A Question of Priorities: Lilly Prasugrel Prospects Looking Up

Lilly shareholders woke up this morning to find their company suddenly worth $1.4 billion more than it was at the close of trading yesterday.

Why? Because the Food & Drug Administration agreed with Lilly and Daiichi Sankyo that the new drug application for the clot-busting drug prasugrel (proposed trade name: Effient) merits a priority review. That means FDA plans to complete its initial review of the application in six months (by June 26) rather than 10 (October 26).

On paper, that sure doesn't seem like it justifies the 2.5% jump in Lilly shares prompted by the news. But Lilly should be used to that by now. Its shares have been on a rollercoaster ride while investors handicap the prospects for a critical new drug for the company.

In this case, the rollercoaster is heading back up, since many on Wall Street view the priority designation as more than just a possible four-month faster review time.

With good reason. A priority review designation implies a much higher probability of a "first-cycle" approval--meaning that not only will FDA provide an answer sooner than it would on a standard application, that answer is much more likely to be "yes" (an approval letter) rather than some form of "maybe" ("approvable" or "not approvable.")

In recent years, first cycle approvals for "standard" applications have become about as rare as white elephants. (We published that data in The RPM Report last year.) But priority applications still have been approved on the first go-around more often than not.

So, statistically speaking at least, the priority designation could mean the difference between a 2008 launch for prasugrel and a 2010 launch. That is a very big deal--especially since Lilly and Daiichi Sankyo desperately want to establish the drug before the market leader Plavix faces renewed generic competition in 2011.

Then there is what the priority designation suggests about the Lilly's plans to position prasugrel as superior to Plavix. Recall that the pivotal study of the drug--TRITON--compared prasugrel head-to-head versus Plavix, and found a significant reduction in cardiovascular events in favor of prasugrel. It also, however, showed an increased risk of major bleeding--though not nearly as big a risk as the magnitude of the efficacy advantage, especially when you exclude some high-risk subpopulations from the analysis.

Still, in a safety-first regulatory climate, the TRITON data spooked Wall Street, prompting concerns that FDA might not approve the drug at all without more data.

The "priority" designation does not guarantee that FDA will approve the drug without more data. It does, however, mean that the agency decided not to use the excess bleeding risk as an excuse to buy more time with a standard review designation.

FDA certainly could have gone that route: Bristol and Sanofi Aventis, for example, will argue that the apparent superiority of prasugrel in TRITON is simply an artifact of the loading dose of Plavix used in the study. A higher dose of Plavix, they say, would have shown the same reduction in cardiovascular events (and the same increase in major bleeds).

By granting a priority review, FDA is accepting the sponsors' claim that the drug would be an advance over Plavix based on the TRITON data. And the agency is also saying that it won't avail itself of an extra four months to dig into the data before making a decision.

Last but not least, the stock market's reaction reflects the element of surprise. Just yesterday, Daiichi Sankyo hosted an analysts briefing in Japan which included a slide suggesting an action deadline of October 26 for prasugrel.

The company said that it still hadn't heard from the agency regarding the formal designation of the application, but they sure seemed to be joining in the general belief that when it comes to priority designations, no news is bad news.

FDA's procedures call for notification to the sponsor of priority or standard status 60 days after filing. However, since 60 days is already one-third of the way through a priority review schedule, the agency often alerts sponsors that they have priority status well before that deadline.

So Wall Street, at least, seemed resigned to a standard review timeline. Now they have to reassess their perceptions of the drug.

The next milestone for prasugrel will be the scheduling of an advisory committee. Daiichi Sankyo says it fully expects one for prasugrel, noting that the new FDA Amendments Act directs FDA to convene committees for all new molecular entities or else provide written justification for skipping one. Separately, the agency also has to answer to Congressional overseers who want to see open discussion of any dissenting views on applications--making it even more perilous for the agency to skip a committee if there is anything but total consensus on approvability.

For now, FDA's next tentatively scheduled meeting of the Cardio-Renal Drugs Advisory Committee is June 24-25. If prasugrel is added to that committee, it clearly won't be approved by the end of June. But there is nothing (apart from logistics) to prevent FDA from scheduling a meeting before those dates. FDA typically announces a meeting agenda at least a month in advance, so that would imply a notice in the March/April timeframe.

One thing you can bet on: this rollercoaster ride isn't over yet.