Drug combo shows promise for treating sleep apnea

During decades of lab experiments and dozens of clinical trials, scientists have searched in vain for drugs to defeat obstructive sleep apnea, the risky and increasingly prevalent condition in which a person’s upper airway repeatedly collapses during sleep, causing them to briefly stop breathing dozens or hundreds of times each night. Now, a new drug combination has reawakened hopes.

A team led by researchers in Boston has identified a pair of medications—approved for other uses and with solid safety records—that appear to work in concert during sleep to activate the muscles that dilate the upper airway. In a study of 20 patients, the scientists found that a combination of atomoxetine and oxybutynin, taken as two pills at bedtime, reduced patients’ frequency of airway obstruction—called the apnea-hypopnea index, or AHI—from a median of 28.5 hourly obstructions on placebo to 7.5 on the pills. In the 15 patients with the highest AHIs, the median reduction was 74%—and every patient experienced at least a 50% reduction, Andrew Wellman and Luigi Taranto-Montemurro at Brigham and Women’s Hospital in Boston reported today at the European Respiratory Society’s International Congress in Paris. Patients’ blood oxygenation also improved strikingly, the group found.

“We’ve never had a drug combination, or any sort of a drug, that consistently improved everybody’s AHI. That’s actually unbelievably exciting,” says Sigrid Veasey of the University of Pennsylvania (UPenn), a physician-researcher who studies sleep. It’s “a great first step,” adds Martina Mason, a sleep physician at the Royal Papworth Hospital in Cambridge, U.K., who co-authored a 2013 review of 30 previous, underwhelming drug trials.

The trial turned up one potentially problematic finding: Although the drug combination reduced patients’ AHIs, their number of subconscious arousals—the subtle awakenings that leave patients exhausted—remained high. But if this combination proves safe and effective in larger trials, it could free many sleep apnea patients from the current gold-standard remedy, the cumbersome “continuous positive airway pressure” (CPAP) machines that blow air into the throat to keep the airway open, but require users to wear a mask and headgear at night.

Mason, Veasey, and other sleep apnea experts caution, however, that the findings are extremely preliminary. They note that the pilot study, although double-blind and randomized, included just a small number of patients who took the drug combination for just 1 night.

The search for sleep apnea treatments has become pressing as its prevalence has grown, as widespread noncompliance with CPAP has been charted and as researchers have documented the disease’s long-term dangers. In addition to enduring daytime sleepiness, sleep apnea sufferers—some 13% of U.S. men and 6% of women aged 30 to 70—are at higher risk for depression, cognitive impairment, high blood pressure, heart attack, stroke, and premature death. The obesity epidemic is thought to be increasing the incidence of sleep apnea, though thin individuals can also be afflicted.

Opening a blocked airway In obstructive sleep apnea, the muscles that maintain an open upper airway collapse repeatedly. The hypoglossal nerve controls many of these muscles, including the crucial tongue muscle, the genioglossus. A pair of drugs that acts on the nerve may help keep airways open. Oxybutynin blocks receptors for acetylcho- line on hypoglossal motorneurons, making the genioglossus muscle more responsive during rapid eye movement (REM) sleep. Hypoglossal nerve Normal Collapsed Genioglossus With drug combination Without treatment Trachea Esophagus Uvula Brainstem neurons Atomoxetine prevents norepinephrine from being resorbed by neurons that release it, increasing its signal. In concert with oxybutynin, it boosts responsiveness of the genioglossus in non-REM sleep. Acetylcholine Norepinephrine Presynaptic neuron

Wellman, a physician who has been studying sleep apnea since 2001, began to test various drugs for the condition in clinical trials more than 10 years ago. “I had given up, really,” he recalls. Then, in 2015, an enthusiastic postdoc, Taranto-Montemurro, arrived in his lab. Wellman reluctantly let him launch a new trial of a drug combination suggested by animal studies from other labs. “I wasn’t really happy about it,” Wellman says, “until all of a sudden the data started coming in.”

Atomoxetine, approved by the U.S. Food and Drug Administration in 2002 to treat attention deficit hyperactivity disorder, increases messaging in the brain by the excitatory neurotransmitter norepinephrine, whose levels normally fall off markedly during sleep. Giving a stimulating drug at bedtime seems counterintuitive. But animal work led by Richard Horner, a sleep physiologist at the University of Toronto in Canada, had shown that injecting rats with a norepinephrine-mimicking drug in an area of the brainstem that controls the hypoglossal nerve, which powers the upper airway muscles, improved activity of the genioglossus, a large tongue muscle that is critical for keeping the throat open. The drug was consistently effective only during nonrapid eye movement sleep, not during rapid eye movement (REM) sleep, when throat muscles are especially prone to relaxation and collapse, making sleep apnea worse.

The other half of the combination, oxybutynin, improves genioglossus responsiveness during REM sleep. Again, work by Horner’s team provided the crucial clue. It found that during REM sleep the neurotransmitter acetylcholine acts on certain receptors on the hypoglossal nerve to powerfully inhibit activation of the genioglossus. Oxybutynin, Wellman and Taranto-Montemurro knew, blocks acetylcholine’s action at the same receptors—and it had a long track record as a marketed drug used for decades to treat overactive bladder.

As the drug pair progresses through clinical trials, sleep apnea specialists will be watching to see whether the drugs actually reduce subconscious arousals and improve sleep quality. “What if you can improve the AHI, the obstructions, but the patients are as sleepy as they were before the treatment?” asks UPenn’s Leszek Kubin, a neurophysiologist who studies the mechanisms of sleep-disordered breathing.

The study researchers propose that the patients’ arousals may have been due to the invasive instrumentation attached to them during the night, and the associated discomfort. And they note that in the 13 patients with the highest AHIs, the number of arousals did decline a statistically significant amount on the pill combination.

Some are already betting that the drug pair, on which a patent for use in sleep apnea is expected to be published next month, will find a large and eager market. Apnimed, Inc., a new Cambridge, Massachusetts, company formed to commercialize the discovery, recently landed $25 million from Morningside Venture Capital in Newton, Massachusetts. It is planning a phase II trial involving more than 100 patients, to study dosing and side effects, says CEO Larry Miller. (Wellman and Taranto-Montemurro have a financial interest in the firm but are not involved with planning or running the trial.)

Sleep physicians note that side effects unrelated to breathing may make the drug combination a nonstarter for some sleep apnea patients. In a population at risk for hypertension and heart attacks, the stimulant effects of atomoxetine will have to be watched. And oxybutynin’s dampening effect on bladder muscle activity may prove problematic for a typical group with sleep apnea: “old men who have trouble urinating in the night,” says J. Steven Poceta, a sleep physician at the Scripps Clinic Torrey Pines in San Diego, California. Still, he says, he’s excited about the drug combination’s promise. “It could be great for a lot of people.”