Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2–4 years with Rett syndrome

Background: Trofinetide is the first available treatment for Rett syndrome (RTT) and is approved in the United States in adults and pediatric patients aged ≥2 years. The DAFFODIL study was conducted in girls aged 2–4 years with RTT to examine the safety, tolerability, and efficacy of trofinetide and to validate that the recommended dosage, according to body weight, achieved target exposure. Methods: DAFFODIL was a phase 2/3, open-label study of trofinetide consisting of two treatment periods (12 weeks [period A] and ∼21 months [period B]). Pharmacokinetic samples were collected at regular intervals during period A. Assessments included treatment-emergent adverse events (TEAEs) and exploratory efficacy (Clinical Global Impressions-Improvement [CGI-I], CGI-Severity, caregiver GI-I [CaGI-I], and overall quality of life rating of the Impact of Childhood Neurologic Disability Scale [ICND-QoL]). Optional caregiver exit interviews were also conducted. Findings: Fifteen participants were enrolled. Overall, the most common TEAEs were diarrhea (80.0%) and vomiting (53.3%), which were mild or moderate in severity. Steady-state exposure at clinical doses fell within the target exposure range. RTT symptoms improved throughout the study as measured by the CGI-I, CaGI-I, and change from baseline in the ICND-QoL. In caregiver interviews (n = 7), all caregivers reported they were “very satisfied” or “satisfied” with trofinetide benefits. Conclusions: Trofinetide has acceptable tolerability in girls 2–4 years of age with RTT and provides long-term efficacy. Weight-based dosage achieves target exposure in younger children. Funding: The study was supported by Acadia Pharmaceuticals (San Diego, CA). This study was registered at ClinicalTrials.gov (NCT04988867).