Apnimed Announces Positive Topline Results for MARIPOSA Trial of AD109, Drug Candidate with the Potential to be the First Oral Therapy for Obstructive Sleep Apnea (OSA)

--AD109 Achieved the Primary Endpoint of Reduced Nighttime Airway Obstruction

--AD109 Significantly Improved Daytime Impairment Caused by OSA

--AD109 Was Well-Tolerated

Apnimed, a clinical-stage pharmaceutical company focused on developing oral pharmacologic therapies to treat obstructive sleep apnea (OSA) and related disorders, announced positive topline results from the MARIPOSA Phase 2b trial, an efficacy, safety and dose-finding study of one-month duration. The topline results were positive for the company’s lead candidate for OSA, AD109 (atomoxetine + aroxybutynin). The primary endpoint showed a statistically significant reduction in the Apnea-Hypopnea Index (AHI, the standard measure of OSA severity and nighttime breathing) for both doses studied (p<0.001 vs. placebo). Results from the MARIPOSA trial also demonstrated that AD109 improved daytime symptoms caused by OSA and was safe and well-tolerated. Results from this study support dose and endpoint selection for Apnimed’s Phase 3 studies of AD109, anticipated to start in the first half of 2023, following discussions with the U.S. Food and Drug Administration (FDA).

“MARIPOSA results support the therapeutic potential of AD109 as a convenient, nightly treatment for OSA, which would represent a major breakthrough in the management of this serious disease,” said Paula Schweitzer, Ph.D., an investigator in the MARIPOSA trial and the Director of Research at St. Luke’s Sleep Medicine and Research Center, Chesterfield, MO. “Improved nighttime breathing and sleep, and improved daytime fatigue were observed, which have the potential to dramatically improve quality of life.”

Ron Farkas, M.D., Ph.D., Chief Medical Officer of Apnimed added, “MARIPOSA was a large study that we believe provides compelling evidence, along with earlier Apnimed studies, of AD109’s potential to improve the lives of people with OSA. We plan to request an End of Phase 2 meeting with FDA shortly to obtain further clarity on Phase 3 and our subsequent marketing application for AD109.”

MARIPOSA Study Design

MARIPOSA was a randomized, double-blind, placebo-controlled dose-finding study of one-month duration. A total of 294 participants with a wide range of OSA severity, from mild to severe (AHI4 of 10-45), were enrolled at 25 sites across the United States. Participants were randomized to parallel arms comparing two doses of AD109, two doses of AD504 (a second candidate in an earlier phase of development), atomoxetine alone, and placebo. Enrollment was open both to treatment-naïve participants and to the substantial proportion of OSA patients who are unwilling or unable to tolerate treatment with positive airway pressure devices (e.g., CPAP), the current standard of care therapy for OSA.

MARIPOSA was also designed to incorporate other standard clinical endpoints designed to characterize improvement of oxygenation, sleep, and daytime function in OSA.

It is one of the largest clinical trials ever conducted of promising drug candidates designed to target the underlying cause of OSA.

MARIPOSA Study Results

Patients assigned to the dose of AD109 studied in prior Apnimed trials (atomoxetine 75mg/aroxybutynin 2.5mg) saw a large and statistically significant (p<0.001) reduction in AHI4 at one month vs placebo. These results are consistent with Apnimed’s prior Phase 2 studies of AD109.

In the MARIPOSA trial, AHI4 was reduced from a median of 20.5 to 10.8 events/h in the AD109 75mg/2.5mg dose arm and reduced from 19.4 to 9.5 events/h in the AD109 75mg/5mg arm. Overall, 41% of participants who completed the study achieved an AHI below 10 when treated with AD109; 44% had a greater than 50% reduction from baseline, and 15% of treated patients had an 80% or greater reduction. The AHI reduction benefit occurred across the entire night unlike current standard of care therapies such as CPAP that are often used for only part of the night.

