Solriamfetol Improves Cognitive Performance in Preclinical Models of Sleep Apnea and in a Randomized Placebo-controlled Study of Sleep Apnea Participants (SHARP)
David Gozal1, Hans Van Dongen2, Eileen Leary3, Gregory Parks3, Samantha Floam3, Herriot Tabuteau3
1Marshall University, 2Washington State University, 3Axsome Therapeutics
Objective:
To assess whether solriamfetol, a dopamine-norepinephrine reuptake inhibitor (DNRI) approved to improve wakefulness in adults with obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS), could improve memory performance, preclinically, and cognition in EDS from OSA, clinically.
Background:
OSA can result in EDS, despite effective Positive Airway Pressure (PAP) treatment, causing cognitive impairment leading to occupational and social dysfunction and lowered quality of life.
Design/Methods:
In vitro binding and functional studies were conducted to measure solriamfetol activity. In preclinical studies, mice were exposed to long-term intermittent hypoxia (IH) or sleep fragmentation (SF) protocols that induce declarative memory deficits then given solriamfetol (200mg/kg), modafinil (200mg/kg), or vehicle, and cognitively assessed using the novel object recognition (NOR) task. SHARP (NCT04789174) was a randomized, double-blind, placebo-controlled, crossover trial of participants (n=59) with OSA, EDS, and cognitive impairment. Participants received 2 weeks of treatment: solriamfetol 75mg for 3 days then 150mg/day and placebo and a 1-week washout. Primary endpoint was change from baseline in post-dose Coding Subtest of the Repeatable Battery for the Assessment of Neuropsychological Status (DSST-RBANS) averaged across 2-, 4-, 6-, and 8-hour time points; secondary endpoints included change from baseline on British Columbia-Cognitive Complaints Inventory (BC-CCI).
Results:
In vitro experiments showed that solriamfetol inhibits dopamine and norepinephrine transporters (IC50=3.2μM and 14.4μM, respectively) and has agonist activity at TAAR1 (EC=10–16μM) and 5HT1a (EC50=25μM) receptors within the clinically observed therapeutic plasma concentration ranges. In mice, NOR performance was significantly improved with solriamfetol, but not modafinil. In SHARP, DSST-RBANS and BC-CCI scores were improved for solriamfetol versus placebo (6.49 vs. 4.75, p=0.009, Cohen’s d=0.36; -4.70 vs -3.11, p=0.002; d =0.43, respectively). Common solriamfetol AEs (≥3%) were nausea (6.9%) and anxiety (3.4%); no new safety signals were observed.
Conclusions:
Solriamfetol may be an efficacious and generally safe treatment option for patients with cognitive impairment associated with OSA and EDS.