The NDA was based on the results of 2 pivotal phase 3 clinical studies, SUNRISE 1 and SUNRISE 2, which enrolled approximately 2000 patients, as well as safety studies.
Russell Rosenberg, PhD, D.ABSM
Eisai has announced the submission of a new drug application (NDA) to the FDA for lemborexant for the treatment of insomnia.
The NDA is backed by results of 2 phase 3 clinical trials, SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303), which enrolled roughly 2000 participants, in addition to important safety studies like the assessment of postural stability after awakening in the middle of the night and a next-morning driving study.
“Let me just say from a fairness perspective, there’s no perfect sleep-promoting agent, we know what the ideal sleep agent is, but I think we’re getting closer with lemborexant,” Russell Rosenberg, PhD, D.ABSM, Founder and CEO of NeuroTrials Research and former Chairman of the Board of the National Sleep Foundation and a principal investigator in the lemborexant studies, told NeurologyLive. “If clinicians have patients who either have trouble getting to sleep and/or staying asleep and they have safety concerns over previous uses of benzodiazepine receptor agonist, which are widely known, then this is something that they should seriously consider, and I think will be a valuable tool in their toolbox of treating insomnia and potentially other sleep disorders down the road. As I hope you can tell I’m excited about lemborexant and all the work that will come after once it’s approved.”
The 1-month SUNRISE 1 study included the first phase 3 head-to-head comparison versus zolpidem ER and evaluated the efficacy and safety of lemborexant in 1006 male or female adult patients 55 years and older with insomnia disorder. The trial included a pre-randomization phase of up to 35 days and a randomization phase which consisted of a 30-day treatment period and a minimum 2-week period without treatment prior to the end-of-study visit. Study participants were randomized to receive placebo or 1 of 3 treatment regimens: lemborexant 5 mg, lemborexant 10 mg, or zolpidem ER 6.25 mg.
The main objective was to demonstrate, using polysomnography, that lemborexant at either 5 mg or 10 mg dose is superior to placebo on objective sleep onset, while secondary endpoint objectives included change from baseline in sleep efficiency and wake after sleep onset for both lemborexant doses compared to placebo, and wake after sleep onset for both 5 mg and 10 mg doses compared to zolpidem ER. Both primary and secondary outcomes were achieved.
“What was promising about lemborexant in this particular pivotal study was that patients got to sleep faster, they stayed asleep longer, their total sleep time was longer than placebo, and essentially, they tolerated the medication quite well,” Rosenberg added. “This hits on some of the endpoints [like] getting to sleep and staying asleep through the night and this particular population, by the way, was older adults, and I think that’s particularly important because older adults are certainly more vulnerable to insomnia disorder than younger adults, primarily because some of the other disorders that effect the older population can also have an impact on sleep.”
SUNRISE 2 was the second phase 3 trial of the dual orexin receptor antagonist to report positive data. The 12-month study examined the long-term efficacy and safety of lemborexant in 949 male or female adult participants aged 18 to 88 years with insomnia disorder. The trial included a pre-randomization phase of up to 35 days and a randomization phase comprised of a 6-month placebo-controlled treatment period, a 6-month period of only active treatment and a 2-week period without treatment prior to the end-of-study visit. During the placebo-controlled treatment period, participants were randomized to receive placebo or 1 of 2 treatment regimens: lemborexant 5 mg or lemborexant 10 mg. In the active-only treatment period, participants who received placebo during the first period were re-randomized to receive lemborexant 5 mg or lemborexant 10 mg and those who received active treatment continued on the treatment to which they were originally randomized.
The primary objective was to determine the efficacy of both doses of lemborexant compared to placebo on patient-reported sleep onset latency after 6 months of treatment, while secondary objectives were the mean change in subjective sleep efficiency and subjective wake after sleep onset after 6 months of treatment.
“There was another study [SUNRISE 2], an outpatient study of about 900 subjects, but this included a whole range of ages from 18 to 88 and in this particular study through diary data, the primary outcome measure was subjective sleep onset latency, but of course there was interest in sleep maintenance again, and as well as the adverse events," Rosenberg noted. "In that study patients fell asleep quicker, they stayed asleep longer, they had fewer minutes awake in the middle of the night, a metric that we often use is called WASO, wake after sleep onset, but sleep efficiency again, is tied directly to their WASO. I think the data here is quite promising.”
The most common adverse effects in the SUNRISE 2 study greater than 5% in either treatment arm and greater than placebo were somnolence, headache and influenza. Overall discontinuation rates due to adverse effects were comparable between placebo and the lemborexant 5 mg dose, and higher for the lemborexant 10 mg dose.
The full data from the 12-month SUNRISE 2 trial will be presented at upcoming medical meetings this year.
Lemborexant is also under investigation in a phase 2 trial for treatment of irregular sleep-wake rhythm disorder and mild to moderate Alzheimer disease dementia.
New Drug Application for Insomnia Disorder Treatment Lemborexant Submitted in the United States [news release]. Tokyo and Stamford, Conn.: Eisai Co., Ltd.; Jan. 15, 2019. http://eisai.mediaroom.com/2019-01-15-New-Drug-Application-for-Insomnia-Disorder-Treatment-Lemborexant-Submitted-in-the-United-States?rel=0" ?rel=0" . Accessed Jan. 15, 2019.