At the annual meeting of the Associated Professional Sleep Societies in Boston today, drug giant Merck (NYSE: MRK) released promising data from two late-stage human trials of its experimental insomnia drug, suvorexant. The compound—which promotes sleep through an entirely different pathway in the brain than those targeted by the drugs on the market today—achieved 15 out of 16 of the main endpoints the company had set out to study in the trials. Merck intends to file for FDA approval of suvorexant by the end of this year, says Darryle Schoepp, senior vice president and franchise head of neuroscience and ophthalmology for Merck, which is based in Whitehouse Station, NJ.
In the two trials, which involved more than 2,000 insomniacs in total, suvorexant reduced both the amount of time it took for patients to fall asleep and the middle-of-the-night awakenings, when compared to placebo. All in all, patients on the drug gained about an hour’s worth of extra sleep per night during the three-month study period. The most common side effect of the drug, Merck reports, was next-day drowsiness, though Schoepp points out that it only occurred in about 10 percent of trial participants, even in the year-long safety study that the company performed. “In a one-year study, they had 365 opportunities to say they were sleepy the next day, but 90 percent of patients never reported that,” he says.
Suvorexant is the first of an emerging class of drugs that block orexins—chemical messengers in the brain that direct the transition from slumber to wakefulness. That’s what distinguishes it from most prescription sleep drugs, such as Sanofi’s (NYSE: SNY) blockbuster zolpidem (Ambien). Those drugs enhance the activity of GABA, a different brain chemical that slows down the firing of neurons in the brain, thereby promoting sleepiness. “Essentially they depress the nervous system,” Schoepp says of the current class of insomnia remedies.
Orexin is not nearly as ubiquitous in the brain as GABA is, Schoepp adds, making Merck’s approach to sleep more targeted than that of currently marketed insomnia treatments. “You have billions of neurons in your brain, and GABA is present in about half of them,” he says. “But there are only about 100,000 neurons with orexin. They are a small group, but they’re quite important because they tell your brain to transition into sleep.”
If Merck’s drug is approved, it could grab a large share of one of the richest corners of the pharmaceutical market. Sales of prescription sleep aids totaled $1.8 billion last year, according to healthcare services and information provider IMS Health. That number has actually been declining of late, because of the rise of generic zolpidem, which hit the market in 2007. Any company that succeeds in rolling out a novel entry could push the market back to pre-2007 levels, when sales of sleep drugs exceeded $3.5 billion, according to IMS. And Merck could use a hit drug to make up for declining sales of its $5-billion-a-year asthma drug montelukast (Singulair), which will lose its patent protection and face generic competition in August.
That said, novelty in the sleep market begets uncertainty, so the FDA has required Merck to carry out exceptionally large, lengthy, and wide-ranging studies to prove that suvorexant is safe. It’s no wonder: The drug was making its way through early development at about the time the FDA was receiving bizarre reports of side effects in patients taking zolpidem and other members of the GABA class. Some patients reported that they raided their refrigerators in the middle of the night and woke up with no memory of having eaten everything in sight. Others went on driving expeditions in the wee hours, again with complete amnesia for those events the next day. That’s why advertisements for prescription sleep drugs now include a laundry list of warnings about potential brain-altering side effects.
In addition to tracking some patients for up to a year, Merck studied several different doses of suvorexant. The company also collected separate datasets for elderly patients, who face a higher risk of suffering life-threatening falls and other complications if sleeping pills leave them with next-day hangovers. Merck measured safety and efficacy by asking patients to keep diaries of their sleep patterns and side effects, and by sending some of the trial participants to sleep labs, where they were hooked up to sensors that recorded every reaction to the experimental compound. “We looked at all these different things, and we really saw no [safety] signals,” Schoepp says.
So where did suvorexant underperform during the two trials presented today? In one of the trials, patients taking suvorexant did not fall asleep all that much faster than those taking placebo. Schoepp suspects some of the patients in the control group might have experienced the infamous “placebo effect”—meaning the mere thought they may be getting some help with their insomnia woes was enough to put them to sleep.
Still, Schoepp contends, the one disappointment shouldn’t cast too much of a shadow on the entire study program. “You have to put that one data point in context,” he says. During the trials, Merck measured five aspects of both falling asleep and staying asleep, and it did so over three different time periods. “That’s 15 things we looked at, multipled by two trials. So we had 30 endpoints across all the trials and we met 29 of them. If you look at the overall package, it’s quite effective.”
During the meeting in Boston, Merck will also discuss data from the other trials of suvorexant, including results from a study in which the company monitored the ability of elderly patients to drive the day after taking the drug. The company plans to present additional results from its pivotal trials later this year. All the trials are now complete, Schoepp says, and the company is preparing the package it will submit to the FDA for approval.
Merck is also studying the potential of a compound that’s similar to suvorexant in treating conditions that are related to insomnia. For example, it is researching the drug for preventing migraine headaches, treating neuropathic pain, and enhancing the activity of anti-depressants.
Schoepp, a trained pharmacist, brings an interesting perspective to the neurology market, having started his career in the 1970s as a pharmacy intern. “Back then we didn’t know how the early [insomnia] drugs worked. Later we found out they worked through GABA,” he says. “As time has gone on, we’ve developed newer GABA agents, but essentially the mechanism hasn’t changed.” Suvorexant, on the other hand, was not an accidental discovery, but rather a deliberate effort by Merck’s scientists to exploit a growing understanding of orexin biology. “This is really a targeted mechanism for sleep,” he says. “That’s a rare event in neuroscience.”
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