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Acadia Reports Positive Top-line Results from Pivotal Phase 3 Trial of Trofinetide in Rett Syndrome

December 7, 2021

Acadia Pharmaceuticals reported positive top-line results from the pivotal phase 3 Lavender study evaluating the efficacy and safety of trofinetide in 187 girls and young women aged 5-20 years with Rett syndrome.

Rett syndrome is a rare, debilitating neurological disorder that occurs primarily in females following apparently normal development for the first six months of life and is often misdiagnosed as autism, cerebral palsy, or non-specific developmental delay. Rett syndrome is caused by mutations on the X chromosome on a gene called MECP2. There are more than 200 different mutations found on the MECP2 gene that interfere with its ability to generate a normal gene product.

Rett syndrome causes problems in brain function that are responsible for cognitive, sensory, emotional, motor, and autonomic function. Typically, with symptoms presenting between six to 18 months of age, patients experience a period of rapid decline with loss of purposeful hand use (fine motor skills), development of hand stereotypies, absent or impaired mobility (gross motor skills), loss of communication skills (including eye contact), and inability to independently conduct activities of daily living. Symptoms also include seizures, disorganized breathing patterns, an abnormal side-to-side curvature of the spine (scoliosis), and sleep disturbances. Currently, there are no FDA-approved medicines for the treatment of Rett syndrome.

Trofinetide is an experimental synthetic analog of the amino‐terminal tripeptide of IGF-1 designed to treat the core symptoms of Rett syndrome by potentially reducing neuroinflammation and supporting synaptic function. Trofinetide is thought to stimulate synaptic maturation and overcome the synaptic and neuronal immaturities that are characteristic of Rett syndrome pathophysiology. In the central nervous system, IGF-1 is produced by both major types of brain cells—neurons and glia. IGF-1 in the brain is critical for both normal development and for response to injury and disease. Trofinetide has been shown to inhibit the production of inflammatory cytokines, inhibit the overactivation of microglia and astrocytes, and increase the amount of available IGF-1 that can bind to IGF-1 receptors. Trofinetide has been granted Fast Track, Orphan Drug, and Rare Pediatric Disease designations for Rett syndrome by the U.S. Food and Drug Administration.

The Lavender study was a phase 3, 12-week, double-blind, randomized, placebo-controlled study of trofinetide in 187 girls and young women aged 5-20 years with Rett syndrome, designed to evaluate its efficacy and safety. The co-primary endpoints of Lavender included both a caregiver (Rett Syndrome Behavior Questionnaire [RSBQ]) and physician (Clinical Global Impression–Improvement [CGI-I]) assessment. The key secondary endpoint was also a caregiver assessment designed to evaluate communication skills, the Communication and Symbolic Behavior Scales Developmental Profile Infant‑Toddler Checklist – Social Composite Score (CSBS-DP- IT–Social).

The study demonstrated a statistically significant improvement over placebo for both co-primary endpoints. On the Rett Syndrome Behavior Questionnaire (RSBQ), change from baseline to week 12 was -5.1 vs. -1.7. The Clinical Global Impression–Improvement (CGI-I) score at week 12 was 3.5 vs. 3.8. The RSBQ is a caregiver assessment of the core symptoms of Rett syndrome and the CGI-I is a global physician assessment of worsening or improving of Rett syndrome.

Additionally, trofinetide demonstrated a statistically significant separation over placebo on the key secondary endpoint, the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist–Social composite score (CSBS-DP-IT–Social) change from baseline to week 12, which was -0.1 vs. -1.1.

“These are encouraging results for patients and families affected by Rett syndrome. 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,” said Jeffrey Neul, Annette Schaffer Eskind chair and director, Vanderbilt Kennedy Center; Professor of Pediatrics, Division of Neurology, Pharmacology, and Special Education, Vanderbilt University Medical Center and Lavender study investigator. “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.”

Study treatment discontinuation rates related to treatment emergent adverse events were 17.2 percent in the trofinetide group as compared to 2.1 percent in the placebo group. The most common adverse events were diarrhea (80.6 percent with trofinetide vs. 19.1 percent with placebo), of which 97.3 percent in the trofinetide arm were characterized as mild-to-moderate, and vomiting (26.9 percent with trofinetide vs. 9.6 percent with placebo), of which 96 percent in the trofinetide arm were characterized as mild-to-moderate. Serious adverse events were observed in 3.2 percent of study participants in both the trofinetide and placebo groups. Patients completing the Lavender study had the opportunity to continue to receive trofinetide in the open-label Lilac and Lilac-2 extension studies. More than 95 percent of participants who completed the Lavender study elected to roll-over to the Lilac open-label extension study. The results from this study will be submitted for presentation at upcoming medical meetings.

“The consistent efficacy across primary and key secondary endpoints in the Lavender study demonstrates the potential of trofinetide to treat Rett syndrome,” said Kathie Bishop, senior vice president, chief scientific officer, and head of Rare Disease at Acadia. “We look forward to continuing this important work and potentially delivering an FDA-approved treatment for this rare and devastating disease.”

Acadia is preparing for a pre-NDA meeting with the FDA in the first quarter of 2022 and plans to submit a New Drug Application (NDA) around mid-year 2022. Acadia obtained an exclusive license in a 2018 agreement with Australian biotech Neuren Pharmaceuticals Limited for the development and commercialization of trofinetide for Rett syndrome and other indications in North America.

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

Author: Rare Daily Staff

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