Radiprodil (DB12260): A Comprehensive Report on its Pharmacology, Clinical Development, and Therapeutic Potential

1. Introduction to Radiprodil

1.1. Overview

Radiprodil is an investigational small molecule drug that has been evaluated for a range of neurological conditions. Its development journey has seen a strategic evolution, moving from broader applications to a more focused approach targeting rare, severe neurodevelopmental disorders where its specific mechanism of action is most relevant.[1] Initially explored for conditions such as Infantile Spasms (IS) and Diabetic Peripheral Neuropathic Pain (DPNP), radiprodil is currently under active clinical development primarily for GRIN-related Neurodevelopmental Disorders (GRIN-NDD), Tuberous Sclerosis Complex (TSC), and Focal Cortical Dysplasia (FCD) Type II. This shift underscores a trend towards precision medicine, leveraging a deeper understanding of the drug's molecular interactions and the pathophysiology of specific diseases.

The development pathway of radiprodil highlights the complexities and iterative nature of pharmaceutical research. Early setbacks in demonstrating efficacy for more common conditions have not led to its abandonment but rather to a refined strategy. This redirection is based on emerging clinical data and a clearer understanding of how radiprodil's unique pharmacological profile can address the underlying mechanisms of specific, often genetically defined, patient populations.

1.2. Key Identifiers and Properties

Radiprodil is characterized by several key identifiers and properties that define its nature and therapeutic focus:

• DrugBank ID: DB12260 (User Query)
• CAS Number: 496054-87-6 [2]
• Chemical Formula: C21​H20​FN3​O4​ [2]
• Type: Small Molecule [1]
• Primary Mechanism of Action: Radiprodil functions as a selective negative allosteric modulator (NAM) of the N-methyl-D-aspartate (NMDA) receptor, specifically targeting the NR2B (GluN2B) subunit. This targeted modulation is central to its therapeutic rationale in specific neurological disorders.[1]
• Initial Therapeutic Interests: Infantile Spasms (IS) and Diabetic Peripheral Neuropathic Pain (DPNP).[2]
• Current Key Indications: GRIN-related Neurodevelopmental Disorders (GRIN-NDD), Tuberous Sclerosis Complex (TSC), and Focal Cortical Dysplasia (FCD) Type II.[2]

The trajectory of radiprodil's development from broader indications like DPNP and IS to its current focus on specific, often genetically-defined, rare neurodevelopmental disorders is a clear illustration of the principles of precision medicine in action. Initial trials in DPNP and IS [2] did not yield the desired efficacy outcomes, leading to the discontinuation of these programs.[1] However, the understanding of radiprodil's specific mechanism—selective negative allosteric modulation of GluN2B-containing NMDA receptors [4]—opened new avenues. Conditions such as GRIN-related disorders, which are directly caused by mutations affecting NMDA receptor subunits like GluN2B, and TSC and FCD Type II, which are associated with enhanced GluN2B expression or signaling [4], presented as more suitable targets. Consequently, the current development efforts by GRIN Therapeutics are precisely aimed at these disorders, where the drug's mechanism directly addresses the underlying pathophysiology or a key pathological feature.[6] This strategic pivot reflects a common and increasingly successful approach in drug development: leveraging a detailed understanding of drug-target interactions and disease mechanisms to identify niche patient populations where a drug is most likely to confer significant clinical benefit.

Table 1: Radiprodil - Key Identifiers and Properties

Property	Value/Description
DrugBank ID	DB12260 (User Query)
CAS Number	496054-87-6 2
Chemical Formula	C21​H20​FN3​O4​ 2
Type	Small Molecule 1
Primary Mechanism of Action	Selective negative allosteric modulator (NAM) of the N-methyl-D-aspartate (NMDA) receptor, targeting the GluN2B (NR2B) subunit.1
Initial Indications	Infantile Spasms (IS), Diabetic Peripheral Neuropathic Pain (DPNP).2
Current Key Indications	GRIN-related Neurodevelopmental Disorders (GRIN-NDD), Tuberous Sclerosis Complex (TSC), Focal Cortical Dysplasia (FCD) Type II.2

2. Mechanism of Action

2.1. Primary Target: NMDA Receptor and GluN2B Subunit

Radiprodil is an orally active small molecule that functions as a selective and potent negative allosteric modulator (NAM) of the N-methyl-D-aspartate (NMDA) receptor. Its specificity lies in its interaction with NMDA receptors that incorporate the GluN2B (historically NR2B) subunit.[1]

NMDA receptors are critical components of the central nervous system, acting as ligand-gated ion channels that are permeable to Ca2+. They are fundamental for excitatory synaptic transmission and play essential roles in synaptic plasticity, which underlies processes such as learning and memory, as well as in neuronal development and survival.[4] Structurally, NMDA receptors are heterotetrameric complexes, typically formed by two obligatory GluN1 subunits and two GluN2 subunits. The GluN2 subunit family comprises four distinct types (GluN2A, GluN2B, GluN2C, and GluN2D), and the specific GluN2 subunits included in a receptor complex determine its unique electrophysiological and pharmacological characteristics. These include channel opening times, magnesium ion (

