BALTIMORE – Multiple studies based on phase 3 clinical trials of the investigational drug solriamfetol have found that it may be effective for improving next-day wakefulness and work productivity in people with narcolepsy and obstructive sleep apnea, and that the drug can maintain its effect throughout the day as well as for up to 6 months, investigators reported at the annual meeting of the Associated Professional Sleep Societies.
Solriamfetol, developed by Jazz Pharmaceuticals, is the subject of a new drug application accepted by the Food and Drug Administration in March of 2018 for the treatment of excessive sleepiness due to narcolepsy or obstructive sleep apnea (OSA). Solriamfetol is a selective dopamine and norepinephrine reuptake inhibitor.
The drug was the subject of four different studies presented at SLEEP 2018 that drilled down into its effect on specific aspects of narcolepsy or OSA, or both. One study explored results in narcoleptic patients with and without cataplexy. Another study investigated the drug’s maintenance of efficacy after 6 months of treatment. A third study looked at the drug’s impact on next-day function, work productivity, and quality of life in patients with narcolepsy. And the fourth study researched how solriamfetol helped maintain wakefulness throughout the day.
Yves Dauvilliers, MD, reported that the 150- and 300-mg doses of solriamfetol were effective in improving both sleep latency, as measured with maintenance of wakefulness test (MWT), and Epworth Sleepiness Scale (ESS) scores in both cataplexic (n = 117) and noncataplexic (n = 114) narcolepsy. The objective of the study was to reevaluate the safety of solriamfetol in these narcoleptic subgroups from the phase 3 trial, said Dr. Dauvilliers, a faculty member at Centre Hospitalier Universitaire de Montpellier (France).
In patients with cataplexy, the 150-mg dose increased sleep latency from a baseline of 0 to 7.9 after a week and sustained that for 12 weeks; doubling the dose raised that to 10.3 after a week, reaching 10.7 in week 12. Gains were even more dramatic in noncataplexic patients, with the 150-mg dose improving sleep latency to 12.8 at week 1 and 11.6 at week 12, and the 300-mg dose resulting in a gain of 16.8 after a week, trailing off to 13.8 after 12 weeks, Dr. Dauvilliers said.
The study also evaluated ESS scores for three dosing levels – 75, 150, and 300 mg – plus placebo. In the group with cataplexy, ESS at week 12 improved from a baseline of 0 to –3.1, –5.6, and –6.3 for the three dosing groups, respectively, vs. –1.8 for placebo. In the noncataplexy patients with narcolepsy, the improvements in ESS at week 12 were –4.5, –5.2 and –6.4, respectively, vs. –1.5 for placebo.
“At 150 mg and 300 mg, solriamfetol seems to be very effective in treating excessive sleepiness with narcolepsy, with the same efficacy in the group with and without cataplexy – with efficacy even after just 1 week of treatment,” Dr. Dauvilliers said.
Atul Malhotra, MD, and his coresearchers investigated the long-term safety and efficacy of solriamfetol out to 42 weeks in patients with narcolepsy or OSA who completed previous clinical trials, which were 6- and 12-week trials. The study involved an open-label phase from weeks 14 to 27, a 2-week randomized withdrawal phase and then safety follow-up after week 40. In the open-label phase, ESS scores for the overall treatment group (n = 519) improved from 15.9 at baseline to 8.3 at week 40, with variation between the OSA (n = 333) and narcolepsy (n = 186) groups: from 15.2 at baseline to 6.5 at week 40 for the former and from 17.3 to 11.4 for the latter.
In the randomized withdrawal phase, ESS scores for those on solriamfetol (n = 139) migrated upward from 7.3 to 8.5 – but for the placebo group (n = 141) ESS rose from 7.8 to 12.6, a difference of 3.7 favoring the treatment group, said Dr. Malhotra, chief of pulmonary and critical care medicine and the Kenneth M. Moser Professor in the department of medicine, University of California San Diego, La Jolla. Most patients in the placebo group had worsening of symptoms based on global impression of change – 64.5% vs. 28.2% in the treatment group in the self-reported cohort, and 63.8% vs. 28.7% in the clinician-evaluated cohort.
Dr. Atul Malhotra
“The open-label phase demonstrated maintenance-of-efficacy after 1 year,” Dr. Malhotra said. “The safety profile was consistent with prior placebo-controlled studies of solriamfetol. Epworth sleepiness score and adverse event data demonstrated a lack of rebound sleepiness or withdrawal after abrupt discontinuation of solriamfetol during the randomized washout phase. So the bottom line is it looks to be a durable, effective treatment without major side effects.”
