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Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2-4 years with Rett syndrome
Percy, A. K., Ryther, R., Marsh, E. D., Neul, J. L., Benke, T. A., Berry-Kravis, E. M., Feyma, T., Lieberman, D. N., Ananth, A. L., Fu, C., Buhrfiend, C., Barrett, A., Doshi, D., Darwish, M., An, D., Bishop, K. M., & Youakim, J. M. (2025). Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2-4 years with Rett syndrome. Med (New York, N.Y.), 100608. Advance online publication. https://doi.org/10.1016/j.medj.2025.100608
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).