Daniel G. Glaze, Jeffrey L. Neul, Walter E. Kaufmann, Elizabeth Berry-Kravis, Sean Condon, George Stoms, Sean Oosterholt, Oscar Della Pasqua, Larry Glass, Nancy E. Jones, Alan K. Percy, Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology. In press.
Objective To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available.
Methods This was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT.
Results All dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns–Visual Analog Scale, and Clinical Global Impression Scale–Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure.
Conclusion These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials.
Classification of evidence This study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.
“Disease burden is severe for Rett patients and their families, and the impact of the disorder is life-long,” said Daniel Glaze, M.D., study author, Baylor College of Medicine, Department of Pediatrics and Neurology and Director at the Blue Bird Circle Rett Center, Texas Children’s Hospital. “The data reported in this study show that females treated with trofinetide experienced lessened neurobehavioral impairments including social communication deficits, anxiety-like behavior, and mood dysregulation. These are very promising data for the Rett community that is currently without any U.S. FDA-approved treatment option.”…
“Rett syndrome is a condition that leads to severe neurological impairments and is not only debilitating for the person with the disease, but also very hard on the families and caregivers of the children, mostly females, who are often unable to speak, walk, eat, and even breathe normally,” said Steve Kaminsky, Ph.D., Chief Science Officer of RSO. “These results are very encouraging because they provide strong evidence that trofinetide may be a potential treatment for Rett syndrome.”…
Trofinetide is a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 designed to treat the core symptoms of Rett syndrome by reducing neuroinflammation and supporting synaptic function. In the central nervous system, IGF-1 is produced by both of the major types of brain cells – neurons and glia. IGF-1 in the brain is critical for both normal development and for response to injury and disease. Trofinetide has been granted Fast Track Status and Orphan Drug Designation in the U.S. and Orphan Drug Designation in Europe for both Rett syndrome and Fragile X syndrome.
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