Regulatory Decision Summary for Wakix

This Supplemental New Drug Submission (SNDS) was filed to obtain market authorization for a pediatric indication for Wakix (pitolisant).

After review, the addition of the pediatric indication for children aged 6 years and above and weighing at least 30 kilograms was granted.

The request for approval of a pediatric indication was based upon an 8-week safety and efficacy study (Study P11-06), a single-dose pediatric pharmacokinetic (PK) study (Study P11-11), both in patients aged 6 to 17 (the former is new data, the latter was submitted with the initial New Drug Submission [NDS]), and a Population PK analysis (PopPK) (revised from that submitted in the original NDS); and two juvenile toxicology studies in rats.

Study P11-06 was a randomized, placebo-controlled, 8-week double-blind safety and efficacy study in children with narcolepsy (n = 90 with cataplexy; n = 20 without cataplexy) randomized 2:1 drug to placebo.

The dosing regimen consisted of up-titration of Wakix as tolerated during the first 4 of the 8 weeks, initiating at 5 milligrams per day (mg/day) (corresponding to 50% of adult starting dose) and increasing up to the adult maximum of 40 mg/day if the weight was equal to or exceeding 40 kilograms (kg), and otherwise dosing was limited to 20 mg/day.

The primary efficacy outcome (change from baseline in Ullanlinna Narcolepsy Scale [UNS] total score; a validated assessment of both Excessive Daytime Sleepiness [EDS] and cataplexy in pediatrics) demonstrated a statistically and clinically significant difference between drug and placebo. This was also the case with the first two key secondary endpoints (tested in fixed-sequence in order to control for Type 1 error), namely; the Pediatric Daytime Sleepiness Scale (PDSS) and the UNS-Cataplexy subscore. The third secondary outcome of Weekly Cataplexy Rate showed a numerical but not significant difference. Various sensitivity analyses supported the findings.

With respect to safety, approximately 30% of patients in each arm presented with at least one treatment-emergent adverse event. There were no deaths, nor serious adverse events (AE). The most commonly reported individual AEs were: headache (14 [19%] vs 3 [8%] placebo), insomnia (5 [7%] vs 1 [3%] placebo), and hypertension (9 [3%] vs 0). No signal of worsened safety compared to adults was found on analysis of the trial AE data, other than the reports of insomnia that continued until drug discontinuation. No signal was found in the laboratory values, vital signs (other than 2 cases of mild self-resolving hypertension), or depression/suicidality measure. Withdrawal symptoms were reported on Day 7 of single-blind drug washout period (following completion of double blind portion), at higher rates than in placebo. These findings were added to the Product Monograph (PM).

Additionally, for clarity regarding pediatric dosing for subpopulations at risk of higher exposure (that is poor metabolizers; renal or hepatic impairment), the existing cautionary PM language was revised to state the principle that the daily dose should not exceed 50% of recommended maximum for the pertinent age/weight. The PM was also updated to include lack of data on the long-term effects of Wakix. There is an ongoing open-label extension trial to assess this, and the results will be made available to Health Canada once completed.

The primary objective of Study P11-11 was to determine the PK parameters of Wakix in narcoleptic children (12 in each subgroup of 6 to 12 years of age and 13 to 17 years of age), administered a single oral dose of 20 mg, with 6 sampling points between pre-dose and 10 hours post-dose. The available data, including PopPK modelling, showed clear correlation between weight and observed exposure (area under the curve from 0 to 10 hours, representing the extent of exposure [AUC_0-10]) for those weighing less than or equal to 50 kg. However, the PopPK model was considered by Health Canada to be inadequate to perform exposure simulations within this weight subset. Therefore, in order to manage the risk of over-exposure in lower-weight pediatric patients, the dosing recommendations in the PM were changed, based on a starting dose of 5 mg/day, with the following conditions; namely, a maximum dose of 20 mg/day until reaching 50 kg bodyweight (vs 40 kg), and a minimum bodyweight of 30 kg to initiate the drug.

Pitolisant was studied for toxicity with chronic administration (oral and intraperitoneal ) in young rats (from age 7 to 70 days). These two studies did not indicate any specific effect of treatment with pitolisant on developing organ systems, or on growth, but as was observed with the adult toxicology data, the safety margins (based on the extent of exposure defined by area under the curve (AUC)) were very low. As this factor contributes to the risk of overexposure in pediatrics, this information was added to the PM.

An updated Risk Management Plan for Wakix was reviewed by Health Canada and considered acceptable.

The benefit-harm-uncertainty profile for Wakix was considered acceptable for the treatment of Excessive Daytime Sleepiness and cataplexy in pediatric patients with narcolepsy when used under the conditions described in the approved PM. Therefore, a Notice of Compliance was recommended.

For further details about Wakix, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.