GRIN Therapeutics: Seeking to address unmet needs in rare neurodevelopmental disorders

GRIN-related neurodevelopmental disorder (GRIN-NDD) is a family of rare, genetically defined neurodevelopmental disorders caused by mutations in GRIN genes and abnormal activity of the N-methyl-D-aspartate (NMDA) receptor subunits.

GRIN-NDD was first classified in 2010. While symptoms can present as early as infancy, a diagnosis is often not confirmed until age two or later, when a child fails to reach developmental milestones. Currently, only symptomatic therapies, such as anti-seizure medicines, are available to help treat people living with GRIN-NDD, and the burden of disease is devastating. There is a significant need for therapies with the potential to target the underlying disease biology.

Last week, our round-up of recent biotech financings was headed by a $140 million Series D for GRIN Therapeutics, which also scored a $570 million licensing deal with Angelini Pharma. The New York-based biotech is focused on radiprodil, a glutamate NMDA modulator. The new funding comes after GRIN reported encouraging results in a Phase 1b Honeycomb trial of radiprodil in children with confirmed GoF mutations across GRIN genotypes.¹ Currently, the company plans to launch a pivotal Phase 3 trial to evaluate the impact of radiprodil on seizures, behavioural abnormalities, and functional outcomes associated with GRIN-NDD.

Before the Series D financing, pharmaphorum had spoken with Dr Bruce Leuchter, CEO of GRIN Therapeutics and Neurvati Neurosciences, to find out more.

Can you give a brief overview of why the historical development of new treatments for neurodevelopmental disorders has faced significant challenges?

While all drug development programmes can face challenges, there are a number of factors that are important to consider when planning for and executing programmes targeting neurological and psychiatric disorders. One of the most significant is that the patient populations are often highly heterogeneous, meaning they present with clinical phenotypes and symptoms that can vary significantly in severity and frequency from person to person, especially depending on age of disease onset. Another issue is that clinical trial endpoints for neurotherapeutics are commonly based on observations or rater-based outcomes that can be subjective and open to multiple interpretations. These factors can make it especially difficult to develop accurate patient profiles, recruit appropriate participants for clinical trials, and execute studies. They can also impair the ability to produce statistically significant and clinically meaningful data that will meet regulatory criteria to advance development programmes to the final stages of review and approval.

In recent years, however, there have been innovations that have led to meaningful advances in neurologic research, in the form of genetic testing to support both accurate diagnoses for many diseases and conditions and strong successes in the use of appropriate biomarkers in clinical research. In many development programmes, these advances are making it easier to identify and recruit patients for clinical trials and to set protocols for clinical programmes that are positioned to increase the likelihood of achieving the quantifiable and statistically significant outcomes data that regulators want.

What new strategies are emerging to take advantage of the opportunities available in this space?

It might not be accurate to describe them as entirely new strategies, but some targeted and customised approaches have the potential to identify and advance more promising therapies and bring them to patients. Interestingly, success in many cases might be supported by having a deep understanding of the onset and progression of neurological and psychiatric diseases while using a business model that can streamline and improve development programme protocols and timelines.  

Compared to a classic venture-backed model that typically searches for and funds very early-stage clinical research where available data is limited, an emerging private equity (PE) model based on four key steps (identify, evaluate, invest, and develop) can help identify and advance proven assets supported by extensive data later in the development lifecycle, thereby avoiding the risks associated with translational and early-stage development.

It is important to highlight that this PE model often requires highly specialised skills and expertise. Teams must be able to identify and assess drug candidates based on early-stage clinical data, which in many cases may be candidates that failed in clinical development and were then de-prioritised. In these cases, comprehensive data reviews by neuroscience specialists can help identify cases where a promising drug is stalled for reasons that are surmountable. Leveraging their expertise, teams must be able to discern and confirm biological activity that indicates strong chances for success in the same or a different neurological indication based on a demonstrated mechanism of action. Once the review is complete, drug developers must then have the business contacts and foundation to rapidly bring together the financial and professional resources necessary to support a development programme through mid- and late-stage clinical trials.

There is strong evidence to suggest that there are potentially hundreds of promising therapeutic candidates that have stalled in development and may have applications in the treatment of many different neuropsychiatric disorders. With the right teams and experience in place, drug developers can unlock their full potential, streamline efforts to advance them quickly, and bring more, new options to patients.

How has understanding of genetic factors associated with neurodevelopmental disorders evolved in recent years, and how is the industry taking action with this knowledge in mind?

This is an especially exciting area. Advances in genetic technology are making it possible for more drug developers to use insights in key areas including human genetics, multi-omics, imaging, neurophysiology, and plasma and cerebral spinal fluid (CSF) biomarkers, to better understand the genetic components and underlying biology of neurological diseases and how to target them more effectively.

Looking at a few examples, genomic sequencing technology now provides unprecedented visibility of underlying DNA structures, making it possible to identify and confirm genetic mutations, including rare mutations, associated with symptoms that may overlap with other more common neurodevelopmental disorders. Also, recent use of advanced multi-omics approaches, including transcriptomics and proteomics, can help better stratify patient populations and ensure therapies are being studied in the most relevant subgroups.

Drug developers are also increasingly utilising AI technology to optimise molecule design and better understand the impact on patients and their underlying genetic mutations. As AI models become more widely used in drug discovery and development, they may offer new insights into disease biology, treatment response, and the potential to accelerate the path from discovery to clinical impact.

Can you discuss the mechanism of action of investigational radiprodil and how it will help address the underlying disease-specific biology in patients with GRIN-related neurodevelopmental disorder?