Mg2+) block sensitivity, and affinity for agonists and antagonists. The GluN2B subunit is particularly abundant during early brain development and its expression patterns change dynamically with age, though it remains present in certain brain regions, such as the hippocampus and forebrain, throughout adulthood.[5]

As a NAM, radiprodil exerts its effect by binding to an allosteric site on the GluN2B-containing NMDA receptor complex. This binding site is distinct from the orthosteric sites where the primary agonist glutamate and the co-agonist glycine (or D-serine) bind. Upon binding, radiprodil induces a conformational change in the receptor that reduces the probability or extent of ion channel opening when agonists are bound. This leads to a decrease in the receptor's overall activity and Ca2+ influx, but crucially, it does so without completely blocking the receptor. This modulatory action is key to its therapeutic rationale, which is to dampen neuronal hyperexcitability associated with the dysfunction or overexpression of GluN2B-containing NMDA receptors in specific neurological disorders.[4]

2.2. Relevance to Pathophysiology and Therapeutic Rationale

The targeted modulation of GluN2B-containing NMDA receptors by radiprodil is directly relevant to the pathophysiology of several neurological conditions:

• Infantile Spasms (IS): The increased neuronal excitability observed during early postnatal development, which is characteristic of the period when IS typically manifests, is thought to be at least partially mediated by the heightened expression and/or function of GluN2B-containing NMDA receptors.[5] Radiprodil was investigated in IS with the hypothesis that its NAM activity on these receptors could reduce the neuronal hyperexcitability underlying the spasms.
• GRIN-related Neurodevelopmental Disorders (GRIN-NDD): These are a group of severe, rare genetic disorders caused by pathogenic mutations in the GRIN genes that encode the various GluN subunits of the NMDA receptor. Gain-of-function (GoF) mutations, particularly in GRIN2B (the gene encoding the GluN2B subunit), can lead to constitutively overactive NMDA receptors. This results in excessive calcium influx, neuronal hyperexcitability, and excitotoxicity, manifesting clinically as severe early-onset epilepsy, developmental delay, intellectual disability, movement disorders, and behavioral problems.[4] Radiprodil's NAM activity is precisely suited to counteract this specific receptor overactivity. Importantly, in vitro electrophysiological studies have demonstrated that radiprodil maintains its pharmacological modulatory profile on human NMDA receptors that express certain NR2B GoF mutations known to be associated with IS and other severe epileptic encephalopathies.[5]
• Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) Type II: The therapeutic rationale for using radiprodil in TSC and FCD type II is supported by in vitro analyses of resected human brain tissues from lesions characteristic of these conditions. These studies have shown an enhanced expression of GluN2B-containing NMDA receptors.[4] This overexpression suggests that these receptors contribute to the epileptogenesis and neuronal hyperexcitability that are hallmarks of TSC and FCD, making them a rational target for radiprodil's modulatory action.
• Diabetic Peripheral Neuropathic Pain (DPNP): NMDA receptors, including those containing GluN2B subunits, are well-established mediators of nociceptive signaling in the peripheral and central nervous system. They are critically involved in the development and maintenance of central sensitization, a key mechanism underlying many chronic pain states, including DPNP.[25] While the specific rationale for DPNP was based on this general understanding of NR2B antagonism, the lack of efficacy observed in clinical trials suggests that the modulation provided by radiprodil was either insufficient to significantly impact the complex pain pathways in this condition, that adequate drug concentrations were not achieved at the relevant sites of action, or that other, non-NMDA receptor-mediated mechanisms played a more dominant role in the DPNP experienced by the trial participants.

The age-dependent expression of the GluN2B subunit is a significant factor in understanding radiprodil's therapeutic potential. GluN2B subunit expression is highest during early brain development and generally declines in many brain regions with age, although it persists in areas like the hippocampus and forebrain.[5] Preclinical studies investigating radiprodil for IS demonstrated its most potent anti-seizure effects in juvenile rats (specifically at postnatal day 12), an age that corresponds to late infancy in humans—a critical period for the onset of IS.[5] This observation aligns with the hypothesis that the hyperexcitability in IS is linked to the transient overexpression or specific functional role of GluN2B-containing NMDA receptors during this developmental window. This suggests a "developmental therapeutic window" for radiprodil, where its efficacy might be maximized in conditions manifesting during periods of high GluN2B functional relevance, providing a strong rationale for its current focus on pediatric neurodevelopmental disorders like GRIN-NDD, which often present early in life.

