The drugmaker's once-a-day tablet, which is under development and called Fablyn, may increase the chances of death from cancer or stroke, according to an FDA review posted on the agency web site in advance of a September 8 advisory committee meeting.
The drug was rejected by the FDA in September 2005, but Pfizer and Ligand Pharmaceuticals last year resubmitted their application after re-examining safety data. Safety issues, however, will again be front and center at next week's meeting. The FDA reviewers wrote the following on page 73:
"The principal safety concerns identified during review of the lasofoxifene (Fablyn) clinical trials were: • An increased percentage of subjects who died in the lasofoxifene treatment group compared to the placebo treatment group; • An increased percentage of subjects with serious venous thromboembolic events in the lasofoxifene treatment group compared to the placebo treatment group; • An increased percentage of subjects with gynecological adverse events (i.e., endometrial polyps, increased endometrial thickness, and vaginal bleeding) or undergoing uterine surgical procedures in the lasofoxifene treatment group compared to the placebo treatment group.
In its own briefing documents, Pfizer maintained the increase in deaths cited by the FDA reviewers for the low-dose version of Fablyn may be due to chance. A statistically significant increased risk wasn't seen at the higher dose for which the company is seeking approval.
"No dose-response relationship, pattern of death causality, or plausible mechanistic explanation accounts for the observed difference in numbers of deaths,'' the drugmaker wrote (see page 70). "Rather, the observed difference appears to be due to an unusually low mortality rate for the placebo group'' in one of the regions where the study was conducted.
Last time around, the drug was rejected because the FDA was concerned it may lead to cancer in the lining of the uterus, according to Pfizer. There were no increases in uterine cancer in the most recent study, although at the lower dose of 0.25 mm there was a rise in combined fatalities from all cancers.
"The higher proportion of deaths in the 0.25-milligram lasofoxifene group was statistically significant compared to that in the placebo group, based on 5-year data,'' the FDA reviewers wrote. "The excess number of cancer-related deaths in the lasofoxifene-treated subjects does not appear to be focused on any specific organ system.''
The Pearl study followed more than 8,000 patients for five years, although results have never been published. There were 38 percent more deaths among those taking the lowest dose compared with those on placebo, with a total of 228 deaths among all patients on the drug. There were 14 more cancer deaths, a 70 percent increase, in those on the low dose Fablyn compared with a placebo after five years. Deaths from stroke occured more than twice as much.