Oral Epilepsy Drug Eases Symptoms of OSA

An epilepsy drug sold in Europe as Ospolot and also known as sulthiame showed promise in reducing sleep disordered breathing and other symptoms of obstructive sleep apnea (OSA), based on data from nearly 300 individuals presented in a late-breaking study at the European Respiratory Society Congress 2024.

“Current therapies are mechanical and based on the notion of an airway splint,” said presenting author Jan Hedner, MD, professor of respiratory medicine at Sahlgrenska University Hospital and the University of Gothenburg, Gothenburg, Sweden, in an interview. “In other words, applying an airflow at elevated pressure (continuous positive airway pressure) or advancing the jaw with a dental device,” he said. “Adherence to this type of therapy is limited. In the case of continuous positive airway pressure (CPAP), it is < 50% after 3-4 years of therapy," he added. Therefore, there is a need for a better tolerated therapy, such as a drug, and possibly a combination of mechanical and pharmaceutical therapies, he told Medscape Medical News.

The use of medication has emerged as a viable option for OSA, with a high rate of compliance and acceptable safety profile, Hedner said in his presentation.

“Modified carbonic anhydrase activity may be a pathophysiological mechanism in OSA,” said Hedner. Sulthiame, a carbonic anhydrase inhibitor, showed safety and effectiveness for improving OSA in a previous phase 2b trial, he said.

In the current study, the researchers sought to determine the most effective dose of sulthiame for patients with OSA. They randomized 298 adults with OSA who could not accept or tolerate oral splints or CPAP to 100 mg, 200 mg, or 300 mg of sulthiame daily (74, 74, and 75 patients, respectively) or placebo (75 patients).

The mean age of the patients was 56 years, 26.2% were women, and the average apnea-hypopnea index (AHI3a) at baseline was 29 n/h. Patients were treated at centers in Spain, France, Belgium, Germany, and the Czech Republic. Baseline demographics and clinical characteristics were similar among the treatment groups.

The primary endpoint was the change in AHI3a from baseline to 15 weeks, and significant changes occurred in patients who received the 100 mg, 200 mg, and 300 mg doses, with decreases of 17.8%, 34.8%, and 39.9%, respectively.

Peak efficacy occurred in the range of 200-300 mg and was similar for patients with moderate or severe OSA, Hedner said in his presentation.

Notably, in a post hoc analysis, apnea improved by 47.1% at a 300 mg dose when the AHI4 measure (apnea/hypopnea with ≥ 4% O2 desaturation) was used in a placebo-adjusted dose-dependent reduction, the researchers wrote. The changes in AHI4 from baseline in this analysis also were significant for 200 mg and 100 mg doses (36.8% and 26.2%, respectively).

Patients underwent polysomnography at baseline and at weeks 4 and 12.

Mean overnight oxygen saturation also improved significantly from baseline with doses of 200 mg and 300 mg compared with placebo (P < .0001 for both).

In addition, scores on the Epworth Sleepiness Scale (ESS) improved from baseline to week 15 in all dosage groups, and the subgroup of patients with ESS scores of ≥ 11 at baseline showed even greater improvement in ESS, Hedner said in his presentation.

Total arousal index and sleep quality also improved from baseline compared with placebo, and no clinically relevant reduction in REM sleep was noted, Hedner added.

Treatment-emergent adverse events were in line with the known safety profile of sulthiame and included paresthesia, headache, fatigue, and nausea; these were mainly moderate and dose-dependent, with no evidence of cardiovascular safety issues, he said.

Although the study results were not surprising given previous research, the investigators were pleased with the potency of the therapy, Hedner told Medscape Medical News. “We are also happy about potential added values such as a blood pressure lowering effect, which is beneficial in this group of patients; however, we need to further study these mechanisms in detail,” he noted.

The study findings were limited by the relatively small scale, and larger studies on long-term efficacy and tolerability are also needed, Hedner told Medscape Medical News.

“The current study was a dose-finding study, and we now have useful information on most suitable dose,” he said.

However, the results support sulthiame as an effective, well tolerated, and promising novel candidate for drug therapy in patients with OSA, worthy of phase 3 studies, Hedner said.

Oral Option Could Be Game-Changer, But Not Yet

The gold standard of treatment for OSA is a CPAP machine, but the effectiveness is limited by patient tolerance, said Q. Afifa Shamim-Uzzaman, MD, an associate professor and a sleep medicine specialist at the University of Michigan, Ann Arbor, Michigan, in an interview.

“Presently, there are no effective pharmacological treatments for OSA — having a pill that treats OSA would be a total game changer and huge advance for the treatment of OSA and the field of sleep medicine,” said Shamim-Uzzaman, who was not involved in the study. “More patients may be able to obtain treatment for OSA and thereby reduce the potential complications of untreated OSA,” she said.

“Carbonic anhydrase inhibitors such as acetazolamide and sulthiame have been studied with limited success for the treatment of other forms of sleep disordered breathing such as central sleep apnea (CSA) but have shown less efficacy for OSA and are presently not recommended in the treatment of OSA by the American Academy of Sleep Medicine,” Shamim-Uzzaman told Medscape Medical News.

Recently, emerging evidence about different phenotypes of OSA suggests that nonanatomic features (such as high loop gain) may play a role in patients with OSA, not only in those with CSA, she said. Whether carbonic anhydrase inhibitors could play a greater role in treating sleep apnea in patients with predominantly nonanatomic pathophysiologic traits remains to be seen, she emphasized.

The sulthiame data are promising, but more research is needed, Shamim-Uzzaman said. Although patients in the highest dose group showed a reduction in AHI of nearly 40%, they still would have moderate OSA, and the OSA did not appear to decrease to a normal range in any of the treatment groups, she noted.

“More research is needed to identify which types of patients would be responders to this form of therapy, to understand if these effects are maintained long term (beyond 15 weeks), to evaluate patient-centered outcomes, especially in different sleep apnea subgroups (such as phenotypes with high loop gain vs those without), and to assess interactions with other therapies,” she said.

The study was supported by manufacturer Desitin.

Hedner disclosed serving as a consultant to AstraZeneca, Bayer, CereusScience, Jazz Pharmaceuticals, MSD, Weinmann GmbH, Desitin, SomnoMed, and Itamar Medical; serving on the speakers’ bureau for Almirall, AstraZeneca, Jazz Pharmaceuticals, ResMed, Philips Respironics, and Weinmann; and receiving grants or research support from Bayer, ResMed, Philips Respironics, and SomnoMed. He also disclosed shared ownership of intellectual property related to sleep apnea therapy.

Shamim-Uzzaman had no financial conflicts to disclose.