FDA Accepts NDA for Rett Syndrome Drug

If approved, trofinetide will be the first drug available for the treatment of Rett syndrome, a rare, genetic neurological disorder mostly in girls. The FDA action date is March 12, 2023.

The FDA has accepted Acadia Pharmaceuticals’ new drug application (NDA) of trofinetide to treat patients with Rett syndrome. The FDA has granted a priority review and assigned a Prescription Drug User Fee Act action date of March 12, 2023.

Rett syndrome is a neurodevelopmental disorder that affects mostly girls and is caused by mutations on the X chromosome on a gene called MECP2. Children experience normal early growth followed by slowing of development. Gradually, mental and physical symptoms appear, causing progressive loss of motor skills and the ability to communicate. The incidence in the United States is one in 10,000 girls.

“Rett is a complex disease that can present with a diverse array of symptoms. In clinical trials, trofinetide demonstrated a significant improvement in a range of Rett syndrome symptoms,” study investigator Jeffrey L. Neul, M.D., Ph.D., said in a press release. He is the Annette Schaffer Eskind chair and director, Vanderbilt Kennedy Center, professor of Pediatrics, Division of Neurology, Pharmacology, and Special Education at Vanderbilt University Medical Center.

Trofinetide is a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 that is thought to stimulate synaptic maturation. In the central nervous system, IGF-1 is produced by both of the major types of brain cells – neurons and glia. Trofinetide has been shown to inhibit the production of inflammatory cytokines, inhibit the overactivation of microglia and astrocytes, and increase the amount of available IGF-1 that can bind to IGF-1 receptors.

The NDA is supported by results from the pivotal phase 3 Lavender study evaluating the efficacy and safety of trofinetide versus placebo in 187 girls and young women aged 5 to 20 years with Rett syndrome. The study demonstrated a statistically significant improvement over placebo on the co-primary endpoints, the Rett Syndrome Behavior Questionnaire (RSBQ) total score change from baseline to 12 weeks and the Clinical Global Impression-Improvement (CGI-I) scale score. In the RSBQ, a caregiver assessment of the core symptoms of Rett syndrome, the score for trofinetide was -5.1 compared with -1.7 for placebo. In the CGI-I, a global physician assessment of worsening or improving of Rett syndrome, the score for trofinetide was 3.5 compared with 3.8 for placebo.

In addition, the study also met its key secondary endpoint, the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist–Social composite score change from baseline to week 12, a caregiver scale of the ability to communicate.

Acadia submitted an NDA in July 2022.

In 2018, Acadia entered into an exclusive license agreement with Neuren Pharmaceuticals for the development and commercialization of trofinetide for the treatment of Rett syndrome and other indications in North America.