Is trofinetide a future treatment for Rett syndrome? A comprehensive systematic review and meta-analysis of randomized controlled trials

Background Rett syndrome (RTT) is a rare, life-threatening, genetic neurodevelopmental disorder. Treatment in RTT encounters many challenges. Trofinetide, a modified amino-terminal tripeptide of insulin-like growth factor 1, has demonstrated clinically promising results in RTT. In this study, trofinetide efficacy and safety in RTT are systematically reviewed and meta-analyzed. Methods A systematic search of five electronic databases was conducted until January 2024. Review Manager 5.4 software was used for the analysis. The analysis was based on a weighted mean difference and standard error with a confidence interval (CI) of 95%, and a statistically significant P-value was considered if it was < 0.05. The study was registered on PROSPERO with registration number CRD42024499849. Quality of evidence was assessed using GRADE. Results Three randomized controlled trials (RCTs) with 276 patients were included in the analysis. Trofinetide improved both caregiver outcomes and clinical scales by improving the Rett Syndrome Behavior Questionnaire (RSBQ) (mean difference (MD): - 3.46 points, 95% CI: - 5.63 to - 1.27, P = 0.0002) and Clinical Global Impression Scale-Improvement (CGI-I) (MD: - 0.35, 95% CI: - 0.51 to - 0.18, P < 0.0001), respectively. However, trofinetide neither improved the Caregiver Top 3 Concerns Visual Analog Scale nor the Rett Motor Behavioral Assessment. Regarding safety, trofinetide was significantly associated with vomiting compared to placebo (odds ratio (OR): 3.17, 95% CI: 1.57 to 6.43, P = 0.001). After solving heterogeneity, results showed a statistically significant incidence of diarrhea in the trofinetide (200 mg) group compared to placebo (OR: 18.51, 95% CI: 9.30 to 36.84, P <= 0.00001). Conclusions Trofinetide demonstrated statistically significant improvements in CGI-I and RSBQ in pediatrics and adult patients with Rett. Side effects are limited to vomiting and diarrhea. Although diarrhea yielded an insignificant result in our analysis, it emerged as a cause for treatment discontinuation in the participating trials, and a statistically significant risk for diarrhea emerged when excluding the study using a lower dose of the drug, hence causing heterogeneity, in the meta-analysis. Given the diverse genetic landscape of RTT, future RCTs investigating correlations between RTT genotype and phenotypic improvements by trofinetide will be beneficial. RCTs encompassing male patients with larger and longer cohorts are recommended.