Regulatory Decision Summary for Daybue

This New Drug Submission was filed to obtain market authorization for Daybue (trofinetide) for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older. The submission was filed and reviewed under the Priority Review Policy.

Rett syndrome (RTT) is an X-linked, severe, progressive neurodevelopmental disorder occurring in approximately 1 in 10,000 to 15,000 live female births. Rett syndrome is generally characterized by the loss of communication skills, loss of gross and fine-motor skills, development of hand stereotypies, and progression in four characteristic stages: 1) developmental stagnation, 2) rapid regression, 3) plateau period and 4) motor deterioration.

Patients with RTT commonly experience multi-system comorbidities, which evolve across a patient’s lifespan. These often include seizures, scoliosis, gastrointestinal dysfunction, sleep dysfunction, behaviour disturbances, movement disorders, apraxia, vision impairments, autonomic dysfunction and impaired growth. Cardiorespiratory issues are the most common cause of death in Rett syndrome, and 26% of deaths are sudden and unexpected. Individuals with RTT have a yearly death rate of 1-2%, but over 70% of patients with classic Rett syndrome survive until the age 50 years old. Longitudinal supervision is required in Rett syndrome as physical, behavioural and cognitive limitations do not allow for independent living, requiring lifelong care and assistance with all aspects of daily living. There are currently no approved treatments to treat the core symptoms of RTT in Canada.

Data supporting the efficacy of Daybue (trofinetide) for the treatment of Rett syndrome was based on the submission of six clinical studies, reflective of treatment in 260 unique patients with RTT. These included a single pivotal trial (ACP-2566-003), two open-label extension studies (ACP-2566-004 [40 weeks] and ACP-2566-005 [32 months]), two supportive Phase 2 studies (Neu-2566-RETT-001 and Neu-2566-RETT-002) and an open-label study in patients 2-4 year old with RTT (ACP-2566-009) to support extrapolation of efficacy to younger patients with RTT. Additional supportive safety data was provided from patients with other conditions and with renal impairment, all who received at least one dose of Daybue.

The pivotal trial (ACP-2566-003) was a 12-week, randomized, double-blind, placebo-controlled study. A total of 187 female patients with classic RTT between 5 and 20 years of age were enrolled and were required to have a documented disease-causing mutation in the methyl-CpG-binding protein 2 gene (MECP2), a Rett Syndrome Clinical Severity Scale (RTT-CSS) rating of 10 to 36, and a Clinical Global Impression of Severity (CGI-S) score of greater than or equal to 4. Patients were stratified by age and disease severity, then randomized 1:1 to either placebo (N = 94) or trofinetide (N = 93). Two co-primary endpoints were assessed: a caregiver-rated, 45-item, Rett Syndrome Behavioural Questionnaire (RSBQ), and a clinician-rated Clinical Global Impression of Improvement (CGI-I), measured on a 7-point Likert scale.

Both co-primary endpoints exhibited statistically significant improvement, including a RSBQ score change (baseline to Week 12) of mixed model for repeated measures (MMRM) least squares mean (LSM) difference -3.1 (95% CI [-5.7, -0.6]; p = 0.0175; Cohen’s d effect size 0.37), and a CGI-I (Week 12) between group score difference of MMRM LSM difference -0.3 (95% CI [-0.5, -0.1]; p = 0.0030, Cohen’s d effect size 0.47). Sensitivity analyses were supportive of the primary analysis; however high rates of discontinuations violated the missing at random assumption which forms the basis of the MMRM approach, and functional unblinding due to adverse events of diarrhea introduced an additional bias.

The RSBQ is well-validated instrument designed to identify core signs and symptoms of RTT and distinguish individuals with RTT from other females with other causes severe to profound intellectual disability. The Clinical Global Impression of Improvement (CGI-I) is well-established in the use of neurodevelopmental disorders, and a RTT-specific anchor scale was developed specifically for evaluation of improvement or worsening in patients with RTT. Improvement on both these outcome measures was felt to provide evidence of a meaningful clinical change in an individual patient. The clinical meaningfulness of the magnitude of change on the co-primary endpoints (RSBQ and CGI-I) at the group level was less clear and was further complicated by the lack of an established, clearly defined minimally clinically important difference for these outcome measures in RTT.

