Sunosi (solriamfetol), a drug marketed by Axsome Therapeutics Inc, met the primary endpoint in the “SHARP” study and significantly improved cognitive function as compared to placebo in cognitively impaired patients with excessive daytime sleepiness (EDS) associated with obstructive sleep apnea (OSA). Sunosi was compared to placebo using the Digit Symbol Substitution Test subtest of the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS), as well as using patient-reported measures of cognitive function. In the study, Sunosi replicated previous findings by significantly reducing excessive daytime sleepiness symptoms as compared to placebo.

SHARP (Solriamfetol’s Effect on Cognitive Health in Apnea Participants During a Randomized Placebo-controlled Study) was a randomized, double-blind, placebo-controlled, crossover, multicenter, trial in 59 patients with excessive daytime sleepiness associated with OSA, and impaired cognitive function. Patients were all treated with Sunosi for 2 weeks, and with placebo for 2 weeks, with the treatment periods separated by 1 week of down-titration and washout.

On the study’s primary endpoint, Sunosi demonstrated statistically significant improvement in cognitive function compared to placebo as assessed by the change from baseline on the DSST RBANS (6.49 vs. 4.75, p=0.009), with an effect size of 0.36. The DSST RBANS is an objective neuropsychological test that assesses executive function, processing speed and attention. Statistically significant improvement in cognitive function with Sunosi treatment was also demonstrated using the British Columbia Cognitive Complaints Inventory (BC-CCI) overall score compared to placebo (p=0.002), with an effect size of 0.43. The BC-CCI is a patient-reported test that assesses domains of memory, concentration, trouble expressing thoughts, word finding, and problem solving.

Sunosi significantly improved excessive daytime sleepiness symptoms compared to placebo, as measured by the Epworth Sleepiness Scale (ESS). The improvement on the ESS with Sunosi treatment was approximately twice that observed with placebo (p=0.004), with an effect size of 0.50.

The most commonly reported adverse events with Sunosi treatment (incidence ≥3%) were nausea (6.9%) and anxiety (3.4%). The study completion rate was 96.7% for patients randomized to each treatment sequence (Sunosi followed by placebo, or placebo followed by Sunosi).

“Cognitive impairment in patients with EDS associated with OSA is extremely common and one of the most burdensome symptoms for patients,” says Richard Bogan, MD, FCCP, associate clinical professor at the University of South Carolina School of Medicine, associate clinical professor at Medical University of South Carolina, and principal of Bogan Sleep Consultants, in a release. “The results of the SHARP study demonstrate a clinically important improvement in cognitive function with Sunosi treatment in cognitively impaired patients with EDS and OSA. Of importance, the results from the patient-reported outcomes are consistent with the objective measures, meaning that patients themselves were able to perceive improvements in their cognitive performance with Sunosi treatment. The ability to address cognitive symptoms would represent an important advancement in the treatment of EDS associated with OSA.”

Herriot Tabuteau, MD, Axsome CEO, says in a release, “We are excited by the demonstrated effect of Sunosi on cognition, using both objective and patient-reported outcomes in the SHARP trial in patients with EDS and OSA experiencing cognitive impairment at baseline. We plan to discuss these results with the FDA as soon as possible. In addition, we recently presented new data demonstrating that solriamfetol has activity at TAAR1, a previously unrecognized target for this molecule which further supports its exploration in cognition.”

Axsome says that detailed study results will be submitted for presentation at upcoming medical meetings and for publication.

New Data Demonstrating Activation of TAAR1 by Solriamfetol Presented at 2022 Psych Congress

New preclinical pharmacology studies have identified agonist activity at the trace amine-associated receptor 1 (TAAR1) and lower potency agonist activity at 5-HT1A receptors for solriamfetol, in addition to its activity as a dopamine and norepinephrine reuptake inhibitor (DNRI). TAAR1 is a G-protein coupled receptor with affinity for the trace amines, and TAAR1 agonists have demonstrated pro-cognitive and wake-promoting effects in rodents and primates.

Results of the studies demonstrated that solriamfetol activates human TAAR1 in vitro at potencies that are within the clinically relevant plasma concentration range and overlap with observed dopamine and norepinephrine transporter inhibitory potencies. No human TAAR1 activity was observed for the wake-promoting agent modafinil or the DNRI bupropion. In addition, similar to known TAAR1 agonists, solriamfetol reduced the firing frequency of mouse VTA dopamine neurons in a D2-sensitive manner.

These findings were recently presented at the 2022 Psych Congress on September 18, 2022.

The mechanism of action of solriamfetol to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea, and to potentially affect cognition, is unclear.

Photo 85553737 © Andreykuzmin | Dreamstime.com