Results from the phase 3 LAVENDER trial investigating trofinetide (Daybue; Acadia), which supported the first FDA-approved treatment for Rett syndrome, were recently published in Nature Medicine.
Recently published in Nature Medicine, results from the pivotal phase 3 LAVENDER trial (NCT04181723)showed statistically significant differences between trofinetide (Daybue; Acadia Pharmaceuticals)and placebo on efficacy endpoints in patients with Rett syndrome between the ages of 5 to 20 years. These findings suggest trofinetide has the capability to modify the core symptoms consistent with the underlying pathophysiology of the disease.1
At week 12, the data demonstrated statistically significant improvement compared with placebo on both coprimary efficacy end points, as measured by the change from baseline in Rett Syndrome Behaviour Questionnaire (RSBQ) total score (P = .018) and the Clinical Global Impression-Improvement (CGI-I) scale score (P= .003). In March 2023, these results supported the FDA approval of the treatment, a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 designed to potentially reduce neuroinflammation and support synaptic function.2
“The LAVENDER study was designed to measure the effect of trofinetide treatment on the range of behavioral, communication, and physical Rett syndrome symptoms that significantly impact the quality of life for patients and their loved ones,” lead author Jeffrey L. Neul, MD, PhD, Annette Schaffer Eskind Chair and director of the Vanderbilt Kennedy Center, as well as professor of pediatrics in the Division of Neurology, Pharmacology, and Special Education at Vanderbilt University Medical Center, said in a statement.1 “The publication of the efficacy and safety results for trofinetide reinforces the significance of this study as a critical advancement in Rett syndrome research, furthering our ability to treat this devastating disease.”
LAVENDER included a total of 187 female patients with Rett syndrome between the ages of 5 and 20 years evaluated over a 12-week period. On the RSBQ caregiver assessment, participants treated with trofinetide had a score change from baseline to week 12 of –5.1, compared with –1.7 for those given placebo (P = .0175; effect size = 0.37). Looking at the CGI-I, those treated with trofinetide had a mean score of 3.5 at week 12 compared with those receiving placebo, who had a mean score of 3.8 (P = .0030; effect size = 0.47).
The participants discontinued treatment for a variety of treatment-emergent adverse events (AEs), with 17.2% discontinuing in the trofinetide group versus 2.1% in the placebo group. Diarrhea, the most common AE, was reported by 80.6% of patients in the treatment group versus 19.1% in the placebo group. Vomiting was also reported, affecting 26.9% of patients in the treatment group versus 9.6% in the placebo group. Serious AEs were reported in 3.2% of patients in both groups.
Those who participated in the study also had the option to receive trofinetide in planned extension studies, with 95% of participants electing to continue in the LILAC open-label extension study. In September 2022, the FDA accepted the NDA for the agent and used data from phase 3 of the study.3 Previously, in 2015, trofinetide was granted fast track status, as well as orphan drug designation, for treatment of Rett syndrome.
In December 2021, Acadia Pharmaceuticals announced positive topline results from the phase 3 LAVENDER clinical trial The agent met its coprimary efficacy end points in demonstrating statistically significant improvement in the RSBQ and the CGI-I in comparison with placebo. The trial also met its key secondary end point by demonstrating statistically significant improvement in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist–Social composite score over placebo from baseline to week 12. Those receiving trofinetide had a mean change of –0.1 compared with those receiving placebo, who had a mean change of –1.1 (P = .0064; effect size = 0.43).4
In March 2019, findings from a phase 2 study showed that the 200 mg/kg dose of trofinetide displayed a clinically meaningful and statistically significant benefit for a trio of syndrome-specific efficacy measurements in pediatric patients with Rett syndrome.5 Of the 5 measurements recorded in the trial, the therapy showed a benefit on a pair of clinician assessments and a caregiver evaluation. All told, significant results were observed on the RSBQ (P = .042), the CGI-I (P = .029), and the Rett Syndrome Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC; P = .025).
Additionally, trofinetide is also being assessed in another phase 2/3 trial, DAFFODIL (NCT04988867), in 15 girls aged 2 to 5 years, with primary outcomes of safety and tolerability, as well as measures of whole blood concentration, terminal half-life, and peak drug concentration.
“We are pleased that Nature Medicine has published these important results from the pivotal LAVENDER trial,” Kathie Bishop, the senior vice president, chief scientific officer, and head of rare disease at Acadia, said in a statement.1 “The positive findings from this study were integral to the FDA’s approval of trofinetide 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.”