Targeting GRIN Genes In Drug Development To Treat Neurodevelopment Disorders
A conversation with Michael Panzara, chief medical officer, GRIN Therapeutics
In some cases, neurodevelopmental disorders are associated with dysfunctional N-methyl-D-aspartate (NMDA) receptors, which help regulate various physiological functions, including learning and memory. When these receptors are not working properly, neurodevelopmental syndromes can occur, with symptoms that include seizures, intellectual disabilities, and neurobehavioral complications. The ability to precisely control the activity of NMDA receptors could play a role in the treatment of a range of neurodevelopmental disorders. GRIN Therapeutics is advancing promising R&D to assess the safety and efficacy of the investigational therapy radiprodil for the treatment of serious neurodevelopmental disorders. In this Q&A, Life Science Connect’s Michelle Raley caught up with Michael Panzara, MD, MPH, chief medical officer at GRIN Therapeutics to discuss the company’s approach to early R&D.
Can you tell us about the GRIN genes? Why are there no FDA-approved therapies for GRIN-related neurodevelopmental disorders?
It has increasingly become a routine part of patient care for parents and physicians to request the functional characterization of a mutation through academic labs using published characterization methods.2 It is estimated that as many as one-half of mutations are classified as gain-of-function (GoF). Therefore, modulating the GluN2B subunit and the underlying receptor dysfunction that gives rise to clinical phenotypes has the potential to impact both seizure and non-seizure manifestations in patients with GRIN-NDD.
The unmet clinical need for patients with GRIN-NDD, including variants in GRIN1, GRIN2A, GRIN2B, and GRIN2D, is significant given the severely disabling nature of the disease and the fact there are currently no approved treatments, with most patients experiencing an inadequate response to symptomatic medications. The main therapeutic approach for patients with epilepsy is to use antiseizure medications (ASMs) to reduce seizures. However, many patients with seizures resulting from GRIN genetic variants do not respond to standard ASMs, and others have behavioral symptoms not currently well addressed by other therapies.1
The genetics underlying GRIN-NDD have been characterized relatively recently, and our knowledge of its epidemiology continues to evolve. Furthermore, the concept of precisely targeting the underlying pathophysiology of the disease has only recently led to the goal of modulating the NMDA receptor in GRIN-NDD. It is therefore not surprising that pharma companies have yet to focus on the disorder and that there are no FDA-approved treatments targeting its underlying disease process. It was our interactions with the academic and patient communities, along with radiprodil’s demonstrated mechanism as a selective negative allosteric modulator, that directed us to this condition.
GRIN-related neurodevelopmental disorder was first classified only 15 years ago. How did you approach drug targeting and preclinical drug development for a new disease that we don’t have much information about?
Panzara: While GRIN-NDD is a relatively newly characterized disorder, the development program surrounding our investigational candidate, radiprodil, is extensive, including nonclinical safety and toxicology studies conducted across multiple species, in both adult and juvenile animals. It was originally in clinical development for neuropathic pain and has previously been administered to 460 adults (healthy volunteers and patients with peripheral neuropathy). An increased understanding of the mechanism of action of radiprodil along with progress in the characterization of genetically defined epilepsies led to an initial study of radiprodil in three infants with treatment-resistant infantile spasms. Favorable results in this study were a key factor in the decision to explore the potential of radiprodil in GRIN-NDD in the Phase 1b/2a Honeycomb study of radiprodil in pediatric patients with GRIN-NDD and confirmed GoF mutations. In this study, we found that patients in the qualifying seizure cohort experienced a median reduction of 86% in countable motor seizure (CMS) frequency compared to baseline. Clinicians and caregivers generally assessed patients as improved clinically over the course of the study regardless of the occurrence of seizures as measured by Clinician and Caregiver Global Impressions of Change (CGI-C and CaGI-C) and the Aberrant Behavior Checklist – Community (ABC-C) scalesIn addition, the drug appeared to be generally well tolerated.
From there, we went where the science took us. Tuberous sclerosis complex (TSC) is a monogenetic disease caused by mutations in either the TSC1 or TSC2 gene and affects multiple organ systems. One of the hallmark manifestations of TSC is cortical malformations referred to as cortical tubers. Despite available pharmacological and surgical treatments, TSC-associated epilepsy is often resistant to treatment, with only one-third of patients achieving seizure freedom from existing treatments (Salussolia et al., 2019). Cortical tubers have altered electrophysiologic properties due to increased expression of NMDA and AMPA receptors, which may contribute to epileptogenesis by enhancing fast excitatory neurotransmission in the brain. Specifically, dysplastic neurons demonstrate increased expression of GluN2B and GluN2C but decreased GluN2A-containing NMDA receptors (Salussolia et al., 2019). This suggested a promising role for modulation of the NMDA receptor.
The case is similar with focal cortical dysplasia (FCD), where studies demonstrated greater expression of GluN2B in human dysplastic cortex compared to lateral temporal lobe regions (Möddel et al., 2005) with responsiveness to GluN2B inhibition. Epileptiform field potentials (EFP) were then elicited in vitro by omission of magnesium from the bath, which resulted in multiple after discharges occurring at a higher repetition rate in dysplastic versus non-dysplastic slices. When exposed to an NR2B-specific NMDA receptor inhibitor, EFP was suppressed in dysplastic slices but not in non-dysplastic. However, EFP was suppressed in both dysplastic and non-dysplastic slices by a non-specific NMDA antagonist or AMP receptor antagonist. This suggested that a potential role for the NMDA NR2B subunit in seizures associated with FCD, which may be addressed through NMDA antagonism (Möddel et al., 2005).
With our extensive preclinical package, encouraging clinical data from studies in infantile spasm and GRIN-NDD, and these data suggesting the importance of the GluN2B in the pathophysiology and TSC and FCD, that led to the start of a Phase 1b/2a basket study, called Astroscape, evaluating the effects of radiprodil on seizure and non-seizure outcomes in these conditions.
What are your learnings from obtaining your IND from the FDA that you’d like to share with other drug companies that may be proceeding to their own IND submission?
Panzara: The learnings from our IND submission are going to be different from other drug companies given the extensive clinical and preclinical data that was available prior to our initiation of the Honeycomb Phase 1b/2a study in GRIN-NDD.
Nonetheless, the best advice I can give is the advice I’ve been given by FDA leadership many times over the years that I have been doing this: Engage early and engage often. The FDA has a shared interest in advancing promising treatments to patients. In the setting of rare or ultrarare conditions with high unmet need, the motivation on all sides is greater. There are incentives and mechanisms that exist to facilitate the development of promising new treatments that should be taken advantage of when possible. Our recent Orphan Drug designation and Breakthrough Therapy designation provide examples of two such programs.
Transparent communication and engagement with regulatory authorities and the patient community throughout the drug development process are essential.
References
- T. Benke, K. Park, I. Krey, C. Camp, et al., “Clinical and therapeutic significance of genetic variation in the GRIN gene family encoding NMDARs,” Neuropharmacology 199 (2021) 108805.
- S. Myers, H. Yuan, R. Perszyk, J. Zhang, et al., “Classification of missense variants in the N-methyl-d-aspartate receptor GRIN gene family as gain- or loss-of-function,” Human Molecular Genetics, Volume 32, Issue 19, 1 October 2023, Pages 2857–2871, https://doi.org/10.1093/hmg/ddad104