DUBLIN – Idorsia Ltd. plans to file an NDA before the year-end for its insomnia drug, daridorexant, following a read-out of top-line data from a second phase III study, which the company said closely tracked an earlier phase III study, although it failed to meet one of two primary endpoints with statistical significance.

The present study, dubbed ‘302, tested once-daily 10-mg and 25-mg doses of daridorexant (dora), a dual orexin receptor antagonist. It works by blocking the interaction of two neuropeptide hormones, orexin A and orexin B, which normally promote wakefulness by interacting with the widely distributed orexin receptors.

The study recruited 924 participants with moderate or severe insomnia, who received either the drug or placebo during a three-month treatment period. Those on the 25-mg daily dose attained one of two primary endpoints, sleep maintenance, with statistical significance at both one month and three months. However, they narrowly failed to attain the second primary endpoint, a reduction in time to sleep onset, with statistical significance, at either one month or three months. The dose did significantly improve total sleep time, a secondary endpoint. Those on the 10-mg dose showed a numerical trend toward efficacy but did not meet either primary endpoint with statistical significance at either timepoint.

The two primary endpoints are independent, Guy Braunstein, Idorsia’s head of global clinical development, told analysts on a conference call July 6. Attaining either one is sufficient for the trial to be regarded as positive, he said. In the previous trial, which compared 25-mg and 50-mg doses of daridorexant with placebo, each dose of the drug met each of the two primary endpoints with statistical significance at both one month and three months.

Guy Braunstein, head of global clinical development, Idorsia

Because the two trials followed the same design, the company will conduct a pooled analysis, although the timing of its completion is uncertain at this point. “I can’t guarantee it will be done before filing,” Braunstein said. He dismissed any suggestion that the pooled analysis will not be statistically significant as being “extremely unlikely.” 

“I wouldn’t even consider it,” he said. The company is not releasing numerical data prior to publication in a journal or at a relevant conference, however. An ongoing blinded extension study will read out shortly. “We expect the data to be available prior to interaction with the FDA,” he said. That will contain 12-month safety data.

Daridorexant is in line to become the third dora to gain regulatory approval, following those of Merck & Co. Inc.’s Belsomra (suvorexant) in 2014 and Eisai Co. Ltd.’s Dayvigo (lemborexant) last year. Idorsia has positioned the drug as being on a par in terms of nocturnal efficacy in supporting sleep onset and maintenance but superior in terms of next-day performance. “We don’t see any sleepiness or hangover in this population,” Braunstein said. In the second study, however, the effect of daridorexant on daytime functioning, while numerically consistent with the observations reported in the earlier study, was not statistically significant. “It’s very, very difficult to comment on very low numbers,” Braunstein said. “We have a very low level of somnolence across all dose levels.” A next-day driving study in healthy volunteers has yet to report.

Two trial participants – one in each dose group – reported suicidal ideation, although there were “clear alternative causes,” Idorsia said. The problem is also associated with the other dora drugs, however, and each carries a label warning. Braunstein admitted that daridorexant could receive similar treatment. “That’s a possibility,” he said. In addition, three patients experienced adverse events associated with sleep paralysis and hallucination. On the plus side, there was no evidence of insomnia rebound or withdrawal following treatment cessation.

Jefferies analyst Peter Welford noted that regulatory caution could impair sales. “It may be challenging for daridorexant to avoid insomnia drug category label warnings on next day impairment, which could be key to drive uptake,” he wrote in an investor note. Belsomra has “fallen short of hopes,” with 2019 sales of $306 million, he noted. Dayvigo is a recent arrival on the market, so sales figures are not yet available.

Welford forecast peak worldwide sales of $1 billion and attached a 70% probability of success to the daridorexant program. H.C. Wainwright & Co. has maintained a 90% likelihood of approval for daridorexant and has not altered guidance following the latest set of results, which, together with the earlier data, “provide a deep understanding of its efficacy and tolerability profile,” noted analyst Raghuram Selvaraju.

Idorsia investors gave a cautious welcome to the data. Idorsia’s stock (Zurich:IDIA) edged up 2.8% July 6 to close at CHF32.20 (US$34.20).

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