Sage Therapeutics, a clinical-stage biopharmaceutical company developing medicines to treat central nervous system (CNS) disorders, announced positive results from a Phase 1/2, double-blind, placebo-controlled study of SAGE-217 in the treatment of healthy adult volunteers using a 5-hour phase advance model of insomnia using polysomnography. SAGE-217, administered as a single dose at either 30 or 45 mg, significantly improved sleep efficiency, the primary endpoint of the trial, to a median of 85% (30 mg; p<0.0001) and 88% (45 mg; p<0.0001), respectively, compared with a median sleep efficiency of 73% for placebo. SAGE-217 also demonstrated statistically significant improvements in total sleep time as well as sleep maintenance as measured by time spent awake after sleep onset, although there was not a significant impact on sleep onset in this model as measured by latency to persistent sleep. SAGE-217 was generally well tolerated and all adverse events were mild, with no serious adverse events or adverse events leading to discontinuation. Based on these positive results, Sage expects to initiate clinical development of SAGE-217 in disorders of sleep in 2018.
“Disturbances of sleep have a profound impact on the quality of life for many individuals, whether occurring as a primary disorder or as associated with other illness,” says Jeff Jonas, MD, chief executive officer of Sage Therapeutics, in a release. “There is a significant need to create an improved patient experience for the treatment of sleep dysfunction, and our work with the GABA mechanism identified an opportunity to develop a potential solution. These findings support the unique potential of SAGE-217 across a variety of psychiatric and neurological disorders with unifying focus on related symptoms, including disorders of mood, sleep, and motor function.”
Jim Doherty, PhD, chief research officer of Sage Therapeutics, says, “Key to the experimental medicine capability at Sage is translating insights between compounds and indications for better odds of success across the pipeline. Our evaluation of SAGE-217 in multiple clinical trials, across several indications, suggests that the drug’s mechanism of action may rebalance fundamental brain circuitry, therefore supporting SAGE-217’s development across a broad variety of disorders. These findings suggest that SAGE-217 has the potential to assist sleep maintenance, and we were pleased with the tolerability demonstrated for both doses in this trial.”
Top-line Trial Results
- Sleep efficiency (primary endpoint): the percentage of time in bed spent asleep, as determined by polysomnography. SAGE-217, 30 and 45 mg, administered as a single dose significantly improved Sleep Efficiency (SE) to a median of 84.64% (p<0.0001) and 87.55% (p<0.0001), respectively compared with a median SE of 72.92% for placebo.
- Wake after sleep onset (secondary endpoint): total wake time, in minutes, from persistent sleep onset to lights-on, as determined by polysomnography. SAGE-217, 30 and 45 mg, decreased time of wake after sleep onset (WASO) to a median of 55.0 minutes (p<0.0001) and 42.5 minutes (p<0.0001), respectively, compared with 113.0 minutes for subjects on placebo.
- Total sleep time (secondary endpoint): duration of total sleep time (non-REM and REM) from lights-off to lights-on during recording with polysomnography. SAGE-217 increased total sleep time, compared with a median of 350.00 min in subjects treated with placebo, to 406.25 (p<0.0001) and 420.25 (p<0.0001) minutes, respectively for the 30 and 45 mg doses of SAGE-217.
- Latency to persistent sleep (secondary endpoint): duration in minutes from lights-off to the first epoch of 20 consecutive non-wake epochs, as determined by polysomnography. Compared with placebo, SAGE-217 did not have a significant impact on latency to persistent sleep (p=0.7049) with either dose.
- Safety and tolerability: SAGE-217 was generally well tolerated in this study. Adverse event rates were low across all dose groups (4.8% SAGE-217 45 mg, 11.4% SAGE-217 30 mg and 9.8% placebo) and all adverse events (AEs) were mild. There were no serious AEs and no AEs leading to discontinuation.
Comprehensive data, including additional secondary endpoint measures, will be presented at a future scientific conference.
In this double-blind, placebo-controlled crossover study (treatment periods 1, 2 and 3), healthy volunteers (n=45) were randomized to receive either 30 mg or 45 mg of SAGE-217 or placebo on three separate visits. Each participant received each dose level and placebo once.
Treatment Period 1 began on Study Day 1 and continued until Study Day 2, using a 5-hour phase advance model of insomnia (lights out and polysomnography recording began five hours (± 30 minutes) prior to participants habitual bedtime). Thirty minutes (±15 minutes) prior to lights out, blinded study drug (SAGE-217 30 mg, SAGE-217 45 mg, or placebo) was administered and participants were required to remain in bed for eight hours. Treatment Period 2 (Visit 4, Study Days 8 to 9) and Treatment Period 3 (Visit 5, Study Days 15 to 16) followed similar procedures.
SAGE-217 is a next generation positive allosteric modulator that targets synaptic and extrasynaptic GABA receptors and has a pharmacokinetic profile intended for daily oral dosing. The GABA system is the major inhibitory signaling pathway of the brain and CNS and contributes significantly to regulating CNS function. SAGE-217 is currently being developed in the treatment of MDD and certain other affective disorders, Parkinson’s disease, and sleep disorders.