ATS 2023 Updates: AD109’s Potential as the First Oral Medication for Obstructive Sleep Apnea (OSA)

• Apnimed’s AD109 has the potential to be the first oral pharmaceutical drug that remedies both, the primary cause of OSA, nocturnal airway obstruction, and the daytime symptoms of OSA, such as fatigue.
• The dual mode of action of AD109 leads to upper airway dilatation as well as enhanced breathing and oxygenation during sleep.
• Results of the MARIPOSA Phase IIb trial, an efficacy, safety, and dose-finding study for AD109 support the advancement of the drug to Phase III.
• If successful, AD109 could substantially alter the treatment of patients with varying disease intensities ranging from symptomatic snoring to more severe OSA.

Sleep disorders have become a major public health concern that affects millions of North Americans. Obstructive sleep apnea (OSA) is the most common type of sleep-related breathing disorder, marked by abnormal breathing during sleep. This life-altering disorder is characterized by episodes of a complete (apnea) or partial collapse (hypopnea) of the upper airway with an associated decrease in oxygen saturation or arousal from sleep. It occurs when the muscles in the back of the throat fail to keep the airway open, causing brief episodes of breathing cessation. As per Delveinsight’s Obstructive Sleep Apnea Epidemiology report, in 2022, there were approximately 7.6 million males and 5.7 million females with OSA in the US. 

OSA is a serious condition that can have significant health consequences if left untreated. The treatment of OSA aims to alleviate the symptoms, improve sleep quality, and reduce associated health risks. The specific treatment options may vary depending on the severity of the condition. Weight loss and exercise, CPAP therapy (the first line of treatment for OSA), bilevel-positive airway pressure (BPAP) equipment (if CPAP therapy is ineffective), and surgery are the recommended treatments for the illness. Excessive Daytime Sleepiness, the most common OSA-associated condition is treated with drugs such as modafinil, armodafinil, solriamfetol, pitolisant, and others. However, no drugs currently exist to treat OSA directly. 

Apnimed is one of the few companies actively engaged in developing potential treatments for OSA and other sleep-related disorders. Its oral pharmaceutical drug addresses the disease’s underlying neurobiology to stimulate upper airway muscles and keep an open airway during sleep. Apnimed’s AD109 (aroxybutynin + atomoxetine) is a first-in-class, oral pharmaceutical combination dosed once daily at bedtime; the US FDA has granted it Fast Track Designation. Through a dual mode of action, the medication targets two neurochemical pathways that govern the upper airway musculature during sleep. It combines a selective norepinephrine reuptake inhibitor, atomoxetine, with a novel selective antimuscarinic, aroxybutynin. 

At the recently held American Thoracic Society (ATS) International Conference, 2023, for the first time, the company presented positive MARIPOSA Phase IIb (NCT05071612) results on AD109, an investigational oral drug for OSA. A total of 294 participants with OSA severity ranging from mild to severe (Apnea-Hypopnea Index (AHI4, 4% desaturation criteria for hypopneas) of 10⌐45) participated in this Phase IIb trial at 25 sites across the United States. Enrollment was available to both treatment-naive individuals and a significant proportion of OSA patients who refused or were unable to tolerate treatment with positive airway pressure devices (e.g., CPAP), the current standard of care therapy for OSA.

The MARIPOSA trial showed that both dosages of AD109 tested demonstrated a statistically significant reduction in AHI4 as compared to the placebo. In the AD109 2.5mg/75mg dose, AHI4 was reduced from a median of 20.5 to 10.8 events/hour. Overall, 41% of people who finished the trial had an AHI of less than 10, 44% had a higher than 50% drop from baseline, and 15% had an 80% or more reduction. The administration of AD109 resulted in clinically significant decreases in AHI in the majority of individuals with mild, moderate, and severe OSA.

The MARIPOSA findings confirm AD109’s ability to alleviate OSA-related daytime symptoms. A statistically significant improvement in patients taking AD109 (aroxybutynin 2.5mg/atomoxetine 75mg) versus placebo was reported on a daytime functioning assessment called PROMIS-Fatigue (recommended to Apnimed by the FDA). Further, AD109 demonstrated statistically significant improvements on other OSA symptom-evaluating scales like PROMIS-Sleep Impairment and PROMIS-Sleep Disturbance. 

The trial findings also indicated that atomoxetine alone is an ineffective treatment for OSA. Atomoxetine (as monotherapy) did not improve daytime OSA symptoms and significantly impacted nocturnal sleep, both subjectively and by Total Sleep Time (TST). AD109 was well accepted and safe. During the trial, there were no major adverse events (SAEs) and no new or unexpected adverse events. The most prevalent side effects in AD109 patients were dry mouth, sleeplessness, and nausea. 

Following successful discussions with the US FDA in February 2023, Apnimed intends to progress AD109 into Phase III. The company plans to submit additional findings and analyses at upcoming scientific conferences. According to key opinion leaders, as the investigational addresses some of the major shortcomings of the current standard-of-care treatments that are poorly tolerated (e.g., CPAP and oral devices) and/or intrusive (e.g., surgery or implanted devices), there is hope that AD109 may become one of the more important treatments for OSA. Among the emerging drugs in the OSA pipeline, there are limited drugs that could make it to launch to fill the gaps in the treatment, most of them small molecules. The OSA market remains highly opportunistic and untouched. With not many new agents being developed and tested as potential treatments for OSA, AD109 is expected to reign the OSA market until any new therapy receives approval.