BioWorld International Correspondent

LONDON - The FDA issued Vernalis plc and its partner Endo Pharmaceuticals Inc. a not approvable letter for the supplemental new drug application for Frova (frovatriptan) in the treatment of menstrual migraine, questioning if the positive clinical data were "clinically meaningful" and saying the possibility of serious vascular adverse events could not be ruled out.

The partners are annoyed that the FDA did not get in touch to discuss the data, after extending the review period twice. Simon Sturge, CEO of Vernalis, told BioWorld International, "We are just so surprised with the reaction from the FDA."

The agency had not engaged the companies in any dialog during the extended review cycle to discuss its interpretation of the file. Sturge said attempts to communicate with the FDA, including phone calls and emails, were not acknowledged.

Triptans have a vaso-constricting effect, and carry a class warning to avoid their use in patients with heart problems. The FDA said that although no such side effects emerged in the clinical development program of Frova for menstrual migraine, an increased risk, compared to acute use of the drug, could not be ruled out.

"Triptans as a class are known to have this effect, so we can't rule it out," Sturge said. "We are being asked by the FDA to prove a negative, in which case, we may as well all pack up and go home."

Sturge also is frustrated because the design of the safety trial, in which 300 women took Frova six days per month for a year, was agreed on by the FDA. Most of the women elected to continue treatment at the end of the 12-month trial. The two efficacy trials involved 1,000 women.

The FDA's letter acknowledges that both pivotal efficacy trials submitted as part of the application met their primary endpoints, significantly improving the number of headache-free perimenstrual periods. Peter Lankau, president and CEO of Chadds Ford, Pa.-based Endo, said he believes the data were "sufficiently compelling" to secure the extension of the labeling.

The ruling has implications for Endo's 2007 financial results, and Landau said he expects to provide further guidance with its third-quarter results.

FDA approval would have triggered a $40 million milestone payment to Winnersh, UK-based Vernalis from Endo, and Vernalis was proposing to use $20 million of that to pay down a loan from Endo, which it is due to repay by 2009.

Shares in Vernalis (LSE:VER) fell more than 50 percent Monday to close at 20 pence. Shares of Endo (NASDAQ:ENDP) dropped 66 cents Monday to close at $30.35.

Sturge stressed that Vernalis has another product, Apokyn for Parkinson's disease, on the market, and seven in clinical development. However, the FDA decision will prompt a rethink. "We have already been evaluating a number of options for our overall operations, which we shall now review in the light of the FDA decision."

Even with the $40 million, Vernalis needed to raise money at some point. "We need to clarify what the shareholders' appetite will be now," Sturge added. "It's impossible to say what we need to raise and when. But there are also questions about what sort of company we would be asking shareholders to invest in, can we renegotiate the [Endo] loan terms and so on."

The two companies had said they would start marketing Frova in the new indication beginning in January, and were keen to note the FDA's decision does not reflect on the current approved labeling of frovatriptan, a selective 5-HT receptor agonist for acute use.

For the six months prior to June 2007, sales of frovatriptan by Endo and Vernalis's European marketing partner Menarini increased by 23 percent over the same period in 2006 to $38.6 million. Approximately $11 million of that came to Vernalis as royalties.

While Endo and Vernalis were frustrated by the delays in completing the review of the application, they felt confident of approval, since the FDA did not ask for any additional information.

Menarini is due to file the same data for European approval. "Knowing the robustness of the data, there's no reason why Menarini shouldn't file," Sturge said. However, he had not had the opportunity to discuss the implications of the FDA's not approvable letter with the company.