Furthermore, radiprodil's classification as a NAM, rather than a direct channel blocker or competitive antagonist, is a crucial pharmacological distinction. NAMs bind to an allosteric site, distinct from the agonist binding site, inducing conformational changes that reduce receptor activation without completely abolishing receptor function.[4] This "dampening" effect contrasts with the "on/off" switch often associated with competitive antagonists or channel blockers. Given that NMDA receptors are vital for normal brain function, complete blockade can lead to severe side effects, such as the psychotomimetic effects and cognitive impairment seen with drugs like ketamine or phencyclidine (PCP). The NAM approach offers the potential to normalize pathologically overactive receptors—as seen in GRIN GoF mutations or conditions with GluN2B overexpression—while preserving essential physiological receptor activity to a greater extent than full antagonists. This refined modulatory mechanism likely contributes to the generally well-tolerated safety profile observed for radiprodil in recent clinical trials, particularly in vulnerable pediatric populations.[6] It allows for a more targeted "tuning down" of receptor activity, which is critical for treating disorders of receptor hyperexcitability without inducing widespread neuronal depression.

3. Development History and Key Stakeholders

The development of radiprodil has been a multi-stage process involving several pharmaceutical entities, reflecting a common trajectory for investigational drugs as their therapeutic potential and target indications are refined over time.

3.1. Discovery and Early Development

Radiprodil, initially identified by the code RGH-896, was discovered by Gedeon Richter Plc..[1] This foundational work set the stage for its initial exploration in broader neurological indications.

3.2. Development for Diabetic Peripheral Neuropathic Pain (DPNP)

Following its discovery, Gedeon Richter collaborated with Forest Laboratories for the development of radiprodil in chronic neuropathic pain conditions, with a specific focus on DPNP. Forest Laboratories licensed the rights for radiprodil in the United States and Canada for this indication.[1] A key Phase II clinical trial (NCT00838799) was conducted to evaluate its efficacy and safety in this patient population.[2] However, the DPNP development program was ultimately discontinued due to a lack of demonstrated efficacy; radiprodil did not achieve clinically meaningful reductions in pain scores compared to placebo.[1] Despite this outcome, these early adult trials provided valuable human safety and pharmacokinetic data that informed subsequent development efforts.[5]

3.3. Development for Epilepsy and Infantile Spasms (IS)

UCB Biopharma S.P.R.L. took the lead in investigating radiprodil's potential for treating Infantile Spasms.[1] A Phase 1b study involving three infants with treatment-resistant IS yielded promising preliminary results, demonstrating safety, a predictable pharmacokinetic profile, and signs of potential efficacy, with one infant becoming spasm-free.[5] Following this, a Phase 2 study (NCT02829827) was initiated to further evaluate radiprodil in subjects with drug-resistant Infantile Spasms.[2] This Phase 2 trial was later terminated.[2] While the specific reasons for the termination of NCT02829827 are not explicitly detailed in the provided research snippets [38], the broader development for epilepsy and infantile spasms by UCB was discontinued, as noted in AdisInsight.[1]

3.4. Current Development Focus: GRIN-related NDD, TSC, FCD

The current phase of radiprodil's development is spearheaded by GRIN Therapeutics, Inc. This company is focusing on rare, genetically-linked neurodevelopmental disorders where the drug's mechanism of action aligns closely with the underlying pathophysiology. These include GRIN-related Neurodevelopmental Disorders (GRIN-NDD), Tuberous Sclerosis Complex (TSC), and Focal Cortical Dysplasia (FCD) Type II.[2]

GRIN Therapeutics operates as an affiliate of Neurvati Neurosciences and has received substantial backing from Blackstone Life Sciences (BXLS), which has made significant capital commitments to advance radiprodil's development.[6] A major strategic partnership was formed with

Angelini Pharma, which acquired exclusive rights for the development and commercialization of radiprodil outside of North America (United States, Canada, and Mexico). This collaboration involves upfront payments, potential milestone payments, and an equity investment from Angelini Pharma into GRIN Therapeutics.[13]

Other entities mentioned in connection with radiprodil's past development include PRA Health Sciences, likely as a contract research organization (CRO), and Algernon Pharmaceuticals, though their specific roles and the timelines of their involvement are not extensively detailed.[1] AbbVie is also noted in some databases alongside GRIN Therapeutics, suggesting a potential past or ongoing collaboration or licensing agreement, but specifics are not provided in the reviewed materials.[21]

3.5. Clarification on Psyadon Pharmaceuticals and Ovid Therapeutics

Based on the available research, there is no direct evidence linking Psyadon Pharmaceuticals or Ovid Therapeutics to the development of radiprodil.

