Abstract Details

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

Topic Sleep

Presentation(s) P9 - Poster Session 9 (8:00 AM-9:00 AM)

Poster/Presentation
Number 9-004

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.

Authors/Disclosures
Gregory S. Parks, PhD (Axsome Therapeutics) PRESENTER	Dr. Parks has received personal compensation for serving as an employee of Axsome Therapeutics. Dr. Parks has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Dr. Parks has stock in Axsome Therapeutics. Dr. Parks has stock in Jazz Pharmaceuticals.
David Gozal	No disclosure on file
Hans Van Dongen (Washington State University)	Hans Van Dongen has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Jazz Pharmaceuticals. Hans Van Dongen has received intellectual property interests from a discovery or technology relating to health care. Hans Van Dongen has received publishing royalties from a publication relating to health care.
Eileen Leary, PhD (Axsome Therapeutics)	Dr. Leary has received personal compensation for serving as an employee of Centessa Pharmaceuticals. Dr. Leary has received personal compensation for serving as an employee of Axsome Therapeutics. Dr. Leary has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Clinical Partners Group. Dr. Leary has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pulse Infoframe. Dr. Leary has or had stock in Jazz Pharmaceuticals.Dr. Leary has or had stock in Axsome Therapeutics.Dr. Leary has or had stock in Centessa Pharmaceuticals.
Samantha Floam, DMD (Axsome Therapeutics)	Dr. Floam has received personal compensation for serving as an employee of Axsome Therapeutics.
Herriot Tabuteau (Axsome Therapeutics)	Herriot Tabuteau has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Axsome Therapeutics.

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