Alan K Percy, Robin Ryther, Eric D Marsh, Jeffrey L Neul, Timothy A Benke, Elizabeth M Berry-Kravis, Timothy Feyma, David N Lieberman, Amitha L Ananth, Cary Fu, Colleen Buhrfiend, Amy Barrett, Dilesh Doshi, Mona Darwish, Di An, Kathie M Bishop, James M Youakim
{"title":"trofinetide在2-4岁Rett综合征女孩中的2/3期DAFFODIL研究结果。","authors":"Alan K Percy, Robin Ryther, Eric D Marsh, Jeffrey L Neul, Timothy A Benke, Elizabeth M Berry-Kravis, Timothy Feyma, David N Lieberman, Amitha L Ananth, Cary Fu, Colleen Buhrfiend, Amy Barrett, Dilesh Doshi, Mona Darwish, Di An, Kathie M Bishop, James M Youakim","doi":"10.1016/j.medj.2025.100608","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Funding: </strong>The study was supported by Acadia Pharmaceuticals (San Diego, CA). This study was registered at ClinicalTrials.gov (NCT04988867).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100608"},"PeriodicalIF":12.8000,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2-4 years with Rett syndrome.\",\"authors\":\"Alan K Percy, Robin Ryther, Eric D Marsh, Jeffrey L Neul, Timothy A Benke, Elizabeth M Berry-Kravis, Timothy Feyma, David N Lieberman, Amitha L Ananth, Cary Fu, Colleen Buhrfiend, Amy Barrett, Dilesh Doshi, Mona Darwish, Di An, Kathie M Bishop, James M Youakim\",\"doi\":\"10.1016/j.medj.2025.100608\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Funding: </strong>The study was supported by Acadia Pharmaceuticals (San Diego, CA). This study was registered at ClinicalTrials.gov (NCT04988867).</p>\",\"PeriodicalId\":29964,\"journal\":{\"name\":\"Med\",\"volume\":\" \",\"pages\":\"100608\"},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2025-02-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Med\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.medj.2025.100608\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2025.100608","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
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).
期刊介绍：
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.
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