Washington Editor

Cypress Bioscience Inc. and its partner Forest Laboratories Inc. submitted a new drug application (NDA) for milnacipran to treat fibromyalgia, a disorder characterized by pain, fatigue, muscle stiffness, cognitive dysfunction and insomnia.

Currently, only Pfizer's Lyrica (pregabalin), an alpha-2 delta ligand, is approved in the U.S. to treat fibromyalgia, which affects up to 6 million Americans. Milnacipran, a norepinephrine-serotonin-reuptake inhibitor, already is sold in about 50 nations outside the U.S. for depression and other nonpain indications.

San Diego-based Cypress in August 2001 gained the rights from Paris-based Pierre Fabre Medicament to develop and market the drug in the U.S. and Canada for fibromyalgia. The firms in 2003 expanded the agreement to include any product containing milnacipran as an active ingredient for any indication in the U.S. and Canada.

Cypress formed a partnership with New York-based Forest in January 2004 under which Forest will be responsible for marketing milnacipran in the U.S. Specific financial details of that deal were not disclosed, but Cypress said it could bank up to $250 million when certain milestones were achieved in addition to an undisclosed amount in royalties based on sales.

In a joint statement, Cypress and Forest said Monday that the NDA for milnacipran is based on a composite responder analysis that requires each patient to experience concurrent and clinically meaningful improvements in pain, patient global impression of change in disease status and physical function. The composite responder approach, the companies contended, is considered a more stringent assessment of therapeutic effect than the evaluation of individual symptoms.

Results of two double-blind, placebo-controlled Phase III studies of 2,084 patients showed that milnacipran demonstrated improvement in treating fibromyalgia syndrome and its associated pain. However, results released in September 2005 of the first Phase III trial of 888 participants, known as FMS-031, showed that the drug missed its primary endpoint of achieving statistical significance. (See BioWorld Today, Sept. 30, 2005.)

The FDA later revised its guidelines for approval of fibromyalgia therapies and agreed to allow the firms to reassess the data based on an updated analysis approach, which included a change from last observation carried forward to baseline observation carried forward (BOCF), and other changes in the use of primary endpoints for efficacy evaluation.

Using the revised analysis, a daily dose of 200-mg milnacipran produced statistically significant differences compared with placebo for both the fibromyalgia syndrome and pain of fibromyalgia composite endpoints, the firms said in November.

At a daily dose of 100 mg, milnacipran produced a statistically significant difference on the fibromyalgia syndrome composite endpoint and trended toward significance on the pain of fibromyalgia composite endpoint using the BOCF analysis, the companies added.

Results issued in May of the second Phase III trial of 1,196 patients, known as MLN-MD-02, showed that the drug had achieved statistical significance in its primary endpoint using the BOCF analysis. (See BioWorld Today, May 24, 2007.)

About 25 percent of patients treated with 100-mg milnacipran and 26 percent of those who received 200 mg in study MLN-MD-02 met the composite syndrome responder criteria compared with 13 percent on placebo, the firms said.

About 39 percent of patients receiving 100 mg and 46 percent of those given 200 mg met the composite pain responder criteria compared with 25 percent of patients taking placebo, the companies added.

Shares of Cypress (NASDAQ:CYPB) were down 12 cents Monday, to close at $11.03. Shares of Forest (NYSE:FRX) were down 71 cents, to close at $36.45.