• Psyadon Pharmaceuticals: Information indicates that Psyadon Pharmaceuticals was acquired by Emalex Biosciences for the development of ecopipam, a D1 receptor antagonist for Tourette Syndrome, not radiprodil.[14]
• Ovid Therapeutics: Ovid Therapeutics' pipeline focuses on other compounds such as soticlestat, OV329, OV888, and OV350.[15] While radiprodil has appeared in broader epilepsy pipeline overviews that include Ovid, it is consistently attributed to GRIN Therapeutics as the developer.[15]

The development trajectory of radiprodil illustrates a common "lifecycle" for investigational drugs. A novel compound with a specific mechanism (GluN2B NAM) is initially tested in broader indications where the target is thought to be relevant (e.g., neuropathic pain, general epilepsy). When efficacy is not demonstrated in these larger, more heterogeneous populations [1], development may be discontinued or the asset may be out-licensed. However, if the drug's mechanism of action is well-understood and a reasonable safety profile has been established, new entities, often specialized biotech companies or those backed by venture capital (like GRIN Therapeutics with support from Blackstone Life Sciences and Neurvati Neurosciences), may acquire or license the asset.[6] The subsequent strategy often involves targeting niche populations or orphan diseases where the drug's specific mechanism has a higher probability of success, particularly in genetically-defined subgroups like GRIN-NDD with GoF mutations.[4] This path highlights the resilience in pharmaceutical R&D, where initial setbacks can inform and pave the way for success in more precisely defined therapeutic contexts. The safety and pharmacokinetic data gathered from earlier, albeit unsuccessful, trials become valuable assets for these later, more targeted development efforts.

Table 2: Radiprodil - Development History and Key Stakeholders

Era/Approx. Period	Key Developer(s)/Sponsor(s)	Indication(s) Pursued	Key Development Phase(s)	Major Outcomes/Status
Early - ~2010s	Gedeon Richter	Discovery, Neuropathic Pain	Preclinical, Phase I/II	Discovered RGH-896 (radiprodil). Initiated development for neuropathic pain.1
~2009 - ~2010s	Forest Laboratories, Gedeon Richter	Diabetic Peripheral Neuropathic Pain (DPNP)	Phase II (NCT00838799)	Co-development. Trial failed to meet primary efficacy endpoints. Development for DPNP discontinued.1
~2016 - ~2020s	UCB Biopharma S.P.R.L.	Infantile Spasms (IS)	Phase 1b, Phase 2	Phase 1b showed safety and potential efficacy in 3 infants.5 Phase 2 trial (NCT02829827) initiated but later terminated. Development for IS discontinued.1
~2023 - Present	GRIN Therapeutics, Inc. (affiliate of Neurvati Neurosciences)	GRIN-related Neurodevelopmental Disorders (GRIN-NDD)	Phase 1b (NCT05818943)	Honeycomb trial showed positive results: significant seizure reduction, good tolerability.6 Phase 3 pivotal trial planned for mid-2025.6 Multiple regulatory designations obtained (Orphan Drug, Breakthrough Therapy, PRIME).6
~2024 - Present	GRIN Therapeutics, Inc.	Tuberous Sclerosis Complex (TSC), Focal Cortical Dysplasia (FCD) Type II	Phase 1b/2a (NCT06392009)	Astroscape trial initiated and recruiting.2
2025 (Announced)	GRIN Therapeutics, Angelini Pharma, Blackstone Life Sciences	GRIN-NDD (Global, ex-North America for Angelini)	Commercialization Rights	Angelini Pharma collaboration for development & commercialization outside North America. Significant Series D financing led by Blackstone and Angelini.13

4. Clinical Development and Efficacy

The clinical development of radiprodil has spanned several indications, with varying degrees of success. Initial explorations in broader neuropathic pain and infantile spasms have given way to a more targeted approach in rare neurodevelopmental disorders.

4.1. Diabetic Peripheral Neuropathic Pain (DPNP)

Radiprodil (RGH-896) was evaluated in a Phase II, randomized, double-blind, placebo- and active comparator-controlled (pregabalin 100mg) trial (NCT00838799) for the treatment of DPNP.[2] The study, sponsored by Forest Laboratories and Gedeon Richter, enrolled 458 outpatients with painful polyneuropathy due to type 1 or type 2 diabetes. Participants received radiprodil at doses of 15mg, 30mg, or 45mg, pregabalin, or placebo for 14 weeks.[26] The primary endpoint was the change from baseline to Week 14 in mean daily pain rating.[25] The trial failed to demonstrate statistically significant or clinically meaningful reductions in mean daily pain scores for any of the radiprodil dosages compared to placebo.[25] Consequently, the development of radiprodil for DPNP was discontinued due to this lack of efficacy.[1]

4.2. Infantile Spasms (IS)

The investigation of radiprodil for IS was based on preclinical evidence showing its anti-seizure effects in juvenile animal models, which correlated with the high expression of the NR2B subunit during early development—the typical onset period for IS.[5]

A Phase 1b study conducted by UCB Biopharma involved three infants (2-14 months old) with IS resistant to standard treatments (vigabatrin and prednisolone). These infants received individually titrated doses of radiprodil for up to 34 days. The study reported that radiprodil was safe and well-tolerated, with an expected pharmacokinetic profile. In terms of efficacy, one infant became spasm-free, and this response persisted after radiprodil withdrawal. The other two infants showed clinical improvement but did not achieve spasm freedom, and their seizures worsened after withdrawal, necessitating other treatments.5

Following these initial findings, a Phase 2 study (NCT02829827) was initiated by UCB Biopharma to further evaluate radiprodil in subjects with drug-resistant IS.2 However, this trial was subsequently terminated.2 The specific reasons for the termination of NCT02829827 are not explicitly provided in the available snippets, but the overall development for IS was discontinued.1

