Glaze DG, Neul JL, Percy A, Feyma T, Beisang A, Yaroshinsky A, Stoms G, Zuchero D, Horrigan J, Glass L, Jones NE. A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome. Pediatr Neurol. 2017 Nov;76:37-46.
This study aimed to determine the safety and tolerability of trofinetide and to evaluate efficacy measures in adolescent and adult females with Rett syndrome, a serious and debilitating neurodevelopmental condition for which no therapies are available for its core features.
This was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, dose-escalation study of the safety and tolerability of trofinetide in 56 adolescent and adult females with Rett syndrome. Subjects were randomly assigned in a 2:1 ratio to 35 mg/kg twice daily of trofinetide or placebo for 14 days; 35 mg/kg twice daily or placebo for 28 days; or 70 mg/kg twice daily 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 Rett syndrome.
Both 35 mg/kg and 70 mg/kg dose levels of trofinetide were well tolerated and generally safe. Trofinetide at 70 mg/kg demonstrated efficacy compared with placebo based on prespecified criteria.
Trofinetide was well tolerated in adolescent and adult females with Rett syndrome. Although this study had a relatively short duration in a small number of subjects with an advanced stage of disease, consistent efficacy trends at the higher dose were observed in several outcome measures that assess important dimensions of Rett syndrome. These results represented clinically meaningful improvement from the perspective of the clinicians as well as the caregivers.
Melbourne, Australia, 12 November 2014: Neuren Pharmaceuticals (ASX: NEU) today announced topline results from its Phase 2 clinical trial in Rett syndrome, which successfully demonstrated clinical benefit from treatment with NNZ-2566. Neuren intends to submit applications to the US Food and Drug Administration (FDA) for both Orphan Drug and Breakthrough Therapy designation. Neuren expects to meet with the FDA in the first quarter of 2015 to discuss the trial results and the requirements for the further development of NNZ-2566 in Rett syndrome.
There are currently no approved medicines for the treatment of Rett syndrome, which is a severe
neurological disorder caused by mutations of the MECP2 gene on the X chromosome. The disorder has an onset in early childhood and is often progressive into adolescence and adulthood. Neuren’s trial was conducted at Baylor College of Medicine (Daniel Glaze MD and Jeffrey Neul MD), University of Alabama at Birmingham (Alan Percy MD) and Gillette Children’s Specialty Healthcare (Tim Feyma MD and Art Beisang MD). This was the first multi-site, sponsor-led clinical trial in Rett syndrome and was the first trial in an adolescent and adult population.
Walter Kaufmann MD, Professor of Neurology at Harvard Medical School and Director of the Rett
Syndrome Program at the Boston Children’s Hospital, who was not involved in the trial, commented:
“The outcome of this trial is very promising in terms of both safety and clinical improvement. It was a challenging study since the older age of the cohort and the short duration of the trial made it less likely to show a positive effect. It opens not only the possibility of successful treatment of adults with Rett syndrome, but also of early interventions modifying the course of the disease.”
Alan Percy MD, Professor of Pediatric Neurology at the University of Alabama was one of the trial
investigators. He commented: “The results of this trial suggest a very promising proof of concept as we continue on the pathway to develop a disease-altering treatment for girls and women with Rett
syndrome. Not only was this short-term trial managed successfully, but also the data analyses were
conducted in a very robust fashion.”
The trial was supported by the International Rett Syndrome Foundation (IRSF). Steven Kaminsky PhD, IRSF Chief Science Officer, commented: “These are exciting times for Rett syndrome and this trial firmly sets our rudder in the water for the near future. The results will enable engagement with the FDA on the further development of NNZ-2566. This is what we, as the Rett community, have been hoping for.”