Trofinetide

Trofinetide, a synthetic analog of glycine-proline-glutamate (GPE), is the first food and drug administration–approved treatment for Rett syndrome. Gastrointestinal side effects (primarily diarrhea) are common, but severe immune-mediated reactions have not been described. We report a case of a young girl with genetically confirmed Rett syndrome who developed emesis, pallor, and lethargy after 2 months of treatment with trofinetide. An attempt was made to restart the medication after being held for a week, but the patient again experienced adverse symptoms and the drug was held. After 3 months without the medication, she experienced recurrence of initial symptoms within hours of rechallenge, consistent with food protein–induced enterocolitis syndrome (FPIES). The medication was not continued after the re-challenge. The concept of drug-induced enterocolitis syndrome (DIES) has been reported with other agents; however, to our knowledge, this represents the first reported case of FPIES/DIES triggered by trofinetide. This case expands the spectrum of trofinetide-related adverse reactions and emphasizes the need to distinguish immune-mediated enterocolitis from dose-dependent osmotic diarrhea and highlights the importance of clinician vigilance when initiating similar therapies in children with complex neurodevelopmental disorders.

Trofinetide is the only drug approved worldwide for the treatment of Rett syndrome, a rare pediatric disease. However, its extremely short half-life, large oral dose, high incidence of gastrointestinal adverse reactions, and consequently high treatment costs pose formidable clinical and economic challenges. To address these issues, we employed a diketopiperazine strategy to design a novel class of trofinetide prodrugs, aiming to alter the administration route and optimize its pharmacokinetic properties. Through the determination of solubility and in vitro conversion half-life, and based on the established screening criteria, TFD 10 was selected from the series of qualified compounds as a representative for pharmacokinetic evaluation. TFD 10 exhibited efficient conversion to trofinetide both in vitro and in vivo. Compared to oral administration of trofinetide, subcutaneous injection of TFD 10 markedly prolonged the half-life (6-fold) and substantially increased systemic exposure (40-fold), successfully achieving the design objectives. This study validates the feasibility of this strategy, and TFD 10, as a proof-of-concept lead compound, demonstrates significant potential for further development.