Regulatory Decision Summary for Dyanavel XR

The purpose of this New Drug Submission was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Dyanavel XR tablets (amphetamine mixed salts) 5, 10, 15, and 20 milligrams (mg) and Dyanavel XR oral suspension (amphetamine sulfate, amphetamine aspartate monohydrate and dextroamphetamine sulfate) 2.5 milligram (mg)/1 millilitre (ml), filed by Kye Pharmaceuticals. Upon review of the submitted data package, Health Canada authorized Dyanavel XR for the treatment of Attention Deficit Hyperactivity Disorder in Children (6 - 12 years of age) and Adults (18 years of age and older).

Amphetamine has been a well-established therapeutic agent for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) for several decades. This New Drug Submission was to seek approval of Dyanavel XR Oral Suspension (amphetamine extended-release oral suspension) and Dyanavel XR Tablets for the treatment of ADHD in pediatric, adolescent, and adult populations.

The clinical program evaluated the safety, efficacy, pharmacokinetics (PK), and bioequivalence of Dyanavel XR across ten clinical trials. Approval was mainly supported by two well controlled Phase 3 efficacy and safety studies in pediatric ADHD patients aged 6-12 and adult ADHD patients aged 18 and older. The sponsor also submitted Phase 1 PK and/or comparative bioavailability studies, as well as a Population Pharmacokinetic (Pop-PK) modelling study to support efficacy in adolescents.

The two Phase 3 studies (TRI102-ADD-001 and TRI108-ADD-400) comprised the main supportive evidence that were evaluated for approval. The primary efficacy endpoints demonstrated that Dyanavel XR significantly improved ADHD symptoms when compared to placebo and that this improvement was maintained throughout the day in both pediatric (aged 6-12) and adult patients. Improvement in symptoms was measured with the Swanson, Kotkin, Agler, M-Flynn and Pelham Rating Scale combined scores (SKAMP CS) for pediatric patients and the Permanent Product Measure of Performance Total (PERMP-T) for adult patients. Dyanavel XR treatment was significantly more effective than placebo for the control of ADHD symptoms in both populations. Secondary endpoints of onset and duration of clinical effect were supportive of the primaries.

When divided by cohorts (adults are typically tested in classroom-based subgroups) only one adult cohort showed significant improvement on the PERMP-T assessments relative to placebo (study TRI108-ADD-400). However, a requested sensitivity analysis demonstrated that the primary endpoint was still met following the removal of this one significant cohort. Additionally, greater doses did not confer additional efficacy (but were also not accompanied by additional safety concerns). Finally, while the duration of effect peaked at 4 hours, it was nonetheless sustained and began to decrease at a time nearing bedtime (thus alleviating potential concerns regarding sleep disturbances).

A total of 207 subjects were exposed to the amphetamine oral suspension test product in three PK studies and the Phase 3 TRI103-ADD-001 study. Of these 207 subjects, 28 were exposed to prototype formulations and 179 were exposed to the to-be marketed Dyanavel XR Oral Suspension. In the three PK, single-dose studies, doses of the amphetamine test product were 18.8 mg amphetamine base. In the Phase 3 study, pediatric subjects with ADHD received 5 weeks of the 2.5 mg amphetamine base per mL of the to-be marketed formulation (titrated up in 5-10 mg increments) followed by one week of double-blind treatment of the oral suspension (20 mg) or placebo.

A total of 126 subjects were exposed to the tablet formulation in one PK study and the Phase 3 TRI108-ADD-400. Twenty-eight of them received the prototype formulation and ninety-eight received the to-be marketed formulation. The dose in the Phase 1 studies was 20 mg. In the Phase 3 adult study, the starting dose was 5 mg then titrated up by 5 mg increments each week to a final dose of 20 mg for 14 days.

The safety evaluation comprised data from ten clinical studies of Dyanavel XR Oral Suspension: four single-dose PK studies in healthy adult subjects and the two multiple-dose Phase 3 studies in pediatric patients with ADHD (aged 6-12 years) and adult patients respectively.

The safety analysis demonstrated that Dyanavel XR is safe and well tolerated at all dose levels. Overall, the types and frequencies of adverse events observed in the clinical studies were similar to other amphetamine products. No new safety signals of concern were identified.

Because the Phase 3 studies included patients ranging in age from 6-12 and over 18 years of age, the indication was limited to these age groups only. The Product Monograph reflects this restriction.

The chemistry and manufacturing information submitted for Dyanavel met Health Canada requirements.

Following review and requested revisions, the final labelling and Product Monograph were acceptable.

The benefit-harm uncertainty for Dyanavel XR was favourable for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

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