Regulatory Decision Summary for Slenyto

The purpose of this New Drug Submission, filed by Neurim Pharmaceuticals Ltd., sought to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Slenyto (melatonin) 1 and 5 milligram extended-release tablets. Upon review of the submitted package, Health Canada authorized Slenyto for the treatment of insomnia in children and adolescents aged 2 to under 18 years with autism spectrum disorder (ASD) and/or Smith-Magenis syndrome (SMS), where sleep hygiene measures alone had proven insufficient.

This New Drug Submission was to seek approval of Slenyto (melatonin) 1 and 5 milligram (mg) extended-release tablets for the treatment of insomnia in children and adolescents aged 2 to under 18 years of age with autism spectrum disorder (ASD) and/or Smith-Magenis syndrome (SMS).

The clinical development program for Slenyto included studies in adult patients using Circadin (extended-release melatonin), and pediatric-specific pharmacokinetic and safety and efficacy studies using Slenyto. Study CHDR1742 confirmed that the dose-normalized rate and extent of melatonin exposure is comparable between Slenyto and Circadin formulations.

Pharmacokinetic studies in adults demonstrated that peak plasma concentrations following ingestion of Circadin 2 mg tablets were reached at approximately 2 hours, with plasma levels declining by 50% within 6 hours and returning to baseline by 12 hours. This profile closely mirrors the endogenous nocturnal secretion pattern of melatonin. The mean maximum plasma concentration (C_max) following a 2 mg dose was approximately eight times higher than physiological nighttime levels.

Pharmacokinetic evaluation of Slenyto in children included an open-label study in children with ASD and insomnia aged 7 to under 18 years. Measured endogenous melatonin and 6-SMT (its major metabolite) were reduced in this population, but they retained a diurnal rhythm of higher levels at night than during the day - reflecting a typical diurnal rhythm in this population. Following administration of Slenyto, time to maximum concentration was approximately 2 hours, with a half-life of about 5 hours, similar to adults and more closely mimicking the release pattern of endogenous melatonin. Sedative effects after a 2 mg dose peaked at the time to maximum concentration (T_max), indicating a pharmacokinetic–pharmacodynamic correlation.

The pivotal pediatric clinical study (NEU_CH_7911) was a randomized, double-blind, placebo-controlled trial evaluating extended-release melatonin (Slenyto) in children and adolescents aged 2 to under 18 years with ASD or SMS and persistent insomnia despite behavioral interventions. Participants entered after a 2-week run-in period and received extended-release Slenyto at stepped doses (2 mg with optional escalation to 5 mg in the double-blind phase and higher doses in the open-label extension) or placebo for 13 weeks, with a 91-week extension and 2-week placebo run-out for longer follow-up.

Slenyto significantly increased total sleep time (primary endpoint) by more than 30 minutes, reduced sleep onset latency by 25 minutes, and decreased the number of night awakenings. Improvements in caregiver-reported sleep quality and child daytime behavior were also observed. Benefits were maintained through the open-label extension, with no evidence of tolerance or rebound insomnia upon discontinuation.

Slenyto was generally well tolerated. The most common adverse events were mild and included fatigue, somnolence (consistent with its mechanism of action), and headache. Serious adverse events were rare and not considered treatment-related. Long-term safety data (up to 2 years) did not reveal new safety signals.

The heterogeneity of comorbidities in patients in the study, including ADHD and epilepsy, provided a degree of real-world representativeness. The inclusion of participants receiving a range of concomitant medications allowed for assessment of Slenyto’s safety and efficacy across common clinical scenarios.

No major key non-clinical findings were observed.

The chemistry and manufacturing information submitted for Slenyto has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

The final labelling and Product Monograph were reviewed and deemed acceptable by Health Canada.

A Risk Management Plan for Slenyto was reviewed by Health Canada and considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Slenyto 1 mg and 5 mg extended-release tablets for the approved indication when used under the conditions of use recommended in the approved Product Monograph. A Notice of Compliance was issued.

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