Helene A. Emsellem, MD, led a study into how solriamfetol can impact daily activity in patients with narcolepsy. “Solriamfetol at 300 mg reduced activity impairment outside the workplace and, at 150 mg, reduced activity and work impairment from baseline to week 12 on the measures of functionality at work and in private life,” said Dr. Emsellem, of George Washington University Medical Center, Washington. She is medical director of the Center for Sleep & Wake Disorders, Chevy Chase, Md.
Patients on 300 mg solriamfetol (n = 43) gained an average 3.01 on the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10) total score from baseline to week 12. That compares with gains of 2.57 in the 150-mg group (n = 51), 2.39 in the 75-mg group (n = 49), and 1.56 in the placebo group (n = 52, P = .05). The study looked at activity across four different measures in terms of reduced impairment, as measured by percentage reductions in the negative. The 150-mg group showed most improvement in impairment while working and overall work impairment, with changes of –22.02% and –19.77%, respectively, vs. –11.62% and –10.59% for the 300-mg dose. However, the higher dose showed greater improvement in general activity impairment: –21.17% vs. –17.84% in the 150-mg dose (P less than .05).
Dr. Helene A. Emsellem
Notably, there was little difference across the dosing groups in improvement in work time missed, “I think mostly because there wasn’t much absenteeism to start with,” Dr. Emsellem said.
The 300-mg group also showed greater gains in physical component summary, based on answers to the 36-item Short Form Health Survey, averaging a gain of 3.29 from baseline vs. 2.65 for 150 mg, 2.54 for 75 mg, and 1.06 for placebo. However, on the mental component summary of the survey, the 300-mg group showed the smallest increase: 0.68 vs. 2.05 (150 mg), 1.55 (75 mg), and 0.78 (placebo), respectively (P less than . 05).
In reporting on the effects of solriamfetol through the day, Paula K. Schweitzer, PhD, director of research at the Sleep Medicine and Research Center at St. Luke’s Hospital, Chesterfield, Mo., noted that sustained full-day efficacy may be a limitation of other wake-promoting medications (Clin Neuropharmacol. 2003;26:252-57; Curr Med Res Opin. 2006;22:761-74). The objective of her study was to evaluate the efficacy of solriamfetol through the day over five sequential MWT trials. Her research involved two double-blind, 12-week studies in patients with either narcolepsy (n = 231) or OSA (n = 459) who were randomized to placebo or one of four doses of solriamfetol: 37.5 mg (in OSA only) and 75, 150, and 300 mg. Patients took the drug orally in the morning.
“Solriamfetol significantly increased sleep latency on all five sequential MWT trials at doses of 150 and 300 mg in the narcolepsy patients, and at doses of 75, 150, and 300 mg in the OSA patients.” Dr. Schweitzer said.
Dr. Paula K. Schweitzer
The 150- and 300-mg doses showed the greatest improvement over smaller doses and placebo in both the narcolepsy and OSA groups. In the narcolepsy patients, changes from baseline in MWT sleep latency in the first trial, at approximately 1 hour post dose, were 9.9 (150 mg), 9.9 (300 mg), and –0.6 (placebo) minutes; and in the fifth trial, approximately 9 hours post dose, were 9.3 (150 mg), 12.3 (300 mg), and 3.1 (placebo) minutes. In the OSA patients, changes from baseline in the first trial were 10.9 (150 mg), 12.5 (300 mg), and –0.4 (placebo) minutes; and in the fifth trial, changes were 8.1 (150 mg), 7.6 (300 mg), and 0.2 (placebo) minutes.
“These data demonstrate sustained efficacy over approximately 9 hours following morning dosing for solriamfetol at 150-300 mg in narcolepsy patients and 75-300 mg in OSA patients.” Dr. Schweitzer said.
She also noted that rates of insomnia through the day were less than 5% in each study population combined across dose groups.
Reporting of adverse events was similar across treatment groups in all four studies. The most common adverse event was headache, ranging from around 10% for OSA to 24.2% in patients with cataplexic narcolepsy (n = 91), followed by nausea, decreased appetite, anxiety, and nasopharyngitis. Dr. Malhotra’s study, which involved the largest population of OSA (n = 417) and narcolepsy (n = 226) patients, showed overall rates of at least one adverse event of 75.1% and 74.8%, respectively. His study also showed an overall rate of 5% for respiratory tract infection, and nine patients (1.4%) who had serious cardiovascular adverse events – two cases of atrial fibrillation, and one each of acute MI, angina pectoris, chest discomfort, chest pain, noncardiac chest pain, cerebrovascular accident, and pulmonary embolism.
Dr. Schweitzer noted that the adverse events were mild to moderate in severity, with discontinuation rates of 5% to 7% in the treatment group. Dr. Dauvilliers said the safety results were consistent with previous studies.
All four researchers reported receiving grant/research support from Jazz Pharmaceuticals, sponsor of the study.