Adverse event rates in the pivotal trial were higher in the Daybue group as compared to the placebo group. The most common adverse events in the Daybue-treated patients compared to the placebo-treated patients were diarrhea (80.6% versus [vs] 19.1%), vomiting (26.9% vs 9.6%), weight loss (12.9% vs 4.7%) seizure (8.6% vs 5.3%), pyrexia (8.6% vs 4.3%) and decreased appetite (5.4% vs 2.1%). Four deaths were reported in Daybue-treated patients (all in ACP-2566-005), 3 of which were considered treatment-emergent (causes of death were sudden unexplained death in epilepsy, cardiac arrest, and aspiration of gastric contents). Adverse reactions of special interest included QTc prolongation, diarrhea, vomiting and aspiration pneumonia which are described in the Warnings and Precautions section and Monitoring and Laboratory Test sections of the approved Product Monograph (PM).

In the pivotal trial and associated open-label extension studies (N = 178), adverse events resulted in dose modification in 109 unique patients (61.2%) and study drug or study discontinuation in 77 unique patients (43.3%). Diarrhea was experienced by 85% of patients treated with Daybue, with a concomitant anti-diarrheal medication used to manage the diarrhea in 126 patients (70.8%), and a concomitant anti-propulsive medication (loperamide) used in 103 patients (57.9%). Serious adverse event rates increased from 3 patients (3.2%) in the pivotal trial to 19 patients (12.3%) in ACP-2566-004 and 23 patients (29.9%) in ACP-2566-005.

Given the medication is intended for continuous, life-long use, the issue of tolerability is particularly relevant in product labelling and clinical consideration. Dosing considerations and recommendations were included in the Product Monograph (PM) to mitigate the risk of adverse events in patients with RTT syndrome. These included slow dose up-titration to the recommended dose, temporary dose reduction with onset of intolerable adverse reactions, and modified doses for renal impairment. Further, the PM suggests the discontinuation of Daybue if a patient is unable to tolerate the recommended dose on an ongoing basis as the drug has not demonstrated efficacy at lower doses. It is also suggested that if a patient does not experience beneficial effects after 12 months of use, Daybue should be discontinued as no additional benefit has been demonstrated after 1 year of treatment.

The exclusion of patients with less common forms of RTT from the 6 clinical studies (Neu-2566-RETT-001, Neu-2566-RETT-002, ACP-2566-003, ACP-2566-004, ACP-2566-005 and ACP-2566-009) resulted in a lack of data regarding the clinical efficacy and safety of Daybue in less common patient populations with RTT. Despite the mechanism of action of Daybue remaining unclear and ongoing uncertainty regarding which sub-populations of patients with RTT will demonstrate improvements with Daybue, the extrapolation of an indication to include less common RTT subgroups (that is [i.e.], males, atypical/variant RTT, etc.) was deemed acceptable based on the assumption of similar underlying pathophysiology. These limitations of use are included in the PM to inform the prescriber.

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

Comparative bioavailability data was reviewed and demonstrated that a high-fat, high-calorie meal did not significantly impact the rate and extent of exposure of trofinetide in the commercial formulation of Daybue.

A Risk Management Plan (RMP) for Daybue was submitted by Acadia Pharmaceuticals Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.

The final labelling and PM were considered acceptable.

Rett syndrome is a rare, neurodevelopmental disorder with a high unmet need. Therefore, a single pivotal trial and limited long-term exposure of Daybue in patients with RTT were considered acceptable. The modest improvements in the core symptoms of RTT seen in some patients in the clinical development program are relevant given the high baseline level of impairment experienced by these patients and the significant impact that small improvements can have on the daily lives of patients with RTT and their caregivers. Risk mitigation and labelling strategies have been employed to ensure the safe prescription of Daybue.

Overall, the benefit-harm-uncertainty profile was considered favourable for Daybue for the approved indication when used under the conditions of use recommended in the approved PM. Therefore, a Notice of Compliance was recommended.

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