Pitolisant may manage residual sleepiness in OSA patients on CPAP

The histamine H3-receptor antagonist/inverse agonist pitolisant showed a favourable risk-benefit profile in managing residual excessive daytime sleepiness (EDS) in individuals receiving continuous positive airway pressure (CPAP) for obstructive sleep apnoea (OSA), according to data from the HAROSA 1 trial presented at ERS 2021.

“CPAP is essentially the first-line therapy in symptomatic OSA. In general, for [most] patients, CPAP is highly effective in reducing symptoms, particularly sleepiness, and in improving quality of life,” said Professor Jean-Louis Pépin from the CHU Grenoble Alpes, Grenoble, France, during his presentation.

However, based on evidence and clinical practice, residual EDS may persist even with CPAP therapy, potentially requiring pharmacotherapy, Pépin pointed out. “Studies consistently demonstrate that ~10–15 percent of patients continue to exhibit an Epworth Sleepiness Scale (ESS) score of ≥11 even in the context of a well-managed OSA treatment, including CPAP adherence.” [J Sleep Res 2013;22:389-397]

As such, Pépin and colleagues sought to evaluate the efficacy and safety of pitolisant in this patient setting. The team randomized 244 participants (mean age 53 years, 83 percent male) 3:1 to receive pitolisant or placebo daily for 12 weeks. Pitolisant was initially administered at a dose of 5 mg for a week. After the starting dose, pitolisant 5 or 10 mg was given for a week, and then 5, 10, or 20 mg in the ensuing 10 weeks. A 40-week open-label phase ensued thereafter. [ERS 2021, presentation ID 4381]

Week 12 saw a significantly greater reduction in ESS with pitolisant compared with placebo (mean change, –5.97 vs –2.59; p<0.001). Mean blood pressure (BP; 128.7/79.9 mm Hg) and heart rate (HR; 70 beats per minute [bpm]) were not remarkably different when compared against baseline levels (131.6/81.2 mm Hg [BP] and 71.1 bpm [HR]) and placebo (129.1/81.4 mm Hg and 70.3 bpm, respectively). [Chest 2021;159:1598-1609]

“[These findings suggest] an improvement in subjective sleepiness without a significant impact on cardiovascular outcomes … which is important in this [patient subgroup],” said Pépin.

At 1 year, participants who have received pitolisant in the double-blind period had an additional mean ESS reduction of –1.21 during the open-label phase, while those who were initially receiving placebo presented with a –4.07 ESS reduction. “[These imply that] the efficacy of pitolisant was maintained for a year,” said Pépin.

The most frequent side effects associated with pitolisant use were headaches (11 percent), insomnia (7 percent), and gastrointestinal disorders (7 percent). More importantly, Pépin underscored the very good cardiovascular safety profile of pitolisant, as reflected by the cardiovascular parameters observed at week 12.

“[We saw] a very classic population of OSA – middle-aged, predominantly male, obese patients, with a … lot of cardiovascular and metabolic comorbidities … [The] summary of both trial [phases reflect] the sustained efficacy and safety of pitolisant [for] residual EDS in OSA patients with CPAP,” said Pépin.

“[As such, our findings suggest that] pitolisant is an effective pharmacotherapy for residual sleepiness in OSA patients on CPAP … In the future, pitolisant could be one of the pharmacologic agents [that may be] used in routine practice for these patients,” concluded Pépin.