Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need

Abstract

Rett syndrome (RTT) is a rare disability causing female-oriented pediatric neurodevelopmental unmet medical need. RTT was recognized in 1966. However, over the past 56 years, the United States Food and Drug Administration (USFDA) has authorized no effective treatment for RTT. Recently, Trofinetide was approved by the USFDA on 10 March 2023 as the first RTT treatment. This article underlines the pharmaceutical advancement, patent literature, and prospects of Trofinetide. The data for this study were gathered from the PubMed database, authentic websites (Acadia Pharmaceuticals, Neuren Pharmaceuticals, and USFDA), and free patent databases. Trofinetide was first disclosed by Neuren Pharmaceuticals in 2000 as a methyl group containing analog of the naturally occurring neuroprotective tripeptide called glycine-proline-glutamate (GPE). The joint efforts of Acadia Pharmaceuticals and Neuren Pharmaceuticals have developed Trofinetide. The mechanism of action of Trofinetide is not yet well established. However, it is supposed to improve neuronal morphology and synaptic functioning. The patent literature revealed a handful of inventions related to Trofinetide, providing excellent and unexplored broad research possibilities with Trofinetide. The development of innovative Trofinetide-based molecules, combinations of Trofinetide, patient-compliant drug formulations, and precise MECP2-mutation-related personalized medicines are foreseeable. Trofinetide is in clinical trials for some neurodevelopmental disorders (NDDs), including treating Fragile X syndrome (FXS). It is expected that Trofinetide may be approved for treating FXS in the future. The USFDA-approval of Trofinetide is one of the important milestones for RTT therapy and is the beginning of a new era for the therapy of RTT, FXS, autism spectrum disorder (ASD), brain injury, stroke, and other NDDs.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2023

“…Rett syndrome is a rare genetic neurodevelopmental disorder that is characterized by X-linked methyl-CpG-binding protein 2 (MECP2) mutation that can lead to permanent neurological damage or death in children (Hudu et al 2023;Parent et al 2023). Trofinetide is the first treatment approved for Rett syndrome in adults and pediatric patients (≥ 2 years) (Keam 2023e).…”

“…Trofinetide was granted priority review, orphan, and fast track drug designations. Trofinetide is a synthetic peptidase-resistant analogue of the neuroprotective tripeptide glycine-proline-glutamate, a product of the cleavage of insulin-like growth factor 1 in the brain (Hudu et al 2023). The exact mechanism of action of trofinetide is not fully understood.…”

“…The exact mechanism of action of trofinetide is not fully understood. However, there is evidence that it modulates the insulin-like growth factor 1 pathway, improves synaptic function, and reduces levels of inflammatory mediators, apoptosis, and oxidation (Hudu et al 2023;Parent et al 2023). The most frequent AE are diarrhea and vomiting (Keam 2023e).…”

Trofinetide—a new chapter in rett syndrome’s treatment

“…Trofinetide is a water-soluble analogue of glycine-proline-glutamate (GPE). GPE is an N-terminal tripeptide product of the cleavage of insulin-like growth factor 1 (IGF-1) found in the brain ( Hudu et al, 2023 ) and is neuroprotective at minimal doses. The mechanism of action of Trofinetide for treating Rett syndrome is not entirely understood, but it is thought to work on the same principle as GPE but with a longer half-life ( Bickerdike et al, 2009 ).…”

“…The mechanism of action of Trofinetide for treating Rett syndrome is not entirely understood, but it is thought to work on the same principle as GPE but with a longer half-life (Bickerdike et al, 2009). Many studies have indicated that Trofinetide exerts its effect by enhancing synaptic activities, restoring synaptic structure, suppressing the effects of inflammatory compounds in the brain, increasing antioxidative reactions, decreasing injury-triggered cell death, and Frontiers in Pharmacology frontiersin.org 01 increasing the presence of IGF-1 in the central nervous system (Hudu et al, 2023). According to the results of the LAVENDER trial, this drug has demonstrated a promising improvement in the Rett syndrome behavioral questionnaire (RSBQ) total score compared to the placebo.…”