Real-World Treatment Landscape of Individuals with Rett Syndrome Treated and Untreated with Trofinetide in the United States

Background Trofinetide (TROF) became the first approved pharmacologic treatment for Rett syndrome (RTT) in the United States in March 2023; however, real-world evidence comparing TROF-treated and untreated individuals is limited. Objective This study aimed to compare the baseline demographic and clinical profiles of those treated with TROF vs untreated in routine clinical practice. Methods This retrospective cohort study used linked IQVIA Anonymized Patient Level Database medical claims and a specialty pharmacy database. Individuals with ≥1 medical claim for RTT between 01/01/2021 and 09/30/2024 (study period) were identified. Treated individuals had ≥1 TROF prescription during 04/01/2023 to 09/30/2023 (identification period), with first prescription set as index; untreated individuals had no TROF prescription. A risk-set sampling approach was used to assign proxy index dates to untreated individuals to improve comparability and reduce immortal time bias. Individuals with cerebrovascular disease or brain trauma before RTT diagnosis and those without 12 months pre-and post-index enrollment were excluded. Baseline characteristics were assessed during the 12 months pre-index. Results Of 8047 individuals with RTT identified, 2950 met eligibility criteria; 766 (26.0%) were treated with TROF and 2184 (74.0%) remained untreated. Treated individuals were younger at index (15.4 vs 23.5 years), and a greater proportion were pediatric (≤17 years; 66.6% vs 38.3%). Females predominated in both groups, while males represented a smaller proportion of the treated (4.6% vs 10.8%). Treated individuals more frequently had documented nonspecific developmental delay (31.3% vs 21.6%), autism spectrum disorder (19.1% vs 15.7%), and core RTT-related neurodevelopmental features such as loss of acquired communication skills (23.8% vs 12.9%) and loss of acquired motor skills (11.1% vs 4.9%). Child neurology was the most common prescriber specialty in both groups and was more frequent among treated individuals (50.3% vs 26.8%). Overall comorbidity burden was broadly similar between groups. Conclusion In this real-world analysis, only one-quarter of eligible individuals with RTT initiated TROF during the early post-approval period. TROF uptake appeared concentrated in younger, specialist-managed individuals with more clearly documented RTT-related features, while three-quarters remained untreated. These findings highlight the need to better understand treatment pathways and barriers to initiation in males and adults in routine RTT care.