Over 20 years ago in 1995, Dr. David White was asked at a sleep conference in Australia to gaze into the future and speculate on how we would be treating sleep apnea patients. Dr. White said, "If CPAP is still the way we are treating sleep apnea in 20 years, we will be a failed field!" In the audience was none other than Dr. Colin Sullivan, the first person to ever describe continuous positive airway pressure (CPAP) for humans.
Dr. Sullivan disagreed and speculated that CPAP would still be present but would become as comfortable and normalized as a pair of eyeglasses. As it turns out, it appears that neither of these legendary sleep stalwarts was quite accurate. CPAP is still the primary therapy for most sleep apnea patients. While great strides have been made to CPAP masks and headgear designs, they hardly can be considered as comfortable as eyeglasses.
So what exactly does the near future look like for sleep apnea treatment and diagnosis? We are living in a time where sleep testing devices are becoming more robust and dynamic in their race to become a lab-quality home sleep test (HST) option. This progress is not limited solely to how efficiently and conveniently we can test and diagnose patients, but also how best to treat their sleep apnea after diagnosis. Sleep medicine appears to be in an exciting and dynamic time; and according to Dr. White, a non-CPAP mask option, in the form of a pill, is not too far away.
I had the pleasure to discuss the future of sleep medicine with Dr. White and it was a fascinating and exciting discussion. Dr. White is a legend in the sleep medicine field and has played an important role in the exploration of sleep phenotyping. He has held many titles in his career in sleep medicine, including director of the sleep disorders program at Brigham and Young Hospital, medical officer and consultant for Philips Respironics and past president of the American Academy of Sleep Medicine (AASM).
His work revolves around the mindset that if we can understand the cause of apnea for each individual, then a customized solution can be offered that is specific to the unique needs of each patient. There are several different physiological variables that occur and cause patients to develop sleep apnea. The focus will be on identification of each patient's pathology and physiology. Therefore, treatment will vary from the options available today. Other than CPAP, oral appliances and surgical treatments, few other options are available right now. Of course, CPAP therapy dominates the therapeutic treatment arena.
While many patients are treated and do well with CPAP therapy, many others struggle with the mask and hose option, while others are not even diagnosed, in part because they "don't want to sleep with a mask." What follows is a debrief of my conversation with Dr. White on a new, oral, CPAP alternative.
Dr. White, you are currently involved with a few new alternatives for CPAP, one of which is with Apnimed. You're also involved in and/or knowledgeable about other fascinating therapy modes currently in human trials. One such non-mask option being the Inspire hypoglossal nerve stimulation.
Inspire is doing very well. It's interesting technology! The other one that is out there that you should look at is CRYOSA. CRY means cold. You know how some people do cold sculpting of the stomach to try and get rid of fat? They are doing something similar- cold sculpting the tongue. There is reasonable data that sleep apnea patients have an increased amount of fat in their tongues so researchers are applying cooling to patients' tongues to get rid of "tongue fat" to treat sleep apnea. They are in human trials now so that's evolving.
It appears there are interesting happenings around the corner! So what exactly is Apnimed working on with their pharmacological trials?
Apnimed's primary offering is AD109, which is a combination of two drugs- atomoxetine and aroxybutynin- that work together to mitigate the collapse of the airway muscles during sleep. Atomoxetine is a norepinephrine reuptake inhibitor. The reason we picked a drug like this is that animal (rat) data suggests that loss of muscle activation during sleep, particularly loss of pharyngeal dilator muscle activation during non-rapid eye movement (NREM) sleep, is primarily due to decreased norepinephrine input to the motor neurons that control the muscle, i.e., the neurons in your brain that produce norepinephrine decrease their firing rate. They project directly to nerves that activate your upper airway muscles. When you go to sleep, these norepinephrine neurons reduce their firing and eventually quit firing primarily in rapid eye movement (REM) sleep. What you are doing is losing an excitatory neural input to these muscles and their activity goes down. The reuptake inhibitor increases the amount of norepinephrine that is in the synapse between these neurons and increases muscle activity. Increasing norepinephrine levels increased muscle activity in rats quite a bit. Thus, a norepinephrine reuptake inhibitor was one choice.
Aroxybutynin is an anticholinergic. When you go into REM sleep there is active inhibition of virtually all muscles. The skeletal muscles are paralyzed when you are in REM sleep. However, the mechanism of this reduced muscle activity during REM sleep in the upper airway muscles is different from other skeletal muscles. The pharyngeal muscles have active cholinergic inhibition during REM sleep. And so, we thought let's get an anticholinergic to work in REM sleep.
We thought a norepinephrine reuptake for NREM and an anticholinergic for REM sleep might work and did a study with this combination on approximately 20 human patients in Boston out of our lab.
How did the study turn out? Are there any insights you can share with readers?
There was a substantial and clinically important reduction in sleep apnea severity on this drug combination, which we found very exciting. We also demonstrated that muscle activity went up substantially during sleep on these medications.
After this and further work, we are quite comfortable that the norepinephrine is working by activating the muscles. Exactly how the aroxybutynin is working is still unclear. Is it working purely as an antimuscarinic agent as a means of blocking this inhibition or is it just sedating the patient and overcoming the alerting effects of the atomoxetine? We don't fully understand this at this time, but do know that the combination of the two drugs does work pretty well.
To wrap things up, what are three takeaways that we should know about this new type of "sleeping pill for apnea"?
One, there is a pretty high probability that in the next two to four years a pharmaceutical will come out to treat OSA. Two, it will treat a reasonable slice of sleep apnea patients but not everyone. And three, the side effects associated with each agent will be modest.
It was a great honor to speak with Dr. White and this is another fascinating look into the near future for sleep medicine. Each day we are introduced to new diagnostic and treatment research and development. This advancement would certainly be a major disruptor in the sleep medicine field and yet another solution out there for the millions that suffer from sleep apnea- especially those that will not or cannot tolerate CPAP masks!
Author's Note: Since my conversation with Dr. White, Apnimed has received U.S. Food and Drug Administration (FDA) fast track designation. This designation is intended to facilitate and expedite the review of new drugs to fill an unmet medical need. Per an Apnimed company news release from June 28, 2022, they are completing Phase 2 clinical trials and hope to then meet with the FDA to discuss the Phase 3 development program.