FDA is extending the user fee goal date for action on Bristol-Myers Squibb/AstraZeneca's DPP-4 inhibitor antidiabetic Onglyza (saxagliptin) to July 30.

Given what already looked like an inevitable delay beyond the initial April 30 user fee goal date, a formal extension of the deadline is probably the best possible outcome for Bristol and AstraZeneca.

"We remain confident in the comprehensiveness of our overall development program and submission for Onglyza," Bristol says.

For those trying to read the tea leaves about the prospects for an approval on the new deadline, Bristol reports that "routine pre-approval inspections have begun" for the application. That milestone is often an important indicator that FDA is, in fact, in the final stages of a review.

Post-Marketing Study Under Review

Onglyza cleared a critical milestone April 1, when an FDA advisory committee said the data in the NDA are sufficient to meet new cardiovascular safety guidelines for diabetes medications. However, it was clear at the time of the committee review that approval would not be forthcoming by the first user fee action deadline, April 30 (¹ Also see "Bristol/AZ Saxagliptin Clears Cardiovascular Safety Hurdle; Approval Timing Still Uncertain" - Pink Sheet, 1 April, 2009.).

One key reason for the delay is the need for Bristol/AstraZeneca and FDA to agree on a cardiovascular outcomes trial that will likely be a post-marketing study requirement upon approval. Bristol told the committee that it is eager to do what could be a landmark trial in that area--one designed to demonstrate a cardioprotective effect of saxagliptin--but said it was awaiting the outcome of the committee vote to even begin discussions of the study with FDA (² Also see "Post-Marketing Trial Key To Saxagliptin Approval – And Commercial Potential" - Pink Sheet, 6 April, 2009., p. 9).

Under FDA's rules for the user fee system, the agency can extend the review deadline by three months when the sponsor makes a major amendment to its NDA near the end of the first review period.

In this case, Bristol confirms that it has submitted a proposal for the post-marketing trial to the agency and that presumably constitutes the grounds for the extension. Beyond that, the company says there is no significant new information for the agency to consider since the advisory committee review.

Best Interim Outcome

A three-month extension is no guarantee of a positive outcome of approval, but from the sponsors' perspective it is probably the best interim step towards that goal.

The other potential outcomes as of April 30 would have been a "complete response" letter or a missed application deadline. A "complete response"--even if it raised only minor issues--would almost certainly mean a delay of much longer than three months before the next communication by FDA.

In this context, a "complete response" would also have signaled that FDA still had questions about approvability of the application unrelated to the cardiovascular safety issues discussed by the advisory committee. The April 1 committee review was unusual in that it focused solely on the application of the new CV guidelines; FDA carefully avoided any discussion of its view of the efficacy data or other safety issues.

The other option--a missed user fee deadline--would have put saxagliptin into a state of regulatory limbo, with no certain time point for further communication from the agency. While FDA often completes formal action on overdue applications in a matter of weeks, other sponsors--including Takeda with its DPP-4 inhibitor alogliptin--experience much longer delays.

Alogliptin's initial user fee deadline was October 2008, but that deadline lapsed without action by the agency. In December, Takeda said it had a new action date at the end of June. That timeline puts alogliptin back ahead of saxagliptin for FDA action. However, approval at that date looks extremely unlikely for the Takeda drug, given the company's disclosure that its current dataset is not sufficient to meet the new CV safety guidelines (³ Also see "Novo Nordisk Makes Case For Alogliptin-Shadowed Victoza" - Pink Sheet, 6 March, 2009.).

-- Michael McCaughan (m.mccaughan@elsevier.com)

Bristol/AZ Saxagliptin Review Deadline Pushed Back; Tea Leaves Still Look Good For Approval

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