It looks like FDA's decision on Eli Lilly's anti-clotting drug prasugrel will not come before March 2009 at the earliest.

Members of FDA's Cardiovascular and Renal Drugs Advisory Committee have been contacted about their availability for a February panel meeting specifically on prasugrel, sources say. The agency's Drug Safety and Risk Management Advisory Committee may also be convened.

FDA already has scheduled a Dec. 10 meeting of the Cardio-Renal advisory committee. The agenda for that session, however is set: Acusphere's IMAGIFY (perflubutane polymer microspheres) injectable suspension imaging agent. The odds of a change are practically zero.

The potential February advisory committee date means it is almost impossible for FDA to deliver a decision before March. In fact, a March decision is probably the best-case scenario for Lilly and partner Daiichi Sankyo at this point.

Prasugrel, which will be marketed as Effient if approved, has been closely watched by FDA observers, drug sponsors and the investment community alike because of the drug's blockbuster potential in a primary care market and as a marker of the current state of FDA drug reviews as the agency continues to miss multiple user fee deadlines (See "Running Late: What It Means When FDA Misses a Deadline," ¹ Also see "Running Late: FDA Review Timelines Lengthen For New Product Applications" - Pink Sheet, 1 September, 2008. ).

Developments thus far in the review support those who argue that FDA is exhibiting overly cautious decision-making in an era of drug safety.

Lilly submitted the prasugrel NDA on December 26, 2007; FDA designated a six month priority review for the application in February. At the end of June, FDA extended the review by another three months due to supplemental information submitted to the agency (² Also see "Boehringer’s Aptivus Approved For HIV In Kids" - Pink Sheet, 24 June, 2008.). Then, FDA missed the September 26 deadline (³ Also see "Lilly Prasugrel Review Extended: Why No News May Be Good News" - Pink Sheet, 29 September, 2008.).

"This is a very large and complex submission, and it should not be surprising that delays occur," Lilly said. "We are working diligently with the FDA as they continue their review of the prasugrel NDA."

But the size of the NDA does not appear to be the cause for the delay with the review now in its 10 month.

A serious internal disagreement in FDA has developed over whether to approve the drug as it stands.

The decision to grant priority review in the first place suggests that the top review managers - namely, Office of Drug Evaluation I director Bob Temple and director of the division of cardio-renal drug products Norman Stockbridge - are excited about the potential for the drug. However, it appears that another party has made a compelling argument against approval of the application in its current state.

Three issues appear to have impeded an FDA decision: (1) the increase in minor and major bleeding and concerns of related deaths in the prasugrel arm; (2) more cancers discovered in the prasugrel group compared to clopidogrel in TRITON; and (3) a recent formulation issue either related to the active ingredient or excipient substance.

In Lilly's 13,000-patient TRITON clinical study, prasugrel produced a 19 percent reduction in the composite primary endpoint of cardiovascular death, non-fatal heart attacks or non-fatal strokes when compared with Bristol-Myers Squibb/Sanofi-Aventis's Plavix (clopidogrel).

TRITON also demonstrated a statistically significant 32 percent increase in minor and major bleeding. However, when you consider the primary endpoint, those bleeds didn't lead to deaths, heart attacks or strokes.

Time is of the essence when it comes to Lilly's marketing plans for the anti-platelet therapy, which the company hopes will replace Plavix as the standard of care. (Annualized U.S. revenue of Plavix would be approximately $4.8 billion based on second-quarter sales of $1.2 billion). Plavix is scheduled to go generic in 2011 meaning prasugrel will have to compete against generic clopidogrel in clinical practice and on drug coverage formularies.

In other words, timing of the approval is of critical commercial importance to Lilly.

- Ramsey Baghdadi (r.baghdadi@elsevier.com)

Lilly Prasugrel Delay Could Extend Well Into 2009

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