By Sree Roy

Fresh off reporting its MARIPOSA Phase 2b study findings, Apnimed’s clinical development lead says the company plans to test its obstructive sleep apnea (OSA) drug candidates—AD109 (primary) and AD504 (follow-on)—in two longer clinical trials, which could ultimately lead to US Food and Drug Administration (FDA) approval of the first oral pill for OSA.

At ATS 2023, Paula Schweitzer, PhD, an investigator in the MARIPOSA trial and the director of research at St. Luke’s Sleep Medicine and Research Center, presented data that AD109 (aroxybutynin + atomoxetine) reduced the apnea-hypopnea index (AHI) compared to placebo in most patients with mild, moderate, and severe OSA. “MARIPOSA results also showed that AD109 improved daytime fatigue, an often-debilitating effect of poor sleep,” Schweitzer said in a release about her presentation.

AD109 had previously shown efficacy over one night of treatment in patients with mild OSA. The results presented at ATS are an important step in showing safety and efficacy over a longer duration and in more severe OSA patients. 

The next two clinical trials take the duration and severity tests to the next level. Apnimed plans a six-month and a one-year trial and has opened both trials to patients with an AHI greater than 5 with a 4% or greater fall in oxyhemoglobin saturation. These will be Phase 3 pivotal trials in which the data is intended for an FDA new drug application.

“We want to continue to be laser-focused on efficacy—that it does what we want it to do—but we also are sensitive to the mandate per the FDA that we need to show this is safe in a population of patients with sleep apnea,” says John Cronin, MD, Apnimed’s senior vice president of clinical development, to Sleep Review. “The good news with our compounds is there is a lot of safety data already available with atomoxetine, and aroxybutynin is an enantiomer of oyxbutynin, which is currently in the clinical realm.”

Atomoxetine is a treatment for attention-deficit hyperactivity disorder, and aroxybutynin is a novel, Apnimed-developed form of oxybutynin, a treatment for overactive bladder. Since the population with sleep apnea is older and with other differences from people currently on these drugs, further studies on a population with OSA could be reassuring. “We’ve heard that from the field, and we want to really attend to that and see what it shows,” Cronin says.

The MARIPOSA Phase 2 revealed other interesting findings. The median AHI reduction was just shy of 50%. “It was about 47%, which in my mind parallels a lot of alternative therapies to PAP,” Cronin says. 

Some responders were even treated to resolution with the drug candidate. “There are people on our team who are scientifically looking at AI [artificial intelligence] models of responders and non-responders, looking at things like oximetry signals,” Cronin says. “I think Phase 3 will help us really understand this.”

An arm of the MARIPOSA trial also investigated follow-on OSA drug candidate AD504. Apnimed sees this oral pharmacological candidate as having potential for certain subpopulations of people with OSA, such as people with COMISA (comorbid insomnia and OSA) who are generally harder to treat, according to Cronin. “That is part of our research pipeline in terms of what’s next,” Cronin says.

Apnimed will soon begin focusing on patient recruitment for its two Phase 3 trials, which will take place at more than 120 sites in the United States and Canada. The trials are designed for OSA patients with a baseline AHI greater than 5 who are unwilling or unable to use CPAP and who have daytime fatigue, which Apnimed will analyze as a secondary outcome. 

“One of the things that plagues our field is people will do an intervention and ask if it improved the Epworth Sleepiness Scale score, but many times the Epworth score in the group starts out as normal,” Cronin says, resulting in a floor effect. “If we’re actually treating patients who are symptomatic, we think that’s important. We want to alleviate that type of symptom,” he says.

Should Apnimed’s AD109 and/or AD504 become FDA-approved, it will be interesting to see how an oral sleep apnea pill is incorporated into clinical practice. Cronin says, “I’ve been a sleep physician for almost 25 years, and we’re evolving as a field…The way I look at it personally as a clinician is this is another tool in the toolbox. We have more targeted precision therapy. There are a lot of different reasons people have sleep apnea, from obesity to neuromuscular deficiencies to loop gain, and this will sit in a figurative toolbox that clinicians can use.”


21 May 2023. Schweitzer P, Ojile JM, Thein S, et al. The oral agent AD109 improves objective and subjective outcomes in obstructive sleep apnea patients. Results from the MARIPOSA study, a randomized, controlled clinical trial. Presented at ATS 2023 Session A18.

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