Pitolisant Shows No Cardiac Safety Signals in Narcolepsy

William Winter, MD

Pooled analysis from 2 randomized studies and a 12-month open-label study presented at SLEEP 2020 demonstrated that treatment with the maximum recommended dose of pitolisant (Wakix; Harmony Biosciences) did not show any cardiac safety signals.1

The analysis conducted by William Winter, MD, sleep medicine specialist, Charlottesville Neurology and Sleep Medicine, and colleagues included 166 patients (pitolisant, n = 85; placebo, n = 81) and aimed to assess the safety profile of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist designed to increase histamine in the brain, in patients with narcolepsy.

Winter and colleagues documented a mean change in heart rate from baseline to end-of-treatment of –0.5 beats/min with pitolisant and –0.2 beats/min with placebo (least squares [LS] mean difference, –0.4; P = .744). Additionally, they found the mean change for both systolic (LS mean difference, 0.0; P = .983) and diastolic (LS mean difference, –0.6; P = .552) blood pressure were both similar for pitolisant versus placebo.

Because cardiovascular diseases are comorbid in patients with narcolepsy, cardiovascular adverse events (AEs) become a concern for those who take medication to treat their sleep condition. Heart rate increase (n = 4), right bundle branch block (n = 1), sinus tachycardia (n = 1), and palpitations (n = 1) were among the cardiac AEs observed with treatment of pitolisant. Blood pressure increase, found in 1 patient, was the only cardiac AE observed in the placebo group.

Mean change from baseline in QTc interval was 3.1 msec at Month 6 (n = 70) and 6.1 msec at Month 12 (n = 67) in the long-term study. Additionally, 3 patients had a postbaseline increase >60 msec but none had QTc >500 msec.

Investigators noted that in a previous Qt study of healthy volunteers, pitolisant (35.6 mg/day) led to a mean increase of 4.2 msec in QTc interval. These results further characterized the cardiac safety of pitolisant in adults with narcolepsy.

“Because concomitant use of pitolisant with other drugs known to increase the QT interval may add to the QT effects of pitolisant, avoid use of pitolisant in combination with these medications,” Winter and colleagues concluded.

Additional data presented at SLEEP 2020 revealed that pitolisant is associated with improvements in patients with narcolepsy who experience severe symptom burden. The data showed that those randomized to pitolisant experienced significantly greater mean changes in Epworth Sleepiness Scale (ESS) scores (–6.1 points) compared to those on placebo (–2.6 points; P = .0002), as well as significant decreases in cataplexy rates (–17.9) compared to placebo (–2.7; rate ratio, 0.35 [95% CI, 0.26–0.47]; P <.001). At baseline, the respective rates of cataplexy for the pitolisant and placebo groups were 21.8 and 20.9, compared to final rates of 3.9 and 18.2.2

Pitolisant was approved for the treatment of excessive daytime sleepiness in adults with narcolepsy in August 2019. It became the first and only therapy for narcolepsy which is not scheduled as a controlled substance by the DEA.3

REFERENCE

1. Winter W, Wanaski SP, Patroneva A, Dayno JM. Cardiac safety profile of pitolisant in patients with narcolepsy. SLEEP 2020. Abstract 0744.

2. Davis CW, Kallweit U, Krahn LE, Vaughn B, Thorpy MJ. Efficacy of pitolisant in patients with high burden of narcolepsy symptoms. SLEEP 2020. Abstract 0762.

3. WAKIX represents the first and only non-scheduled treatment approved for patients with narcolepsy in the U.S. News release. Plymouth Meeting, PA. Harmony Biosciences. August 15, 2019. finance.yahoo.com/news/harmony-biosciences-announces-fda-approval-120000845.html. Accessed August 15, 2019.