By inhibiting wakefulness rather than enhancing sleepiness, reportedly without the side effects connected with top-selling medicines, an experimental late-stage insomnia drug by Merck & Co. holds potential for reshaping the sleep disorder medicine market.
Earlier this month at SLEEP 2012, Merck announced promising results from two pivotal, three-month-long Phase III efficacy trials and additional results from daily dosing for at least a year for Suvorexant (MK-4305): Patient self-reporting and objective measures showed each trial’s roughly 1,000 patients needed significantly less time to fall asleep, and stayed asleep significantly longer, than placebo patients.
Merck plans to file an NDA for Suvorexant by year’s end, and file for Japanese approval “in the near future.”
Suvorexant could disrupt a $2 billion-a-year, roughly 18 million-patient market generating about 60 million insomnia drug prescriptions last year (IMS Health). Most were for drugs targeting GABA receptors, such as Lunesta (Eszopiclone) and the Ambien (Zolpidem) family of treatments.
“Certainly they’re good at helping enhance sleep, but they also have potential risks for side effects the next day that are problematic, including amnesia and excessive sedation in the morning. Not to mention these are all controlled substances,” Samuel A. Fleishman, M.D., president of the American Academy of Sleep Medicine, told GEN.
About a decade ago, Merck teamed with Lundbeck to develop a GABA drug, Gaboxadol. It failed late-stage trials and was shelved in 2007. A year earlier, Pfizer and Neurocrine Biosciences ended development of indiplon.
These failures and side effects sparked additional sleep research. Narcolepsy studies linked the disease to attacks on neurons of the neuropeptide neurotransmitter orexin in the hypothalamus: “When you lose the neurons, then the orexin peptides are no longer released by the neurons, and it’s the orexin peptides that are involved in promoting wakefulness and helping you transition the right way,” Darryle D. Schoepp, Ph.D., senior VP and franchise head, neuroscience and ophthalmology for Merck Research Laboratories, explained.
Merck incorporated that discovery into a new class of orexin-blocking insomnia drug candidates.
The 70,000 to 100,000 orexin neurons in the hypothalamus offer a much more concentrated target for a sleep drug than the half-billion GABA neurons across the brain and central nervous system.
Actelion and GlaxoSmithKline advanced their orexin antagonist Almorexant to Phase III before ending development last year. Citing a data review without offering specifics, the companies said they would continue working on new orexin antagonist therapies.
While Merck isn’t discussing Suvorexant’s commercial potential, Jefferies predicts annual sales starting at $98 million in 2013, climbing to $520 million in 2017. Leerink Swann declared that Merck “can grow Suvorexant to [more than] $500M in the U.S. sleep market alone,” and much more in other co-morbidity CNS-and-pain indications, for which Merck is studying a backup insomnia treatment, MK-6069.
Results of a six-country Phase IIB trial presented last year showed MK-6069 delivered significant improvement in the primary endpoint of sleep efficiency, and secondary endpoints of wake after sleep onset and latency to persistent sleep. Merck is developing a third insomnia drug, MK-3697, for which Phase II study results have yet to be published.
While GABA drug development won’t disappear, researchers are very interested in other alternatives where sleep disorder drugs are concerned.