Rett syndrome, a rare X-linked dominant disorder primarily affecting females, necessitates more precise clinical endpoints to objectively confirm symptom improvement in clinical studies. The condition, caused by a mutation in the MECP2 gene, typically goes unnoticed for the first 6-18 months of life before impacting brain development, leading to severe physical and mental impairments. Experts advocate for enhanced measures to evaluate the effectiveness of new therapies.
The Need for Fit-for-Purpose Endpoints
Existing outcome measures often lack specificity in assessing gross motor, fine motor (hand function), and autonomic functions, which are core diagnostic criteria for Rett syndrome, according to Dr. Helen Leonard from The University of Western Australia. While Acadia Pharmaceuticals' Daybue (trofinetide) has shown improvements in motor function, communication, and behavior, Dr. Walter Kaufmann from Emory University School of Medicine notes that the effect size and improvements seen across the coprimary RSBQ and CGI-I endpoints, as well as the key secondary endpoint CSBS, were "rather modest."
The Rett Syndrome Behavior Questionnaire (RSBQ) is a 45-item, caregiver-focused checklist designed to delineate the behavioral phenotype and manifestations of Rett syndrome. The Clinical Global Impression-Improvement scale (CGI-I) is a seven-point scoring scale that requires a clinician to assess severity across multiple clinical manifestations.
Advancing Assessment Methods
To address these limitations, the field is considering video motor assessments such as the Rett Syndrome Hand Function Scale (RSHFS) and the Rett Syndrome Gross Motor Scale (RSGMS). These assessments, conducted in-house or at home, would allow a uniform rater to evaluate videos of patients and provide a more objective evaluation, explains Leonard. These scales have been developed by researchers at the Telethon Kids Institute at the University of Western Australia.
Integrating Biomarkers and Wearable Devices
Dr. Drew Jones, vice president of clinical development at the International Rett Syndrome Foundation (IRSF), suggests expanding evaluations beyond behavior to include biomarkers and mobility assessments. Validated wearable devices that can track improvements in movement, breathing, and sleep are also under consideration. Jana von Hehn, CSO and head of clinical development at the Rett Syndrome Research Trust (RSRT), emphasizes that questionnaires are not effective at directly and objectively measuring symptoms in Rett syndrome patients, highlighting the need for biosensors to shift the paradigm of symptom data measurement.
RSRT is currently evaluating biosensors in the VIBRANT (Validating Innovative Biosensors in Rett for AutoNomic Symptom Tracking) study (NCT06338267). This study tests devices that assess symptoms such as sleep, breathing, heart rate, movement, and oxygen saturation. The wearable FDA-cleared biosensors being evaluated include RespiraSense, Vivalink (VV330) ECG patch, and the Kids O2 pulse oximeter ring, along with the non-FDA-cleared Emerald sensor.
Challenges and Future Directions
Despite the promise of biosensor-collected biomarker data, challenges remain. Dr. Kaufmann notes the logistical complexities of processing, storing, and sharing the continuously collected data. Dr. Alan Percy, director of the Rett Syndrome Clinic at Children’s of Alabama, points out the difficulty in differentiating between stereotypies and functional motor use when using sensors. Additionally, some biomarkers lack emphasis on function and quality of life (QOL) data, which is important for characterizing treatment impact.
Looking ahead, the field must conduct more observational and non-clinical studies to validate how these biosensor or biomarker measures perform. Since biomarkers cannot capture function and QOL, incorporating a QOL measure into the clinical and sensor data points will be essential.
