FDA staffers found clear evidence to prove that Merck's blockbuster drug candidate suvorexant is quite effective in promoting sleep, but the internal review cites multiple safety issues for the high doses studied in clinical trials. And agency staffers are asking an upcoming meeting of FDA experts to determine whether or not patients should be started off on an even lower dose of the insomnia drug than Merck ($MRK) is seeking an approval on.
Merck has repeatedly highlighted suvorexant as one of its top pipeline prospects, bullishly indicating blockbuster potential even though generics of therapies like Ambien are dominating a shrinking market. But the FDA staff review--which concludes that there's little difference in efficacy between the 10 mg dose or higher doses of suvorexant--instead zeroes in on the safety issues linked to the drug. And even though the FDA is steering the experts toward a lower dose of the drug, some of these safety issues could seriously hamper Merck's attempt to market the new drug.
"The lowest strength proposed for marketing by the sponsor is 15 mg," says the FDA review. "If a dosage strength lower than 15 mg is unavailable, we would need to consider if the drug could be marketed safely at all, if we believe that a substantial proportion of the indicated population needs a lower dose."
"The documents are tough, in our opinion," ISI analyst Mark Schoenebaum writes. "The high dose is deemed unsafe, and the FDA wonders if there is enough data at the safer low dose to draw firm safety conclusions."
The GABA inhibitors--Lunesta and Ambien--are known to work on regions of the brain which have contributed to cognition issues for patients. Suvorexant blocks orexins, which help keep the body alert. The theory is that targeting this new mechanism will give insomniacs--a whopping 10% of the American population--a better shot at a good night's sleep with fewer safety issues.
But making that case just got harder.
"Suvorexant clearly causes dose related, next day effects, including sedation, which can be of significant concern," concludes the FDA review. "For example, as noted above, there is an 8-fold increase in the incidence of next day somnolence between the low and high doses of suvorexant in the three-month controlled trial data that led to discontinuation (0.2 and 1.7%, respectively). The incidence of somnolence continues to increase for at least 60 days after initiation of treatment, and the duration of somnolence in suvorexant patients was longer than the duration of somnolence in placebo patients. There was also a dose-related increase in the incidence of somnolence and severe somnolence, and, interestingly, although this was also true in both age groups, elderly patients had a lower incidence of somnolence at each dose (low and high) than did the non-elderly patients."
Non-elderly patients also had next-day driving problems, regardless of the dose.
"Specifically, in a study (P035) of non-elderly adults, both 20 and 40 mgs were associated with an increase in patients who had excessive deviation in lane position the morning after a single bedtime dose taken the night before. This next-morning effect clearly persisted after 8 days of continuous dosing of 40 mg. Further, and critically, four women had to discontinue the testing due to excessive somnolence."
The staff review highlights 8 cases of suicidal behavior in the drug arm, compared to zero in the placebo arm. And the staff also wasn't buying Merck's assertion that there were no cases of cataplexy that could be linked to suvorexant.
"Specifically, in controlled trials, suvorexant caused an increase in the incidence of excessive daytime sleepiness, sleep paralysis, and hypnogogic/hypnopompic hallucinations. There were also numerous reports (N=45) of suspected cases of cataplexy. Although an adjudication panel did not consider any of these cases to be cataplexy, our independent review suggests that at least one, and perhaps several more, could reasonably have been cases of actual cataplexy."
"In our view," the review continues, "the data taken together (both safety and effectiveness, as well as pharmacokinetics) suggest that a lower dose should be recommended, at least as an initial dose."
- here's the FDA review (PDF)