Belsomra: a First Look Sleep Medicine’S Newest Addition Has a Novel Mechanism and an Undecided Future
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COVER FOCUS Belsomra: A First Look Sleep medicine’s newest addition has a novel mechanism and an undecided future. BY ZAC HAUGHN, SENIOR ASSOCIATE EDITOR n the early 2000s, investment analysts anticipated a boom THE LITERATURE in the insomnia drug market.1 Indiplon and ramelt- The FDA considered Belsomra effective after it was eon (Rozerem) were on the verge of release, and Serpacor studied in three clinical trials involving more than 500 par- was testing eszopiclone, a nonbenzodiazepine hypnotic ticipants. In the studies, patients taking the drug fell asleep Iagent that a glowing “luna moth” would introduce to the faster and spent less time awake during the remainder of public as Lunesta in one of the most memorable pharma- the night compared to people taking placebo.4 The Agency ceutical ad campaigns in recent history. noted Belsomra was not compared to other drugs approved Despite Lunesta’s success and Rozerem’s approval, the to treat insomnia, so it is unknown if there are differences in anticipated boom was barely audible. Indiplon fizzled out safety or effectiveness between Belsomra and other insom- and the FDA made more sleep medicine headlines for rolling nia medications. back dosing than rolling out approvals. All of which makes The trials included two similarly designed, three-month, their recent approval of suvorexant (Belsomra) more intrigu- randomized, double-blind, placebo-controlled, parallel- ing: the oral drug is a substantially different product. group studies. Researchers examined Belsomra 20 and 40mg New to pharmacy shelves in early 2015, Belsomra is indi- in patients in non-elderly adults (age < 65 years) and 15 and cated for the treatment of insomnia characterized by dif- 30mg in elderly patients (age ≥ 65 years).2 Belsomra was ficulties with sleep onset and/or sleep maintenance in four superior to placebo for sleep latency as assessed both objec- different strengths: 5, 10, 15, and 20 milligrams; it is contra- tively by polysomnography and subjectively by patient-esti- indicated in patients with narcolepsy. Its novel mechanism is mated sleep latency; it was also superior to placebo for sleep clear, but where it fits in is less so. maintenance, as assessed both objectively by polysomnogra- phy and subjectively by patient-estimated total sleep time.5 THE MECHANISM In the third study, a one-month crossover, Belsomra 10mg Belsomra is an orexin receptor antagonist, making it the and 20mg were superior to placebo for sleep latency and first approved drug of its type. Pharmacological approaches to sleep maintenance in non-elderly adults, as assessed objec- the treatment of insomnia have previously included GABA-A tively by polysomnography. receptor agonists (for example, the benzodiazepine temazepam In clinical trials of patients with insomnia treated with and the non-benzodiazepine zolpidem), melatonin receptor Belsomra 15mg or 20mg, the most common adverse reac- agonists (ramelteon), and histamine H1 receptor antagonists tion (reported in 5 percent or more of patients treated with (doxepin).2 The discovery that orexin was involved with sleep Belsomra and at least twice the placebo rate) was somno- was prompted by studies of narcolepsy; it is estimated 90 per- lence (Belsomra 7 percent; placebo 3 percent).5 cent of people with narcolepsy are orexin-deficient.3 At doses of 15 or 20mg, the incidence of somnolence was The orexin peptides A and B bind selectively to the orexin higher in females (8 percent) than in males (3 percent). Data 1 receptor (OX1R) and orexin 2 receptor (OX2R), and drugs from two studies showed several adverse reactions occurred that bind to both OX1R and OX2R are referred to as dual in women at an incidence of at least twice that in men: orexin receptor antagonists (DORAs).2 headache, abnormal dreams, dry mouth, cough, and upper “It works like nothing before it, by antagonizing the hypo- respiratory tract infection. Further, there is evidence of a cretin neurotransmitter system, which has the function of dose relationship for many of the adverse reactions, particu- promoting altertness,” said Erik K. St. Louis, MD, Head of larly for certain CNS reactions. Sleep Neurology at the Mayo Clinic and Foundation and Associate Professor of Neurology at the Mayo Clinic College A CAUTIOUS FDA of Medicine. “Belsomra therefore works against alertness so Many in the sleep community expected Belsomra to it promotes sleep by that novel mechanism. No previously receive FDA approval in the summer of 2013, and perhaps, marketed drug has done this.” at a different dose. 16 PRACTICAL NEUROLOGY MARCH 2015 COVER FOCUS The final rule, of course, is with the FDA: officials at an BELSOMRA (SUVOREXANT) QUICK NOTES advisory committee meeting in May 2013 said there was lit- • The recommended dose for Belsomra is 10mg, taken tle evidence to show Belsomra was more effective at higher no more than once per night and within 30 minutes of doses and considerable evidence to show it was less safe.8 going to bed, with at least seven hours remaining before the planned time of awakening. If the 10mg dose is well- WHERE IT FITS tolerated but not effective, the dose can be increased. At a presentation at the Barclays Global Healthcare The FDA’s maximum recommended dose is 20mg once Conference, CFO Rob Davis said Belsomra has surpassed daily. 