Statistics aside, it's the absolute efficacy benefit of Serada in VMS that will be the central review issue. I expect the FDA and the experts on its advisory panel to raise questions and concerns about the placebo-adjusted frequency and severity scores. Serada's inability to demonstrate durable effect at 24 weeks -- the regulatory benchmark for approval of VMS drugs -- will also be problematic for Depomed.
Let's now discuss the third phase III trial that Depomed conducted of Serada in VMS, this time under a Special Protocol Assessment agreement with FDA. BREEZE-3 was a double blind, placebo-controlled study of approximately 600 patients, randomized to receive a Serada total dose of 1800 mg or placebo. The co-primary efficacy endpoints were reductions in the mean frequency of moderate-to-severe hot flashes and the average severity of hot flashes, measured after four and 12 weeks of stable treatment. As in the prior BREEZE-1 trial, the treatment duration of the study was six months to establish the regulatory requirement for persistence of efficacy.
Mixed results from BREEZE-3 were reported in October 2012: Using the pre-specified, statistical analysis plan, Serada demonstrated a statistically significant reduction in the average frequency of hot flashes and severity of hot flashes at four weeks. At 12 weeks, Serada failed to demonstrate a statistically significant reduction in the average frequency of hot flashes but did show a statistically significant reduction in hot flash severity.
At 24 weeks, Serada failed to demonstrate a statistically significant benefit on either of the two measures of VMS efficacy.While Depomed bulls argue otherwise, it is clear to me that the efficacy of Serada as defined by the SPA agreement was not fully met in the BREEZE-3 study. Like in the previous negative studies, Serada failed to demonstrate a significant reduction in the frequency of hot flashes beyond four weeks. Across all three phase III studies, the data compiled cast major doubts against Serada's proving a meaningful benefit in VMS, especially when women experience symptoms for months to years. Bulls also contend that Serada should be approved because women suffering from VMS deserve a safer alternative than the current standard treatment, hormone replacement therapy. While hormone replacement therapy can be used safely for prolonged periods of time in a lot of cases, I agree that there will be some women for whom an alternative therapy is preferred. Luckily, the FDA panel on March 4 will be reviewing just such a safe, effective treatment for VMS on the same day that it shoots down Serada. I'm referring to Noven Pharmaceuticals' Low-Dose Mesylate Salt of Paroxetine (LDMP), which is also currently under FDA review for the treatment of VMS associated with menopause. Paroxetine is a highly selective serotonin-reuptake inhibitor and the potential mechanism of its action in VMS would relate to normalizing serotonin signaling in the brains' temperature control area.