A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia.

BACKGROUND: Filorexant (MK-6096) is an orexin receptor antagonist; here, we evaluate the efficacy of filorexant in the treatment of insomnia in adults. METHODS: A double-blind, placebo-controlled, randomized, two 4-week-period, adaptive crossover polysomnography study was conducted at 51 sites worldwide. Patients (18 to <65 years) with insomnia received 1 of 4 doses of oral filorexant (2.5, 5, 10, 20mg) once daily at bedtime during one period and matching placebo in the other period in 1 of 8 possible treatment sequences. Polysomnography was performed on night 1 and end of week 4 of each period. The primary endpoint was sleep efficiency at night 1 and end of week 4. Secondary endpoints included wakefulness after persistent sleep onset and latency to onset of persistent sleep. RESULTS: A total of 324 patients received study treatment, 315 received ≥1 dose of placebo, and 318 ≥1 dose of filorexant (2.5mg, n=79; 5mg, n=78; 10mg, n=80; 20mg, n=81). All filorexant doses (2.5/5/10/20mg) were significantly superior to placebo in improving sleep among patients with insomnia as measured by sleep efficiency and wakefulness after persistent sleep onset on night 1 and end of week 4. The 2 higher filorexant doses (10/20mg) were also significantly more effective than placebo in improving sleep onset as measured by latency to onset of persistent sleep at night 1 and end of week 4. Filorexant was generally well tolerated. CONCLUSIONS: Orexin receptor antagonism by filorexant significantly improved sleep efficiency in nonelderly patients with insomnia. Dose-related improvements in sleep onset and maintenance outcomes were also observed with filorexant.

Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis.

BACKGROUND: This study explored whether antagonism of orexin receptors might be an effective mechanism for migraine prevention. METHODS: We conducted a randomized, double-blind, placebo-controlled, pilot trial. Patients experiencing four to 14 days with migraine during a one-month baseline period were randomized to the orexin receptor antagonist filorexant 10 mg nightly or placebo for three months. Efficacy was assessed by mean monthly migraine days (headache plus at least one associated migraine symptom) and headache days. Safety and tolerability were assessed by adverse event reports and laboratory tests. RESULTS: Of 120 patients treated with filorexant and 115 treated with placebo, 97 (81%) and 101 (88%), respectively, completed the trial. There was no statistically significant difference between treatments for change from baseline in mean monthly migraine days (filorexant = -1.7, placebo = -1.3, difference = -0.4 (95% CI: -1.3, 0.4)) or headache days (filorexant = -1.7, placebo = -1.2, difference = -0.5 (95% CI: -1.4, 0.4)). Filorexant was generally well tolerated but was associated with a higher proportion of patients who reported adverse events than placebo (47% vs 37%), particularly somnolence (13% vs 4%). CONCLUSIONS: These data fail to provide evidence that antagonism of orexin receptors with filorexant, when administered at night, is effective for migraine prophylaxis.

Retinal Optical Coherence Tomography Metrics Are Unchanged in Verubecestat Alzheimer's Disease Clinical Trial but Correlate with Baseline Regional Brain Atrophy.

BACKGROUND: We performed exploratory analyses of retinal thickness data from a clinical trial of the AßPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer's disease (AD). OBJECTIVE: To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy. METHODS: Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo. RESULTS: Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson's r values≤0.23, p-values < 0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant. CONCLUSION: BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline. TRIAL REGISTRATION: Clinicaltrials.gov NCT01739348 (registered December 3, 2012; https://clinicaltrials.gov/ct2/show/NCT01739348).

Orexin Receptor Antagonism in Painful Diabetic Neuropathy: A Phase 2 Trial With Filorexant.

OBJECTIVES: To evaluate whether orexin receptor antagonism with filorexant provides pain relief in patients with painful diabetic neuropathy (PDN). METHODS: In this double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal proof-of-concept study, patients with PDN (aged 18 to 75 y) entered a 2-week, single-blind active run-in period with filorexant 10 mg nightly, before randomization 1:1 to placebo or filorexant in a 2-week, double-blind treatment period. The primary efficacy endpoint was time to efficacy failure among "primary responders" (≥30% decrease in evening pain intensity during the run-in). Secondary endpoints were time to efficacy failure among "all responders" (≥20% decrease in evening pain intensity during the run-in) and mean change from baseline in evening pain intensity throughout last 3 days of the double-blind period. RESULTS: Of the 182 patients treated during the run-in, 170 were randomized in the double-blind period, including 65 primary responders and 88 responders. There was no significant difference in proportion of patients with efficacy failure during the double-blind period with filorexant versus placebo among primary (24.3% vs. 32.1% [P=0.411]) or all (34.0% vs. 43.9% [nominal P=0.302]) responders or in mean change from baseline in evening pain intensity scores (estimated treatment difference: -0.587 [P=0.269], primary; -0.687 [P=0.108], all). Adverse events were reported by 24.7% of patients during the run-in. A higher proportion of patients treated with filorexant versus placebo reported adverse events during the double-blind period (23.9% vs. 13.4%). DISCUSSION: These data do not provide evidence for the efficacy of nightly filorexant for the treatment of PDN.