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Randomized Controlled Trial
. 2024 Mar:152:63-72.
doi: 10.1016/j.pediatrneurol.2023.11.005. Epub 2023 Nov 23.

Trofinetide Treatment Demonstrates a Benefit Over Placebo for the Ability to Communicate in Rett Syndrome

Jeffrey L Neul  1 , Alan K Percy  2 , Timothy A Benke  3 , Elizabeth M Berry-Kravis  4 , Daniel G Glaze  5 , Sarika U Peters  1 , Eric D Marsh  6 , Di An  7 , Kathie M Bishop  7 , James M Youakim  8
Affiliations
Free article
Randomized Controlled Trial

Trofinetide Treatment Demonstrates a Benefit Over Placebo for the Ability to Communicate in Rett Syndrome

Jeffrey L Neul et al. Pediatr Neurol. 2024 Mar.
Free article

Abstract

Background: Trofinetide was approved by the US Food and Drug Administration for the treatment of Rett syndrome (RTT) in March 2023. Benefiting the ability to communicate in RTT is often identified as the most important caregiver goal for new therapies. This analysis reports the communication-related end points from the phase 3 LAVENDER study of trofinetide in RTT.

Methods: Females with RTT, aged five to 20 years, were randomized 1:1 to trofinetide or placebo for 12 weeks. Secondary efficacy end points related to communication were based on change from baseline to week 12 and included the caregiver-rated Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite score (key secondary end point; scores ranged from 0 to 26 [higher scores indicated better communication]) and novel clinician rating scales (0 [normal] to 7 [severe impairment]) measuring the ability to communicate choices nonverbally (RTT-COMC) and verbally (RTT-VCOM).

Results: Trofinetide demonstrated a statistically significant difference versus placebo for the CSBS-DP-IT Social Composite score (least squares mean [LSM] difference = 1.0; 95% confidence interval [CI], 0.3 to 1.7; P = 0.0064; Cohen's d effect size = 0.43) and a nominally significant difference for the RTT-COMC (LSM difference: -0.3; 95% CI, -0.6 to -0.0; P = 0.0257; Cohen's d effect size = 0.36). As expected, there was no difference for the RTT-VCOM.

Conclusions: Significant treatment benefit for trofinetide versus placebo was observed in scales measuring the ability to communicate. These scales may be appropriate for future clinical studies in RTT and other neurodevelopmental disorders.

Keywords: LAVENDER study; Neurodevelopmental disorder; Nonverbal communication; Rett syndrome; Trofinetide.

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Conflict of interest statement

Declaration of competing interest Dr. Neul has received research funding from the National Institutes of Health, the International Rett Syndrome Foundation, and Rett Syndrome Research Trust; received personal consultancy for Acadia Pharmaceuticals Inc, Analysis Group, AveXis, GW Pharmaceuticals, Hoffmann-La Roche, Myrtelle, Neurogene, Newron Pharmaceuticals, Signant Health, and Taysha Gene Therapies, and the preparation of CME activities for PeerView Institute and Medscape; serves on the scientific advisory board of Alcyone Lifesciences; is a scientific cofounder of LizarBio Therapeutics; and was a member of a data safety monitoring board for clinical trials conducted by Ovid Therapeutics. Dr. Percy is coeditor of Translational Science of Rare Diseases, received research funding from the National Institutes of Health, and is a consultant for Acadia Pharmaceuticals Inc, AveXis, GW Pharmaceuticals, and Anavex Life Sciences Corp., as well as adviser to the International Rett Syndrome Foundation. Dr. Benke received research funding from GRIN2B Foundation, the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, and Simons Foundation; received consultancy for Alcyone, GRIN Therapeutics, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neurogene, Takeda Pharmaceutical Company Limited, Ultragenyx, and Zogenix/UCB; and performs clinical trials with Acadia Pharmaceuticals Inc, GW Pharmaceuticals, Marinus Pharmaceuticals, Ovid Therapeutics, and Rett Syndrome Research Trust; all remuneration has been made to his department. Dr. Berry-Kravis has received funding from Acadia Pharmaceuticals Inc, Alcobra Pharmaceuticals, AMO Pharma, Asuragen, AveXis, Biogen, BioMarin, Cydan Development, EryDel, Fulcrum Therapeutics, GeneTx, GW Pharmaceuticals, Ionis Pharmaceuticals, Jaguar Health Inc, Lumos Pharma, Marinus Pharmaceuticals, Neuren Pharmaceuticals, Neurogene, Neurotrope, Novartis, Orphazyme, Ovid Therapeutics, Retrophin, Roche, Seaside Therapeutics, Taysha Gene Therapies, Tetra Bio-Pharma, Ultragenyx, Yamo Pharmaceuticals, Zynerba Pharmaceuticals, and Vtesse/Sucampo/Mallinckrodt Pharmaceuticals, to consult on trial design or run clinical or laboratory validation trials in genetic neurodevelopmental or neurodegenerative disorders, all of which is directed to Rush University Medical Center in support of rare disease programs; Dr. Berry-Kravis receives no personal funds, and Rush University Medical Center has no relevant financial interest in any of the commercial entities listed. Dr. Glaze has received personal compensation and research support from Acadia Pharmaceuticals Inc, Neuren Pharmaceuticals, and Newron Pharmaceuticals. Dr. Peters has received funding from the National Institutes of Health and the International Rett Syndrome Foundation and personal consultancy for Acadia Pharmaceuticals Inc. Dr. Marsh has received research support from the National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Human Development, Eagles Autism Foundation, Penn Orphan Disease Center, the International Rett Syndrome Foundation, Rett Syndrome Research Trust, International CDKL5 Research Foundation, and the Loulou Foundation. He has been a site principal investigator for trials from Stoke Therapeutics, GW Pharmaceuticals, Zogenix, Acadia Pharmaceuticals Inc, and Marinus Pharmaceuticals. He has received personal compensation for consulting from Stoke Therapeutics and Acadia Pharmaceuticals Inc. Drs. An, Bishop, and Youakim are employees of and stockholders in Acadia Pharmaceuticals Inc.

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