Idorsia Ltd announced positive results for the comprehensive Phase 2 program with the dual orexin receptor antagonist ACT-541468 (DORA) in insomnia, with zolpidem as an active reference. The program comprised 2 placebo-controlled dose-response studies to evaluate the safety and efficacy of ACT-541468 in adult and elderly patients with insomnia, with a total of 418 patients participating in the trials.

Martine Clozel, MD, and chief scientific officer of Idorsia, says in a release, “Our scientists have been true pioneers in the field of orexin antagonism. More than 20,000 compounds were synthesized and studied before ACT-541468 was selected. Its discovery is the result of an extensive effort to combine two important characteristics of a sleep medication: maintaining efficacy throughout the night, and a low potential for a next-day residual effect. I am delighted to see that the positive readouts from this comprehensive Phase 2 program are consistent with our preclinical predictive models, for both adult and elderly patients with insomnia.”

The first study in 360 adults (ranging from 18 to 64 years) with a treatment duration of 4 weeks showed a significant dose-dependent decrease in WASO (wake after sleep onset) at Day 1 & 2 (average decrease of wake time after sleep onset from baseline on the first 2 nights of treatment, measured by polysomnography). In addition, ACT-541468 significantly decreased LPS (latency to persistent sleep) in a dose-dependent manner.

Treatment with ACT-541468 was generally well tolerated. There were no reports of serious adverse events related to ACT-541468.

The positive readouts of a second study, conducted in 58 elderly patients (ranging from 65 to 85 years), confirmed the efficacy and safety profile of ACT-541468 in this population. The results of this study also showed a significant decrease in WASO and LPS at Day 1 & 2 in a dose-dependent manner.

The overall results of the Phase 2 program with ACT-541468 in insomnia support the decision to initiate efficacy and safety confirmatory studies in both adult and elderly patients.

Detailed results of the Phase 2 program will be made available through scientific disclosure at upcoming congresses and in peer-reviewed publications.

Guy Braunstein, MD, and head of global clinical development of Idorsia, says: “The positive results of the Phase 2 program demonstrate that our DORA can deliver on the potential its mechanism of action offers in insomnia. We have observed a fast onset of sleep and a duration of action which does not exceed a normal night’s sleep. We will now consult with health authorities and progress this important asset into the Phase 3 program as quickly as possible.”

ACT-541468 is a dual orexin receptor antagonist (DORA) which targets the orexin system and is intended to treat insomnia. Based on preclinical data, dual orexin receptor antagonism maintains natural sleep architecture. Preclinical data suggests that ACT-541468 will have a low potential for abuse. Data from a comprehensive Phase 1 program indicates that ACT-541468 has a suitable pharmacokinetic and pharmacodynamic profile to deliver fast onset of sleep, a duration of action which is well suited for appropriate sleep maintenance, and low potential for next day residual effect. These properties are being explored clinically and, if confirmed, will give ACT-541468 the potential to be differentiated from current sleep medication.

Jean-Paul Clozel, MD, and CEO of Idorsia, says, “We couldn’t have asked for a better start for Idorsia. First the excellent results with aprocitentan, where we are in discussions with health authorities to move into Phase 3 for development in resistant hypertension, and now our dual orexin receptor antagonist moving into Phase 3 for insomnia. This will take us an important step closer to delivering on one of our major strategic objectives – to bring at least three products to market within the next 5 years that have the potential to substantially change the treatment options in their target disease.”