July 3, 2012 6:22 pm
This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com
Merck’s (NYSE:MRK) experimental sleep drug suvorexant may play a greater role in patients with chronic insomnia, sleep experts told BioPharm Insight.
The drug does not mean the end of benzodiazepines, the current standard of care, as some patients may still prefer their use, experts added.
Suvorexant is part of a new class of sleep drugs that blocks the neurotransmitter orexin, the brain chemical that regulates wakefulness.
In the first of two Phase III trials, after three months patients reported suvorexant reduced the time it took to fall asleep by 25.7 minutes, and patients were able to sleep 60.3 minutes longer than before treatment. After three months of therapy in the second Phase III trial, patients were able to fall asleep 33.7 minutes faster and sleep 62.8 minutes longer than before treatment, according to a company press release. The most common adverse effects included sleepiness and headache.
Merck has guided it would file a new drug application (NDA) with the FDA in 2012. The company does not plan on filing in the EU in 2012.
Suvorexant has a good chance of attaining approval as there is a strong need for new, well-tolerated drugs for insomnia, said Dr Elemer Szabadi, professor emeritus of psychiatry and consultant psychiatrist at the University of Nottingham, UK.
Several experts agreed, indicating suvorexant has comparable efficacy with the largely generic benzodiazepine drugs currently on the market for insomnia, including Sanofi’s (NYSE:SNY) Ambien and Eisai’s (TYO:4523) Lunesta. Ambien is generically available, while Lunesta faces an August 2012 patent expiry.
Dr Takeshi Sakurai, professor, department of molecular neuroscience and integrative physiology, Kanazawa University, Japan, noted his only concern with suvorexant is that it has a tendency to increase REM (rapid eye movement) sleep time and shorten REM sleep latency, the period of time from sleep onset to the first appearance of REM sleep. This might affect how refreshed one feels after sleep, Sakurai said.
Benzodiazepines decrease REM sleep, which might aid with the subjective feeling of “good sleep,” Sakurai said. He added some patients might prefer benzodiazepines over suvorexant for that reason.
Yet, suvorexant does not change the EEG (electroencephalography) profile of sleep, Darryle Schoepp, senior vice president and head of Neuroscience and Ophthalmology franchise at Merck, noted. The observed increase in REM sleep time is because all stages of sleep are increased with suvorexant, Schoepp said, noting the drug does not shift the profile or overall ratio that people spend in various sleep stages.
Jamie Zeitzer, assistant professor, psychiatry and behavioral sciences, Stanford University, agreed with Sakurai’s assessment, though noted since benzodiazepines suppress deeper stages of sleep, there is variety in patients’ feeling of restfulness. Schoepp added some patients experience “hangovers,” or carryover sedation after waking up when using benzodiazepines.
Benzodiazepines, which enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA), work by forcing a state of “pseudo” sleep that is not natural, Zeitzer said. He explained suvorexant works by reducing wake drive, Since insomnia is an abnormality of wakefulness, a drug that affects wakefulness is conducive to a more normal sleep.
Suvorexant does not mean the end of benzodiazepines, however, Zeitzer said. He noted patients with acute sleep issues, for example, those that have trouble sleeping due to a death in the family, or another traumatic incident, may prefer benzodiazepines as they are more powerful than suvorexant in terms of promoting sleep.
In the acute setting, patients just want to be asleep. But in chronic insomnia, suvorexant may be better as it promotes more natural sleep, Zeitzer said. Chronic insomnia is a growing condition, and most patients fall into the chronic, rather than acute setting, he noted.
Benzodiazepines, while effective in the acute setting, should not be given for longer than a few weeks, as tolerance and dependence can develop, Szabadi said. He noted suvorexant was found to be effective in the chronic setting in Phase III assessment and did not demonstrate a rebound effect sometimes seen with benzodiazepines, where insomnia worsens after the drug is withdrawn.
Additionally, unlike benzodiazapines, suvorexant does not have any addictive qualities as it does not increase dopaminergic tone, experts said. Sakurai noted the agent may actually decrease the activity of dopaminergic neurons and could have a role in treating patients with drug addictions as a result.
Once suvorexant is on the market, doctors will probably treat both acute and chronic insomnia patients at first, but there is bound to be a settling out as doctors find a more specific utility for the drug in chronic patients, Zeitzer said.
Schoepp noted suvorexant was studied and found to work in both acute and chronic settings.
Potential safety concerns
While experts praised suvorexant’s safety profile, Zeitzer noted a complete block of the orexin receptor could be concerning as it may lead to symptoms analogous to narcolepsy. It is a potential concern that suvorexant-treated patients could develop sleep state dissociations or cataplectic episodes, which are characterized by a sudden occurrence of muscle weakness, Zeitzer said. However, Zeitzer as well as other experts noted there has not been any evidence of this in clinical assessment of the drug thus far.
Long-term safety of suvorexant needs to be further scrutinized, Zeitzer said. He noted if low enough doses are used, there is less concern for this potential effect. The dose can be adjusted in patients who experience daytime sleepiness, Zeitzer added.
Schoepp noted there should not be concern over potentially inducing narcolepsy as patients take the drug at night, and the next morning, the orexin system is back to normal. He noted there has been no evidence of cataplexy or complex sleep behaviors such as sleep walking in Phase III assessment. Further, in patients who exhibit daytime tiredness, there are high dose and low dose options, he said.
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