Pitolisant: New weapon in the battle to stay awake among CPAP-adherent OSA patients

The selective histamine H3-receptor antagonist pitolisant appears to quell excessive daytime sleepiness in obstructive sleep apnoea (OSA) patients adherent to continuous positive airway pressure (CPAP) therapy, as shown in a phase III HAROSA I trial.

“Residual excessive daytime sleepiness in individuals with OSA who adhered to CPAP therapy improved significantly with pitolisant. Such an improvement was reported both subjectively by a reduction in Epworth Sleepiness Scale (ESS) and objectively by the Oxford Sleep Resistance (OSleR) maintenance of wakefulness test,” according to the investigators.

“This was confirmed by both patient-reported outcomes and the physicians’ Clinical Global Impressions scale of efficacy, without any significant safety signal,” they added.

Pitolisant exerts strong wake-promoting effects well tolerated in patients with narcolepsy. In another trial, the drug also works in reducing daytime sleepiness and fatigue in the specific phenotype of sleepy OSA patients who decline CPAP or are nonadherent to CPAP therapy. These data “nicely complement” the current results, the investigators said. [Lancet Neurol 2017;16:200-207; Lancet Neurol 2013;12:1068-1075; Sleep 2019;42:zsz174; Am J Respir Crit Care Med 2020;201:1135-1145]

HAROSA I randomized 244 moderate-to-severe OSA patients (mean age 53.1 years, 82.8 percent men, mean Apnea Hypopnea Index with CPAP 4.2/h, baseline ESS score 14.7) to receive pitolisant at 20 mg/day (n=183) or matching placebo (n=61) for 12 weeks. CPAP adherence was defined as nightly use of >4 hours.

At treatment conclusion, the primary endpoint of ESS score decreased to a much greater extent in the active treatment group than in the placebo group (difference, −2.6, 95 percent confidence interval [CI], −3.9 to −1.4; p<0.001). [Chest 2021;159:1598-1609]

Likewise, significantly more patients on pitolisant achieved ESS ≤10 or change in the score of ≥3 (71.0 percent vs 54.1 percent; p=0.013).

Both physicians and patients attested to the wake-promoting effect of pitolisant at the end of the 12 weeks treatment via the Clinical Global Impressions scale of change and the global opinion of effect, respectively. 

Pitolisant had a good safety profile consistent with that reported in patients with narcolepsy and in patients declining CPAP. Treatment-emergent adverse events (TEAEs) occurred with slightly but significantly greater frequency in the active treatment group (47.0 percent and 32.8 percent; p=0.03). Headache, insomnia, diarrhoea, and back pain are among the most common TEAEs. There was no cardiovascular or other significant safety concerns reported.

“In this study, the magnitude of improvement in ESS with pitolisant was close to that previously reported in studies of modafinil, armodafinil, and solriamfetol, [all of which are the currently used wakefulness agents], in OSA patients,” according to the investigators.  

The maximum daily dose of pitolisant tested was 20 mg, which was used by most participants (79.8 percent in the active treatment group and 88.5 percent in the placebo group). This is half the maximum dose tested in narcolepsy studies and approved by both the Food and Drug Administration and the European Medical Agency.

“It is unclear whether higher doses might yield a more impressive benefit on sleepiness. An ongoing study, HAROSA III, is testing this hypothesis. However, the true answer in terms of comparison of efficacy merits evaluation by head-to-head comparisons between the different classes of wake-promoting agents,” the investigators said.

They also hoped to see additional studies addressing combinations of drugs with different mechanisms of action.