Trofinetide as an Option for Rett Syndrome Treatment


Study investigator Jeffrey L. Neul, MD, PhD, offered his perspective on the current understanding of trofinetide (Acadia Pharmaceuticals) and its potential in Rett syndrome if approved by the FDA in the coming months.

Jeffrey L. Neul, MD, PhD, Annette Schaffer Eskind Chair, and director, Vanderbilt Kennedy Center; professor of pediatrics, Division of Neurology, Pharmacology, and Special Education, Vanderbilt University Medical Center

Jeffrey L. Neul, MD, PhD

Last week, the FDA approved a new drug application (NDA) for trofinetide, an investigational treatment for Rett syndrome developed by Acadia Pharmaceuticals. The treatment, formerly known as NNZ-2566, was granted fast track status, as well as orphan drug designation, in 2015 for treatment of Rett syndrome, and in 2020, a rare pediatric disease designation.1

The agency is set to review the NDA by March 12, 2023. Acadia noted that the agency did not request an advisory committee meeting for the therapy. Trofinetide’s NDA is supported by data from the phase 3 LAVENDER study (NCT04181723), which assessed the synthetic analog of the amino‐terminal tripeptide of IGF-1 in 187 girls and women with Rett syndrome. The findings, announced in December 2021, showed that trofinetide met its coprimary efficacy end points in demonstrating statistically significant improvement in the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression of Improvement (CGI-I), when compared with placebo.2

To find out more about the potential impact of this therapy for Rett syndrome, NeurologyLive® briefly inquired with study investigator Jeffrey L. Neul, MD, PhD, Annette Schaffer Eskind Chair, and director, Vanderbilt Kennedy Center; professor of pediatrics, Division of Neurology, Pharmacology, and Special Education, Vanderbilt University Medical Center. He shared his insight into what is currently know about trofinetide and how it may affect care.

NeurologyLive®: If approved, what immediate impact might trofinetide have on the treatment paradigm in Rett?

Jeffrey L. Neul, MD, PhD: There are currently no FDA approved treatments for Rett syndrome, so this will provide an approved treatment that clinicians can readily incorporate into their treatment paradigm.

In that same vein, are there any challenges in care the possible approval of this agent may aid?

The results from the Lavender trial indicated that trofinetide had impact across a variety of areas of clinical concern, suggesting that approval and utilization might address a number of challenges people with Rett syndrome face.

Are there any particular findings from LAVENDER that you feel are important to point out?

Importantly, not only is the first phase 3 study that has meet primary endpoints in Rett syndrome, but it is also one of the first times a successful phase 3 trial has been completed in any neurodevelopmental disorder. There has been significant concern about the potential to develop therapies in these disorders because of many previous failed phase 2 trials, and this demonstrates that successful phase 3 trials are possible in neurodevelopmental disorders and provides hope that future successful phase 3 trials can be completed in these challenging disorders.

What has trofinetide’s safety profile revealed? Is there anything of which physicians should be aware?

Broadly, trofinetide was safe. Physicians should be aware of the increased frequency of diarrhea in people on trofinetide compared with placebo, which is unusual as people with Rett syndrome typically have severe constipation and are on medical treatments such as laxatives to address this problem. If trofinetide is approved by the FDA for use in Rett syndrome, adjustments to ongoing constipation treatments and monitoring for clinical issues related to diarrhea will need to be considered by physicians who prescribe this drug to people with Rett syndrome.

Transcript edited for clarity.

1. Acadia Pharmaceuticals Announces Trofinetide New Drug Application for the Treatment of Rett Syndrome has been Accepted for Filing and Review by U.S. FDA. News release. Acadia Pharmaceuticals. September 12, 2022. Accessed September 16, 2022.
2. Acadia Pharmaceuticals announces positive topline results from the pivotal phase 3 Lavender trial of trofinetide in Rett syndrome. News release. Acadia Pharmaceuticals. December 6, 2021. Accessed September 12, 2021.
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