The FDA has previously granted the Acadia Pharmaceuticals treatment fast track status and orphan drug designation for Rett syndrome.
Positive topline results from the phase 3 LAVENDER study (NCT04181723) of the investigational drug trofinetide (formerly NNZ-2566; Acadia) in Rett syndrome were announced by Acadia Pharmaceuticals. The treatment met its coprimary efficacy end points in demonstrating statistically significant improvement in the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression of Improvement (CGI-I), when compared with placebo.
The phase 3 study included a total of 187 girls and adolescent women with Rett syndrome between the ages of 5 and 20 years, evaluated over a 12-week period. On the RSBQ caregiver assessment, participants treated with trofinetide had a score change from baseline to week 12 of –5.1, compared with –1.7 for those given placebo (P = .0175; effect size = 0.37). Looking at the CGI-I, those treated with trofinetide had a mean score of 3.5 at week 12, compared with those receiving placebo, who had a mean score of 3.8 (P = .0030; effect size = 0.47).
The trial also met its key secondary end point by demonstrating statistically significant improvement in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist–Social composite score over placebo from baseline to week 12. Those receiving trofinetide had a mean. change of –0.1, compared those receiving placebo, who had a mean change of –1.1 (P = .0064; effect size = 0.43).
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A meeting with the FDA to discuss a new drug application (NDA) for the treatment is planned for the first quarter of 2022, with Acadia planning to submit the NDA in mid-2022. Trofinetide was granted fast track status, as well as orphan drug designation, in 2015 for treatment of Rett syndrome. In 2020, the treatment was granted rare pediatric disease designation.
“These are encouraging results for patients and families affected by Rett syndrome. 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,” LAVENDER study investigator 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, said in statement. “The positive LAVENDER study results support a potential treatment for Rett syndrome and represent an important step forward in addressing this rare and serious neurological disease.”
Participants discontinued treatment for a variety of treatment emergent adverse events, with 17.2% discontinuing in the trofinetide group versus 2.1% in the placebo group. Diarrhea was among the most common adverse events, reported by 80.6% of patients in the treatment group versus 19.1% in the placebo group. Vomiting was also reported, affecting 26.9% of patients in the treatment group versus 9.6% in the placebo group. Serious adverse events were reported in a combined 3.2% of patients in both groups. Those who participated in the study also had the option to receive trofinetide in planned extension studies, with 95% of participants electing to continue in the LILAC open-label extension study.
“The consistent efficacy across primary and key secondary endpoints in the LAVENDER study demonstrates the potential of trofinetide to treat Rett syndrome,” Kathie Bishop, PhD, senior vice president, chief scientific officer, and head of rare disease, Acadia Pharmaceuticals, said in a statement. “We want to thank the patients, their caregivers, study site personnel, physicians and everyone who participated in the LAVENDER study for their contribution to making this milestone a reality. We look forward to continuing this important work and potentially delivering an FDA-approved treatment for this rare and devastating disease.”