4.3. GRIN-related Neurodevelopmental Disorders (GRIN-NDD)

The current primary focus for radiprodil development is GRIN-NDD, a group of rare, severe conditions caused by mutations in GRIN genes. Radiprodil's mechanism as a GluN2B NAM is particularly relevant for gain-of-function (GoF) mutations that lead to NMDA receptor hyperactivity.[4]

The Phase 1b Honeycomb trial (NCT05818943), sponsored by GRIN Therapeutics, is a global, open-label, multicenter study in pediatric patients (≥6 months to ≤12 years) with GRIN-related NDD and confirmed GoF mutations across various GRIN genotypes (GRIN1, GRIN2A, GRIN2B, GRIN2D).[2] Part A of the study included a screening period, a dose titration period (starting at 0.05 mg/kg, adjusted based on tolerability, PK, and predicted receptor occupancy), and an 8-week maintenance period. Part B is an ongoing open-label extension.[18] Topline results from the 15 participants in Phase 1b (Part A) were highly promising:

• Seizure Reduction: In the qualifying seizure cohort, patients experienced a median reduction of 86% in countable motor seizure (CMS) frequency from baseline. This effect was reported to be consistent across different GRIN genotypes with GoF variants.[6]
• Responder Rates: 71% of treated patients achieved a ≥50% reduction in CMS, and 43% experienced a >90% reduction.[9]
• Seizure Freedom: Six out of seven patients in the qualifying seizure cohort were seizure-free for ≥80% of days during the 8-week maintenance period, with one patient reported as completely seizure-free during this period.[9]
• Global and Behavioral Outcomes: Clinicians and caregivers generally assessed patients as improved clinically, as measured by the Clinician Global Impression of Change (CGI-C) and Caregiver Global Impression of Change (CaGI-C) scales. There was also a trend towards improved irritability scores on the Aberrant Behavior Checklist – Community (ABC-C), irrespective of seizure occurrence.[6]

Based on these positive results, GRIN Therapeutics plans to initiate a global Phase 3 pivotal trial for radiprodil in GRIN-NDD in mid-2025 (some sources cite early 2025).[6] This trial will be randomized, double-blind, and placebo-controlled, enrolling patients with confirmed GoF mutations in

GRIN1, GRIN2A, GRIN2B, or GRIN2D genes. It is expected to include cohorts of patients both with and without qualifying CMS to assess the drug's impact on a broader range of disease manifestations, including seizures, behavioral abnormalities, and functional outcomes.[6]

4.4. Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) Type II

The rationale for investigating radiprodil in TSC and FCD type II is based on findings of enhanced GluN2B NMDA receptor expression in brain lesions associated with these conditions.[4]

The Phase 1b/2a Astroscape trial (RAD-GRIN-201; NCT06392009), sponsored by GRIN Therapeutics, is currently recruiting children and adolescents (6 months to 18 years) with TSC or FCD type II who have seizures uncontrolled by at least two prior anti-seizure medications.2 This open-label study will assess the safety, tolerability, and pharmacokinetics of radiprodil, as well as its potential efficacy on seizure frequency and severity, behavioral symptoms, sleep, and quality of life. Part A of the study will last up to 6 months, followed by Part B, a long-term treatment period of one year or more.3 The target enrollment is approximately 20 participants with TSC and 10 with FCD type II.4

4.5. Pharmacokinetic (PK) Studies in Healthy Volunteers

Multiple Phase 1 studies have been conducted to characterize the PK profile, safety, and tolerability of radiprodil in healthy adult volunteers. These studies have evaluated various oral formulations (e.g., solution, spray-dried dispersion), dosing conditions (fasted vs. fed state), and potential drug-drug interactions (e.g., with rabeprazole, carbamazepine, itraconazole).[2] Data from these early adult studies, including those from the DPNP program, helped establish a well-tolerated exposure range that informed dose selection for subsequent pediatric studies, such as the IS trial.[5] At least 118 healthy volunteers have received radiprodil in these studies.[30]

The approach to dosing in the pediatric studies, particularly the Phase 1b IS study with individually titrated doses [5] and the Honeycomb trial's design involving dose escalation based on tolerability, PK, and predicted receptor occupancy [18], underscores the importance of individualized dosing. This is particularly critical in pediatric populations with neurodevelopmental disorders, which often exhibit significant genetic and phenotypic heterogeneity. Fine-tuning the modulation of NMDA receptors, which are vital for brain function, requires careful dose adjustment to maximize therapeutic benefit while minimizing potential adverse effects.

Furthermore, the inclusion of non-seizure endpoints—such as behavioral assessments, sleep parameters, and quality-of-life measures—in the Astroscape trial [4] and the planned Phase 3 GRIN-NDD trial [6] reflects a comprehensive approach to evaluating radiprodil's clinical value. Neurodevelopmental disorders like GRIN-NDD, TSC, and FCD impose a multifaceted burden that extends far beyond seizures.[3] The promising effects on global impression scales observed in the Honeycomb trial [6] suggest potential benefits in these broader domains. Demonstrating improvements in overall functioning and well-being will be crucial for establishing the holistic therapeutic impact of radiprodil for patients and their families.

