AAN 2023: Daybue easing Rett symptoms in girls, ages 2-4, in DAFFODIL trial
Reasonable treatment safety and life quality gains also being seen
Daybue (trofinetide) is easing the neurobehavioral symptoms of Rett syndrome with acceptable safety in girls ages 2 to 4, according to early data from the open-label DAFFODIL Phase 2/3 trial.
These results were consistent with previous clinical trials in Rett patients starting at age 5 that supported U.S. approval of the therapy, developed by Acadia Pharmaceuticals. Daybue, the disease’s first treatment, was approved for Rett patients ages 2 and older.
The Phase 2/3 DAFFODIL (NCT04988867) trial opened in younger children in September 2021, and the study — whose main goals are safety and tolerability — is due to conclude in July.
Details on its interim data were presented in the poster, “Trofinetide for the treatment of Rett syndrome: an open-label study in girls 2 to 4 years of age,” at the recent American Academy of Neurology annual meeting.
Trial in young girls as Rett typically is diagnosed by age 3
Rett is a rare neurodevelopmental disorder mainly affecting females. Neurobehavioral symptoms of the disease are thought to be driven by increased inflammation and impaired function of synapses, the connections between nerve cells.
Daybue’s active ingredient is trofinetide, which is similar to glypromate, a protein fragment that naturally occurs in the brain and helps maintain and restore brain function. The therapy, a liquid solution administered by mouth or a feeding tube, is designed to mimic glypromate, with the goal of lowering inflammation and promoting synaptic health.
Data from the Phase 3 LAVENDER clinical trial (NCT04181723) supported Daybue’s approval. Enrolling 187 girls and women with Rett, ages 5 to 20, study participants were randomly assigned to twice daily Daybue or a placebo for about three months. Results showed that Daybue significantly lessened core symptoms of Rett with an acceptable safety profile.
Because Rett is typically diagnosed by age 3, the open-label (no placebo group) DAFFODIL trial was launched for girls, ages 2-4, with Rett syndrome. The ongoing study is assessing Daybue’s safety, tolerability, and pharmacokinetics (how it moves into, through, and out of the body). Evidence of efficacy is an exploratory goal.
Participants are receiving 10-30 mL of Daybue solution twice daily for 12 weeks, with doses based on body weight. Those who complete the trial’s first part may continue on the therapy for up to an additional 21 months in its extension.
At the time of the interim analysis, with data collected through mid-March 2022, 14 patients were enrolled at its U.S. sites, and 10 had completed the trial’s 12-week main phase.
Twelve patients (85.7%) reported at least one treatment-emergent adverse event, with diarrhea (64.3%) and vomiting (35.7%) being the most common side effects. One patient left the study due to treatment-related diarrhea. No serious treatment-related adverse event or deaths were reported, and lab tests and heart assessments were all within the normal range.
Preliminary evidence of efficacy was seen via better Clinical Global Impression Scale-Improvement (CGI-I) scores, a clinician’s assessment of overall health. Mean scores dropped from 3.6 at two weeks of treatment to 3.3 by week 12.
The mean score for Caregiver Global Impression–Improvement (CaGI-I), as rated by caregivers of the Rett patients, was 2.2 by week 12, corresponding to “much improved” relative to scores before treatment.
Quality of life gains also were observed in the patients, with an increase from 3.9 to 4.2 points by week 12, as assessed with the Overall Quality-of-Life Rating on the Impact of Childhood Neurologic Disability Scale (ICND-QoL).
“Consistent with data from phase 2 and 3 trials with participants [older than] 5 years, treatment with [Daybue] was well tolerated and appeared to result in improvements in [Rett]-related efficacy measures in girls aged 2–4 years,” the researchers wrote.
Better communicative abilities seen with Daybue in LAVENDER trial
Gains in communicative abilities reported in the LAVENDER study also were presented at AAN, in the poster, “Treatment with trofinetide shows benefit compared to placebo for the ability to communicate in individuals with Rett syndrome: a secondary analysis of the LAVENDER study.”
Secondary efficacy outcomes related to verbal and non-verbal communication were adapted for Rett patients or developed for this study.
Compared with patients on a placebo, Daybue-treated patients showed significantly improved communication ability, as assessed by the caregiver-rated Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist-Social (CSBS-DP-IT Social) Composite score. Here, a decrease from the study’s start of 0.1 was seen with Daybue’s use, and a decrease of 1.1 with a placebo, reflecting better scores.
Significant treatment-related improvements also were evident in participants’ practical ability to communicate nonverbally, as measured by the Rett-Clinician Rating of Ability to Communicate Choices (RTT-COMC). Scores among Daybue-group patients were lower (better) than placebo-group scores after 12 weeks of therapy.
“In the LAVENDER study, differences for trofinetide versus placebo were observed in scales measuring ability to communicate,” the researchers wrote, with benefits unaffected by differences in age, disease severity at trial start, and mutation severity.
“The communication scales used in this study may be useful in future trials for [Rett] and other neurodevelopmental disorders,” they added.