The MARIPOSA topline results also support the potential of AD109 to improve daytime symptoms caused by OSA. MARIPOSA was designed to explore several scales used to measure symptoms important to OSA patients’ daily function and quality of life. These scales are important for designing the Phase 3 studies required for approval of AD109. On the Epworth Sleepiness Scale (ESS), a 5-point decrease in median ESS over one month from 12.0 to 7.0 was observed with AD109 (atomoxetine 75mg/aroxybutynin 2.5mg) compared to a 2-point decrease observed for placebo. On a scale called PROMIS-Fatigue (suggested to Apnimed by FDA), statistically significant improvement on AD109 (atomoxetine 75mg/aroxybutynin 2.5mg) vs placebo (p<0.05) was observed. AD109 also demonstrated a trend towards statistical significance on scales measuring other important OSA symptoms.

AD109 was safe and well tolerated. There were no serious adverse events (SAEs) and no new or unexpected adverse events in the MARIPOSA trial. The most common adverse events in patients treated with AD109 were dry mouth, insomnia and nausea.

We believe the overall data from MARIPOSA supports advancing the AD109 atomoxetine 75mg/aroxybutynin 2.5mg dose into Phase 3, following discussions with FDA.

As part of Apnimed’s mission to improve the lives of patients with sleep disorders, MARIPOSA also included an exploratory sub-study of two doses of AD504, a second investigational oral medication being developed by Apnimed. These studies revealed promising efficacy in OSA as well.

Apnimed plans to present additional findings and analyses at upcoming scientific conferences.

About AD109

AD109 has the potential to be the first oral pharmacologic that both treats the underlying cause of OSA, airway obstruction at night, and improves daytime consequences of OSA such as fatigue. It is a potential first-in-class, novel, investigational combination dosed once daily at bedtime, designed to treat OSA patients across a broad spectrum of disease severity. AD109 combines a selective norepinephrine reuptake inhibitor (atomoxetine) with Apnimed’s novel selective antimuscarinic (aroxybutynin). AD109 targets key neurological pathways in OSA that activate upper airway dilator muscles to maintain an open airway during sleep. AD109 has the potential to become a safe, effective, and convenient treatment for OSA, addressing some of the key limitations of current standard of care treatments that can be poorly tolerated (e.g., CPAP) and/or invasive (e.g., surgery or implanted devices).

AD109 has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA).

About Obstructive Sleep Apnea

Obstructive Sleep Apnea (OSA) is one of the most common and serious sleep disorders. It is estimated to affect more than 35 million Americans, though underdiagnosis continues to be a serious problem. OSA is characterized by partial or complete upper airway obstruction that occurs during sleep, which often leads to poor sleep, and in the long term, has been shown to exacerbate hypertension, diabetes, cardiovascular disease, and stroke. Additionally, OSA can impair work productivity, reduce functional ability, and lower quality of life. Sleep-related muscular relaxation driven by the central nervous system is a key neurologic mechanism that causes OSA. In patients with OSA, a reduction in neuromuscular control of the upper airway during sleep leads to a corresponding relaxation of the upper airway dilator muscles. The vast majority of diagnosed patients are prescribed positive air pressure therapy devices such as continuous positive airway pressure, or CPAP, but many patients are dissatisfied with these mechanical nighttime devices and fewer than half are compliant long term, leaving a significant population untreated, undertreated and at risk.

About Apnimed

Apnimed is a clinical-stage pharmaceutical company working to transform the treatment of sleep apnea based on a simple idea – patients with obstructive sleep apnea could benefit from treatment with a safe and effective oral medication dosed once daily at bedtime. Apnimed’s lead development program targets the neurologic control of upper airway muscles to maintain an open airway during sleep. Based in Cambridge, Mass., the company is developing a portfolio of novel pharmacologic therapies for sleep apnea and related disorders. Learn more at apnimed.com or follow us on Twitter and LinkedIn.

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