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In the Pipeline-Obstructive Sleep Apnea

An Anti-Inflammatory MS Drug Shows Promise for Obstructive Sleep Apnea

Moran, Mark

doi: 10.1097/01.NT.0000544106.57056.cd
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ARTICLE IN BRIEF

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A randomized placebo-controlled trial found that four months of treatment with dimethyl fumarate, an immunomodulatory agent commonly used to treat multiple sclerosis, had a significant treatment effect on obstructive sleep apnea severity compared to placebo.

Dimethyl fumarate (DMF), an immunomodulatory agent commonly used to treat multiple sclerosis, could provide a new avenue for the treatment of obstructive sleep apnea (OSA), according to a May 25 online report in the journal Sleep.

A randomized placebo-controlled trial found that four months of treatment with DMF had a significant treatment effect on apnea severity compared to placebo.

Experts who reviewed the study and study authors themselves agree much more research is necessary, but they agree as well that the study represents progress in finding pharmacologic alternatives to mechanical positive airway pressure devices for OSA.

“Dimethyl fumarate has anti-inflammatory effects, making it a useful therapy for certain inflammatory conditions,” lead study author and principal investigator Tiffany Braley, MD, MS, assistant professor of neurology at the University of Michigan, told Neurology Today. “Previous evidence has also suggested a role for inflammation in the pathogenesis of OSA, which is further supported by our findings. Although additional research is needed to understand the inflammatory processes underlying OSA, our study suggests that a medication believed to modulate systemic inflammation may partially improve apnea severity.”

“There is a critical need to find alternative therapies for OSA for people who cannot tolerate CPAP,” she said. “Our findings offer new insight into alternative strategies to treat OSA in the future for candidates who are intolerant of CPAP.”

Senior author Ronald D. Chervin, MD, MS, professor of neurology and director of the Sleep Disorders Center at the University of Michigan, added that “further work to define which patients are most responsive to dimethyl fumarate could lead to patient-centered care and the ability to offer a segment of patients with OSA — especially those who are intolerant of CPAP — a medication alternative to traditional treatment.”

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STUDY DETAILS

A total of 65 participants with OSA who deferred positive airway pressure therapy were randomized (2:1) to receive DMF or placebo for four months. Participants underwent polysomnography before the start of treatment, and again after four months on treatment. Blood was collected monthly. The primary outcome was the mean change in respiratory disturbance index (RDI), a measure of OSA severity, before and after treatment and between groups. Secondary analyses focused on the association between treatment effect of DMF on RDI and plasma cytokines levels, as well as expression of nuclear factor kappa B (NFκB) signaling molecules in peripheral blood mononuclear cells.

The majority of participants had been prescribed PAP prior to enrollment, and most had reported discontinuation due to intolerance. The second most commonly-reported reason for PAP discontinuation was choice to pursue weight loss as a treatment modality.

Fifty participants — 35 on dimethyl fumarate and 15 given placebo — had finished the study, thereby completing follow-up polysomnography at month four for primary final analyses. The mean difference in RDI before and after treatment between groups was 13.3 respiratory events per hour, with a mean RDI change of -3.1 events in the dimethyl fumarate group and +10.2 events in the placebo group post-treatment. That treatment effect was maintained in mixed effects models; statistical analysis demonstrated a treatment effect of a 38 percent decrease in RDI compared to placebo group, when controlling for baseline RDI.

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Among DMF completers, 15 of 35 had at least a 20 percent reduction in RDI, and 31.4 percent of participants transitioned by RDI to a lower severity OSA category — from severe (defined as 30 or more respiratory events per hour) to moderate (15-29.9), or from moderate/severe to mild (5-14.9), or mild to no OSA (0-4.9).

However, DMF treatment in comparison to placebo was associated only with non-significant reductions in levels of TNF-alpha — an inflammatory cytokine produced by macrophages/monocytes during acute inflammation — between baseline and month four, and non-significant increases in anti-inflammatory interleukin-10 and interleukin-13 levels over the same interval. However, significant group differences in change in expression of NFκB signaling molecules pre- and post-treatment, were noted between DMF treatment responders (participants who had at least a 20 percent reduction in RDI) and the placebo group.

Dr. Chervin added that generalized inflammation may not just be a downstream effect of OSA but may exacerbate the condition. “Efforts to reduce generalized inflammation may with further development provide an effective medication alternative to mechanical and surgical treatments for this common and consequential sleep disorder,” he said.

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EXPERT COMMENTARY

Sleep experts who were not involved with the study said the investigators employed an intriguing approach to a condition for which there have been limited pharmaceutical therapies.

“Since inflammatory molecules have been shown to be associated with sleep apnea and immunomodulatory or immunosuppressive agents have been reported to reduce OSA severity or OSA frequency, the authors proposed that these agents could potentially be used as a treatment for OSA,” Rachel Marie E. Salas, MD, FAAN, associate professor of neurology at Johns Hopkins University, told Neurology Today.

“I think the study is interesting, but more work needs to be done before this goes ‘primetime’ in the clinical setting,” she said. “This is one of the first studies showing some real promise in this area, and as a sleep neurologist, I am interested in seeing where this goes.”

Douglas B. Kirsch, MD, FAAN, medical director of Carolinas HealthCare Sleep Medicine, said it is clear that OSA may cause inflammation, and recent research reveals that inflammation may worsen OSA. “This study is intriguing, using a novel method of action to potentially treat OSA via medication, rather than physical interaction such as CPAP or oral appliances,” he said. “It's exciting to see new areas of active research in OSA treatment, particularly in unexpected and novel areas.”

But Dr. Kirsch said that the relatively small sample size makes it harder to interpret the apparently beneficial treatment effects of dimethyl fumarate. “I think the most challenging finding of this study was that the OSA severity didn't change much in the treatment group, and the major reason for the difference was that the OSA unexpectedly worsened in the control group,” he said. “Some level of OSA variability occurs due to sleep position and sleep stage changes, thus the OSA severity changes seen in small groups of patients may not represent a change due to treatment.”

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“RDI was chosen as the primary outcome metric, which is less commonly used in OSA assessment than the more commonly used apnea-hypopnea index,” he pointed out. “This choice may have been made to assess for subtle respiratory event change, but at the same time, subtle event scoring is more variable on the technical side and may be challenging to replicate between scorers.”

“While this type of treatment is still very new and unproven, patients with OSA should be given hope that there is another pathway for future treatment beyond the current options,” Dr. Kirsch said.

The take-home message for clinicians? “There is novel and interesting work being done to better manage patients with sleep apnea and hopefully in the future, we will have a wider treatment selection available for patients with OSA,” said Dr. Salas.

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DISCLOSURES

Dr. Braley conducts investigator-initiated studies funded by the National Multiple Sclerosis Society, the American Sleep Medicine Foundation, and the Patient-Centered Outcomes Research Institute. Dr. Braley and Dr. Chervin are named in a pending University of Michigan patent application describing portions of the findings reported in this study. In addition, Dr. Chervin is named in or has developed patented and copyrighted materials owned by the University of Michigan designed to assist with assessment or treatment of sleep disorders.

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LINK UP FOR MORE INFORMATION:

•. Braley TJ, Huber AK, Segal BM, et al A randomized, subject and rater-blinded, placebo-controlled trial of dimethyl fumarate for obstructive sleep apnea https://academic.oup.com/sleep/article-lookup/doi/10.1093/sleep/zsy109. Sleep 2018; Epub 2018 May 25.
    © 2018 American Academy of Neurology