Idorsia Ltd reports positive top-line results of the first pivotal Phase 3 study investigating 25 and 50 mg doses of its dual orexin receptor antagonist, daridorexant, in 930 adult and elderly patients (39.1% ≥ 65 years) with insomnia. The study demonstrated efficacy of treatment with daridorexant on objective and subjective sleep parameters and daytime performance with no residual effect in the morning, and no evidence of rebound or withdrawal symptoms upon treatment discontinuation.

Daridorexant at both 25 and 50 mg significantly improved sleep onset and sleep maintenance as measured objectively in a sleep lab by polysomnography. Daridorexant also significantly improved subjective total sleep time as measured daily with a patient diary at home. The results were consistently statistically significant at month 1 and at month 3, indicating sustained benefit. Furthermore, treatment with daridorexant improved patients’ daytime performance from baseline at month 1 and month 3.

Idosria chief executive officer Jean-Paul Clozel, MD, says in a release, “While we designed daridorexant to have the optimal profile for a sleep medicine, I am none-the-less stunned by the results. Once approved, by providing daridorexant to the millions of patients with insomnia, Idorsia will have a major impact on this medical, social, and economic problem. It has struck me particularly in these times of confinement that we are living through, that sleep problems are a major issue and require an extremely safe and effective drug that can be used by the many. With these results Idorsia is entering into a new era; less than 3 years since its creation, Idorsia is taking a huge step forward in delivering on the vision to become a fully-fledged biopharmaceutical company.”

Thomas Roth, PhD, director of the Sleep Disorder and Research Center at Henry Ford Hospital, says, “Pharmacological treatment for insomnia should not only help patients to fall asleep quickly and to stay asleep but also address the negative impact of poor sleep on daytime functioning. I believe that the optimal way to achieve this is through blocking the action of orexin and therefore turning down overactive wakefulness seen among insomnia disorder patients. This will allow patients to sleep throughout the night, while avoiding the adverse effects, associated with many sleep medications that act through broad sedation of the brain. The excellent results seen in this Phase 3 study of 3-month duration suggests that daridorexant can fulfil this significant need for patients with insomnia.”

Guy Braunstein, MD, and head of global clinical development of Idorsia, says, “When designing our program, we had to show the effect of daridorexant on objective sleep measures. It was also very important to us to deliver on what the patient really needs. The program therefore aimed to determine whether daridorexant improved patients’ perception of their sleep and their performance during the day. To measure this, we developed and validated a specific patient reported outcome instrument. It was a big commitment, and we were confident that if any drug could show a positive impact it was daridorexant. We knew that this information was missing from the science of sleep.”

Primary and Secondary Efficacy Endpoints Overview

Daridorexant significantly improved sleep onset as measured by a decrease in latency to persistent sleep (LPS) from baseline compared to placebo. Daridorexant significantly improved sleep maintenance as measured by a decrease in wake time after sleep onset (WASO) from baseline compared to placebo. Total sleep time subjectively (sTST) assessed daily by patients increased significantly from baseline compared to placebo. All of these sleep measures were significantly improved with both 50 mg and 25 mg daridorexant at both 1- and 3-month timepoints. The impact of insomnia on patients’ daytime performance was measured daily using the sleepiness domain score from the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) a Patient Reported Outcome (PRO) instrument, validated according to the US Food and Drug Administration (FDA) Guidance for Industry. Daridorexant improved daytime performance, as measured by patients feeling less physically and mentally tired, less sleepy and more energetic during the day. The results were significant with 50 mg and showed a numerical trend with 25 mg, at both month 1 and month 3. Overall, the primary and secondary endpoints analyses showed consistency across doses, objective and subjective endpoints, through both night and day, and the effect was maintained over time.

About Safety in the Study

The rate of adverse events was comparable between placebo and daridorexant at both treatment doses. Treatment-emergent adverse events (TEAEs) during the double-blind study period were reported in 37.7% and 37.7% of the patients treated with 25 and 50 mg daridorexant, respectively (34.0% for placebo). The most frequent TEAE reported over 3% incidence and higher than placebo was nasopharyngitis, headache. The number of serious adverse events were higher in the placebo group compared to the daridorexant treatment groups (25 mg, 2 patients; 50 mg, 3 patients; placebo, 7 patients). Based on independent, blinded adjudication, potential narcolepsy-like symptoms denoting excessive daytime sleepiness were balanced across all groups (four patients in total), and those describing complex sleep behavior were observed in three patients in total. There was no next-morning residual effect assessed by a visual analog scale every morning. There was no rebound insomnia, or withdrawal symptoms upon discontinuation, and no suicide, suicidal ideation or self-injury were observed.

Guy Braunstein, says, “I want to say a big thank you to the study team, both at the investigation sites and at Idorsia and all the study participants, for delivering a comprehensive and robust study, which has given us a wealth of data to judge the strength of daridorexant. The results from this pivotal study are truly remarkable for the consistency of the benefit in sleep measures. Moreover, this is the first study to demonstrate an insomnia product can improve how the patient feels during the day. If you ask anybody who suffers from insomnia that is what they want—to sleep longer and feel better during day. Daridorexant is addressing real patient problems. The results are made even more remarkable when you see that the efficacy is achieved without compromising safety. We now look forward to the results from the second pivotal study of daridorexant 10 and 25 mg.”

Martine Clozel, MD, chief scientific officer of Idorsia, says, “Our research team has been working on the science of orexin and orexin receptors since their first description in 1998. Our initial work led us to the conclusion that antagonism of the orexin system was the key to providing a natural sleep architecture for patients with insomnia. We did not discover daridorexant by chance—we have worked very hard preclinically and clinically to find the ideal compound to unlock this amazing potential. We wanted a dual antagonist with a rapid effect, and a duration of action sufficient for the night but short enough to avoid any negative residual activity the following morning. The results we share today have made it all worthwhile and prove that we were right to persevere for over 20 years on the project. It just shows what can be achieved with tailored drug design. I am incredibly proud of the discovery team that created daridorexant.”

Simon Jose, chief commercial officer of Idorsia, says, “The millions of people suffering from insomnia are seeking new treatment options to help them sleep well at night and—very importantly—perform well during the day. This is the first time a sleep medicine has demonstrated not only an improvement in sleep onset and sleep maintenance, but also in daytime performance. We look forward to bringing this medication to patients with difficulty sleeping, after review by regulatory authorities. We are confident that with such a wealth of evidence we can make this unique non-sedating sleep medication a huge success and are excited by the opportunity to lead the transformation and modernization of the sleep market.”

Detailed study results will be made available through scientific disclosure at upcoming congresses and in peer reviewed publications.

About the Phase 3 Registration Program

The Phase 3 registration program comprises two confirmatory studies of 3-month duration, together with a 40-week extension study which has recruited around 1,800 patients with insomnia (900 in each study) from over 160 sites across 18 countries.

The confirmatory multi-center, double-blind, randomized, placebo-controlled, parallel-group, polysomnography studies assess the efficacy and safety of daridorexant on objective and subjective sleep and daytime performance parameters in adult and elderly patients with insomnia. The first study, reported here, evaluated treatment with 25 mg and 50 mg doses over 3 months, while the second study will measure treatment with 10 mg and 25 mg doses over 3 months and is expected to report results in the third quarter of 2020. The 40-week extension study will measure the effect of all three doses, generating data for long-term treatment of insomnia.