Q&A: ‘Dawn of a new era for OSA care’ moving into 2025

Key takeaways:

• Treatments for OSA should consider neuromuscular dysfunction and airway narrowing.
• Mid-2025 is the expected timeframe for phase 3 trial data on AD109, a new oral therapy for OSA.

Entering 2025, adults with moderate to severe obstructive sleep apnea and obesity have a new FDA-approved treatment option that takes the form of a GIP/GLP-1 dual agonist, according to a press release from Eli Lilly and Company.

Researchers observed that tirzepatide (Zepbound, Eli Lilly) reduced apnea-hypopnea index (AHI) events per hour and led to greater weight loss at 1 year vs. placebo in two phase 3, double-blind, randomized controlled trials (SURMOUNT-OSA). One trial consisted of adults not using positive airway pressure (PAP) therapy, whereas the other consisted of adults using PAP therapy.

Looking ahead, AD109 (Apnimed), a combination of aroxybutynin and atomoxetine, is currently being studied in phase 3 trials as a treatment option for patients with OSA. As Healio previously reported, this oral combination drug taken for 4 weeks lessened OSA severity in the multicenter, randomized, placebo-controlled, parallel arms phase 2b MARIPOSA clinical trial.

Healio spoke with Larry Miller, MD, CEO of Apnimed, to learn more about obesity and neuromuscular dysfunction in patients with OSA, the use of GLP-1s in OSA care and the trials assessing AD109.

Healio: How prevalent is obesity in patients with OSA? How does obesity negatively impact treatment?

Miller: While obesity is a common risk factor for OSA, recent epidemiological research confirms that most people with OSA do not have obesity. Obesity in the neck and tongue contributes to anatomic airway narrowing in OSA. Recent trials indicate that in those living with obesity, weight loss can be helpful to reduce OSA severity. However, even in patients who lose substantial weight, significant residual OSA remains even after weight loss and requires further treatment.

Healio: How does neuromuscular dysfunction present in patients with OSA? How can this condition negatively impact care/treatment for OSA (ie, CPAP)?

Miller: Neuromuscular dysfunction in OSA is characterized by an abnormal loss of muscle tone in the upper airway muscles during sleep, leading to repeated airway collapse through the night. This dysfunction often occurs in conjunction with anatomical narrowing, which can result from various factors, one of which is obesity.

CPAP and other PAP treatments are designed to compensate for neuromuscular dysfunction by using air to “push” the upper airway muscles out of the way. This can be effective, but the requirements for a tight-fitting mask and pressurized air are so uncomfortable that the majority of patients either abandon or underuse CPAP over time.

Healio: Why do treatment approaches for OSA need to address both neuromuscular dysfunction and metabolic factors?

Miller: The critical point is that OSA in most patients occurs due to two components: a narrowed upper airway and neuromuscular dysfunction. Airway narrowing alone is generally not sufficient to lead to OSA.

As in many chronic diseases with multiple causative mechanisms, multiple treatment modalities are needed to address the diversity of the population and complexity of the disease. Weight loss in patients with obesity is an important component, but further treatment with CPAP, a pharmacologic or other modalities is likely to be necessary. For those without obesity, treatment of neuromuscular dysfunction is the primary approach.

Healio: Can you describe some of today’s trends in OSA care? How do GLP-1s fit into this care?

Miller: To truly transform OSA care, we must adopt an expansive approach to treatment — one that addresses the diverse needs of people with OSA and targets the two key mechanisms of the disease: airway narrowing and neuromuscular dysfunction.

To be sure, GLP-1s will play an important role in patients with OSA and obesity, but an additional treatment modality is likely to be necessary. For those without obesity, the focus will remain on treatment for neuromuscular dysfunction.

We at Apnimed and others believe that pharmacotherapies will play an increasingly important role in the treatment of OSA.

Healio: Can GLP-1s, CPAP and pharmacological innovations be used in combination with one another?

Miller: We believe the answer is “yes,” and our preliminary data support this conclusion. We expect to have further data in the coming months. Given the different mechanisms of action, these therapies can be complementary rather than competitive. We envision a future that allows for a multi-faceted and tailored approach to managing OSA based on the individual patient.

Healio: What are some notable treatments being developed for OSA that clinicians should keep an eye on?

Miller: We are at the dawn of a new era for OSA care. There are multiple innovations being developed to address the gap.

There is tremendous excitement about the potential role of pharmacologics in OSA, such as Apnimed’s AD109 to treat neuromuscular dysfunction, GLP-1s in patients with obesity, carbonic anhydrase inhibitors such as sulthiame in a subgroup of patients, etc. Among devices, we can expect improvement in CPAP and implantable neurostimulation efforts.

Healio: Can you provide more details about the mechanism of how AD109 works to address OSA?

Miller: AD109 is a first-in-class oral therapy designed to address the neuromuscular dysfunction underlying OSA. In patients with OSA, the upper airway muscles no longer fire physically at night, leading to muscle collapse and partial (hypopnea) or complete airway obstruction (apnea). AD109 works by restoring muscle firing, which in turn limits collapse and maintains airway patency.

Healio: Could you provide details about the current phase 3 trials investigating AD109?

Miller: Apnimed is conducting two large pivotal phase 3 trials with more than 1,300 participants enrolled. Both trials evaluate AD109’s efficacy, safety and tolerability across a diverse OSA patient population.

The LunAIRo trial focuses on people with mild to severe OSA assessing reductions in the AHI and improvements in sleep quality and daytime functioning over 12 months of treatment. The SynAIRgy trial uses a similar approach over 6 months of treatment.

Both trials enroll people with OSA (mild, moderate and severe) with and without obesity, as well as a broad range of ages and disease severity. Results from these trials, expected by mid-2025, will provide robust data to support regulatory submission. If successful, AD109 could become the first oral therapy specifically designed to treat OSA, offering a simpler and potentially more accessible alternative to device-based treatments like CPAP.

Healio: What is the next step in this research?

Miller: Completion of the phase 3 trials will be followed by data analysis and reporting. The results will be presented at a scientific conference and submitted to a peer-reviewed journal. Apnimed is also developing additional pharmacotherapies to target more specific subgroups of patients with OSA.

When you observe the current dynamics and trends in OSA today, it is easy to envision a category that is on the brink of fundamental change and one that will look very different within the next few years. Simpler, less invasive diagnostics are in development, convenient disease monitoring devices are in testing now and novel pharmacotherapies are likely to transform the treatment of OSA.

Reference:

• FDA approves Zepbound (tirzepatide) as the first and only prescription medicine for moderate to severe obstructive sleep apnea in adults with obesity. https://investor.lilly.com/news-releases/news-release-details/fda-approves-zepboundr-tirzepatide-first-and-only-prescription. Published Dec. 20, 2024. Accessed Jan. 3, 2025.