Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2-4 years with Rett syndrome
- PMID: 40043705
- DOI: 10.1016/j.medj.2025.100608
Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2-4 years with Rett syndrome
Abstract
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).
Keywords: DAFFODIL; Rett syndrome; Translation to patients; pediatric population; trofinetide.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests A.K.P. has received funding from the National Institutes of Health; funding for consulting from Acadia Pharmaceuticals, Anavex Life Sciences, AveXis, and GW Pharmaceuticals; he is an adviser to the International Rett Syndrome Foundation and has served as a member of a data safety monitoring board for clinical trials conducted by Taysha Gene Therapies. R.R. has received funding for clinical trials from Acadia Pharmaceuticals, Anavex Life Sciences, and GW Pharmaceuticals and funding from the International Rett Syndrome Foundation to support travel expenses. E.D.M. has received funding from the International Rett Syndrome Foundation, the National Institutes of Health, and the Rett Syndrome Research Trust; has received funding for clinical trials from Acadia Pharmaceuticals, Curaleaf, Marinus Pharmaceuticals, SK Life, Stoke Therapeutics, Takeda Pharmaceuticals, and Zogenix Pharmaceuticals; has received consultancy fees from Acadia Pharmaceuticals and Stoke Therapeutics; and has received speaker’s fees from The France Foundation, Medscape, and Novartis. J.L.N. has received research funding from the US Department of Defense, the International Rett Syndrome Foundation, the National Institutes of Health, and the Rett Syndrome Research Trust and personal consultancy fees from Acadia Pharmaceuticals, Analysis Group, EcoR1 Capital, GW Pharmaceuticals, Hoffmann-La Roche, Myrtelle, Neurogene, SignantHealth, Taysha Gene Therapies, and Ultragenyx; he serves on the scientific advisory board of Alcyone Lifesciences; he is a scientific cofounder of LizarBio Therapeutics; and he is a member of a data safety monitoring board for clinical trials conducted by Ovid Therapeutics and Ultragenix. T.A.B. has received funding for consulting from Acadia Pharmaceuticals, Alcyone Therapeutics, GRIN Therapeutics, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neuren Pharmaceuticals, Neurogene, Ovid Therapeutics, Takeda Pharmaceuticals, Ultragenyx, and Zogenix Pharmaceuticals and has received funding for clinical trials from Acadia Pharmaceuticals, GW Pharmaceuticals, Marinus Pharmaceuticals, Ovid Therapeutics, and the Rett Syndrome Research Trust; all remuneration has been paid to his department. E.M.B.-K. has received funding from Acadia Pharmaceuticals, Biogen, BioMarin, Cydan Development, Erydel, ESCAPE Bio, Fulcrum Therapeutics, GeneTx Biotherapeutics, GW Pharmaceuticals, Healx, Ionis Pharmaceuticals, Jaguar, Lumos Pharma, Mallinckrodt Pharmaceuticals, Neuren, Neurogene, Novartis, Orphazyme, Ovid Therapeutics, REGENXBIO, Roche, Taysha, Tetra Therapeutics, Ultragenyx, Yamo Pharmaceuticals, Zevra, and Zynerba Pharmaceuticals to consult on trial design or development strategies in neurodevelopmental or neurodegenerative disorders; all remuneration was paid to Rush University Medical Center. T.F. has received speaker’s fees from Acadia Pharmaceuticals and PTC Therapeutics. D.N.L. has received funding for clinical trials from Acadia Pharmaceuticals, Anavex Life Sciences, GW Pharmaceuticals, Neurogene, and the Rett Syndrome Research Trust; he has received consultancy fees from Acadia Pharmaceuticals, Neurogene, and Taysha Gene Therapies. A.L.A. has received funding for clinical trials from Anavex Life Sciences and Acadia Pharmaceuticals. C.F. has received funding for clinical trials from Zogenix Pharmaceuticals and consultancy fees from Acadia Pharmaceuticals. A.B. is an employee of RTI Health Solutions, which received funding from Acadia Pharmaceuticals for the design, conduct, and analysis of the exit interviews. D.A., D.D., M.D., and J.M.Y. are employees of and stakeholders in Acadia Pharmaceuticals. K.M.B. was an employee of Acadia Pharmaceuticals when this work was conducted and is currently a consultant for Acadia Pharmaceuticals.
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