Mariposa: oral therapy ad109 improves objective & patient reported outcomes in osa. randomized, placebo controlled clinical trial

Abstract Introduction Obstructive sleep apnea (OSA) is a common disorder with often poorly tolerated treatment . While there is currently no approved pharmacotherapy for OSA, the combination of noradrenergic and antimuscarinic drugs, counteracting sleep-related upper airway muscle hypotonia, has recently shown encouraging results. AD109 is a combination of the norepinephrine reuptake inhibitor atomoxetine and the antimuscarinic aroxybutynin, the R-enantiomer of oxybutynin which recently showed efficacy over 1-night treatment in mild OSA patients. Safety and efficacy data over longer periods and in more severe OSA patients are needed. Methods Mariposa was a 25-center, randomized, controlled, parallel arms clinical trial designed to evaluate efficacy, safety, and tolerability vs placebo of 2 doses of AD109 (75/2.5mg and 75/5mg) and atomoxetine 75mg alone administered for 4 weeks in OSA patients with an apnea-hypopnea index (AHI4, 4% desaturation definition for hypopneas) between 10 and 45. The primary outcome was the change in AHI4, AD109 vs. placebo. Patient reported outcome questionnaires (PROMIS) were studied as exploratory outcomes. Results 211 patients (41% female) with median (IQR) age 55 (48-60) years and BMI 32.2 (28.0-35.2) kg/m2 were randomized. AHI4 was reduced from 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 75/2.5mg dose arm and from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the 75/5mg arm (both p< 0.0001 vs placebo). AHI4 was reduced from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (p< 0.01 vs placebo) and from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) on placebo. Overall, 44% had a reduction from baseline greater than 50% when treated with AD109. On AD109 75/2.5 dose, there was an improvement of PROMIS fatigue scores (p< 0.05 vs placebo and atomoxetine alone). Despite improving AHI4, atomoxetine alone reduced by 20+ minutes total sleep time vs placebo and AD109 (p< 0.05). There were no severe adverse events on AD109 with the most common side effects being dry mouth, insomnia, and nausea. Conclusion AD109 objectively and subjectively improved OSA severity in a group of patients with a wide range of AHI4 over 4 weeks of treatment. Results from the Mariposa trial are central for the design of phase 3 trials of AD109 in OSA. Support (if any) This study was supported by Apnimed.