For context, GRIN-related neurodevelopmental disorder (GRIN-NDD) is a family of rare, genetically defined neurodevelopmental disorders caused by mutations in GRIN genes and abnormal activity of the N-methyl-D-aspartate (NMDA) receptor subunits. In the brain, NMDA receptors help regulate various physiological functions, including learning and memory. When these receptors are dysfunctional, they are associated with the onset and progression of a wide variety of neurological symptoms, such as severe epilepsy, developmental delay, intellectual disabilities, hypotonia, movement disorders, spasticity, feeding difficulties, and behavioural problems.

We are developing radiprodil, an investigational therapy that directly targets the underlying biology and potentially modifies the natural course of disease in patients with GRIN-NDD with gain-of-function (GoF) mutations. It is a selective and potent negative allosteric modulator of the NMDA receptors containing the GluN2B subunit, reducing excessive excitatory neurotransmission without entirely blocking NMDA receptor function. Rather than fully turning activity on or off, radiprodil is designed to modulate receptor activity. In simpler terms, think of a light switch versus a dimmer for a lamp. The dimmer provides a higher level of control to produce the desired result. This innovative design also positions radiprodil to target the disease in totality, including potential impact on seizures as well as behavioural abnormalities.

A very important consideration with radiprodil is also that its mechanism of action may have potential applications in the treatment of other neurodevelopmental disorders. In GRIN-NDD, radiprodil has been shown to target the activity of the abnormal NMDA receptor. We are also assessing the potential of radiprodil in the treatment of two other diseases – tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) – that are each associated with the overexpression of normally functioning NMDA receptors.  

What do you anticipate the future of neuroscience research and development to look like in the next several years?

There are early signs that we may be entering a peak era for neuroscience research and drug development. For example, last year, the FDA approved a schizophrenia drug with the first new mechanism of action in 70 years, potentially transforming the quality of life for about 24 million people worldwide.

Continued engagement with the FDA and global regulatory agencies will be essential to ensure new safe and effective therapies reach patients as quickly as possible. Multiple regulatory pathways have been introduced in the US and European Union to support more efficient drug development and approval - especially for novel rare disease treatments, given the often high unmet medical need for patients. Some examples are EMA Priority Medicine (PRIME) and FDA Orphan Drug and Breakthrough Therapy designations, both of which we were pleased to receive recently for radiprodil.^2,3,4

As an industry, our continued success also hinges on our ability to incorporate precision technologies at every stage of therapeutic development, especially for rare, genetically defined diseases such as GRIN-NDD. Concurrently, advances in neurophysiology, neuroimaging, and plasma and CSF biomarkers are supporting the enrichment of patient populations in clinical trials, increasing the potential to enhance efficacy and ultimately allow for better outcomes.

In my discussions across the neuroscience ecosystem – whether with the lead of an early-stage biotech or an executive at a large-cap biopharma company – there is strong evidence that we are prioritising development of precision medicines for diseases of the brain and nervous system more than ever before, especially for those with rare conditions. A key factor driving this is access to many new and more advanced technologies to support research at every stage. I am very hopeful that we can leverage this momentum to deliver transformational new treatments for the patients and caregivers who are counting on us.

References:

1.    GRIN Therapeutics. (2024, December 9). GRIN Therapeutics presents data from Honeycomb trial of radiprodil at the American Epilepsy Society Annual Meeting. Retrieved from https://neurvati.com/wp-content/uploads/AES-2024-Press-Release-Final-PDF.pdf 

2.    GRIN Therapeutics. (2025, April 1). GRIN Therapeutics receives Priority Medicines (PRIME) designation from EMA for radiprodil in the treatment of GRIN-related neurodevelopmental disorder. Retrieved from https://neurvati.com/wp-content/uploads/PRIME-EMA-Designation-Press-Release-Final.pdf

3.    GRIN Therapeutics. (2025, March 17). GRIN Therapeutics receives FDA Orphan Drug designation for radiprodil for the treatment of GRIN-related neurodevelopmental disorder. Retrieved from https://neurvati.com/wp-content/uploads/Radiprodil-Orphan-Drug-Announcement-Release-FINAL.pdf

4.    GRIN Therapeutics. (2025, February 25). GRIN Therapeutics receives FDA Breakthrough Therapy designation for radiprodil for the treatment of seizures associated with GRIN-related neurodevelopmental disorder. Retrieved from https://neurvati.com/wp-content/uploads/Radiprodil-Breakthrough-Therapy-Designation-Final.pdf

About the interviewee

Bruce Leuchter, MD, is CEO and president of GRIN Therapeutics, an affiliate of Neurvati Neurosciences, a Blackstone Life Sciences portfolio company. He has deep-rooted, wide-ranging experience spanning neuroscience, clinical neuropsychiatry, biotechnology equity research, healthcare investment banking, and entrepreneurship. A physician by training and neuropsychiatrist by specialty, Dr Leuchter completed residency training in neurology and psychiatry at New York Presbyterian Hospital and Weill Cornell Medical College and is a Diplomate of the American Board of Psychiatry and Neurology. Dr Leuchter served as Director of Clinical Neuropsychiatry at Weill Cornell Medical College and maintains a voluntary faculty appointment in the Department of Psychiatry. He serves as a member of the Scientific Advisory Committee for the Daedelus Fund for Innovation at Weill Cornell Medical College, as a member of the Life Science Institute Leadership Council at the University of Michigan, and as a Business Advisory Board member at FOXG1 Research Foundation.