SynAIRgy Phase 3 Trial Aims to Assess Pharmacological Activation of Upper Airway Muscles to Treat Obstructive Sleep Apnea

Patrick J. Strollo Jr., MD, FACP, FCCP, FAASM

At the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, investigators presented an outline of the phase 3 SynAIRgy trial (NCT05813275), a randomized, controlled study evaluating the efficacy and safety of AD109 (Apnimed), a combination of antimuscarinic aroxybutynin and atomoxetine, as a potential treatment for obstructive sleep apnea (OSA). AD109, a first-in-class once-daily medication, aims to be the first oral pharmacologic therapy that targets key neurological pathways in OSA that activate upper airway dilator muscles to maintain an open airway during sleep.¹

The study, which is currently ongoing, includes approximately 640 participants with OSA who are randomly assigned 1:1 to either AD109 or placebo for a 26-week treatment period. Those in the trial are adults who either decline or unable to tolerate continuous positive airway pressure (CPAP) treatment, otherwise considered the gold standard for OSA. In addition, eligible patients have an apnea-hypopnea index(AHI)-4 (4%) desaturation definition for hypopneas) greater than 5 and a body mass index less than 42 kg/m2 for women and less than 40 kg/m2 for men.

Led by Patrick J. Strollo Jr., MD, FACP, FCCP, FAASM, a pulmonologist at the University of Pittsburgh, the primary end point is response rate of AD109 vs placebo, defined as at least a 50% reduction in AHI4 over the 26-week period using a polysomnogram (PSG). In the study, participants will have a PSG on treatment at week 4. Other secondary end points include changes domains of fatigue, sleep impairment, and hypoxic burden on Patient Reported Outcome Measurement Information System (PROMIS) scale, as well as Patient Global Impression of Severity for fatigue, and the Epworth Sleepiness Scale.

In a previous phase 2 trial, dubbed MARIPOSA (NCT05071612), treatment with AD109 demonstrated statistically significant improvements on both objective and subjective outcomes in patients with OSA. The study featured 211 patients (41% female) with a median age 55 (48-60) years and BMI of 32.2 (28.0-35.2) kg/m2 who were randomized to AD109, atomoxetine, or placebo. All told, AHI4 was reduced from a median of 20.5 to 10.8 events/hour in the AD109 2.5mg/75 mg dose (P <.001 vs placebo).

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Additional data showed that 41% of participants who completed the study achieved an AHI below 10 when treated with AD109, 44% had greater than 50% reduction from baseline, and 15%. Of treated patients had an 80% or greater reduction. Notably, atomoxetine, dosed as a monotherapy, did not improve daytime OSA symptoms, and statistically significantly worsened nighttime sleep subjectively and by the measurement of total sleep time, indicating that atomoxetine alone is an inappropriate therapy for OSA.

AD109-treated patients also demonstrated statistically significant improvements vs placebo in PROMIS-Fatigue, a scale of daytime functioning (P <.05). The investigational agent also showed a trend towards statistical significant on scales measuring other important OSA symptoms such as PROMIS-Sleep Impairment and PROMIS-Sleep Disturbance.

SynAIRgy will also assess the safety of AD109, incorporating multiple in-office measurements of heart rate and blood pressure throughout the treatment period. In MARIPOSA, the treatment was considered safe and well tolerated, with no serious adverse events (AEs) and no new unexpected AEs observed. Overall, the most common AEs in patients treated with AD109 were dry mouth, insomnia, and nausea.

At the time of the MARIPOSA data release, Paula Schweitzer, PhD, an investigator of the study and director of Research at St. Luke’s Sleep Medicine and Research Center, said in a statement, "MARIPOSA results also showed that AD109 improved daytime fatigue, an often-debilitating effect of poor sleep due to OSA. For those who cannot tolerate current treatments, AD109 has the potential to be a convenient, oral pill that could improve people’s quality of life both at night and during the day."²

AD109 is also being currently evaluated in the LunAIRo study, a randomized, double-blind, placebo-controlled, 1-year parallel-arm study of patients with mild to severe OSA. The trial is currently enrolling at least 640 participants in clinical centers across the US.

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REFERENCES
1. Strollo P, Taranto-Montemurro L. Aroxybutynin and atomoxetine for the treatment of OSA: rationale and design of the SYNAIRGY phase 3 RCT. Presented at: 2024 SLEEP Annual Meeting; June 1-5; Houston, TX. ABSTRACT 0546.
2. Apnimed presented positive phase 2b results on AD109, an investigational oral drug for obstructive sleep apnea, for the first time at ATS 2023. News release. Apnimed. May 21, 2023. Accessed June 3, 2024.