Table 3: Summary of Key Radiprodil Clinical Trials (Discontinued/Historical)

Trial ID (Name)	Phase	Sponsor(s)	Indication	Key Design Features	Primary Outcome(s)	Key Efficacy Results	Safety Summary	Status/Reason for Discontinuation
NCT00838799	II	Forest Laboratories, Gedeon Richter	Diabetic Peripheral Neuropathic Pain (DPNP)	Randomized, double-blind, placebo- and active comparator-controlled (pregabalin), dose-response (15mg, 30mg, 45mg radiprodil), 14 weeks, 458 patients 26	Change in mean daily pain score 25	No statistically significant or clinically meaningful reduction in pain scores vs. placebo 25	Most common: dizziness, fatigue, insomnia. Rare serious AEs (balance disorder, confusion, suicidal ideation, TIA) in some patients with prolonged exposure 27	Discontinued due to lack of efficacy 1
Phase 1b (Unnamed)	Ib	UCB Biopharma	Infantile Spasms (IS)	Open-label, escalating repeated dose in 3 infants with treatment-resistant IS, up to 34 days 5	Safety, tolerability, PK, preliminary efficacy	1 infant spasm-free, 2 showed clinical improvement. Expected PK 5	Safe and well-tolerated 5	Completed; informed subsequent Phase 2
NCT02829827	II	UCB Biopharma S.P.R.L.	Drug-resistant Infantile Spasms (IS)	Not detailed in snippets	Not detailed in snippets	Not detailed in snippets	Not detailed in snippets	Terminated 2 (Specific reason for NCT02829827 not detailed, but IS program discontinued 1)

Table 4: Overview of Key Ongoing/Recent Radiprodil Clinical Trials (GRIN Therapeutics)

Trial ID (Name)	Phase	Indication(s)	Sponsor	Status (as of latest snippets)	Key Objectives/Endpoints	Reported/Anticipated Key Outcomes
NCT05818943 (Honeycomb)	Ib/IIa	GRIN-related Neurodevelopmental Disorders (GRIN-NDD) with GoF mutations	GRIN Therapeutics, Inc.	Part A completed, Part B (OLE) ongoing. Active, not recruiting for Part A 2	Safety, tolerability, PK, efficacy (seizure reduction, global/behavioral outcomes) 6	Median 86% reduction in CMS; 71% had >50% CMS reduction. Generally well-tolerated. Improvements in CGI-C, CaGI-C, ABC-C.6
Planned Pivotal Trial	III	GRIN-related Neurodevelopmental Disorders (GRIN-NDD) with GoF mutations	GRIN Therapeutics, Inc.	Planned for mid-2025 6	Efficacy (seizures, behavioral abnormalities, functional outcomes), safety	To be determined. Will include cohorts with and without qualifying CMS.6
NCT06392009 (Astroscape / RAD-GRIN-201)	Ib/IIa	Tuberous Sclerosis Complex (TSC), Focal Cortical Dysplasia (FCD) Type II	GRIN Therapeutics, Inc.	Recruiting 2	Safety, tolerability, PK, potential efficacy (seizures, behavioral symptoms, sleep, QoL) 3	To be determined.
Various Phase 1 PK studies (e.g., NCT02647697, NCT06965881)	I	Healthy Volunteers	UCB Biopharma S.P.R.L., GRIN Therapeutics, Inc.	Some completed, some not yet recruiting/ongoing 2	Safety, tolerability, PK of different formulations, DDI	Established PK profile, generally well-tolerated in adults.5

5. Safety and Tolerability Profile

The safety and tolerability of radiprodil have been evaluated across different patient populations and in healthy volunteers, with the profile appearing to evolve with the target indication and age group.

5.1. Overview from Diabetic Peripheral Neuropathic Pain (DPNP) Trials (Adults)

In the DPNP program, radiprodil was administered to 332 adult patients, in addition to 118 healthy volunteers in Phase 1 studies.[5] The most frequently reported adverse events (AEs) in DPNP patients treated with radiprodil were dizziness, fatigue, and insomnia.[27] While generally considered to have an acceptable tolerability range for these earlier studies, some rare but serious AEs were noted as possibly related to radiprodil, particularly with continuous exposure exceeding one week. These included balance disorder, mental status changes, confusion, and suicidal ideation. A transient ischemic attack (TIA) was observed in one patient who had predisposing risk factors. These serious events were reported to be reversible upon discontinuation of the drug.[30]

5.2. Overview from Infantile Spasms (IS) Trial (Infants)

In the Phase 1b study involving three infants with treatment-resistant IS, radiprodil was reported to be safe and well-tolerated.[5] Specific adverse event details for this very small cohort are limited in the provided summaries beyond this general statement.

