd, M.D.
Sidney Wolfe, M.D.
Cc: Joshua Sharfstein, M.D., Janet Woodcock, M.D., Norman Stockbridge, M.D., Ph.D.
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