Sunday, April 30, 2023

Trofinetide for Rett syndrome

This spring, Acadia Pharmaceuticals Inc. announced that FDA approved DAYBUE (trofinetide) for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. DAYBUE is the first and only drug approved for the treatment of Rett syndrome.

The UNC School of Medicine was part of this multi-site clinical trial, led by Yael Shiloh-Malawsky, MD, associate professor of neurology. Co-investigators were Diana Cejas, MD, MPH, and Jane Fan, MD, professor of neurology. The lead study coordinator was Yulissa Gonzalez.

Rett syndrome is a complex, rare, neurodevelopmental disorder typically caused by a genetic mutation on the MECP2 gene. It is characterized by a period of normal development until six to 18 months of age, followed by significant developmental regression with loss of acquired communication skills and purposeful hand use. Symptoms can also include hand wringing and clapping and gait abnormalities. Rett syndrome is believed to affect 6,000 to 9,000 patients in the U.S., with a diagnosed population of approximately 4,500 U.S. patients.

The FDA approval of DAYBUE was supported by results from the pivotal Phase 3 LAVENDER study evaluating the efficacy and safety of trofinetide versus placebo in 187 female patients with Rett syndrome five to 20 years of age. In the study, treatment with DAYBUE demonstrated statistically significant improvement compared to placebo on both co-primary efficacy endpoints, as measured by the change from baseline in Rett Syndrome Behavioor Questionnaire and the Clinical Global Impression-Improvement scale score.

“This is a historic day for the Rett syndrome community and a meaningful moment for the patients and caregivers who have eagerly awaited the arrival of an approved treatment for this condition,” said Melissa Kennedy, Chief Executive Officer of the International Rett Syndrome Foundation. “Rett syndrome is a complicated, devastating disease that affects not only the individual patient, but whole families. With the FDA decision, those impacted by Rett have a promising new treatment option that has demonstrated benefit across a variety of Rett symptoms, including those that impact the daily lives of those living with Rett and their loved ones.”

Neul JL, Percy AK, Benke TA, Berry-Kravis EM, Glaze DG, Peters SU, Jones NE, Youakim JM. Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome. Contemp Clin Trials. 2022 Mar;114:106704. doi: 10.1016/j.cct.2022.106704. Epub 2022 Feb 8. PMID: 35149233.


Introduction: Rett syndrome (RTT) is a debilitating neurodevelopmental disorder with no approved treatments. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor 1. In a phase 2, placebo-controlled trial in 82 females with RTT aged 5-15 years, a significant (p ≤ 0.042) improvement over placebo was observed with the highest trofinetide dose (200 mg/kg twice daily [BID]) on three measures: Rett Syndrome Behaviour Questionnaire (RSBQ), Clinical Global Impression-Improvement (CGI-I), and RTT-Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC-VAS). Trofinetide was well tolerated at all doses (50, 100, and 200 mg/kg BID). A phase 3 trial utilizing disease-specific and novel scales was designed to investigate the efficacy and safety of trofinetide in girls and women with RTT.

Methods: This 12-week, double-blind, randomized, placebo-controlled study (LAVENDER; NCT04181723) will evaluate trofinetide in 187 females, aged 5-20 years, with RTT. Co-primary endpoints are the RSBQ and CGI-I scales. Clinical domains of the CGI-I include communication, ambulation, hand use, seizures, attentiveness, and social (eye contact) and autonomic (breathing) aspects. Secondary endpoints will leverage four novel RTT-specific clinician ratings (derived from the RTT-DSC-VAS) of hand function, ambulation, ability to communicate, and verbal communication, and existing scales, to evaluate other core symptoms of RTT, quality of life and caregiver burden. A 40-week, open-label extension study will follow.

Discussion: This study was designed using disease-specific scales optimized to demonstrate changes in core symptoms of RTT and may provide the first phase 3 data demonstrating drug efficacy in individuals with RTT.


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