1,000 weekly prescriptions since its Feb. 5 launch in the US. The product is currently rolling out in Japan, which puts • When combined with other CNS depressant drugs, dos- Belsomra’s potential market at some 2 billion doses per year, age adjustment of Belsomra and/or the other drug(s) combined. “Obviously,” noted Tracy Staton from Fierce may be necessary because of potentially additive effects. PharmaMarketing, “Belsomra has a long way to go.”9 • The recommended dose of Belsomra is 5mg when used “Its mechanism is probably the most intriguing point,” Dr. with moderate CYP3A inhibitors, and the dose generally St. Louis said. “I will be interested to determine if it may be a should not exceed 10mg in these patients. It is not rec- drug of choice for patients who have previously experienced ommended for use with strong CYP3A inhibitors. amnestic NREM parasomnias, i.e., sleep walking or sleep • Belsomra falls under controlled substance schedule IV, the eating,” he said. “On the other hand, in some patients who same class as Ambien (zolpidem) and others. also have hypersomnia symptoms, there may be a concern of possible adverse effect/reaction of precipitating cataplexy if the patient has previously undiagnosed narcolepsy, so Merck’s initial proposal to market up to 40mg was there is a note of caution to perhaps be cautious with its use scuttled over concerns of next-day somnolence, including in that subset of patients—i.e., insomnia with concurrent how those effects impacted driving ability. Studies showed hypersomnia.” impaired ability on next-morning driving performance 9 Although the studies do show it promotes sleep, Dr. Bazil hours after dosing, and patients using the 20mg strength said he is taking a wait-and-see approach because of the lack should be cautioned against next-day driving or activities of head-to-head studies against existing drugs like Ambien. requiring full mental alertness.5 “I suspect it will initially be used where existing treatments The issues also came during a time the Agency heightened don’t work or have problems; as we get more real world their focus on the next morning impairment of the so-called experience it may become more popular.” “z drugs” (Ambien, Sonata, etc.) and lowered dosing recom- Merck noted in a presentation that 30 percent of patients mendations. Data from clinical trials and driving simulation thus far are “continuous treaters” who were seeking new studies prompted the FDA “to better characterize the risk of alternatives.10 Indeed, Dr. St. Louis believes it could possibly driving impairment caused by specific blood levels of zolpi- be a replacement for patients who have built up a tolerance dem and to recognize the increased risk of driving-impairing to the “z drug” class. “I’ve anecdotally already had a couple blood levels of zolpidem in women.”6 In May of 2014, the of patient successes, at least short term, with very brittle Agency also decreased the recommended starting dose of insomnia or intolerance to other traditional agents,” he said. Lunesta to 1mg at bedtime. A study of Lunesta found that “That said, our paradigm now in chronic insomnia is mostly the previously recommended dose of 3mg can cause impair- to emphasize behavioral therapies, such as cognitive behav- ment to driving skills, memory, and coordination that can ioral therapy and sleep hygiene education.” n last more than 11 hours after receiving an evening dose.7 “The FDA is, I think, rather nervous about a new sleep 1. Crean, D. A history of insomnia medication and sleeping pills. http://www.sleepdex.org/medhistory.htm 2. Citrome, L. Suvorexant for Insomnia: A Systematic Review of the Efficacy and Safety Profile for This Newly Approved drug, given the recent reports of residual drowsiness in Hypnotic. Int J Clin Pract. 2014;68(12):1429-1441. women on zolpidem, and possibly some other areas such 3. Zeitzer JM, Nishino S, Mignot E. The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interven- tions. Trends Pharmacol Sci. 2006 Jul;27(7):368-74. as mood disorders and memory problems linked to some 4. FDA News Release. FDA approves new type of sleep drug, Belsomra; August 13, 2014. sleep drugs,” said Carl Bazil, MD, PhD, Director of Division 5. Belsomra® [package insert] Whitehouse Station, NJ. Merck; 2014. of Epilepsy and Sleep and Caitlin Tynan Doyle Professor of 6. FDA release. Questions and Answers: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem; Jan.