Sleep research led to a new sleep apnea drug

A University of Toronto professor’s research on the physiology of sleep and breathing has paved the way for a new sleep apnea treatment that recently reported positive results in a phase 3 clinical trial.

Richard Horner is a professor of medicine and physiology at U of T’s Temerty Faculty of Medicine who studies the nerves, muscles and mechanisms that control breathing during sleep. His work over the past three decades has led to breakthrough discoveries about how we breathe while asleep and what happens when those processes malfunction, like in people with obstructive sleep apnea.

Now, a drug targeting the two pathways he and his team identified as key drivers of sleep apnea is one step closer to helping people with the condition improve their sleep, overall health and quality of life.

“Sleep apnea is the most common and most serious sleep problem,” says Horner.

According to a 2024 study in the Canadian Journal of Public Health, more than one in four Canadians are estimated to have obstructive sleep apnea, but less than 10 per cent of people with the chronic condition have a formal diagnosis. The condition is estimated to affect 1.6 billion adults globally.

Sleep apnea occurs when the muscles in the upper airway repeatedly collapse during sleep, leading to frequent breathing interruptions. In the long-term, untreated sleep apnea can increase a person’s risk of high blood pressure, heart disease, metabolic disorders and cognitive impairment.

“People with sleep apnea can wake up hundreds of times a night and they aren’t necessarily aware of it,” says Horner. “So they’re sleepy, and their brains and bodies experience less oxygen continuously overnight, which has a whole host of negative consequences.”

Horner’s journey in sleep research began in the early 90s as a PhD student at the University of London where he worked in one of the first sleep labs in the United Kingdom. He says U of T’s reputation as a leader in sleep research drew him to the city to pursue a postdoctoral fellowship with Eliot Phillipson, a clinician-scientist at U of T who established one of North America’s first human sleep labs in 1978 to study breathing disturbances.

After a second postdoc fellowship at the University of Pennsylvania, Horner returned to U of T as a faculty member in 1997. His first priority was to develop new tools and models that researchers could use to more effectively study sleep and breathing. Until that point, most models only mimicked sleep-like behaviour.

“No one had developed models to actually investigate natural sleep,” says Horner.

“That's what I wanted to set my lab up to do so that we could conduct very basic neuroscience studies looking at the circuits that control the muscles responsible for breathing.”

The Horner lab pioneered models to identify the key brain chemicals and receptors modulating breathing muscle activity in sleep.

In 2006, the researchers were the first to identify the neurotransmitter noradrenaline as playing a significant role in activating the tongue muscle during wakefulness and certain phases of sleep.

The tongue is important for speech and swallowing, but Horner says it is also the largest and most impactful upper airway muscle when it comes to maintaining airflow into our lungs.

Noradrenaline levels in the brain drop during rapid eye movement (REM) sleep — when most dreams occur and brain activity is high — leading to a loss of muscle tone in the tongue and, in some people, difficulties breathing.

In 2013, the researchers published another seminal discovery showing that a family of proteins called muscarinic receptors suppress tongue movement during REM sleep. When they blocked muscarinic receptors with a drug, they saw a strong activation of the tongue muscle.

These breakthroughs from the Horner lab uncovered the two key drivers of sleep apnea — loss of a noradrenaline “go” signal and a muscarinic receptor-mediated “stop” signal — that act together to block tongue movement and disrupt breathing during sleep.

By mapping the neural circuits that lead to this common condition, work from the Horner lab laid the foundation for AD109, a new treatment developed by researchers in Boston to specifically target the two pathways that contribute to sleep apnea. The daily oral medication contains two drugs: one that increases noradrenaline levels and another that blocks muscarinic receptors.

In a recently published phase 3 randomized clinical trial, people with mild to severe sleep apnea who received AD109 had less airway obstruction and higher oxygen levels than those who received a placebo. On average, per hour of sleep, participants on AD109 had four fewer events where they stopped breathing or had very shallow breathing.

Currently the most commonly prescribed treatment for sleep apnea is continuous positive airway pressure (CPAP) therapy, which involves sleeping while wearing a mask connected to a machine that delivers constant air pressure. The treatment is extremely effective, but Horner notes that many people have a hard time sticking with CPAP because they find it uncomfortable and cumbersome. He says that if AD109 receives regulatory approval, it would provide a valuable alternative for people who cannot tolerate CPAP.

Horner, who was not directly involved in the development of AD109, says he is pleased and surprised to see the impact of his research expand into clinical treatments.

“As a basic scientist, I always intended to just understand how things work,” he says. “I didn’t anticipate this storyline.”

Horner’s research has been continuously supported by the Canadian Institutes of Health Research since 1998.