Sleeping Pill Update: The Orexin Blockers

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Blog posts I’ve written about sleeping pills get a lot of traffic. Among people with sleep problems, interest in drugs to relieve insomnia is high.

Pharmaceutical companies don’t seem to share this interest, though. A quick survey suggests that few companies are actively working on new drugs for the treatment of insomnia. Those with sleeping pills in the pipeline are developing drugs similar to suvorexant (Belsomra). Here’s more about this relatively new class of insomnia drugs.

Calming the Orexin System

Suvorexant and other similar medications achieve their soporific effects by blocking the activity of neurons that produce two neuropeptides called orexin A and orexin B. These orexin-producing neurons, located in the hypothalamus and numbering about 70,000 in all, project to neurons that regulate wakefulness, arousal, attention, and motivation.

When the orexin neurons are firing in full force, we’re up and alert and doing things. But the orexin neurons are mostly quiet during sleep.

Studies have shown that an overabundance of orexin in mice and zebrafish results in insomnia-like states. The problem of insomnia might have to do with the overexpression of orexin, researchers reasoned, and drugs that could counteract the expression of orexin at night might help insomniacs sleep. In fact, studies subsequently showed that drugs that blocked orexin activity in mice, rats, dogs, and humans helped to promote sleep.

Development of Orexin Drugs

There are two types of orexin receptors in the human brain: OX1 and OX2. Early testing determined that arousal was mainly governed by OX2 receptor signaling, and that OX2 receptors had a more important role in maintaining a balance between sleep and waking than OX1 receptors. Blockade of OX2 receptors was also more effective at promoting sleep. Blockade of both receptors appeared to be even more effective.

So pharmaceutical companies starting formulating and testing drugs called “dual orexin receptor antagonists” (DORAs) that blocked both OX1 and OX2. Research on the first of these drugs, almorexant, was discontinued due to safety concerns. But the second DORA, suvorexant (Belsomra), made it through stage III testing and was approved for the treatment of insomnia by the FDA in 2014. Merck’s launch of Belsomra on the U.S. market occurred near the end of the year.

During the first half of 2015 (according to the most recent information I can find), sales of Belsomra were brisk. As the first insomnia drug in its class—and purportedly carrying fewer risks than other insomnia drugs—it was bound to have face appeal.

But people with sleep problems have offered different opinions on the drug’s effectiveness. Some reviewers have praised the drug on this website (see my blog post on Belsomra’s benefits and risks). More have complained about side effects and a lack of effectiveness. Among 170 reviewers weighing in on, Belsomra gets an average of 3.7 points out of 10.

Orexin Drugs in the Pipeline

Despite what looks like a rather lackluster start, as of the end of May 2016, two drug companies—Eisai Inc. and Minerva Neurosciences—were developing sleeping pills that would act on the orexin system. Eisai’s drug, a DORA, was to enter Phase III testing (the final round of testing a drug must go through before its maker can apply for approval from the FDA) near the end of 2015.

Minerva’s drug is a “selective orexin-2 receptor antagonist,” or SORA, that blocks only OX2 receptors. Results of lab experiments suggest it increases sleep time in rodents while preserving normal sleep staging. It was undergoing Phase II clinical trials as of December 2015.

Whether these insomnia drugs will ever come to market—and whether they’ll be better than Belsomra—is anybody’s guess. For now, insomniacs will have to look elsewhere in the quest for a better night’s rest. Check out CBT for insomnia if you haven’t tried it yet.