Trofinetide Mechanism of Action to Treat Rett Syndrome

Kathie Bishop, PhD, Chief Scientific Officer, Acadia Pharmaceuticals, describes the mechanism of action of trofinetide, an orphan drug in development to treat Rett syndrome, which was recently assigned a PDUFA date of March 12, 2023.

Rett syndrome is a rare progressive neurodevelopmental condition that primarily affects girls. These girls appear to have normal psychomotor development during the first 6 to 18 months of life, followed by a developmental “plateau,” and then rapid regression in language and motor skills.

As Dr. Bishop explains, trofinetide is a synthetic analog of the amino‐terminal tripeptide of IGF-1. It is designed to treat the core symptoms of Rett syndrome by potentially reducing neuroinflammation and supporting synaptic function. Trofinetide is thought to stimulate synaptic maturation and overcome the synaptic and neuronal immaturities that are characteristic of Rett syndrome pathophysiology. In the central nervous system, IGF-1 is produced by both neurons and glia, and is critical for both normal development and for response to injury and disease.

Recently, Acadia Pharmaceuticals announced that the FDA has accepted its new drug application (NDA) of trofinetide for the treatment of Rett syndrome. The FDA has granted a priority review and assigned a PDUFA date of March 12, 2023. The acceptance of the NDA is based on positive results from the Phase 3 Lavender study, which evaluated the efficacy and safety of trofinetide versus placebo in 187 girls and young women aged 5-20 years with Rett syndrome. The study demonstrated treatment with trofinetide led to a statistically significant improvement over placebo on the co-primary endpoints, the Rett Syndrome Behaviour Questionnaire (RSBQ) total score change from baseline to 12 weeks (p=0.0175) and the Clinical Global Impression-Improvement (CGI-I) scale score (p=0.0030). If the FDA approves trofinetide, it will be the first targeted therapy approved for the treatment of Rett syndrome.