Trofinetide Promising for Patients With Rett Syndrome

Trofinetide is a novel synthetic analogue of the amino-terminal tripeptide of IGF-1 designed to treat the core symptoms of Rett syndrome.

Positive topline results were announced from a phase 3 study evaluating trofinetide in Rett syndrome, a rare, debilitating neurological disorder caused by mutations on the MECP2 gene.

Trofinetide is a novel synthetic analogue of the amino-terminal tripeptide of IGF-1 designed to treat the core symptoms of Rett syndrome by reducing neuroinflammation and supporting synaptic function. The randomized, double-blind, placebo-controlled Lavender study ( Identifier: NCT04181723) evaluated the efficacy and safety of trofinetide in 187 females 5 to 20 years of age with Rett syndrome.

Patients were randomly assigned to receive trofinetide or placebo orally or via gastrostomy tube twice daily for 12 weeks. The coprimary endpoints were change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire (RSBQ) total score (a caregiver assessment) and the Clinical Global Impression-Improvement (CGI-I) score (a physician assessment). 

Results showed that treatment with trofinetide demonstrated a statistically significant improvement on the RSBQ of -5.1 compared with -1.7 for placebo (P =.0175; effect size =0.37). A statistically significant improvement over placebo was also observed on the CGI-I (3.5 vs 3.8; P =.003; effect size =0.47).

Trofinetide also met a key secondary endpoint demonstrating a statistically significant improvement from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist–Social composite score compared with placebo (-0.1 vs -1.1; P =.0064; effect size =0.43).

“Patients reported improvements in core symptoms, like being able to respond to a choice when asked by their parents, or experiencing more freedom from the repetitive hand movements that create obstacles in other areas of their lives,” said Jeffrey L. Neul, MD, PhD, Annette Schaffer Eskind Chair and Director, Vanderbilt Kennedy Center; Professor of Pediatrics, Division of Neurology, Pharmacology, and Special Education, Vanderbilt University Medical Center and Lavender study investigator.

The most common adverse events for trofinetide and placebo were diarrhea (80.6% vs 19.1%, respectively) and vomiting (26.9% vs 9.6%). The trofinetide arm had higher study discontinuation rates related to treatment emergent adverse events compared with the placebo arm (17.2% vs 2.1%, respectively).

Patients who completed the Lavender study were eligible to continue treatment with trofinetide in the open-label Lilac ( Identifier: NCT04279314) and Lilac-2 extension studies.

The Food and Drug Administration (FDA) previously granted Fast Track and Orphan Drug designations to trofinetide for this indication. The Company plans to submit a New Drug Application to the FDA around mid-year 2022.


Acadia Pharmaceuticals announces positive top-line results from the pivotal phase 3 Lavender trial of trofinetide in Rett syndrome. News release. Acadia Pharmaceuticals Inc. Accessed December 7, 2021.