INNOVATION & PIPELINE
For the treatment of Insomnia and Mood Disorders
Seltorexant is an innovative selective orexin 2 receptor antagonist under development for the treatment of insomnia and related mood disorders. Insomnia is the repeated difficulty with sleep initiation, maintenance or quality that occurs despite adequate time and opportunity for sleep, resulting in daytime impairment. Insomnia can be the primary condition for patients or a secondary symptom of, and contributor to, another medical or psychiatric condition, such as mood disorders or schizophrenia.
In the brain, the orexin system is involved in the control of several key functions, including metabolism and wakefulness. Seltorexant seeks to inhibit the activity of the neurons that promote wakefulness by selectively blocking the orexin 2 receptor. Rather than making an individual sleepier, blocking the orexin 2 receptor reduces the level of the neurotransmitters that signal the brain to maintain vigilance and wakefulness, which can be helpful for patients with insomnia. In addition, we believe this approach may help preserve physiologic and restorative sleep, with improved safety and tolerability over current treatments. Recent research also shows that the orexin system affects the secretion and control of stress hormones like the ones involved in the hypothalamic-pituitary-adrenal or HPA axis (e.g., adrenocorticotropic hormone and cortisol). The HPA axis is known to be overactive in depressed patients a significant proportion of whom suffer from insomnia. We are jointly developing Seltorexant under a co-development and license agreement with Janssen Pharmaceutica N.V., a Johnson & Johnson company.
Recent Developments and Next Steps
ISM 2005 Trial
On June 24, 2019, we announced results of a Phase 2b clinical trial (ISM2005) of seltorexant in patients with insomnia disorder that demonstrated highly statistically significant (p ≤0.001) and clinically meaningful improvement on Latency to Persistent Sleep (LPS) at Night 1, the primary endpoint of the study. The mean decrease from baseline at Night 1 in LPS was 15 minutes for placebo, 30 minutes for seltorexant 5 mg, 50 minutes for seltorexant 10 mg, and 48 minutes for seltorexant 20 mg.
For the key secondary endpoint, Wake After Sleep Onset over the first six hours (WASO-6) at Night 1, the mean improvement from baseline at Night 1 was 15 minutes for placebo, 23 minutes for seltorexant 5 mg, 43 minutes for 10 mg, and 45 minutes for 20 mg of seltorexant. Furthermore, multiple secondary endpoints were also improved versus placebo and standard of care zolpidem, which is available under the brand name Ambien.
We believe these findings demonstrate that seltorexant significantly improves sleep induction and prolongs sleep duration. The results also show that seltorexant resulted in a significantly greater improvement in these sleep parameters compared to zolpidem.
In addition, the beneficial effects on LPS and WASO of seltorexant on elderly patients in the study, in conjunction with a favorable tolerability profile, suggest its potential benefit in the large and growing population of elderly patients whose prevalence of insomnia is higher than in younger patients, thus representing an important therapeutic option.
Based on these results and those from the MDD2001 study (see below), observations of seltorexant include a clinically meaningful improvement in symptoms of depression in patients not responding adequately to first line therapies (SSRIs and SNRIs) and a clinically meaningful effect on insomnia in a wide age range of patients. We believe the demonstration of a significant benefit across a broad spectrum of patients who suffer with depression and/or insomnia and who have not responded adequately to existing therapies points to a differentiated clinical profile and a new way to address an underserved patient population.
On May 13, 2019, we announced results of a Phase 2b clinical trial (aMDD2001) of seltorexant as adjunctive therapy to antidepressants in adult patients with major depressive disorder (MDD) who have responded inadequately to selective serotonin reuptake inhibitors (SSRIs) and/or serotonin norepinephrine reuptake inhibitors (SNRIs).
In this dose finding study, the 20 milligram (mg) dose of seltorexant showed a statistically significant improvement in the MADRS (Montgomery-Asberg Depression Rating Scale) score compared to placebo. The least squares mean (LS mean) difference from placebo of the change in MADRS total score at the end of week 6 was 3.1 for the 20 mg dose of seltorexant, and the 2-sided p-value was 0.083, which is below the pre-specified 2-sided type I error level of 0.1.
After three weeks of treatment, seltorexant at the 20 mg dose also showed a statistically significant improvement over placebo, highlighting its ability to improve mood symptoms over a short period of time. In addition, a key secondary outcome measure, which was based on patient stratification according to baseline insomnia severity index (ISI), showed an even greater difference from placebo for the seltorexant 20 mg arm in patients with clinically significant insomnia (ISI ≥ 15) with LS mean difference versus placebo of 4.9 on the MADRS total score and a 2-sided p-value of 0.050 compared to the overall patient population in this trial.
The 40 mg dose, to which further enrollment was stopped following the interim analysis, showed an improvement in the MADRS total score versus placebo at the end of week 6 but did not reach statistical significance. Results for the 10 mg dose were not interpretable due to the small sample size of patients assigned to this dose.
Seltorexant was well tolerated, and adverse events recorded were similar to those observed in previous studies and similar to or lower than the rate observed in the placebo group.
We believe the results of this study represent the first clinical observation in a large, late-stage study that a selective orexin molecule can achieve a positive effect as an adjunctive treatment in patients with MDD who have an inadequate response to SSRIs and SNRIs. These findings, if confirmed in Phase 3 studies, point to a completely novel approach which would give hope to patients and to the professionals who treat them for a potential new treatment for MDD with an improved safety profile compared to existing therapies.
In December 2017, we announced the enrollment of the first patient in a Phase 2b clinical trial comparing seltorexant versus quetiapine as adjunctive therapy in patients with major depressive disorder (MDD) who have responded inadequately to antidepressant therapy.
The primary objective of this multi-center, double-blind, randomized, flexible-dose, parallel-group study is to assess the efficacy of flexibly dosed seltorexant compared to flexibly dosed quetiapine as adjunctive therapy to a baseline antidepressant drug in delaying time to all-cause discontinuation of study drug over a 6-month treatment period. Time to all-cause discontinuation is defined as the number of days from administration of the first dose of study drug to administration of the last dose of study drug.
The trial consists of three phases: a screening phase lasting up to four weeks, a six-month double-blind treatment phase and a two-week follow-up phase. Approximately 100 patients 18 to 64 years of age are planned to be randomized at approximately 34 sites in the U.S. to receive either flexibly dosed seltorexant, 20 milligrams (mg) or 40 mg, or flexibly dosed quetiapine XR, 150 mg or 300 mg. Subjects will continue to take their baseline antidepressant therapy of either an SSRI (selective serotonin reuptake inhibitor) or an SNRI (serotonin-norepinephrine reuptake inhibitor) at the same dose throughout the screening, double-blind and follow-up phases.