PC3008: Efficacy and Safety of Trofinetide for the Treatment of Girls and Young Women with Rett Syndrome: Results from the Randomized, Double-blind, Placebo-controlled, Pivotal, Phase 3 LAVENDER Study

Background: Rett syndrome (RTT) is a rare, debilitating, X-linked, neurodevelopmental disorder for which there is no approved treatment. RTT symptoms include fine and gross motor impairment, loss of verbal and nonverbal communication, hand stereotypies, seizures, and gastrointestinal symptoms, including severe constipation. Trofinetide is a synthetic analog of glycine–proline–glutamate, the amino-terminal tripeptide naturally cleaved from insulin-like growth factor 1. In phase 2 studies in RTT, oral twice-daily trofinetide demonstrated a clinical benefit over placebo in clinician- and caregiver-assessed efficacy measures and was well tolerated. This randomized, double-blind, placebo-controlled, phase 3 study (LAVENDER ClinicalTrials.gov identifier: NCT04181723) investigated the efficacy and safety of trofinetide in girls and young women with RTT.

Methods: Females with RTT aged 5–20 years were randomized 1:1 to twice-daily oral trofinetide or placebo for 12 weeks. Coprimary efficacy endpoints were the change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire (RSBQ) total score, a caregiver assessment of core RTT symptoms, and the Clinical Global Impression–Improvement (CGI-I) score at week 12. The key secondary efficacy endpoint was the change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist-Social (CSBS-DP-IT Social) composite score. The coprimary and key secondary endpoint were assessed at multiple post-baseline visits and analyzed using the mixed-effects model for repeated measures method. Effect size was determined with Cohen’s d (least squares [LS] mean difference/standard deviation). Safety assessments included reporting treatment-emergent adverse events (TEAEs). Following the double-blind portion of the study, participants could enroll in a 40-week open-label extension study (available data will be presented).

Results: Overall, 187 participants were randomized to trofinetide (n=93) or placebo (n=94). After 12 weeks of treatment, trofinetide demonstrated a statistically significant difference over placebo in the co-primary and key secondary endpoints. Mean change from baseline to week 12 in the RSBQ total score for trofinetide vs. placebo was -5.1 vs. -1.7 (p=0.0175 for LS mean [LSM]; Cohen’s d effect size = 0.37; Figure 1), and the mean CGI-I scores at week 12 were 3.5 vs. 3.8 (p=0.0030 [LSM]; Cohen’s d effect size = 0.47; Figure 2). Mean change from baseline to week 12 in the CSBS-DP-IT Social composite score was -0.1 vs. -1.1 (p=0.0064 [LSM]; Cohen’s d effect size = 0.43). Serious TEAEs were reported in 3.2% of participants in each group. The most common TEAE in the trofinetide and placebo groups was diarrhea (80.6% and 19.1%, respectively), with 98% of all cases reported as mild-to-moderate in severity.

Conclusion: In this phase 3 study in patients with RTT, statistically significant differences between trofinetide and placebo were observed in efficacy endpoints that are relevant to RTT; no safety concerns were identified.