New data from the Phase 1b Honeycomb study (NCT05818943) indicates that radiprodil, an investigational drug developed by GRIN Therapeutics, significantly reduced seizure frequency in patients with GRIN-related neurodevelopmental disorder. The study findings suggest that radiprodil, a selective and potent negative allosteric modulator of the N-methyl-D-aspartate receptor subtype 2B (NR2B or GluN2B), is well-tolerated and supports further clinical development.
The analysis included 15 patients with GRIN-related disorder with a gain-of-function (GoF) variant in GRIN1, GRIN2A, GRIN2B, or GRIN2D. The trial was structured in two parts: Part A included a screening period (35 days), a titration period (approximately 51 days), and a maintenance period (up to 53 days). Following the maintenance period, participants could enter Part B (an extended treatment period) or proceed to a tapering period (15 days) and a safety follow-up period (14 days).
Patients were escalated from an initial dose of 0.05 mg/kg, based on tolerability, pharmacokinetics, and predicted GluN2B receptor occupancy, to a maintenance dose administered throughout an 8-week maintenance period. Results from Part A showed a median reduction of 86% in seizure frequency relative to baseline (a secondary endpoint).
During the same period, 71% of treated patients experienced at least a 50% reduction in countable motor seizures (CMS), and 43% experienced a reduction greater than 90%. Notably, one patient became seizure-free following treatment. Clinician and caregiver assessments generally indicated clinical improvement throughout the trial.
Expert Commentary
According to Bruce Leuchter, MD, president and chief executive officer at Neurvati Neurosciences and GRIN Therapeutics, GRIN-related neurodevelopmental disorder is a devastating disease with no FDA-approved treatments. He stated that ongoing research, including the Honeycomb trial results, is deepening the understanding of the disorder and how to best help patients, families, and caregivers. Leuchter expressed excitement about the results and the opportunity to advance a potential first-in-class therapy into a pivotal Phase 3 clinical trial.
The study divided patients into two cohorts based on the frequency of CMS during the 28-day screening period (cohort 1) and the baseline severity of non-seizure behavioral symptoms. Cohort 1 exhibited a higher level of seizure activity at baseline, with a mean CMS of 37.0 and a median CMS of 25.5 per patient (range: 4.8 to 85.9), while no CMS were observed in cohort 2 at baseline.
Background on GRIN-Related Disorders
GRIN-related neurodevelopmental disorder is part of a family of genetic diseases related to ionotropic glutamate receptors, caused by changes in one of seven GRIN genes, including GRIN1, GRIN2A, GRIN2B, and GRIN2D. These genes encode NMDA receptors, which are crucial for learning and memory. While research has explored potential treatments targeting NMDA receptors, there are currently no FDA-approved treatments for GRIN disorders.
Safety and Tolerability
In the Honeycomb study, no deaths were reported. The most common treatment-emergent adverse events (TEAEs) related to radiprodil were associated with infections or underlying disease symptoms, including pyrexia, diarrhea, respiratory tract infection, abnormal behavior, agitation, cough, dystonia, fatigue, and gastroenteritis. Three serious AEs were reported (obstructive bronchitis, viral pneumonia, and adenovirus infection), each in one patient, but none were considered related to the study treatment.
Part B of the Honeycomb study, an open-label extended treatment period for patients who completed Part A and were eligible for continued treatment, is ongoing. This phase involves four visits per year, two requiring overnight stays, followed by a 15-day tapering period and a 14-day safety follow-up period.
Current Treatment Landscape
Despite ongoing efforts, there are no approved treatments for GRIN-related neurodevelopmental disorder. Memantine, an NMDAR antagonist, has shown some efficacy in reducing seizure frequency in some patients with gain-of-function variants. L-Serine, an NMDAR agonist, has been shown to improve motor impairments, cognition, and communication in patients with a GRIN2B loss-of-function variant. A published phase 2a study (NCT04646447) found that L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = .002) and the mean Pediatric Quality of Life total score (P = .00068), regardless of disease severity.
