麻豆传媒

SAN DIEGO -- The anti-epilepsy drug sulthiame significantly improved symptoms of moderate-to-severe obstructive sleep apnea (OSA), a phase IIb randomized European study showed.

Compared with placebo, patients who took the oral drug had a relative change in Apnea/Hypopnea Index with a 3% or greater drop in oxyhemoglobin saturation or an event-related arousal (AHI3a) of -39.9% with the 300-mg dose, -34.8% with the 200-mg dose (both P<0.0001), and -17.8% with the 100-mg dose (P<0.05) from baseline to week 15, reported Jan Hedner, MD, PhD, of Sahlgrenska University Hospital in Gothenburg, Sweden, at the American Thoracic Society (ATS) annual meeting.

Placebo-adjusted mean overnight oxygen saturation was improved by 0.95% with the 200-mg sulthiame dose and 0.87% with the 300-mg dose at week 15 (P<0.0001). Placebo-adjusted sleep quality, as measured by the Arousal Index, changed by -3.1 with the 100-mg dose (P=0.04), -5.7 with the 200-mg dose (P<0.001), and -6.7 with the 300-mg dose (P<0.0001).

In addition, systolic and diastolic blood pressure improved in both the 200-mg and 300-mg groups, although it also improved slightly in the placebo group.

Sulthiame, a carbonic anhydrase inhibitor, is approved in Europe but not in the U.S.

The results are "surprisingly good," Hedner told 麻豆传媒, noting that there's potential that the drug could be used alone in patients with OSA or as a complement to continuous positive airway pressure (CPAP) therapy in patients who don't fully respond to it.

While CPAP is an excellent treatment for OSA and can return breathing disruptions to normal during sleep, compliance with the therapy can be less than 50%, Hedner said. Oral appliances are another treatment option, but there are no FDA-approved drug therapies.

Sulthiame appears to work by creating mild acidosis and preventing hyperventilation, Hedner said.

In the future, he added, the drug therapy would ideally be personalized so patients who respond the most -- perhaps with more than 60% improvement in AHI -- would be the targets. The high responders may make up 30%-40% of patients, he estimated, and non-responders may be around 30%.

There is major interest in drug treatment for OSA, and several potential medications are in development, David M. Rapoport, MD, of the Icahn School of Medicine at Mount Sinai in New York City, told 麻豆传媒 at the ATS meeting.

Rapoport, who was not involved in the study, cautioned against overhyping study findings that show benefits with drugs in OSA. "They come at a price. And the price is that they don't work fully, and they aren't better than CPAP. Nothing is better than CPAP."

As a result, drugs are "particularly attractive as supplementary treatment" to another therapy like CPAP or oral appliances, he noted.

For this , Hedner and colleagues included 298 patients from 33 centers in five European countries. All had moderate-to-severe OSA and either wouldn't accept or couldn't tolerate CPAP/mandibular advancement device therapy. Mean age was 56, and 73.8% were men. Mean body mass index was 29.1, and mean AHI3a was 29.

Patients were randomized to a daily evening dose of sulthiame 100 mg (n=74), 200 mg (n=74), or 300 mg (n=75), or placebo (n=75).

In a post-hoc analysis, a placebo-adjusted dose-dependent reduction in AHI4 (apnea/hypopnea with ≥4% fall in oxyhemoglobin saturation) of 47.1% at week 15 was confirmed.

Treatment-emergent adverse events occurred in 73% of the 100-mg group, 83.8% of the 200-mg group, 90.7% of the 300-mg group, and 61.3% of the placebo group. Gastrointestinal, nervous system (especially paresthesia), and infection/infestation disorders were most common.

In regard to paresthesia, Hedner said patients sometimes felt numbness/tingling in their fingers, hands, or feet. "It appears for 10-20 seconds and disappears," he explained.

The condition was more common in patients who took the higher doses (57.3% of those in the 300-mg group). "It is not a cause of people terminating the trial. People are not concerned to that degree," he said.

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