5.3. Overview from GRIN-related Neurodevelopmental Disorders (GRIN-NDD) Honeycomb Trial (Pediatric)

In the Phase 1b Honeycomb trial in pediatric patients with GRIN-NDD, radiprodil was generally well-tolerated.[6] The most commonly observed AEs were those typically associated with intercurrent infections or manifestations of the underlying complex neurodevelopmental disorder. These included pyrexia, diarrhea, respiratory tract infection, abnormal behavior, agitation, cough, dystonia, fatigue, and gastroenteritis.[6] Three serious adverse events (SAEs) were reported during the trial: obstructive bronchitis, viral pneumonia, and adenovirus infection. Importantly, all three SAEs were assessed by investigators as unrelated to radiprodil, and none of these events led to treatment discontinuation or met study stopping criteria.[6]

5.4. Overview from Healthy Volunteer Studies

Data from 118 healthy adult volunteers who received radiprodil indicated that the most frequently observed AEs were headache, somnolence (feeling sleepy), dizziness, disturbance in attention, insomnia, altered mood, oropharyngeal (throat) pain, and euphoric mood.[30]

5.5. General Safety Considerations

The safety profile of radiprodil appears to differ somewhat based on the patient population and age group. In adult DPNP patients, some CNS effects, including rare instances of suicidal ideation, were observed.[30] In contrast, in the pediatric neurodevelopmental disorder populations studied more recently, AEs have been more commonly characterized as related to infections or symptoms of the underlying condition, with a generally well-tolerated profile reported for radiprodil itself.[6] This distinction warrants careful ongoing monitoring in current and future pediatric trials.

The interpretation of adverse events in vulnerable pediatric populations with severe, complex neurodevelopmental disorders like GRIN-NDD, TSC, or FCD requires careful consideration. Many of the reported AEs, such as infections or behavioral disturbances (e.g., agitation), are common in these patient populations irrespective of investigational drug treatment.[6] Differentiating drug-related AEs from manifestations of the underlying disease or intercurrent illnesses is a known challenge in such studies. The open-label design of some early-phase studies (e.g., Honeycomb, Astroscape) [3] makes definitive attribution of AEs more complex without a concurrent placebo comparator. The planned Phase 3 placebo-controlled trials will be critical for establishing a clearer and more robust safety profile for radiprodil in its target pediatric indications. The positive sign from the Honeycomb trial is that the SAEs observed were deemed unrelated to radiprodil by investigators [6], supporting continued development.

6. Regulatory Status and Designations

Radiprodil has received several important regulatory designations from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), underscoring its potential to address significant unmet medical needs in rare neurodevelopmental disorders.

6.1. US Food and Drug Administration (FDA)

• Orphan Drug Designation (ODD): Radiprodil was granted ODD by the FDA for the treatment of GRIN-related Neurodevelopmental Disorder (NDD).[6] This designation was announced on March 17, 2025.[7] ODD is granted to drugs intended for rare diseases affecting fewer than 200,000 people in the U.S. and provides benefits such as tax credits for clinical trials, exemption from user fees, and the potential for seven years of market exclusivity upon approval.[7]
• Breakthrough Therapy Designation: In February 2025, the FDA granted Breakthrough Therapy designation to radiprodil for the treatment of seizures associated with GRIN-related NDD in patients with gain-of-function (GoF) mutations.[6] This designation is intended to expedite the development and review of drugs for serious or life-threatening conditions where preliminary clinical evidence indicates substantial improvement over available therapies on a clinically significant endpoint. It allows for more intensive FDA guidance and a rolling review of the marketing application.[22]
• Rare Pediatric Disease Designation: Radiprodil has also received Rare Pediatric Disease designation from the FDA for GRIN-NDD.[13] This designation can make the drug eligible for a Priority Review Voucher upon approval, which can be used to expedite the review of a subsequent drug application or sold to another company.

6.2. European Medicines Agency (EMA)

• Priority Medicines (PRIME) Designation: The EMA granted PRIME designation to radiprodil for the treatment of GRIN-related NDD.[6] This was announced on April 1, 2025.[6] The PRIME scheme offers enhanced support to developers of medicines that target an unmet medical need, including early dialogue, scientific advice, and potentially accelerated assessment of the marketing authorization application.[6]
• Orphan Designation: The EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for orphan designation for radiprodil for the treatment of GRIN-related NDD.[11] This was announced on May 6, 2025.[12] Similar to the FDA's ODD, this designation provides incentives such as protocol assistance and market exclusivity in the EU for ten years post-authorization.

The attainment of multiple expedited regulatory designations from both the FDA and EMA is a significant validation of radiprodil's potential in GRIN-NDD. These designations collectively signal strong regulatory support, acknowledging the high unmet medical need in this severe, rare pediatric disorder and the promising nature of the early clinical data emerging from trials like Honeycomb.[6] Such pathways are designed to de-risk development and accelerate the availability of potentially transformative therapies to patients. The combination of Orphan Drug status, Breakthrough Therapy designation in the US, and PRIME designation in Europe provides GRIN Therapeutics with enhanced opportunities for regulatory interaction, guidance on clinical trial design, and potentially faster review timelines, all of which are crucial for navigating the path to market for a novel therapy in a rare disease.

