GRIN Therapeutics Shares Honeycomb Trial Data on Radiprodil at AES Meeting

GRIN Therapeutics, Inc., a key player in developing treatments for severe neurodevelopmental disorders, has shared additional top-line data from their Honeycomb trial. This global Phase 1b open-label trial evaluates radiprodil, a selective and potent negative allosteric modulator of the NMDA receptor subtype 2B (NR2B or GluN2B), designed for treating GRIN-related neurodevelopmental disorders with gain-of-function (GoF) variants. The results were presented at the American Epilepsy Society (AES) Annual Meeting in Los Angeles, California.

Previously reported data indicated that radiprodil was generally well-tolerated. In a key secondary analysis, patients experienced a median reduction of 86% in countable motor seizure (CMS) frequency, consistent across GRIN genotypes with GoF variants. The company also outlined plans for a Phase 3 pivotal trial, which is expected to commence in early 2025.

Bruce Leuchter, MD, president and CEO of GRIN Therapeutics, expressed enthusiasm about the updated data from the Honeycomb trial, emphasizing the significant progress in developing a new treatment for GRIN-related neurodevelopmental disorders. He extended gratitude to patients and families for their dedication and participation, which have been crucial in advancing the development program. Leuchter affirmed the company's commitment to collaborating with regulators, advocates, clinicians, and the broader community.

GRIN Therapeutics plans to launch a randomized, double-blind, placebo-controlled Phase 3 pivotal trial in early 2025. This trial will involve two cohorts of patients with confirmed GoF mutations in the GRIN1, GRIN2A, GRIN2B, or GRIN2D genes. One cohort will include patients with qualifying CMS, while the other will consist of patients without qualifying CMS.

The Phase 3 trial design is based on the positive topline data from the Phase 1b Honeycomb trial, where radiprodil was well-tolerated, with the most common adverse events being infections or symptoms related to underlying diseases. Patients in the qualifying seizure cohort saw a median reduction of 86% in CMS frequency compared to baseline, consistently across GRIN genotypes. During the trial period, 71% of patients experienced more than a 50% reduction in CMS, and six out of seven were seizure-free for at least 80% of days in the eight-week maintenance period. Additionally, there were favorable effects on clinical outcomes, regardless of seizure occurrence, as measured by Clinician and Caregiver Global Impressions of Change (CGI-C and CaGI-C) and the Aberrant Behavior Checklist – Community (ABC-C).

Michael A. Panzara, MD, MPH, chief medical officer of GRIN Therapeutics, highlighted that GRIN-related neurodevelopmental disorder was first characterized in 2010 and formally named in 2014. Since then, research and advocacy communities have been working tirelessly to develop targeted treatments. The results from the Honeycomb trial mark a significant milestone toward providing treatment options for patients with and without seizures who suffer from GRIN-related neurodevelopmental disorder with GoF variants. Panzara emphasized the company's urgency and commitment to quickly transition to a pivotal Phase 3 study.

GRIN-related neurodevelopmental disorder encompasses a group of rare, genetically defined pediatric neurodevelopmental disorders caused by mutations in GRIN genes. Symptoms can appear as early as infancy, though diagnosis often occurs later. Individuals may experience developmental delay, intellectual disabilities, epilepsy, muscle hypotonia, movement disorders, spasticity, feeding challenges, and behavioral issues. Currently, there are no approved therapies for this disorder.

Radiprodil, the investigational drug, is a selective and potent negative allosteric modulator of the NMDA receptor subtype 2B (NR2B or GluN2B). Nonclinical studies have shown that radiprodil potently and selectively modulates GluN2B and has an antiseizure effect in various preclinical seizure and epilepsy models. This includes models characterized by enhanced GluN2B NMDA transmission, which can occur with GoF mutations in GRIN-related neurodevelopmental disorder. In vitro analysis of brain tissues from tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) lesions has shown enhanced GluN2B NMDA expression, indicating the potential of radiprodil to control seizures in these conditions.

GRIN Therapeutics is focused on developing precision therapeutics for pediatric neurodevelopmental disorders, aiming to bring hope to patients and caregivers. The company is conducting two clinical trials to evaluate radiprodil for GRIN-related neurodevelopmental disorder and other neurological conditions, including TSC and FCD type II.