Michael Panzara has more than 20 years of experience in developing therapies for neurological disorders.
Credit: Neurvati Neurosciences
GRIN-related neurodevelopmental disorders (GRIN-NDD) refer to a group of rare, genetically defined conditions caused by mutations in the GRIN (Glutamate Receptor, Ionotropic, N-methyl-D-aspartate) genes. These genes encode essential subunits of the NMDA (N-methyl-D-aspartate) receptor, a ligand-gated ion channel that regulates excitatory neurotransmission and coordinates neuronal network activity at the synapse, contributing to higher brain functions such as learning and memory.
Although individually rare, GRIN-NDD and related conditions highlight a broader challenge in rare disease research: understanding how single-gene mutations disrupt fundamental processes in the brain and translating that knowledge into targeted therapies. Progress has been slowed by the heterogeneity of symptoms, the complexity of NMDA receptor biology, and the absence of validated outcome measures specific to this patient population.
At the same time, advances in molecular genetics, receptor pharmacology, and patient-centered research are opening new paths forward. Researchers and companies are beginning to move beyond symptomatic management to explore treatments that engage directly with the underlying biology. These efforts represent an important shift toward precision medicine for rare neurological disorders.
To learn more about how the field is evolving, DDN spoke with Mike Panzara, Chief Medical Officer at Neurvati Neurosciences and GRIN Therapeutics, about current challenges, the promise of their novel therapeutic, radiprodil, and the role of patients and families in shaping the next generation of clinical studies.
Can you explain what GRIN-NDD is and how it affects patients and families?
For families, the challenges extend far beyond the clinic — care needs are complex and lifelong, often requiring significant coordination across medical, educational, and social systems.
- Michael Panzara , GRIN Therapeutics
GRIN-NDD is caused by mutations in GRIN genes, which encode critical subunits of the NMDA receptor. This receptor plays an essential role in brain development, learning, and memory. Mutations can lead to significant disruptions in neuronal signaling, resulting in a spectrum of symptoms including intellectual disability, epilepsy, movement disorders, and profound developmental delays. For families, the challenges extend far beyond the clinic — care needs are complex and lifelong, often requiring significant coordination across medical, educational, and social systems.
What are the current treatment options, and what are their limitations?
Current treatment paradigms focus on the management of symptoms, including, but not limited to, seizures, involuntary movements, and behavioral manifestations, either through medication or therapies. These approaches can provide some relief, however, there are no approved therapies that can fully address the disease-specific symptoms.
Can you describe radiprodil and why it’s considered a potentially first-in-class therapy for GRIN-NDD?
Radiprodil is GRIN Therapeutics’ investigational therapy in clinical development and is a highly selective negative allosteric modulator of the GluN2B subunit of the NMDA receptor. Certain GRIN-NDD gene mutations can result in faulty NMDA receptor activity, contributing to dysfunctional signaling in the brain. By modulating receptor activity in a targeted way, radiprodil has the potential to restore excitatory-inhibitory balance without broadly suppressing receptor function. This mechanism makes radiprodil a strong drug candidate as the first therapy designed to directly address the underlying biology of GRIN-NDD.
Can you give an overview of radiprodil’s development so far and what the next steps look like?
Radiprodil has shown strong results in both preclinical data and early-stage clinical development. In late 2024, we announced results from our Phase 1B Honeycomb trial, which evaluated 15 pediatric patients with confirmed gain-of-function (GoF) variants in the GRIN1, GRIN2A or GRIN2B genes.
Treatment with radiprodil resulted in a median reduction of 86 percent in seizure frequency relative to baseline, with 71 percent of patients achieving at least a 50 percent reduction in countable motor seizures. One patient achieved seizure freedom. The therapy was well tolerated, with no treatment-related serious adverse events reported.
These findings provided strong rational to advance the program into a later-stage clinical study specifically designed for patients with GRIN-NDD with gain-of-function variants, with endpoints focused on seizure burden and developmental outcomes.
The next steps involve regulatory interactions and clinical trial execution aimed at demonstrating not only safety and efficacy, but also meaningful improvements in quality of life.
How are you measuring the impact of radiprodil on patients’ daily lives, beyond just clinical symptoms?
We are incorporating patient-reported outcomes into our studies, recognizing that improvements in daily living, such as improved behaviors, better communication, or improved motor symptoms are important measures of success. For example, our Beeline trial will use several rating scales, including a newly developed GRIN-specific Clinical Global Impression of Severity (CGI-S) and Change (CGI-C), which will be used by physicians to assess improvements in symptoms and impacts reported as most meaningful by caregivers of patients with GRIN-NDD. These real-world impacts provide context to traditional clinical endpoints and help us evaluate whether radiprodil is delivering benefits on those things not adequately assessed by generic scales.
How have families and caregivers influenced the design of your studies and the outcomes you focus on?
Families’ perspectives ensure we are addressing not only scientific questions but also the lived realities of caring for a child with GRIN-NDD.
- Michael Panzara, GRIN Therapeutics
We have worked with the GRIN-NDD community since the earliest days of our company, and their insights have guided us from the start. This has included receiving feedback on clinical trial design, developing GRIN-NDD-specific CGI scales based on the priorities identified by families, and supporting at-home electroencephalograms to reduce the travel burden. Families’ perspectives ensure we are addressing not only scientific questions but also the lived realities of caring for a child with GRIN-NDD.
What role do regulatory designations or partnerships play in helping GRIN Therapeutics bring radiprodil to patients?
Regulatory designations provide important opportunities for engagement with regulatory authorities to enable more efficient development pathways while avoiding common pitfalls to enable innovative investigational treatments for rare diseases to get to patients as quickly as possible. We are proud that radiprodil has received multiple regulatory designations, including Breakthrough Therapy designation from the FDA for the treatment of seizures associated with GRIN-NDD with GoF variants. Additionally, radiprodil has been granted FDA Orphan Drug designation, European Medicines Agency (EMA) Priority Medicines designation, and a positive opinion for orphan designation from the EMA Committee for Medicinal Products for Human Use for the treatment of GRIN-NDD.
Radiprodil is also being developed for tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCD II). How do you see the potential benefits in these patient populations compared with what you’re observing in GRIN-NDD?
Radiprodil’s selective modulation of NMDA receptor activity supports its potential as a targeted therapeutic approach for symptoms associated with NMDA receptor dysregulation. In both TSC and FCD II, GluN2B-containing NMDA receptors are overexpressed, contributing to the pathophysiology and clinical manifestations of these disorders. Our hope is that what we learn in our GRIN-NDD studies about dosing, safety, and patient outcomes will also inform and accelerate progress in these additional populations, where unmet need is also significant.
This interview has been condensed and edited for clarity.
