Pivotal Study Evaluating Approved Rett Syndrome Therapy Published in Nature Medicine

Rare Daily Staff

Acadia Pharmaceuticals said results from the pivotal phase 3 LAVENDER trial, which provide a basis for the first FDA-approved treatment for Rett syndrome, were published in Nature Medicine.

Rett syndrome is a rare, complex, neurodevelopmental disorder that may occur over four stages and affects approximately 6,000 to 9,000 patients in the United States. A child with Rett syndrome exhibits an early period of apparently normal development until six to 18 months, when their skills seem to slow down or stagnate. This is typically followed by a duration of regression when the child loses acquired communication skills and purposeful hand use. The child may then experience a plateau period in which they show mild recovery in cognitive interests, but body movements remain severely diminished. As they age, those living with Rett may continue to experience a stage of motor deterioration which can last the rest of the patient’s life.

Rett syndrome is typically caused by a genetic mutation of the MECP2 gene. In preclinical studies, deficiency in MeCP2 function has been shown to lead to impairment in synaptic communication, and the deficits in synaptic function may be associated with Rett manifestations. Symptoms of Rett syndrome may also include development of hand stereotypies, such as hand wringing and clapping, and gait abnormalities. Most Rett patients typically live into adulthood and require round-the-clock care.

The LAVENDER trial was a 12-week randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of Daybue in patients with Rett syndrome five to 20 years of age. Daybue is a synthetic version of a naturally occurring molecule known as the tripeptide glycine-proline-glutamate. The mechanism by which Daybue exerts therapeutic effects in patients with Rett syndrome is unknown. In animal studies, Daybue has been shown to increase branching of dendrites and synaptic plasticity signals.

The study showed statistically significant differences between Daybue and placebo on efficacy endpoints relevant to Rett syndrome suggest treatment potentially capable of modifying core symptoms consistent with underlying pathophysiology of disease.

In the study, treatment with Daybue demonstrated statistically significant improvement compared to placebo on both co-primary efficacy endpoints. The mean change from baseline to week 12 in the Rett Syndrome Behavior Questionnaire (RSBQ) total score was −5.1 in the Daybue group and −1.7 in the placebo groups.

“The positive findings from this study were integral to the FDA’s approval of Daybue for Rett syndrome, ushering in the first available treatment option approved by the agency to address a multitude of challenging symptoms in those living with Rett syndrome with the potential to create significant impact for patients and their families,” said Kathie Bishop, senior vice president, chief scientific officer and head of Rare Disease at Acadia.

The LAVENDER study was a phase 3, 12-week, double-blind, randomized, placebo-controlled study of Daybue in 187 girls and young women aged 5-20 years with Rett syndrome, designed to evaluate its efficacy and safety. Patients were randomized to receive Daybue or matching placebo for 12 weeks. The co-primary endpoints of LAVENDER included both a caregiver and physician assessment.

Daybue also demonstrated statistically significant difference versus placebo on the key secondary endpoint, as measured by change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist Social Composite score.

In the study, the most common side effects in the Daybue and placebo groups were diarrhea (80.6 percent Daybue vs. 19.1 percent placebo) and vomiting (26.9 percent Daybue and 9.6 percent placebo). Of the 187 participants in the LAVENDER study, 154 elected to roll over to the open-label LILAC extension study and may be eligible to enter the follow-up LILAC-2 extension study.

Photo: Kathie Bishop, senior vice president, chief scientific officer and head of Rare Disease at Acadia.