UPDATED: FDA panel backs low-dose rollout of Merck's sleep drug suvorexant

A panel of experts assembled by the FDA has given Merck a boost in its quest for an approval of the sleep drug suvorexant. A clear majority endorsed the drug's efficacy and added they were satisfied with the safety profile they saw for the lower doses of the drug that Merck wants to start patients on. But in a final, closer vote, a slight majority of the experts determined that the higher doses Merck ($MRK) wants approved are not safe, which could hamper any future sales effort.

The final decision about suvorexant's future now shifts to the agency, which has already indicated that regulators want to start patients off at a very low dose of 10 mg, which Merck concluded isn't effective. The vote backing the drug came after agency insiders told the panel that higher doses of suvorexant were clearly linked with a host of safety concerns.

By a vote of 12 to 4 and 16 to 0, with one abstention, the panel backed the FDA's conclusion that the drug is effective in inducing and maintaining sleep. Eleven of the panelists voted against requiring Merck to conduct another trial on the 10 mg dose ahead of a formal decision. Most of the experts said they were satisfied that the low dose could work and is relatively safe. Five voted that another trial should be conducted, clearly unconvinced by the Phase II data that was used to support the low dose and left scratching their heads over the fate of a dose that Merck officials clearly stated isn't efficacious enough. 

Panelists also concluded that the safety profile of the 15 mg to 20 mg dose--Merck's ideal starting doses for non-elderly and elderly patients--is acceptable. Many of the panelists clearly indicated that they want alternative sleep therapies to the ones they have now, but analysts are likely to wonder if the FDA will be persuaded to approve a starting dose that the agency review concludes is unsafe.

But Merck lost a close vote on the safety profile of the drug at the high doses, with panelists expressing their fear of the side effects seen when moving patients to higher doses if lower doses are not effective. Eight said they were not satisfied with the safety of the higher doses, with 7 voting in favor of the higher doses. Two abstained.

"We view the vote today as a positive (particularly after the tough briefing documents)," wrote ISI analyst Mark Schoenebaum minutes after the vote. "We believe consensus expectations entering the panel today were low. MRK thinks insomnia is a multi-billion dollar opportunity. We currently carry only ~$700M of risk adjusted peak sales and consensus currently estimates only ~$650M peak sales in 2018 (last year for which we have consensus sales)."

Merck had a high bar to clear. The FDA and a long list of patent groups are acutely concerned about the safety of sleep drugs that will be used on a regular basis by a potentially huge patient population, especially after a host of issues were raised following earlier sleep drug approvals. 

In the FDA review officials for the agency raised a host of safety concerns with suvorexant. Regulators told the panel today that they had concluded that the high doses of the drug--30 mg and 40 mg doses--are unsafe. The 20 mg dose impaired driving ability. There were instances of "suicidal ideation" in the suvorexant arm, as well as "narcolepsy like" symptoms. And if you include all the obese patients, patients taking other drugs and other groups into the mix, even a 15 mg dose appeared to be unsafe for a majority of the patients who could be prescribed the drug. Next-day sleepiness was clearly an issue with regulators.

"I think that some patients will drive who shouldn't be driving and some of those patients will crash," noted the FDA reviewer, Ronald Farkas. Of particular concern for the FDA was the data demonstrating patients weren't really able to tell when they were fully awake enough to drive. A way to minimize those safety concerns would be to identify the lowest dose that could be effective in spurring and maintaining sleep. And in Phase II a 10 mg dose appeared to be safer, raising the possibility that the agency might limit an approval for initial use to that lower dose, even though it wasn't tested in Phase III and Merck officials concluded that the 10 mg dose would not be effective. 

The lower dose also has a far lower rate of efficacy, which could severely hamper any future marketing campaign.

Those safety issues also drew flak from Public Citizen, which noted that the FDA has advised consumers against driving the day after they take Ambien. Suvorexant could be worse. "Suvorexant stays in the body six times longer than zolpidem (Ambien)," said the group, "with patients more often than not unaware of their diminished ability to drive and perform other mental tasks."

Merck was shooting for an approval based on comparison studies with a placebo, avoiding a head-to-head with dominant generics, including knockoff versions of Ambien. And its regulatory team hit hard on some key themes: The drug works and any safety issues were mild and transient. 

Merck has also pushed the notion that a sleep drug like this, with a new mechanism of action that could avoid safety issues associated with currently used drugs, is a major innovation capable of earning blockbuster returns. And as the pharma giant's late-stage pipeline weakened--most noticeably with a delay in the development program for odanacatib--and its revenue eroded, the importance of an approval grew in importance. 

- here's the FDA briefing document (PDF)