In a landmark development for patients with Rett syndrome, the U.S. Food and Drug Administration (FDA) has approved trofinetide as the first-ever treatment for this rare genetic disorder. The approval, which came in March 2023, marks a significant milestone for the Rett syndrome community, which until now has had no FDA-approved therapeutic options.
Rett syndrome is a rare neurodevelopmental disorder characterized by severe developmental delays, intellectual disability, problems with movement and communication, irregular heartbeat, and seizures. The condition, which primarily affects females, is caused by mutations in the MECP2 gene on the X-chromosome.
Breakthrough Treatment After Successful Clinical Trials
ACADIA Pharmaceuticals, the developer of trofinetide, achieved positive results in their pivotal Phase III trial, which evaluated the drug in 187 girls and young women aged 5-20 years with Rett syndrome. The study met both co-primary endpoints as well as a key secondary endpoint.
The co-primary endpoints included the Rett Syndrome Behaviour Questionnaire (RSBQ) total score change from baseline to 12 weeks and the Clinical Global Impression-Improvement (CGI-I) scale score. The RSBQ is a caregiver assessment of core Rett syndrome symptoms, while the CGI-I represents a global physician assessment of improvement or worsening of the condition.
Additionally, the trial met its key secondary endpoint: the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist-Social Composite Score (CSBS-DP-IT-Social) change from baseline to week 12, which measures a patient's ability to communicate.
Dr. Payal Gu, who leads the Rett Syndrome Clinic at Children's Hospital Los Angeles, described the approval as "extremely exciting," noting that "there are quite a few potential therapies being developed for Rett syndrome."
Establishing Biomarkers for Future Research
With trofinetide now approved and additional therapies in development, researchers are focusing on establishing reliable biomarkers to measure treatment efficacy. A multicenter study funded by the National Institutes of Health is currently underway at six centers across the United States, including Children's Hospital Los Angeles—the only participating center on the West Coast.
The study uses electroencephalography (EEG) to identify and validate key biomarkers in Rett syndrome that could be used in future clinical trials to evaluate new treatments, including potential gene therapies.
"We need to find reliable, objective measures of a child's response to a treatment, not only for Rett but for other neurodevelopmental disorders, too," explained Dr. Shafali Spurling Jeste, Chief of Neurology and Las Madrinas Chair at CHLA and principal investigator on the study. "Without that level of precision, we could end up missing out on effective therapies."
Study Design and Patient Recruitment
The biomarker study aims to enroll 132 girls with Rett syndrome across all centers. Eligible participants include girls 18 and under with a known or likely pathogenic variant in the MECP2 gene who are either mid- or post-regression with symptoms consistent with Rett syndrome. Children with a pathogenic mutation who have not yet experienced regression are also eligible.
Participants undergo EEG testing at their first visit, again six months later, and then annually for five years. Younger participants who are pre- or mid-regression are monitored more frequently.
"Measuring these biomarkers in younger children is particularly important because we want to see how electrophysiological patterns and responses change during this early regression period," said Dr. Gu.
ACADIA's Commercial Position
For ACADIA Pharmaceuticals, the approval of trofinetide adds to their commercial portfolio, which is currently led by Nuplazid (pimavanserin). Nuplazid was approved in 2016 for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis and has shown steady sales growth, reaching $484.1 million in 2021 and projected sales of $510-520 million for 2022.
The company reported a strong financial position with $436.6 million in cash, cash equivalents, and investment securities as of September 30, 2022.
Looking Toward a New Treatment Landscape
The approval of trofinetide represents just the beginning of what experts hope will be a transformative period for Rett syndrome treatment. With additional therapies in development and ongoing research to establish reliable biomarkers, the clinical landscape for this rare genetic disorder is evolving rapidly.
The multicenter biomarker study is part of a larger field-wide focus on precision health, which aims to develop more targeted and effective treatments for neurodevelopmental disorders.
As one of the top-recruiting sites for the study, Children's Hospital Los Angeles continues to play a crucial role in advancing Rett syndrome research. The hospital's multidisciplinary Rett Syndrome Clinic, designated as an International Rett Syndrome Foundation Center of Excellence, provides comprehensive care through a team that includes a child neurologist, nurse manager, physical, occupational, and speech therapists, and a registered dietitian.
For families affected by Rett syndrome, these developments offer new hope for improved treatments and quality of life for patients with this challenging condition.
