Idorsia’s daridorexant has experts unsure of its uptake potential due to a lack of differentiation from an already approved insomnia therapy with the same mechanism. While daridorexant may theoretically improve upon Merck’sBelsomra (suvorexant) in easing somnolence, which could be a motivation to switch, additional data is needed to prove such edge.

Experts acknowledged daridorexant’s shorter half-life could improve somnolence, but superiority is a questionable claim without supporting clinical data. While daridorexant has an improved side-effect profile versus other insomnia therapies with a different mechanism, this advantage is also seen with Belsomra.

This is in contrast to three analyst reports projecting favorable-to-blockbuster daridorexant uptake potential over the approved Belsomra, and other dual orexin receptor antagonists (DORAs) in clinical trials, with one report projecting daridorexant sales of about $1bn, with a possible 2022 launch. However, a fourth report advised a wait-and-see approach. Idorsia has a market cap of $3.86bn).

Experts and analysts nonetheless agreed the ongoing Phase III daridorexant trials are likely to be positive, paving the way for possible FDA approval. Daridorexant, previously ACT-541468, is in two identical 900-patient Phase III trials (NCT03545191, NCT03575104) in adults and elderly subjects with insomnia. Results are expected mid-2020, according to Idorsia’s 3Q19 earnings call. Experts noted daridorexant’s mechanism is validated thanks to Belsomra’s FDA approval, as well as daridorexant’s positive Phase II data.

Differentiation pushback due to me-too sentiments

Doctors might stick with Belsomra because they’re familiar with it, but also because of the absence of randomized, controlled trial data between DORA therapies, said Timothy Roehrs, PhD, director of research, Sleep Disorders and Research Center, Henry Ford Health System, Detroit, Michigan. Both Phase III daridorexant trials are placebo-controlled. Experts also noted Eisai’s DORA therapy Davvigo (lemborexant), which was FDA-approved on 23 December 2019, could also suffer from me-too sentiments given its trials are also placebo-controlled, leading to similar mediocre uptake.

Anecdotally, many patients appear to respond well to Belsomra, with little incentive to switch, Roehrs added. Belsomra is currently the only FDA-approved DORA-based therapy for insomnia, with sales of $260m in 2018, according to Merck’s annual report. An Idorsia spokesperson said it does not make comparative statements with other DORAs, but noted daridorexant has a good pharmacokinetic/pharmacodynamic (PK/PD) profile, which shows potential in sleep induction, sleep maintenance, lack of hangover and improved next-day performance.

Daridorexant has a shorter half-life of six-to-eight hours, according to Idorsia’s company presentation, when compared with Belsomra’s 12 hours, as per its label. In theory, this could reduce the daytime sleepiness problem seen with Belsomra due to faster clearing with daridorexant, said Roehrs. Residual sleepiness can occur with Belsomra at higher doses, or perhaps for certain individuals who absorb the drug slower, and so there is room for an improved DORA therapy, even as patients do report improved sleep with Belsomra, said Dr Wallace Mendelson, clinical psychiatrist, Scottsdale, Arizona.

A year-long pivotal safety study of Belsomra versus placebo concluded that excessive daytime sleepiness, considered an adverse event (AE), remained a top concern with 2.5% of patients experiencing this issue (Michaelson, et al, Lancet Neurol. 2014 May;13(5):461-71). Belsomra is approved in 5mg, 10mg, 15mg and 20mg tablets, with a recommended dose of 10mg.

Some doctors might be tempted to try daridorexant upon approval with patients with intolerable residual sleepiness with Belsomra, Roehrs said. However, it is not clear how common this patient subset is, what patient profile might meet that criteria to switch, and it’s impossible to predict PD performance of each patient, Roehrs and Mendelson said.

The most common AE of special interest in the daridorexant Phase II trials was somnolence, with the highest incidence in the 50mg dose, but none in placebo and the generic zolpidem active control. Daridorexant has 10mg, 25mg and 50mg doses being explored in the Phase III trials. The Phase III trial might be too short to conclude on long-term safety with its three-month study duration, Roehrs said. The Phase II trials only studied patients up to a month. A year-long study would help with understanding daridorexant’s long-term safety, he said. Daridorexant has a 1,290-patient 45-week safety trial (NCT03679884) with a completion date of 6 March 2021, according to

Two analyst reports noted daridorexant’s specificity for orexin receptors pushes for uptake over commonly used insomnia ‘Z-drugs’—generic nonbenzodiazepines with benzodiazepine-like action—due to the FDA’s April 2019 issuance of black box warnings on these sedative hypnotics. While daridorexant specificity could present a safety advantage over other insomnia therapies such as Z-drugs, generic benzodiazepines and perhaps off-label, low-dose antidepressants, Belsomra also holds that same advantage, a sleep specialist and Roehrs agreed.

Daridorexant’s teratogenicity risks need more detail, the sleep specialist added. Daridorexant and Belsomra could share similar teratogenicity risks, Mendelson noted. Belsomra is recommended only when benefit justifies the potential risk to the fetus, with its FDA label stating animal models show Belsomra link to decreased fetal body weight. Daridorexant Phase III only includes women of childbearing potential who agree to go on contraceptives.

Few roadblocks for Phase III success

Despite the market dynamics, daridorexant’s potential Phase III success is likely, given the totality of data supporting the DORA therapy class, Roehrs said. Belsomra’s FDA approval and extensive work done on orexin research provide confidence in this mechanism for sleep disorders, added Sabra Inslicht, PhD, associate professor of psychiatry, University of California, San Francisco.

Furthermore, daridorexant has positive Phase II data for optimism in its ongoing Phase III trials, said the sleep specialist. The 360-patient adult (NCT02839200) and 58-patient elderly (NCT02841709) Phase II trials had change in wake after sleep onset (WASO) at Days 1 and 2 as a primary endpoint, and latency to persistent sleep (LPS) at Days 1 and 2 as a key secondary endpoint, according to The Phase III trials have WASO and LPS outcomes at Months 1 and 3 as primary endpoints.

The Phase II trials were announced as positive in July 2017. The adult study achieved significant results versus placebo in WASO (p≤0.0007) and LPS (p<0.05) at Days 1 and 2, and both outcomes had persistent benefit at Days 28 and 29 (p=0.05, p=0.042 respectively) (Dauvilliers, et al, Sleep, Volume 42, Issue Supplement_1, April 2019, Pages A152–A153). The elderly study also had significant WASO results (p≤0.0001) and LPS (p<0.025) at Days 1 and 2 (Zammit, et al, Sleep, Volume 42, Issue Supplement_1, April 2019, Page A165).

by Shuan Sim in New York

Shuan Sim is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.