Radiprodil Significantly Reduces Seizure Frequency in Phase 1b Honeycomb Study of GRIN-Related Neurodevelopmental Disorder

Bruce Leuchter, MD

(Credit: Neurvati Neurosciences)

Newly presented data from the phase 1 Honeycomb study (NCT05818943) showed that treatment with investigational radiprodil (GRIN Therapeutics) was generally well tolerated, with significant impacts on seizure frequency in patients with GRIN-related neurodevelopmental disorder. Overall, the data support the continued development of radiprodil, selective and potent negative allosteric modulator of the N-methyl-D-aspartate receptor subtype 2B (NR2B or GluN2B), in this patient population.¹

At the July 15th cut-off date, 15 patients with GRIN-related disorder with a gain-of-function (GoF) variant in GRIN1, GRIN2A, 2GRINB, or GRIN2D were included for analysis. The study was designed as a 2-part trial, with Part A included a screening period (35 days), titration period (approximately 51 days), and maintenance period (up to 53 days). At the end of the maintenance period, there is an additional overnight stay when the participant is invited to take part in Part B or enter the tapering (15 days) and safety follow-up period (14 days).

Patients were escalated from a starting dose of 0.05 mg/kg based on tolerability, pharmacokinetics, and predicted GluN2B receptor occupancy to a dose level to be maintained through an 8-week maintenance period. During Part A, patients treated with radiprodil showed a median reduction of 86% in seizure frequency, a secondary end point, relative to baseline.

During this same period, 71% of treated patients experienced at least a 50% reduction in countable motor seizures (CMS), with 43% who saw a greater than 90% reduction. Notably, 1 patient was considered seizure free following treatment. In addition, clinician and caregiver-related scales generally assessed patients as improved clinically throughout the trial.

“GRIN-related neurodevelopmental disorder is a devastating disease for which there are no FDA-approved treatments,” Bruce Leuchter, MD, president and chief executive officer at Neurvati Neurosciences and GRIN Therapeutics, told NeurologyLive^®. “Ongoing research, including the promising results from our Honeycomb clinical trial, are deepening our understanding of the disorder and how best to help patients, families and caregivers. Our team is very excited about these results and the opportunity to advance a potential first-in-class ​therapy into a pivotal Phase 3 clinical trial. We are looking forward to working with regulatory authorities and the patient and caregiver communities to advance the development of radiprodil.”

The study was divided into 2 cohorts based on the frequency of CMS experienced during the 28-day screening period (cohort 1) and baseline severity of non-seizure behavioral symptoms. While demographics and baseline disease characteristics were generally balanced between the cohorts, there was a higher level of seizure activity at baseline in cohort 1, as explained by a mean CMS of 37.0 and median CMS of 25.5 per patient (range of 4.8 to 85.9). At baseline, there were no CMS observed in cohort 2.

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GRIN-related neurodevelopmental disorder is part of a larger family of genetic diseases related to ionotropic glutamate receptors and is caused by a change in one of 7 GRIN genes including GRIN1, GRIN2A, GRIN2B, and GRIN2D. These genes contain the code to create NMDA receptors, which are essential for learning and memory. To date, there have been several research studies conducted in the search for possible treatments targeting the NMDA receptors; however, there have been no FDA-approved treatments of GRIN disorders yet.²

In Honeycomb, there were no deaths, and the most common treatment-emergent adverse events (TEAEs) related to radiprodil were those associated with infections or underlying disease symptoms. These included pyrexia, diarrhea, respiratory tract infection, abnormal behavior, agitation, cough, dystonia, fatigue, and gastroenteritis. Investigators observed 3 serious AEs, which were obstructive bronchitis, viral pneumonia, and adenovirus infection, each found in 1 patient. None of these were considered related to the study treatment and none met the study criteria for stopping treatment.

Part B of Honeycomb, an open-label extended treatment period for patients who completed Part A and were eligible for continued study treatment, remains ongoing. During this period, there will be 4 visits per year, 2 of which require overnight stays. At the end of the long-term treatment period, patients will enter a 15-day tapering period, and 14-day safety follow-up period.

Despite increased efforts, there are still no approved treatments for GRIN-related neurodevelopmental disorder. Memantine, an NMDAR antagonist, has been tested in various GoF variants and has been shown to reduce the frequency of seizures in some patients. L-Serine is a NMDAR agonist that has been shown to improve motor impairments, cognition, and communication in patients with a GRIN2B loss-of-function variant. In a published phase 2a study (NCT04646447), treatment with L-serine 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.^2,3

REFERENCES
1. GRIN Therapeutics Announces Positive Topline Data from Honeycomb Trial of Radiprodil in GRIN-Related Neurodevelopmental Disorder. News release. September 9, 2024. Accessed September 9, 2024. https://www.prnewswire.com/news-releases/grin-therapeutics-announces-positive-topline-data-from-honeycomb-trial-of-radiprodil-in-grin-related-neurodevelopmental-disorder-302240847.html
2. All About GRIN Disorder. CureGRIN. Accessed September 9, 2024. https://curegrin.org/grin-disorder/
3. Julia-Palacios N, Olivella M, Sigatullina Bondarenko M, et al. L-serine treatment in patients with GRIN-related encephalopathy: a phase 2a, non-randomized study. Brain. 2024;147(5):1653-1666. doi:10.1093/brain/awae041.