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Eli Lilly and Daiichi Sankyo have revealed plans to seek FDA approval for anti-clotting agent prasugrel imminently, despite new results from a Phase III trial which reveal safety concerns. The safety issues are likely to delay the launch of the drug, which could significantly impact sales due to competition from generic Plavix.
The crux of thrombosis prevention is a delicate balancing act between efficacious clot prevention and bleeding risk. The results of Eli Lilly and Daiichi Sankyo's Phase III TRITON TIMI 38 trial, due for publication on November 15, 2007 suggest that prasugrel's increased potency may upset this balance to increase bleeding risk and raise some serious safety concerns.
The results show that prasugrel's increased potency make it more effective in lowering heart attack risk than Bristol-Myers Squibb and Sanofi-Aventis's Plavix (clopidogrel). Patients prescribed prasugrel were 19% less likely to suffer a fatal, or non fatal, cardiovascular event, compared to those in the Plavix comparator group. The most striking result was a 42% reduction in the risk of recurrent heart attacks resulting in death, although the overall mortality benefit was not significant. The rate of life-threatening bleeds was 0.5% higher in the prasugrel group, and this was borne out in a four-fold increase in fatal bleeds.
Ultimately, these statistics illustrate that in preventing 23 more heart attacks, per 1000 patients, prasugrel will cause six more cases of life-threatening bleeding than Plavix – a concern that is exacerbated by the tendency of clinical trials to overestimate efficacy, and underestimate safety issues. The market has become even more pessimistic about the future of the drug since Lilly suspended two Phase II trials at the recruitment stage – presumably so the dose can be lowered, to reduce risk of bleeding.
The market for antiplatelet therapies – used to control blood clotting through the inhibition of platelet aggregation – is currently dominated by Plavix (clopidogrel), the blockbuster antithrombotic agent which generated over $5 billion of revenue for co-marketers, Bristol-Myers Squibb and Sanofi-Aventis in 2006.
Eli Lilly and Daiichi Sankyo are currently in collaboration to create a "next generation" version of Plavix. Their experimental compound, prasugrel, has an identical mechanism of action – inhibiting platelet aggregation by blocking the P2Y12 receptor on the surface of the platelet – and is essentially a "me-too" drug that aims to erode Plavix's lucrative position in the market.
"Me-too" drugs are frequently justified by arguing they provide back up for patients who don't respond well to the available drugs, and that the competition drives the prices down. Clopidogrel "non-responders" are estimated at 9-26% of patients, and represent the most obvious target population for Lilly/Daiichi Sankyo. However, the companies must also demonstrate prasugrel's superiority in terms of efficacy, or safety, and ideally both.
In late 2004, Lilly/Daiichi Sankyo touted the results from the Phase II JUMBO-TIMI 26 trial, in which prasugrel was compared to clopidogrel, with safety and efficacy as the primary and secondary objectives, respectively. The trial did suggest that prasugrel may be more efficacious in preventing ischemic events than clopidogrel, but it did not go unnoticed that the 300mg dose of clopidogrel was half that recommended by the results of the ISAR-REACT trial, and adopted in standard clinical practice. "More than 50% of interventional cardiologists are using 600mg doses of clopidogrel," said Dr Paul Gurbel, director of The Sinai Center for Thrombosis Research, at Baltimore.
In light of the abrupt withdrawals of the best-selling painkiller, Vioxx, and multiple sclerosis medication, Pargluva, the FDA are subjecting new drug candidates to much closer scrutiny. The current regulatory climate favors drugs most able to demonstrate superior safety, which may pose a significant hurdle for Lilly/Daiichi Sankyo, should they be required to run further, definitive studies, to prove prasugrel is safe for widespread use.
If Lilly/Daiichi Sankyo receive FDA approval for prasugrel, its market opportunity is likely to be restricted to the 9-26% of patients who are clopidogrel non responders, and those deemed a low risk of bleeding. However, even this niche market opportunity will be cannibalized as soon as Plavix is exposed to generic competition in 2011; in this circumstance, physicians are likely to see more sense in doubling, or tripling the dose of clopidogrel until adequate platelet inhibition is achieved.
Datamonitor is bearish in its forecast for prasugrel, predicting major market sales to peak at $1 billion in 2011; the reason for this was not only the potential elevation in bleeding risk expected to result from more potent platelet inhibition, but included the additional competition resulting from the expiry of the Plavix patent. Datamonitor also anticipates prasugrel's launch to be delayed by additional safety studies required by the FDA.
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