Trofinetide for the treatment of Rett syndrome: Results from the open-label extension LILAC study

Abstract

Background Trofinetide was approved for the treatment of Rett syndrome based on the results of the phase 3, randomized, placebo-controlled, 12-week LAVENDER study. Rett syndrome is a chronic disorder requiring long-term treatment. We report the efficacy and safety results of LILAC, a 40-week, open-label extension study of LAVENDER. Methods Females with Rett syndrome aged 5–21 years received open-label treatment with trofinetide for 40 weeks. The primary endpoint was long-term safety of trofinetide; secondary endpoints included the change from baseline at week 40 in the Rett Syndrome Behaviour Questionnaire score and the Clinical Global Impression-Improvement score at week 40. Findings Overall, 154 participants were enrolled and treated with trofinetide in LILAC. The most common adverse events in LILAC were diarrhea (74.7%), vomiting (28.6%), and COVID-19 (11.0%). Diarrhea was the most common adverse event leading to treatment withdrawal (21.4%). The Rett Syndrome Behaviour Questionnaire mean score (standard error) improvement from the LAVENDER baseline to week 40 in LILAC was −7.3 (1.62) and −7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean Clinical Global Impression-Improvement scores (standard error) at week 40 rated from the LILAC baseline were 3.1 (0.11) and 3.2 (0.14) for participants treated with trofinetide and placebo in LAVENDER, respectively. Conclusions Treatment with trofinetide for ≤40 weeks continued to improve symptoms of Rett syndrome. Trofinetide had a similar safety profile in LILAC as in LAVENDER. Funding The study was supported by Acadia Pharmaceuticals Inc. (San Diego, CA, USA). This trial was registered at ClinicalTrials.gov (NCT04279314). • LAVENDER participants were treated with open-label trofinetide for 40 weeks in LILAC • Treatment with trofinetide in LILAC continued to improve the symptoms of Rett syndrome • The safety profile of trofinetide in LILAC was similar to that in LAVENDER Rett syndrome is a rare neurodevelopmental disorder caused by mutations in the MECP2 gene, which results in loss of verbal communication with limited nonverbal skills, loss of fine and gross motor function, behavioral issues, seizures, hand stereotypies, and gastrointestinal problems. Trofinetide is approved for the treatment of Rett syndrome in patients aged ≥2 years based on the results of the 12-week, placebo-controlled, phase 3 LAVENDER study. The authors report on the safety and efficacy of long-term trofinetide treatment from the 40-week, open-label LILAC study. With longer treatment, trofinetide continued to improve the symptoms of Rett syndrome without new safety signals. The findings support the use of trofinetide in individuals with Rett syndrome, a chronic disorder that requires long-term treatment. Trofinetide treatment of individuals with Rett syndrome for up to 40 weeks in LILAC, an open-label extension study of the 12-week, placebo-controlled LAVENDER study, continued to improve the symptoms of the syndrome. There were no new safety signals with longer treatment.

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