Trofinetide for the treatment of Rett syndrome: an open-label study in girls 2 to 4 years of age
Alan Percy1, Robin Ryther2, Eric Marsh3, Timothy Feyma4, David Lieberman5, Jeffrey Neul6, Timothy Benke7, Daniel Glaze8, Elizabeth Berry-Kravis9, Amitha Ananth1, Colleen Buhrfiend10, Srdjan Stankovic11, Kathie Bishop11, Mona Darwish11, James Youakim11
1University of Alabama at Birmingham, 2Washington University School of Medicine, 3Children’s Hospital of Philadelphia, 4Gillette Children'S Specialty Healthcare, 5Boston Children's Hospital, 6Vanderbilt Kennedy Center, Vanderbilt University Medical Center, 7Children’s Hospital of Colorado/University of Colorado School of Medicine, 8Texas Children’s Hospital/Baylor College of Medicine, 9Rush University Children’s Hospital, 10Rush Univeristy Medical Center, 11Acadia Pharmaceuticals Inc.
Objective:
To assess the safety/tolerability, preliminary efficacy, and pharmacokinetics (PK) of trofinetide in girls aged 2–4 years with Rett syndrome (RTT).
Background:
RTT is a rare, debilitating, neurodevelopmental disorder mainly affecting females. Trofinetide, a synthetic analog of a naturally occurring tripeptide in the brain, significantly improved core symptoms of RTT with an acceptable safety profile in studies enrolling females aged ≥5 years with RTT. However, RTT is typically diagnosed by 3 years of age.
Design/Methods:
This ongoing, multicenter, open-label study of trofinetide consists of a 12-week treatment period A and ~21-month treatment period B in females aged 2–4 years with RTT (NCT04988867). Weight-based dosing of trofinetide was administered orally or by gastrostomy tube twice-daily. Interim results (cut-off date March 14, 2022) from treatment period A are presented for safety, exploratory efficacy (Clinical Global Impression–Improvement [CGI-I], Caregiver Global Impression–Improvement [CaGI-I], and the Overall Quality-of-Life Rating on the Impact of Childhood Neurologic Disability Scale [ICND-QoL]), and PK.
Results:
At this interim analysis, 14 participants were enrolled, and 10 completed treatment period A. Twelve (85.7%) participants reported ≥1 treatment-emergent adverse event (TEAE). Diarrhea (64.3%) and vomiting (35.7%) were the most common TEAEs; no serious AEs or deaths were reported. Mean CGI-I scores improved from 3.6 at Week 2 to 3.3 at Week 12. The mean CaGI-I score at Week 12 (2.2) corresponded to “much improved” relative to Baseline. The ICND-QoL also improved, with an increase from 3.9 at Baseline to 4.2 at Week 12. Population PK analysis showed that exposure to trofinetide in this study achieved the target exposure range.
Conclusions:
Consistent with data from phase 2 and 3 trials with participants aged ≥5 years, treatment with trofinetide was well tolerated and appeared to result in improvements in RTT-related efficacy measures in girls aged 2–4 years.