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FDA staff says Merck's sleep drug effective, questions dosage

By Toni Clarke

WASHINGTON (Reuters) - Merck & Co's experimental insomnia drug suvorexant appears generally effective, according to reviewers at the U.S. Food and Drug Administration, but they questioned the company's proposed dosing levels.

The reviewers posted their comments on the FDA's website on Monday, two days ahead of a meeting of outside medical experts which will advise the agency on whether or not it should approve the drug. Merck's shares fell 1.1 percent to $45.49 in midday trading.

Suvorexant is the first in a new class of sleep medications that block chemicals in the brain called orexins that help keep people awake. Known as orexigen receptor antagonists, these drugs are designed both to help patients fall asleep and stay asleep.

Merck studied two different doses of the drug. In one trial, non-elderly patients received 40 milligrams while patients over the age of 65 received 30. In another, non-elderly patients were given 20 milligrams while elderly patients were given 15. A third study examined doses as low as 10 milligrams and as high as 80.

The reviewers said that while there appeared to be clear evidence that the drug was more effective than a placebo, there was little evidence to show that the higher doses are substantially superior to the 10-15 milligram doses and considerable evidence showing they were less safe.

"Suvorexant clearly causes dose related, next day effects, including sedation, which can be of significant concern," the reviewers said. "Perhaps most importantly, the results of a formal driving study demonstrate that suvorexant can cause significant impairment in driving the morning after dosing."

The reviewers said the data suggest that a low dose should be recommended, at least initially.

Peter Kellogg, Merck's chief financial officer, said he is not surprised by the FDA's review, given the agency's broader concerns about sleep drugs.

Speaking in a breakout session at the UBS Global Healthcare Conference in New York, Kellogg said it is "understandable" that the FDA has questions about dosage.

About 60 million prescriptions for sleeping pills were written in the United States in 2011, according to healthcare research firm I.M.S. Of those, roughly 40 million contained zolpidem, the active ingredient in Sanofi SA's Ambien.

In January, the FDA told drugmakers they should lower the recommended dose of zolpidem in women to 5 milligrams from 10 for immediate-release products such as Ambien, Edluar and Zolpimist, while doses for extended-release products should be lowered to 6.25 milligrams from 12.5.

The recommendation came in response to hundreds of reports of driving accidents involving people taking zolpidem. The drug typically stays in women's bodies longer than in men's. The FDA said that for men, healthcare providers should consider prescribing lower doses.

In the case of Merck's drug, even the 15 mg dose -- the lowest proposed for marketing by Merck -- may be too high for certain populations such as obese women, the reviewers noted.

"If a dosage strength lower than 15 mg is unavailable, we would need to consider if the drug could be marketed safely at all," they said.

They also noted that suvorexant seems to increase the risk of suicidal thoughts and behavior in a dose-related fashion, and they said it seems to be associated with certain elements of a "Narcolepsy-like syndrome."

Narcolepsy is a disorder that causes periods of extreme daytime sleepiness. It may also cause cataplexy, in which a patient may experience muscle weakness, sometimes precipitated by strong emotions.

Merck asked an external committee to review reports and suspected reports of cataplexy. The committee reviewed 45 cases of suspected cataplexy and determined that none could be defined as cataplexy. The FDA reviewers said, however, that their own review suggests that at least one, and perhaps several more of those cases could reasonably have been cases of actual cataplexy.

"The documents are tough, in our opinion," said Mark Schoenebaum, an analyst at ISI Group. "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."

If the FDA were to require the company to run an additional low-dose trial, it would take about a year, giving Merck the ability to refile its application in about 18 months.

Given the safety questions raised by the reviewers, "we expect a contentious panel discussion," said Seamus Fernandez, an analyst at Leerink Swann.

While analysts do not expect suvorexant to take a major share of the market for sleeping pills, many of which are now generic, it is expected, if approved, to generate sales of $521 million by 2017 according to an average estimate of 7 analysts polled by Thomson Reuters.

(Reporting by Toni Clarke in Washington; additional reporting by Jessica Toonkel in New York; Editing by Theodore d'Afflisio and Sofina Mirza-Reid)

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