Efficacy and Safety of Trofinetide for the Treatment of Rett Syndrome: Results from the Pivotal Phase 3 LAVENDER Study

Background/Purpose: Rett syndrome (RTT) is a debilitating genetic neurodevelopmental disorder primarily affecting females. Trofinetide is a synthetic analog of glycine–proline–glutamate, a naturally occurring tripeptide cleaved from insulin-like growth factor 1. Phase 2 studies in RTT demonstrated a clinical benefit over placebo in clinician- and caregiver-assessed efficacy measures. Here, we present the results of LAVENDER, a randomized, placebo-controlled, phase 3 study of trofinetide in girls and young women with RTT.

Methods: Females with RTT, aged 5 to 20 years, were randomized 1:1 to twice-daily oral trofinetide or placebo for 12 weeks. Efficacy endpoints included the Rett Syndrome Behavior Questionnaire (RSBQ), a caregiver assessment of core RTT symptoms (co-primary), the Clinical Global Impression-Improvement (CGI-I) scale (co-primary), and the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist-Social (CSBS-DP-IT Social) composite score (key secondary).

Results: Overall, 187 participants were randomized to trofinetide (n = 93) or placebo (n = 94). After 12 weeks of treatment, trofinetide demonstrated a statistically significant improvement over placebo for co-primary and key secondary endpoints. Least squares (LS) mean change from baseline to week 12 in the RSBQ for trofinetide versus placebo was −4.9 versus −1.7 (p = 0.0175; Cohen's d effect size = 0.37), LS mean CGI-I score at week 12 was 3.5 versus 3.8 (p = 0.0030; Cohens’ d effect size = 0.47), and LS mean change from baseline to week 12 in the CSBS-DP-IT Social composite score was −0.1 versus −1.1 (p = 0.0064; Cohen's d effect size = 0.43). Serious adverse events were reported in 3.2% of participants in the trofinetide and placebo groups. The most common adverse event in the trofinetide and placebo groups was diarrhea (80.6 and 19.1%, respectively), with 98% of all cases experiencing mild-to moderate severity.

Conclusion: This study demonstrated that trofinetide is efficacious and has an acceptable safety profile in females with RTT.

Publication History

Article published online:
26 September 2025