Trofinetide Glycine-proline-glutamate (GPE) analogue Treatment of Rett syndrome Treatment of fragile X syndrome

Insulin-like growth factor 1 (IGF-1) is neuroprotective and ameliorates features of neurodevelopmental disorders (NDD) in preclinical models, but potential mitogenic effects limit its therapeutic potential. Glycine-proline-glutamate (GPE) is the N-terminal tripeptide of IGF-1 that confers similar therapeutic effects but is highly unstable. Trofinetide, a methylated GPE analogue, has an improved pharmacokinetic profile and has demonstrated efficacy for individuals with genetically caused NDD, specifically Rett syndrome (RTT) and fragile X syndrome (FXS). Despite an understanding of the genetic basis and availability of disease models, there are no approved therapeutics addressing core features of either disease. Phase II trials of oral trofinetide for RTT and FXS found that the studied doses were generally safe and well tolerated and found improvement on both caregiver- and clinician-based efficacy outcome measures. A phase III trofinetide trial in children and adolescents with RTT is ongoing, which will be critical for determination of efficacy in RTT.