Elizabeth Berry-Kravis1, Joseph P Horrigan2, Nicole Tartaglia3, Randi Hagerman4, Alexander Kolevzon5, Craig A Erickson6, Shivkumar Hatti7, Mike Snape8, Alex Yaroshinsky9, George Stoms9, Larry Glass10, Nancy E Jones10. 1. Department of Pediatrics, Rush University Medical Center, Chicago, Illinois; Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois; Department of Biochemistry, Rush University Medical Center, Chicago, Illinois. Electronic address: Elizabeth_Berry-Kravis@rush.edu. 2. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina. 3. Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado. 4. Department of Pediatrics, University of California Davis MIND Institute, Sacramento, California. 5. Division of Child and Adolescent Psychiatry, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Child and Adolescent Psychiatry, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York. 6. Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. 7. Suburban Research Associates, Media, Pennsylvania. 8. AMO Pharma Ltd., London, UK. 9. Vital Systems, Inc., Rolling Meadows, Illinois. 10. Neuren Pharmaceuticals, Ltd., Melbourne, Victoria, Australia.
Abstract
BACKGROUND: We analyze the safety and tolerability of trofinetide and provide a preliminary evaluation of its efficacy in adolescent and adult males with fragile X syndrome. METHODS: This study was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, parallel group study of the safety and tolerability of orally administered trofinetide in 72 adolescent and adult males with fragile X syndrome. Subjects were randomly assigned in a 1:1:1 ratio to 35 or 70 mg/kg twice daily trofinetide or placebo for 28 days. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and concomitant medications. Efficacy measurements were categorized into four efficacy domains, which related to clinically relevant phenotypic dimensions of impairment associated with fragile X syndrome. RESULTS: Both 35 and 70 mg/kg dose levels of trofinetide were well tolerated and appeared to be generally safe. Trofinetide at the 70 mg/kg dose level demonstrated efficacy compared with placebo based on prespecified criteria. On the basis of a permutation test, the probability of a false-positive outcome for the achieved prespecified success was 0.045. In the group analysis, improvement from treatment baseline was demonstrated on three fragile X syndrome-specific outcome measures. CONCLUSIONS:Trofinetide was well tolerated in adolescent and adult males with fragile X syndrome. Despite the relatively short duration of the study, a consistent signal of efficacy at the higher dose was observed in both caregiver and clinician assessments, based on a novel analytical model incorporating evaluation of multiple key symptom areas of fragile X syndrome. This finding suggests a potential for trofinetide treatment to provide clinically meaningful improvement in core fragile X syndrome symptoms.
RCT Entities:
BACKGROUND: We analyze the safety and tolerability of trofinetide and provide a preliminary evaluation of its efficacy in adolescent and adult males with fragile X syndrome. METHODS: This study was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, parallel group study of the safety and tolerability of orally administered trofinetide in 72 adolescent and adult males with fragile X syndrome. Subjects were randomly assigned in a 1:1:1 ratio to 35 or 70 mg/kg twice daily trofinetide or placebo for 28 days. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and concomitant medications. Efficacy measurements were categorized into four efficacy domains, which related to clinically relevant phenotypic dimensions of impairment associated with fragile X syndrome. RESULTS: Both 35 and 70 mg/kg dose levels of trofinetide were well tolerated and appeared to be generally safe. Trofinetide at the 70 mg/kg dose level demonstrated efficacy compared with placebo based on prespecified criteria. On the basis of a permutation test, the probability of a false-positive outcome for the achieved prespecified success was 0.045. In the group analysis, improvement from treatment baseline was demonstrated on three fragile X syndrome-specific outcome measures. CONCLUSIONS: Trofinetide was well tolerated in adolescent and adult males with fragile X syndrome. Despite the relatively short duration of the study, a consistent signal of efficacy at the higher dose was observed in both caregiver and clinician assessments, based on a novel analytical model incorporating evaluation of multiple key symptom areas of fragile X syndrome. This finding suggests a potential for trofinetide treatment to provide clinically meaningful improvement in core fragile X syndrome symptoms.
Authors: Jack F V Hunt; Meng Li; Ryan Risgaard; Gene E Ananiev; Scott Wildman; Fan Zhang; Tim S Bugni; Xinyu Zhao; Anita Bhattacharyya Journal: Cells Date: 2021-12-27 Impact factor: 7.666
Authors: A Kolevzon; M S Breen; P M Siper; D Halpern; Y Frank; H Rieger; J Weismann; M P Trelles; B Lerman; R Rapaport; J D Buxbaum Journal: Mol Autism Date: 2022-04-08 Impact factor: 7.509