Closely-held GRIN Therapeutics, a Neurvati Neuroscience company, is advancing promising research and development of precision therapeutics for neurodevelopmental disorders, predominately affecting children from infancy to young adults, with its oral investigational treatment, radiprodil.
“Our overarching mission is to focus on neurodevelopmental diseases, including GRIN-related neurodevelopmental disorder and other types of pediatric epilepsy such as tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD),” Bruce Leuchter, MD, president, CEO, and board member of both GRIN and Neurvati, says in an interview with BioTuesdays.
“We created GRIN Therapeutics around radiprodil and immediately began progressing our work in our lead indication, GRIN-related neurodevelopmental disorder. There is a human genetic driver—a strong biological rationale underpinning radiprodil, which gave us the confidence to pursue this program in GRIN, TSC, and FCD, with the potential expansion to other developmental and epileptic encephalopathies.” he adds.
Dr. Leuchter explains that GRIN-related neurodevelopmental disorder, first discovered in 2010, are rare pediatric neurodevelopmental conditions caused by mutations in GRIN genes. Symptoms such as developmental delay, intellectual disabilities, epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavioural issues may appear in infancy, but diagnosis often occurs after age two, when it becomes evident that developmental milestones are not being met. GRIN-related neurodevelopmental disorder is confirmed through genetic testing. Most individuals with GRIN-related neurodevelopmental disorder face lifelong disabilities requiring constant supervision, and there are currently no FDA-approved therapies.
“In some cases, neurodevelopmental disorders are linked to a dysfunctional N-methyl-D-aspartate (NMDA) receptor,” Dr. Leuchter says. “NMDA receptors help regulate neurophysiological functions in the brain, including learning and memory. When these receptors are dysfunctional, neurodevelopmental syndromes can emerge, presenting symptoms such as seizures, intellectual disabilities, behavioral dysregulation, sleep cycle dysfunction, impulsive behavior, and mood disorders.”
GRIN’s lead candidate, radiprodil, a potential first-in-class treatment for GRIN-related neurodevelopmental disorder, as well as TSC and FCD, is an investigational drug that specifically targets and modulates the NMDA receptor. In several studies, radiprodil has effectively reduced receptor activity and has shown potential in preventing seizures in preclinical tests, particularly in cases where increased receptor activity results from genetic mutations.
“GRIN is a genetically defined disease with high morbidity, in which patients can have pathological variants, known as gain-of-function (GoF) mutations, causing hyperactive NMDA receptors,” Dr. Leuchter outlines. “When there’s a GoF mutation, the receptor becomes hyperactive. If we can manage that with a negative allosteric modulator to down-regulate receptor activity, we could treat the broader disorder, not just the seizures associated with it.”
Recently, GRIN announced compelling topline results from its Phase 1b Honeycomb trial of radiprodil in GRIN-related neurodevelopment disorder at the International League Against Epilepsy conference in Rome. The study enrolled 15 pediatric patients with GRIN-related disorders with the primary objective of assessing the safety and pharmacokinetics of radiprodil, and a secondary focus on evaluating efficacy on seizures and non-seizure outcomes.
Dr. Leuchter highlights that radiprodil was generally well-tolerated in patients with GoF variants in GRIN genes, with and without countable motor seizures at baseline. “We observed a median 86% reduction in seizure frequency from baseline, over and above background anti-seizure medications. Additionally, 71% of patients experienced a greater than 50% reduction, 43% saw a reduction greater than 90%, and one patient became seizure free.”
Moreover, clinicians and caregivers generally assessed patients as improved clinically over the course of the study, he adds.
The company aims to leverage these data with regulators to advance radiprodil to a Phase 3 pivotal trial. “The findings from the Honeycomb study in GoF patients with treatment-resistant symptoms represent the first major milestone in our development plans for radiprodil, providing a strong rationale for progressing to Phase 3 as quickly as possible,” Dr. Leuchter says.
GRIN is also actively conducting ongoing Phase 1b studies of radiprodil in TSC and FCD, with data expected in mid-2025.
Recognizing the critical role of community in raising a child with GRIN-related disorder, the company has prioritized building partnerships with patient advocacy communities worldwide, such as the GRIN2B Foundation. “Community is especially important in rare pediatric diseases, particularly when no approved treatments exist, and patients are severely affected, often requiring feeding tubes and maximum assistance,” Dr. Leuchter points out.
“GRIN-related disorder was only classified in 2014, which is a pretty short runway for a disease, so the awareness factor is really important as there is not a lot of information available. We have developed a strong network of key stakeholders, principal investigators, key opinion leaders, patients, caregivers, physicians, and advocates, who are all quite excited about the robust Honeycomb trial data that we’ve been able to demonstrate,” he adds.
“Our goal is to continue to work with global leaders in research, patient care, and advocacy to raise broader awareness and bring hope to patients and caregivers through a disease-specific targeted therapy for these devastating neurodevelopmental disorders,” Dr. Leuchter concludes.
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