Wakix (pitolisant) - 2 indications

• for excessive daytime sleepiness in adults with narcolepsy; approved August 2019
• for cataplexy in adults with narcolepsy; approved October 2020

General Information

Wakix (pitolisant) is a histamine-3 (H3) receptor antagonist/inverse agonist.

Wakix is specifically indicated for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy and for the treatment of cataplexy in adult patients with narcolepsy.

Wakix is supplied as a tablet for oral administration. The recommended dosage range for Wakix is 17.8 mg to 35.6 mg administered orally once daily in the morning upon wakening. Titrate dosage as follows:

• Week 1:  Initiate with a dosage of 8.9 mg (two 4.45 mg tablets) once daily
• Week 2:  Increase dosage to 17.8 mg (one 17.8 mg tablet) once daily
• Week 3:  May increase to the maximum recommended dosage of 35.6 mg (two 17.8 mg tablets) once daily

Dose may be adjusted based on tolerability.  If a dose is missed, patients should take the next dose the following day in the morning upon wakening.

It may take up to 8 weeks for some patients to achieve a clinical response.

Mechanism of Action

Wakix is a selective histamine 3 (H₃) receptor antagonist/inverse agonist. The mechanism of action of Wakix is unclear; however, its efficacy could be mediated through its activity at H₃ receptors, thereby increasing the synthesis and release of histamine, a wake promoting neurotransmitter.

Side Effects

Adverse effects associated with the use of Wakix may include, but are not limited to, the following:

• insomnia
• nausea
• anxiety

Indication 1 - for excessive daytime sleepiness in adults with narcolepsy

approved August 2019

Clinical Trial Results

The FDA approval of Wakix for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy was based on two multicenter, randomized, double-blind, placebo-controlled studies. Patients ≥18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy and who had an Epworth Sleepiness Scale (ESS) score ≥14 were eligible to enroll in the studies. EDS was assessed using the ESS, an 8-item questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities. Each of the 8 items on the ESS is rated from 0 (would never doze) to 3 (high chance of dozing); the maximum score is 24. Study 1 and Study 2 included an 8-week treatment period, a 3-week dose titration phase followed by a 5-week stable dose phase. These studies compared Wakix to both a placebo and an active control.

In Study 1, 95 patients were randomized to receive Wakix placebo, or active control. The dose of Wakix was initiated at 8.9 mg once daily and could be increased at weekly intervals to 17.8 mg or 35.6 mg, based on efficacy response and tolerability. No dose adjustments were permitted during the 5-week stable dose phase. Wakix demonstrated statistically significantly greater improvement on the primary endpoint, the least square mean final ESS score compared to placebo. 

• Wakix (n=31)/Placebo (n=30) 
• Baseline ESS Score Mean was 17.8 and 18.9, respectively
• Final ESS Score LS Mean at Week 8 was 12.4 and 15.5, respectively.

In Study 2, 166 patients were randomized to receive Wakix, placebo, or active control. The dose of Wakix was initiated at 4.45 mg and could be increased at weekly intervals to 8.9 mg or 17.8 mg, based on efficacy response and tolerability. No dose adjustments were permitted during the 5-week stable-dose phase. Wakix demonstrated statistically significantly greater improvement on the primary endpoint, the least square mean final ESS score compared to placebo.

• Wakix (n=66)/Placebo (n=32) 
• Baseline ESS Score Mean was 18.3 and 18.2, respectively
• Final ESS Score LS Mean at Week 8 was 13.3 and 15.5, respectively.

Indication 2 - for cataplexy in adults with narcolepsy

approved October 2020

Clinical Trial Results

The FDA approval of Wakix for cataplexy in adult patients with narcolepsy was based on two multicenter, randomized, double-blind, placebo-controlled studies (Study 3 and Study 1). Patients ≥18 years of age who met the International Classification of Sleep Disorders (ICSD-2) criteria for narcolepsy with cataplexy with at least 3 cataplexy attacks per week and an ESS score of ≥12 were eligible to enroll in Study 3; patients meeting the ICSD-2 criteria for narcolepsy (with or without cataplexy) and an ESS score of ≥14 were eligible to enroll in Study 1.

Study 3 included a 7-week treatment period: a 3-week dose titration phase followed by a 4-week stable dose phase. 105 patients were randomized to receive Wakix or placebo. The dose of Wakix was initiated at 4.45 mg once daily for the first week, increased to 8.9 mg for the second week, and could remain the same or be decreased or increased at the next two weekly intervals to a maximum of 35.6 mg, based on clinical response and tolerability. No dose adjustments were permitted during the 4-week stable dose phase. 65% of patients reached a stable dose of 35.6 mg. Wakix demonstrated statistically significantly greater improvement on the primary endpoint, the change in geometric mean number of cataplexy attacks per week from baseline to the average of the 4-week stable dosing period for Wakix compared to placebo.

Study 1 was described above. In the subset of patients with a history of cataplexy (n=49), Wakix demonstrated statistically significantly greater improvement on the secondary endpoint, the change from baseline in geometric mean daily rate of cataplexy at Week 8 for Wakix compared to placebo.