Development issue analogue reveals promise for Rett syndrome in late-stage trial | Spectrum
New drug use: Trofinetide appears to ameliorate the features of Rett syndrome, but more data are needed.
Investigational drug trofinetide, an insulin-like growth factor 1 (IGF-1) analogue, helps relieve problems like anxiety and breathing problems in girls and young women with Rett syndrome, according to unpublished results from a placebo-controlled study.
Rett syndrome is caused by mutations in MECP2, a gene on the X chromosome. The condition affects mostly girls and is characterized by motor problems, breathing and eating problems, anxiety and autism. There are no drugs approved for treatment.
Injections of IGF-1, a protein produced in the liver, repair faulty synapses in mice lacking MECP2, according to previous studies. These mice showed improved breathing and heart function, but no motor skills or coordination. Trofinetide mimics only part of IGF-1 and has been modified to stay in the body longer and be administered orally.
In the new study, 187 girls and young women with Rett syndrome, aged 5 to 20 years, took a dose of a liquid containing trofinetide or a placebo twice a day for 12 weeks. The 91 participants who took trofinetide had significantly more improvements in Rett syndrome characteristics than those on placebo, according to nurse and doctor assessments.
Acadia Pharmaceuticals, the company that sponsored the study, announced the results in a press release in December. Based on the study results, Acadia plans to submit a new drug application for trofinetide to the U.S. Food and Drug Administration by mid-2022, said Deb Kazenelson Deane, Acadia’s senior director of product communications.
The magnitude of the improvement was small, raising the question of whether the drug’s effect is clinically meaningful. But given the lack of treatments for Rett syndrome, any improvement is important, says Sébastien Jacquemont, associate professor of pediatrics at the University of Montreal in Canada, who was not involved with the study.
“There have been so few studies that have shown a clear, significant effect that at this point, as a researcher and clinician, I don’t care if it’s clinically significant,” says Jacquemont. The statistically significant results suggest the researchers have identified a valid treatment target, he says.
TStudy participants were randomly assigned to treatment and placebo groups, and the study was double-blind, so neither the families nor the researchers knew which group a participant belonged to. Parents or caregivers reported on their child’s progress over the course of the study using the Rett Syndrome Behavior Questionnaire (RSBQ), which asks about common Rett traits. Clinicians rated the severity of participants’ characteristics on the Clinical Global Impressions Scale.
On both measures, participants taking trofinetide showed greater improvement than the placebo group, according to a presentation by Acadia to an investor webcast in December. The RSBQ may not be a reliable outcome measure for clinical trials, according to a 2020 analysis, but the addition of a physician-reported scale supports the validity of the RSBQ results, Deane says.
Exactly how these improvements are clinically meaningful remains to be seen, says co-investigator Elizabeth Berry-Kravis, professor of pediatrics and neurological sciences at Rush University Medical Center in Chicago, Illinois.
“There are people in the rare disease community and many families who would tell you that anything that represents an improvement is a clinically meaningful improvement because we don’t have anything that specifically targets our disease,” she says.
As the Food and Drug Administration becomes more stringent about ensuring that clinical trials produce results that are not only statistically significant but also clinically meaningful, it’s possible that Acadia’s discussions with the regulator will result in requirements to that effect, says Berry- kravis
But future Rett therapies will likely involve a combination of drugs or other therapies, Jacquemont says. “I don’t think one treatment alone would have an effect of clinical importance.”
Cite this article: https://doi.org/10.53053/BMOS2862