Table 5: Summary of Regulatory Designations for Radiprodil

Regulatory Agency	Designation	Indication	Date Granted/Announced	Key Benefits
US FDA	Orphan Drug Designation (ODD)	GRIN-related Neurodevelopmental Disorder (GRIN-NDD)	March 17, 2025 7	Tax credits, user fee waivers, potential 7-year market exclusivity post-approval.7
US FDA	Breakthrough Therapy Designation	Seizures associated with GRIN-related NDD in patients with GoF mutations	February 2025 6	Expedited development and review, intensive FDA guidance, rolling review.22
US FDA	Rare Pediatric Disease Designation	GRIN-related Neurodevelopmental Disorder (GRIN-NDD)	Mentioned 13 (Date not specified)	Potential for Priority Review Voucher upon approval.
EMA	Priority Medicines (PRIME) Designation	GRIN-related Neurodevelopmental Disorder (GRIN-NDD)	April 1, 2025 6	Enhanced interaction, early dialogue, scientific advice, potential for accelerated assessment.6
EMA	Orphan Designation (Positive CHMP Opinion)	GRIN-related Neurodevelopmental Disorder (GRIN-NDD)	May 6, 2025 (Opinion) 12	Protocol assistance, potential 10-year market exclusivity in EU post-authorization.

7. Conclusion and Future Perspectives

7.1. Summary of Development Trajectory

Radiprodil's development journey exemplifies a strategic evolution common in the pharmaceutical industry. Initially investigated for broader neurological conditions such as Diabetic Peripheral Neuropathic Pain and Infantile Spasms, the drug did not demonstrate sufficient efficacy to warrant continued development in these areas. However, rather than being abandoned, its well-defined mechanism of action as a selective negative allosteric modulator of GluN2B-containing NMDA receptors paved the way for its repositioning. The current focus on rare, often genetically-defined, neurodevelopmental disorders like GRIN-NDD, TSC, and FCD Type II represents a targeted, precision-medicine approach where the drug's specific pharmacological activity aligns directly with the known or suspected pathophysiology of these conditions.

7.2. Current Standing and Potential

Radiprodil, under the stewardship of GRIN Therapeutics and its partners, has shown considerable promise in its revised indications. Early clinical data from the Phase 1b Honeycomb trial in pediatric patients with GRIN-NDD have been particularly encouraging, demonstrating significant reductions in seizure frequency and a generally well-tolerated safety profile.[6] These positive findings have been instrumental in securing multiple expedited regulatory designations from both the FDA and EMA, including Orphan Drug, Breakthrough Therapy, and PRIME status.[6] Ongoing trials, such as the Astroscape study for TSC and FCD Type II, will further delineate its therapeutic utility in conditions characterized by GluN2B overexpression or dysfunction.[2] The commitment of significant financial backing and strategic collaborations, notably with Blackstone Life Sciences and Angelini Pharma, provides a robust foundation for late-stage development and potential global commercialization.[6]

7.3. Unmet Needs and Future Outlook

Radiprodil is being developed to address a profound unmet medical need for effective and targeted therapies for severe, rare pediatric neurodevelopmental disorders, for which there are currently no specifically approved treatments.[7] The successful completion and positive outcome of the planned Phase 3 pivotal trial for GRIN-NDD will be a critical determinant of its future. Beyond seizure control, the evaluation of radiprodil's impact on non-seizure endpoints such as behavioral disturbances, cognitive function, sleep, and overall quality of life will be vital in establishing its comprehensive therapeutic value for these complex disorders.

The development of radiprodil is emblematic of the evolving landscape in rare disease drug development. Advances in genetic understanding, the capacity for targeted therapeutic approaches, robust patient advocacy, and supportive regulatory environments (offering incentives and expedited pathways) are collectively making it more feasible to tackle diseases previously considered too niche or complex for pharmaceutical intervention.[4] This confluence of factors fosters an environment conducive to innovation for patient populations with limited or no therapeutic options.

Furthermore, the emphasis in current and planned trials on assessing a broader range of outcomes beyond just seizure frequency—including behavioral, sleep, and quality-of-life measures [3]—signals a critical shift towards more holistic therapeutic goals in the management of neurodevelopmental disorders. While seizure reduction is an important and often primary endpoint, improvements in overall daily functioning, cognitive abilities, and the well-being of both patients and their families are increasingly recognized as vital indicators of a therapy's true impact. Demonstrating benefits across these multifaceted domains will be essential for radiprodil to establish its comprehensive value to patients, caregivers, clinicians, regulatory authorities, and payers. The journey of radiprodil, from its initial explorations to its current focused development, offers a compelling case study in the pursuit of targeted therapies for complex neurological conditions.

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