FDA approvable letter spells bad news for Epix Medical

The walls came tumbling down on Epix Medical on Jan. 14, when the FDA delivered what initially appeared to be good news.

The share price of the publicly traded company dropped 30% immediately following receipt of a letter stating that the company's MR blood pool imaging agent, MS-325, could be approved - but only if the company completes additional clinical studies that demonstrate efficacy.

The stipulations necessary for approval will significantly delay the agent's release to market, according to Michael D. Webb, Epix president and CEO. How long that delay will last is hard to say.

"The specifics of the FDA's requirements won't be known until we have had the opportunity to discuss the issues in detail," Webb said.

Additional clinical testing will likely be necessary to answer lingering questions about how MS-325 relates to noncontrast MR angiograms used for comparison in the phase III trials. The FDA also has questions about the statistical treatment of images that could not be interpreted. The agency expressed no concerns in the approvable letter about safety or possible manufacturing deficiencies.

Approvable letters are usually good news for drug companies. They indicate that the submitted drugs are close to being approved and outline relatively minor issues that need to be resolved. This was not, however, the case for Epix.

The company is preparing to enter into discussions with the FDA to determine what it should do next after learning that key questions raised three months earlier were not adequately answered as part of the original review. The outcome is critical to Epix. MS-325 is the only one of its several products to have entered clinical trials.

The company might begin earning revenues from MS-325 if a pending review for marketing in Europe is successfully completed. But that decision might not be in hand until the end of the year. And the most lucrative market for the drug is the U.S.

The company's U.S. marketing partner, Berlex, the U.S. arm of contrast giant Schering, is also affected by the delay. Berlex has been awaiting the final go-ahead to launch MS-325 since October. The FDA was to have completed its review then, but it extended the deadline to January.

The reasons for the delay were exactly the same as those stipulated in the action letter the FDA issued in October. The agency notified Epix at that time that it had two concerns.

First, the methods for acquiring noncontrast-enhanced images were not standardized. These images were supposed to establish a baseline against which the contrast-enhanced images could be compared. The lack of standardization raised questions in FDA reviewers' minds about the validity of the results.

"Epix responded to the FDA with analyses showing that the superiority of MS-325 MRA over noncontrast MRA does not fundamentally depend on the choice of noncontrast scanning method," Webb said.

The FDA didn't buy that argument, however.

Second, the agency was concerned about the number of uninterpretable scans. Again, this related to the noncontrast-enhanced imaging methods. The FDA questioned whether the high rate of uninterpretable scans might have artificially exaggerated the benefit of MS-325.

"Epix provided reanalysis of the phase III data based on several alternative methods for the statistical handling of the uninterpretable scans in recent submissions," Webb said. "These analyses consistently demonstrated a benefit with MS-325."

Again, the FDA was not convinced.

In the telephone conference following receipt of the approvable letter, Webb stated that Epix, working with Schering, had been responsive to the agency's questions throughout the new drug application review. It had sought and received FDA guidance and pursued a phase III strategy suggested by the agency.

"Despite this," Webb said, "they have indicated that they require additional information."

Now the waiting and the discussions must begin anew. Webb and his colleagues will continue talks with the FDA, he said, in which they hope to define a framework for addressing the agency's concerns.