Novel OSA Agents in Pipeline

BY BRUCE JANCIN
Elsevier Global Medical News

SAN ANTONIO—Although obstructive sleep apnea is closely associated with obesity, not all the drugs being developed for the treatment of OSA are based on weight loss as their mechanism of benefit.

For example, acetazolamide addresses ventilatory instability, which has emerged as a potential novel therapeutic target in OSA. Another early study suggests the sedative eszopiclone (Lunesta) reduces sleep apnea severity and increases sleep duration by raising the respiratory arousal threshold, investigators reported at the annual meeting of the Associated Professional Sleep Societies.

Still, weight loss is the classic source of pharmacologic improvement in OSA. The first drug shown to be of benefit in OSA patients was sibutramine (Meridia), a serotonin and noradrenaline reuptake inhibitor, noted Dr. Ronald R. Grunstein, professor of sleep medicine at the University of Sydney.

He was lead investigator in a study that showed 6 months of sibutramine plusdiet and exercise not only resulted in significant weight loss, but also brought marked improvement in OSA, reduced insulin resistance, raised HDL cholesterol, and decreased visceral, subcutaneous, and hepatic fat, with no change in blood pressure (J. Clin. Sleep Med. 2009;5:416-21).

At the sleep disorders meeting, audiences learned of another weight-loss drug with evidence of efficacy for OSA: Qnexa, an investigational once-daily proprietary combination of phentermine and controlled-release topiramate.

Dr. David H. Winslow presented a double-blind, single-center trial in which 45 obese patients with OSA were randomized to once-daily Qnexa at 15-mg phentermine/92-mg topiramate CR or to placebo for 28 weeks. At week 8, the mean apnea-hypopnea index (AHI) in the Qnexa group had dropped from a baseline of 45.5 to 19.1 events per hour. By week 28, their mean AHI had fallen to 13.5, compared with 27.2 in the placebo arm, reported Dr. Winslow, a chest physician and president of the Kentucky Research Group, Lexington.

The Qnexa group experienced a mean 11% reduction in body weight over the 28 weeks, twice that of the placebo group. Other statistically significant changes in the Qnexa group included a mean 15-mm Hg drop in systolic blood pressure from a baseline of 138 mm Hg, compared with a 7.3-mm Hg drop in controls, along with improvements in arousal index andovernight oxygen saturation.

“I think we may be looking at a new paradigm in the treatment of OSA,” Dr. Winslow said in an interview. Qnexa is under Food and Drug Administration review for a proposed indication as a treatment for obesity; a regulatory decision is expected later this year.

Danny J. Eckert, Ph.D., of Brigham and Women’s Hospital, Boston, presented a double-blind, randomized, crossover trial in which 17 untreated OSA patients received 3 mg of eszopiclone or placebo immediately prior to going to sleep during overnight polysomnography on two occasions in the sleep lab.

The patients’ mean AHI was 24 events per hour on eszopiclone, compared with 31 per hour with placebo. Patients on eszopiclone also had a marked increase in total sleep time, from 5.3 hours on placebo to 6.8 hours, along with fewer arousals per hour and improved sleep quality, he reported.

Dr. Bradley A. Edwards, also of Brigham and Women’s Hospital, presented a preliminary physiologic study in which six CPAP-treated patients with OSA underwent 2 nights of baseline polysomnography, and then took acetazolamide SR 500 mg twice daily for a week. This was followed by another 2 nights of polysomnography in which CPAP was intermittently turned down to subtherapeutic levels in order to see whether acetazolamide reduced ventilatory control instability. This indeed proved to be the case in all six patients. Moreover, five of the six patients experienced an associated reduction in AHI.

Dr. Winslow disclosed serving as a consultant to Vivus, which is developing Qnexa. Dr. Eckert’s study was partly funded by a research grant from Sepracor. Dr. Grunstein’s study was supported by Abbott Laboratories. Dr. Edwards reported no financial conflicts.