Oral combination obstructive sleep apnea drug lowers disorder severity over 1 month

Key takeaways:

• Patients with obstructive sleep apnea ranging from mild to severe showed improvement with an oral combination drug.
• The drug reduced symptoms of fatigue and was safe and well tolerated.

WASHINGTON — A combination of atomoxetine and aroxybutynin taken for 4 weeks lessened obstructive sleep apnea severity, according to an abstract presented at the American Thoracic Society International Conference.

The drug, AD109 (Apnimed), which is made up of both atomoxetine, a norepinephrine reuptake inhibitor, and aroxybutynin, an antimuscarinic that is the R-enantiomer of oxybutynin, received FDA fast track designation in 2022, according to a manufacturer-issued press release and study abstract.

Paula Schweitzer

“CPAP is not well tolerated by many people with obstructive sleep apnea (OSA), and many who do use these devices do not keep them on all night,” Paula Schweitzer, PhD, investigator in the MARIPOSA trial and director of research at St. Luke’s Sleep Medicine and Research Center, told Healio. “Until now, no one has been successful in developing a potential pharmaceutical option to treat OSA that could be an alternative for those who are unable to use CPAP. For those who cannot tolerate current treatments, AD109 has the potential to be a convenient, oral option that could improve people’s quality of life both at night and during the day.”

In the multicenter, randomized, placebo-controlled, parallel arms phase 2b MARIPOSA clinical trial, Schweitzer and colleagues assessed 211 patients (median age, 55 years; 41% women) with mild to severe OSA (apnea-hypopnea index [AHI₄] range, 10 to 45 events per hour) to determine if AD109 was effective, safe and tolerable in patients receiving the treatment for 4 weeks.

According to the abstract, the drug was previously found to be effective in patients with mild OSA who received it for only one night.

Researchers assessed two different doses of AD109 that varied based on the amount of aroxybutynin — 75 mg of atomoxetine/2.5 mg of aroxybutynin and 75 mg of atomoxetine/5 mg of aroxybutynin — against placebo. Additionally, a 75 mg dose of just atomoxetine was compared with placebo.

To observe shifts in AHI₄, researchers had patients complete two polysomnograms at baseline and two on-treatment, each averaged together, and compared them with those of patients on placebo. They also assessed patient reported outcomes questionnaires, including PROMIS-Fatigue, to evaluate daytime functioning.

Of the total cohort, 19.55 events per hour was the median AHI₄ at baseline, according to the press release.

Researchers observed that both doses of AD109 lowered AHI₄, with greater differences between baseline and on-treatment AHI₄ compared with placebo. Patients receiving AD109 75 mg of atomoxetine/2.5 mg of aroxybutynin went from 20.5 events per hour at baseline to 10.8 events per hour, and patients receiving AD109 75 mg/5 mg went from 19.4 events per hour at baseline to 9.5 events per hour, both of which demonstrated greater reductions than placebo with a change of 20.1 events per hour to 16.3 events per hour (P < .0001 for both).

Of those who received AD109, 41% lowered their AHI₄ to fewer than 10 events per hour and 44% reached an AHI₄ that was lower than their baseline AHI₄ by more than 50%, according to the abstract. Notably, the release said achievement of an AHI₄ lower than baseline AHI₄ by at least 80% was observed in 15% of patients given the combination drug.

In terms of patients receiving atomoxetine by itself, researchers saw that the median of 19 events per hour at baseline went down to 11.8 events per hour (P < .01), which was more than the previously described placebo.

Further, both AD109 and atomoxetine treatment by itself lowered hypoxic burden vs. placebo (P < .001), according to the abstract. However, atomoxetine went on to show no positive change in daytime OSA symptoms and cut total sleep time by at least 20 minutes, deeming it an “inappropriate” option for patients with OSA, according to the release.

In addition to lowering AHI₄ events per hour, AD109 consisting of 75 mg atomoxetine and 2.5 mg aroxybutynin significantly improved symptoms of fatigue, measured through PROMIS-Fatigue, compared with placebo (P < .05)

In those receiving AD109, no serious adverse events occurred, but frequent negative outcomes included dry mouth, insomnia and nausea, according to the release.

“The MARIPOSA trial demonstrated that AD109 improved daytime symptoms caused by OSA and was safe and well-tolerated,” Schweitzer told Healio.

“The results we saw in the MARIPOSA phase 2b study confirm the results from previous trials,” she added. “It is interesting to see data from MARIPOSA continue to prove that AD109 had a response in patients across mild, moderate and severe forms of OSA, showing that AD109 has the potential to have an impact across the spectrum of the condition.”

According to the release, the phase 3 trial will focus on the AD109 dose containing 75 mg of atomoxetine and 2.5 mg of aroxybutynin.

“MARIPOSA is the first and largest study that demonstrated significant improvement in OSA with a pharmaceutical treatment,” Schweitzer told Healio. “MARIPOSA puts us on the path to potentially having an oral drug that could be an effective alternative for appropriate patients who are either dissatisfied or noncompliant with existing treatment options.”

Reference:

• Apnimed presented positive phase 2b results on AD019, an investigational oral drug for obstructive sleep apnea, for the first time at ATS 2023. https://apnimed.com/apnimed-presented-positive-phase-2b-results-on-ad109-an-investigational-oral-drug-for-obstructive-sleep-apnea-for-the-first-time-at-ats-2023/. Published May 21, 2023. Accessed May 21, 2023.