Regulatory Decision Summary for Wakix

The Sponsor submitted three pivotal trials to support the efficacy and safety of pitolisant. Harmony I (Study 07-03) and Harmony Ibis (Study 09-15) were submitted to support the efficacy of pitolisant in reducing excessive daytime sleepiness in patients with narcolepsy. Both of these pivotal trials were of 8 weeks duration, with a maximal dose of 40 milligrams (mg) in study 07-03 and 20 mg in study 09-15. Study 07-03 was a double-blind, randomized, controlled trial consisting of three arms with a sample sizes of 30 patients in the placebo arm, 31 patients in the pitolisant arm and 33 patients in the modafinil arm. Study 09-15 was also a double-blind randomized, controlled trial that included 66 patients in the pitolisant arm, 32 patients in the placebo arm and 68 patients in the modafinil arm. These studies demonstrated a statistically and clinically significant difference between pitolisant and placebo in the Epworth Sleepiness Scale score change from baseline to post-pitolisant treatment. Although both of these trials demonstrated statistically significant improvement over placebo for pitolisant, pre-specified analyses did not demonstrate non-inferiority of pitolisant compared to modafinil. The third pivotal trial, Harmony CTP (Study 11-05) was a double-blind, randomized controlled trial that included 51 patients in the placebo arm and 54 patients in the pitolisant treatment arm. This study was submitted to support the efficacy of pitolisant in reducing the weekly frequency of cataplexy in patients with narcolepsy type I compared to placebo. It was distinct from Studies 07-05 and 09-15 by having a different primary endpoint and two treatment arms. Study 11-05 was able to demonstrate a statistically and clinically significant difference in reduction of the frequency of weekly cataplexy events when compared to placebo. A secondary endpoint in Study 07-03, demonstrated a clinically and statistically significant reduction of pitolisant in daily (rather than weekly) cataplexy rates and was considered supportive of the endpoint in Study 11-05.

The safety concerns that were identified in the pivotal studies with the use of pitolisant in patients with narcolepsy have all been addressed in the Canadian Product Monograph (CPM). The use of pitolisant in patients with severe hepatic impairment is contraindicated and use in end-stage renal disease is not recommended. Patients receiving pitolisant need to be monitored for increased exposure, due to hepatic or renal dysfunction, use with concomitant medications which can predispose to increased exposure, and use in patients with cytochrome P450 (CYP) 2D6 slow metabolizer polymorphism. Additionally, pitolisant causes a concentration-dependent prolongation of the QTc interval that was characterized in two ECG assessment studies. Other safety concerns associated with pitolisant include neurological events such as headache and insomnia. Pitolisant has a potential pro-convulsive effect. Pitolisant should be used with caution in patients with a psychiatric history as cases of depression were reported in both clinical trials and post-market surveillance. Serious adverse events included in the CPM include depression and gastrointestinal adverse events. Common adverse event information is included in the CPM.

Overall, the pharmacology and pharmacokinetics (PK) program supporting pitolisant is comprehensive, has been reviewed and is consistent with international guidelines. Regulatory reviews by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were made available by the sponsor and were found to be consistent with Health Canada’s review. The non-clinical review has not identified any major safety concerns.

The clinical pharmacology review demonstrated that pitolisant exposure is increased in poor metabolizers, patients with any degree of renal impairment, and patients with moderate hepatic impairment. Limited PK data were available from elderly subjects. However, some data was suggestive of experiencing greater exposures in elderly patients due to their compromised renal clearance. Additionally, data showed pitolisant to be a weak inducer of CYP3A4 and may have the potential to reduce the efficacy of hormonal contraceptives. Animal studies indicated that pitolisant displays satisfactory safety margins when comparing plasma levels at the no-observed-adverse-effect-level (NOAEL) doses with the plasma levels in humans receiving the drug chronically at therapeutic doses. The metabolites that were shown to have convulsive actions in rats were either not detectable or found in low concentrations in humans. Although a human abuse potential study suggested that pitolisant is unlikely to have an abuse potential that is on par with traditional psychostimulants, there still remains some uncertainty at higher doses which can elicit a feeling of drug high. Because of this observation, combined with methodological concerns regarding the Human Abuse Potential (HAP) study design and issues raised in the non-clinical abuse liability data, relevant statements about abuse potential were included in the CPM.

With regard to the toxicology review, repeat dose studies in rat and monkey provided a safety margin near or below the expected therapeutic exposure. Pitolisant did not show genotoxic or carcinogenic potential. The reproductive and developmental toxicity studies revealed a potential concerns with regards to conception, pregnancy, breastfeeding and offspring development. These potential risks were mitigated by including appropriate statements in the CPM.

Missing information includes long-term safety and efficacy data, use in the pediatric and geriatric population and use of pitolisant in populations with co-morbid conditions such as cardiovascular or psychiatric conditions. A Risk Management Plan (RMP) was submitted and reviewed by the Marketed Health Products Directorate (MHPD) and was considered acceptable.

Overall, the benefit-harm-uncertainty profile of pitolisant is considered favorable for the treatment of excessive daytime sleepiness (EDS) and cataplexy in adult patients with narcolepsy.