The multicenter phase 1b Honeycomb trial enrolled 15 patients aged ≥6 months to ≤12 years with gain-of-function (GoF) mutations in the GRIN1, GRIN2A, or GRIN1B genes. Participants were split into 2 cohorts, with Cohort 1 assessed for the frequency of countable motor seizures (CMS) within a 28-day screening period, and Cohort 2 assessed for baseline severity of nonseizure behavioral symptoms. The study included 2 periods, with participants who completed Part A being eligible for continued study treatment in Part B, consisting of an ongoing open-label extended treatment period.In Part A, participants treated with radiprodil showed an 86% reduction from baseline in seizure frequency. 71% of participants in Part A experienced a >50% reduction in CMS, 43% experienced a >90% reduction, and 1 participant was seizure free.
Radiprodil appeared generally well tolerated throughout Part A and Part B of the study to date.
Treatment emergent adverse events (TEAEs) included pyrexia, diarrhea, respiratory tract infection, abnormal behavior, agitation, cough, dystonia, fatigue, and gastroenteritis, which were associated with infections or underlying disease symptoms.
Astroscape is an open-label phase 1b/2b study that will evaluate radiprodil treatment at different doses for a targeted enrollment of 20 participants aged 6 months to 18 years with TSC or FCD type II with treatment-resistant seizures. Primary endpoints will include safety parameters, tolerability, and pharmacokinetic measures with key secondary endpoints assessing the effect of treatment on epileptic seizure frequency and severity and symptoms related to behavior, sleep, and quality of life. Participants who complete the treatment period may have the option to enroll in a long-term extension study.
"The initiation of treatment in the first patients enrolled in this landmark study is an important milestone for the TSC and FCD communities," said Dr. Manuel Toledo, MD, PhD, Head of the Epilepsy Unit at Vall d'Hebron University Hospital, Barcelona, Spain, who enrolled the first patient in the study. "We appreciate GRIN Therapeutics' commitment to making a positive difference for patients and families impacted by these serious conditions and we look forward to completing this clinical trial and reporting results as quickly as possible."
https://practicalneurology.com/news/favorable-results-for-radiprodil-tx-for-grin-disorders-leads-to-launch-of-study-to-test-treatment-in-those-with-tuberous-sclerosis-or-focal-cortical-dysplasia?
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.
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.
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.
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.
https://www.neurologylive.com/view/radiprodil-significantly-reduces-seizure-frequency-phase-1b-honeycomb-study-grin-related-neurodevelopmental-disorderstudy-grin-related-neurodevelopmental-disorder
Bertocchi I, Cifarelli L, Oberto A, Eva CE, Sprengel R, Mirza NR, Muglia P. Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation. Br J Pharmacol. 2024 Jun;181(12):1886-1894. doi: 10.1111/bph.16361. Epub 2024 Mar 26. PMID: 38529699.
Abstract
Background and purpose: GRIN-related disorders are neurodevelopmental disorders caused by mutations in N-methyl-D-aspartate receptor (NMDAR) subunit genes. A large fraction of these mutations lead to a 'gain of function' (GoF) of the NMDAR. Patients present with a range of symptoms including epilepsy, intellectual disability, behavioural and motor. Controlling seizures is a significant unmet medical need in most patients with GRIN-related disorders. Although several hundred GRIN mutations have been identified in humans, until recently none of the mouse models carrying Grin mutations/deletions showed an epileptic phenotype. The two recent exceptions both carry mutations of GluN2A. The aim of this study was to assess the efficacy of radiprodil, a selective negative allosteric modulator of GluN2B-containing NMDARs, in counteracting audiogenic seizures (AGS) in a murine model carrying the GluN2A(N615S) homozygous mutation (Grin2aS/S mice).
Experimental approach: Grin2aS/S mice were acutely treated with radiprodil at different doses before the presentation of a high-frequency acoustic stimulus commonly used for AGS induction.
Key results: Radiprodil significantly and dose-dependently reduced the onset and severity of AGS in Grin2aS/S mice. Surprisingly, the results revealed a sex-dependent difference in AGS susceptibility and in the dose-dependent protection of radiprodil in the two genders. Specifically, radiprodil was more effective in female versus male mice.
Conclusion and implications: Overall, our data clearly show that radiprodil, a GluN2B selective negative allosteric modulator, may have the potential to control seizures in patients with GRIN2A GoF mutations. Further studies are warranted to better understand the sex-dependent effects observed in this study.
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