‘Encouraging’ Results Seen in Patients in LAVENDER Phase 3 Trial

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by Marta Figueiredo, PhD |

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Trofinetide, Acadia Pharmaceuticals’ experimental therapy, significantly reduced neurobehavioral symptoms and improved communication in girls and young women with Rett syndrome, according to top-line data from the Phase 3 LAVENDER clinical trial.

These results — meeting the trial’s main and key secondary goals — were consistent across age ranges and disease severity, according to a webcast presented by Acadia. Full data are expected to be presented at an upcoming medical meeting.

“These are encouraging results for patients and families affected by Rett syndrome,” Jeffrey L. Neul, MD, PhD, a trial investigator at the Vanderbilt University Medical Center, where he is a professor of pediatrics, said in a press release.

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“Patients reported improvements in core symptoms, like being able to respond to a choice when asked by their parents, or experiencing more freedom from the repetitive hand movements that create obstacles in other areas of their lives,” added Neul, who is also the Annette Schaffer Eskind chair and director of the Vanderbilt Kennedy Center.

“The positive Lavender study results support a potential treatment for Rett syndrome and represent an important step forward in addressing this rare and serious neurological disease,” he said.

Acadia plans to meet with the U.S. Food and Drug Administration (FDA) in the first months of 2022 to discuss the submission of a regulatory application, anticipated by mid-2022, to request trofinetide’s approval.

The FDA has granted fast track, orphan drug, and rare pediatric disease designations to the therapy, which are meant to accelerate its clinical development and regulatory review.

Among other incentives, these designations make the upcoming regulatory application eligible for priority review, shortening the review period to six months from the standard 10 months.

“We look forward to continuing this important work and potentially delivering an FDA-approved treatment for this rare and devastating disease,” said Kathie Bishop, PhD, Acadia’s senior vice president, chief scientific officer, and head of rare disease.

Acadia holds an exclusive license from Neuren Pharmaceuticals to develop and market trofinetide in North America.

Trofinetide (formerly NNZ-2566) is a pharmacologically improved version of glypromate, a protein fragment that is thought to lessen neuroinflammation and promote the development of connections between neurons in the brain — a process that is impaired in Rett patients.

A liquid solution, the therapy is given by mouth or via a gastrostomy tube at a dose based on a patient’s weight.

The now-completed Phase 3 LAVENDER trial (NCT04181723) evaluated trofinetide’s safety and effectiveness in 187 girls and young women, ages 5–20, with Rett syndrome. Participants, recruited at clinical sites across the U.S., were randomly assigned to receive 30–60 mL of trofinetide or a placebo, twice a day for 12 weeks (about three months).

Patients’ average age was 10.9 years, with more than half (54.3%) being younger than age 11, and 20.1% being 16–20 years old.

The trial’s main goals were to assess changes in core neurobehavioral symptoms, as measured by caregivers using the Rett Syndrome Behaviour Questionnaire (RSBQ), and by clinicians via the Clinical Global Impression Scale-Improvement (CGI-I).

RSBQ comprises eight subscales: general mood, breathing problems, hand behavior, face movements, body rocking/expressionless face, night-time behaviors, fear/anxiety, and walking/standing.

Changes in communication skills, assessed with the caregiver-completed Communication and Symbolic Behavior Scales Developmental Profile Infant‑Toddler Checklist – Social Composite Score (CSBS-DP- IT–Social), was a key secondary goal.

Top-line results showed that the trial met its main goals, with trofinetide-treated patients exhibiting significant reductions in neurobehavioral symptoms relative to those given a placebo. Specifically, trofinetide was associated with a greater drop in the RSBQ score (5.1 vs. 1.7) and a lower CGI-I score (3.5 vs. 3.8) — both indicative of reduced symptoms.

The RSBQ subscales showing the greatest reductions included fear/anxiety and body rocking/expressionless face, followed by breathing problems and walking/standing.

Trofinetide was also significantly superior to placebo at improving patient’s communication skills, meeting the study’s key secondary goal.

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The therapy was generally well-tolerated, with most adverse events reported being mild to moderate in severity, and serious events occurring at a similar rate (3.2%) in the trofinetide and placebo groups.

A greater proportion of trofinetide-treated patients experienced adverse events (92.5% vs. 54.3%), as well as side effects leading to treatment discontinuation (17.2% vs. 2.1%), compared with those in the placebo group.

The most commonly reported adverse events included diarrhea (80.6% with trofinetide vs. 19.1% with placebo) and vomiting (26.9% with trofinetide vs. 9.6% with placebo), of which more than 95% in the trofinetide group were characterized as mild-to-moderate.

“The consistent efficacy across primary and key secondary endpoints [goals] in the Lavender study demonstrates the potential of trofinetide to treat Rett syndrome,” Bishop said.

“We want to thank the patients, their caregivers, study site personnel, physicians and everyone who participated in the Lavender study for their contribution to making this milestone a reality,” she added.

More than 95% of patients who completed LAVENDER chose to enroll in the open-label LILAC extension study (NCT04279314), in which they will receive the experimental therapy for nine months.

After completing LILAC, eligible patients may continue treatment for more than 2.5 years in a second extension trial, called LILAC-2 (NCT04776746).

Acadia has launched a Phase 2/3 trial, called DAFFODIL (NCT04988867), to assess the therapy’s safety, tolerability, and pharmacokinetics (movement into, through, and out of the body) in up to 10 toddlers and young girls, ages 2 to 5, with Rett syndrome.

The 12-week trial is currently recruiting children, weighing at least 9 kg (about 20 lbs), at its five U.S. clinical sites. All participants will be given 10–30 mL of trofinetide twice daily, and the study is expected to be completed in July 2023.