Solriamfetol Improves Cognitive Performance in Preclinical Models of Sleep Apnea and in a Randomized Placebo-controlled Study of Sleep Apnea Participants (SHARP)

This work was sponsored by Axsome Therapeutics and Jazz Pharmaceuticals Introduction: Solriamfetol (Sunosi®) is a dopamine and norepinephrine reuptake inhibitor (DNRI) indicated to improve wakefulness in adults with EDS and OSA. Evidence is available on solriamfetol’s binding and functional activity and effect on memory and cognition in mouse models and clinical trials. Methods: In vitro studies measured solriamfetol’s activity. Preclinical studies exposed mice to memory deficit inducing OSA models; memory performance was assessed after solriamfetol, modafinil or vehicle. SHARP was a randomized, double-blind, placebo-controlled, crossover trial in 59 participants with cognitive impairment associated with OSA and EDS. All received solriamfetol and placebo for 2 weeks with 1-week washout. Endpoints included change from baseline in average Coding Subtest of Repeatable Battery for the Assessment of Neuropsychological Status (DSST-RBANS) scores at 2-, 4-, 6-, and 8-hours post-dose and British Columbia Cognitive Complaints Inventory (BC-CCI) scores. Results: In vitro experiments showed solriamfetol inhibits dopamine and norepinephrine transporters (IC50=3.2 and 14.4µM) and has agonist activity at TAAR1 (EC=10–16µM) and 5HT1a (EC50=25µM) receptors. In OSA mouse models, solriamfetol improved memory whereas modafinil did not. In SHARP, solriamfetol improved performance on DSST-RBANS (6.49 vs. 4.75, p=0.009), effect size (Cohen's d) was 0.36 and BC-CCI (-4.70 vs -3.11, p=0.002; d=0.43) compared to placebo. Most common adverse events were nausea (6.9%) and anxiety (3.4%). Conclusions: Solriamfetol is a DNRI with TAAR1 and 5HT1a agonist activity. Solriamfetol improved memory in OSA mouse models and improved cognition in patients with EDS and OSA. Solriamfetol may be an effective treatment for managing cognitive impairment associated with OSA and EDS.