FDA Review Staff Look Into Efficacy Of High Dose Sleep Drug
May 21, 2013

FDA Review Staff Look Into Efficacy Of High Dose Sleep Drug

Lawrence LeBlond for redOrbit.com - Your Universe Online

An experimental insomnia drug from Merck & Co has been shown to be effective, but reviewers with the US Food and Drug Administration (FDA) are questioning the drug´s dosage levels. The comments, posted on the agency´s website Monday, come ahead of a meeting of external medical experts which will advise on whether the drug, called suvorexant, should be approved or not.

The FDA review staff found limited association of better sleep outcomes with higher doses of suvorexant when data was pooled from three phase III studies. Suvorexant is the first in a new class of sleep drugs (orexigen receptor antagonists or ORAs) that block a certain chemical (orexin) in the brain that keep people awake. These drugs are designed to help patients fall asleep and stay asleep through the night.

In three separate clinical trials, Merck studied different doses of suvorexant. In the first trial, non-elderly patients received 40 milligrams (mg) while patients over 65 received 30 mg. In the second trial, non-elderly patients were given 20 mg while elderly patients were given 15 mg of suvorexant. A third study examined doses between 10 and 80 mgs.

In the documents released Monday, FDA reviewers said that while there appeared to be clear evidence that suvorexant was more effective than a placebo, they found no correlation between more of an effect and higher doses. In fact, the reviewers found evidence that dosages above 10 to 15 mg may not only be unnecessary, but also may be less safe.

Russell Katz, MD, director of the FDA´s neurologic products division, said the data from Merck´s trials suggest that all doses between 10 and 80 mg are effective, but there is “little evidence to suggest that the higher doses are substantially superior to 10 to 15 mg, at least for sleep maintenance, and likely for sleep latency as well.”

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

With that information in hand, the reviewers wrote that low doses should be recommended, at least initially.

Merck´s CFO, Peter Kellogg, said he was not surprised by the review. He acknowledged that the FDA has shown a broad concern pertaining to the safety and efficacy of sleep drugs. Speaking at the UBS Global Healthcare Conference in New York, he said it was “understandable” that the FDA would question dosage amounts, according to a report from Reuters´ Toni Clarke.

According to healthcare research group IMS, nearly 60 million sleeping aid prescriptions were filled in the US in 2011, of which 40 million contained the drug zolpidem.

At the beginning of the year, the FDA advised that immediate-release sleep aids containing zolpidem, such as Sanofi SA´s Ambien, should be lowered from 10 mg to 5 mg for women. The agency further advised that extended-release products should be lowered from 12.5 mg to 6.25 mg.

That advisory report followed an increase in driving accidents involving people who had been taking zolpidem-based sleep aids. It had been found that the drug stays in women´s systems longer than in men´s. But the FDA has also recommended that healthcare providers prescribe lower doses to men.

Even the lowest dose (15 mg) in Merck´s proposed lineup may be too high for some people, such as obese women, wrote the FDA reviewers. "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 noted.

Another concern with suvorexant is an increased risk of suicidal thoughts and behavior in higher doses. The review staff also wrote that the drug seems to be associated with certain elements of a “Narcolepsy-like syndrome” and may also cause cataplexy, in which a patient may experience muscle weakness.

After Merck asked an external committee to review reports and suspected reports of cataplexy, that review committee found that none of the 45 cases reviewed could be defined as cataplexy. The FDA reviewers, on the other hand, found at least one case of cataplexy.

The FDA´s Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee will meet on Wednesday to discuss dosing levels of suvorexant and vote on a recommended dosage. If approved, suvorexant will become the first ORA drug that works by blocking brain chemicals that keep people awake.

The external review meeting will not be the final decision on suvorexant. The FDA will likely take a few months to study the review results before making a final decision one way or the other. While the FDA is not bound by recommendations of its advisory committees it usually does follow their lead.

The FDA could also require Merck to conduct an additional low-dose trial. Such a trial would take about a year and would give Merck the ability to re-file its application in about 18 months.

If suvorexant is approved for market, it is expected to generate sales of $521 million by 2017 for Merck, according to a MedPageToday report, citing information from an average estimate of seven analysts polled by Thomson Reuters.