Carisbamate (DB12338): A Comprehensive Monograph on an Investigational Neuromodulator for Epilepsy

Section 1.0: Introduction to Carisbamate: An Investigational Neuromodulator

Carisbamate is an investigational, orally active, small molecule neuromodulator that has been the subject of extensive clinical research for various central nervous system (CNS) disorders, with a primary focus on epilepsy.[1] The developmental trajectory of this compound provides a compelling case study in pharmaceutical lifecycle management, characterized by a strategic repositioning following significant regulatory setbacks. Initially developed for a broad indication as an adjunctive treatment for partial-onset seizures, Carisbamate failed to secure marketing approval from major regulatory bodies. Subsequently, its development was redirected to target Lennox-Gastaut Syndrome (LGS), a rare, severe, and highly refractory form of childhood-onset epilepsy.[5]

Chemically classified as an organochlorine compound and an alkyl-carbamate, Carisbamate is structurally similar to felbamate, an antiepileptic drug (AED) approved in 1993.[5] Felbamate, while demonstrating broad-spectrum anticonvulsant activity, has its use severely restricted due to associations with fatal aplastic anemia and hepatotoxicity.[5] This chemical lineage immediately places Carisbamate's development within a critical context: the pursuit of novel carbamate-based therapies that retain anticonvulsant efficacy while offering a substantially improved safety profile.

The history of Carisbamate's development is a narrative of shifting strategies dictated by clinical trial outcomes and the evolving regulatory landscape. The initial pursuit of approval for partial-onset seizures, a large and competitive market, culminated in a New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) in 2008.[9] However, the subsequent receipt of a Complete Response Letter in 2009 and the withdrawal of its European marketing application in 2010, citing a lack of consistent efficacy across a clinically relevant dose range, marked a significant failure point for the program.[5] This outcome suggested that the drug's risk-benefit profile was deemed insufficient for a market with numerous established therapeutic alternatives.

Following this, the program underwent a strategic pivot. Recognizing that a compound with a modest but potentially meaningful effect and a manageable safety profile might hold value in an area of high unmet medical need, the developer, SK Life Science, secured Orphan Drug Designation for LGS from the FDA in 2017.[12] This move repositioned Carisbamate from a potential competitor in a crowded field to a targeted therapy for a devastating and difficult-to-treat orphan disease. For conditions like LGS, the risk-benefit calculus for both patients and regulators is fundamentally different, creating a new pathway for a drug that had previously failed. This report provides a comprehensive monograph on Carisbamate, detailing its molecular profile, mechanism of action, pharmacokinetics, clinical development history, safety profile, and the complex regulatory journey that has defined its path toward potential therapeutic use.

Section 2.0: Physicochemical Properties and Molecular Profile

Carisbamate is a single enantiomer small molecule, distinguished by a specific set of chemical and physical properties that define its identity and inform its pharmacological behavior. Its unique structure and stereochemistry are central to its activity and metabolic fate.

The compound is systematically identified by its Chemical Abstracts Service (CAS) Registry Number, 194085-75-1, and its DrugBank Accession Number, DB12338.[1] Its molecular formula is

C9​H10​ClNO3​, corresponding to an average molecular weight of 215.63 g/mol and a precise monoisotopic mass of 215.0349209 Da.[1]

The stereospecificity of Carisbamate is a critical feature, formally designated in its International Union of Pure and Applied Chemistry (IUPAC) name: carbamate.[8] This "(S)" configuration at the chiral center is essential for its intended biological activity. The existence of its optical isomer, (R)-Carisbamate, as a distinct chemical entity (CAS 194085-74-0) underscores the stereospecific nature of the drug's development and pharmacology.[17] For computational and database referencing, its structure is represented by the Simplified Molecular-Input Line-Entry System (SMILES) string

C1=CC=C(C(=C1)[C@@H](COC(=O)N)O)Cl and the IUPAC International Chemical Identifier Key (InChIKey) OLBWFRRUHYQABZ-MRVPVSSYSA-N.[8]

Throughout its development, Carisbamate has been known by several code designations, including RWJ-333369, YKP-509, and JNJ-10234094.[4] The proposed brand name for its initial marketing application was Comfyde.[8] These various identifiers are crucial for tracing its extensive history through scientific literature and clinical trial registries. The key physicochemical and identifying properties are summarized in Table 1.

The stereochemistry of Carisbamate is not merely a structural footnote but a fundamental aspect of its in vivo behavior. The active pharmaceutical ingredient is the (S)-enantiomer. However, pharmacokinetic studies have revealed that a minor metabolic pathway involves chiral inversion, leading to the formation of the (R)-Carisbamate enantiomer, which is then subject to O-glucuronidation.[22] This metabolic conversion from the active (S)-form to the (R)-form raises important pharmacological questions regarding the activity and safety profile of the (R)-metabolite. Whether this metabolite is pharmacologically active, inactive, or contributes to the adverse effect profile is a key consideration for a complete understanding of the drug's disposition and effects in the body. This interplay between the drug's specific three-dimensional structure and its metabolic processing highlights the sophistication required in modern drug design, manufacturing, and toxicological assessment.

Table 1: Key Identifiers and Physicochemical Properties of Carisbamate

Property	Value	Source(s)
Generic Name	Carisbamate	1
DrugBank ID	DB12338	1
CAS Number	194085-75-1	8
IUPAC Name	carbamate	8
Molecular Formula	C9​H10​ClNO3​	8
Average Weight	215.63 g/mol	1
Monoisotopic Mass	215.0349209 Da	1
SMILES	C1=CC=C(C(=C1)[C@@H](COC(=O)N)O)Cl	8
InChIKey	OLBWFRRUHYQABZ-MRVPVSSYSA-N	8
Key Synonyms/Codes	RWJ-333369, YKP-509, JNJ-10234094, Comfyde	4

Section 3.0: Preclinical and Clinical Pharmacology

The pharmacological profile of Carisbamate is defined by its effects on neuronal ion channels, leading to broad-spectrum anticonvulsant activity in preclinical models. While its mechanism of action (MoA) has been described in high-level summaries as "unknown," specific molecular targets and functional effects have been well-characterized through in vitro and in vivo studies.[5]

3.1 Mechanism of Action (MoA)

The primary and most extensively documented mechanism of action for Carisbamate is the inhibition of voltage-gated sodium channels.[3] Electrophysiological studies using whole-cell patch clamp recording have demonstrated that Carisbamate produces a concentration-, voltage-, and use-dependent inhibition of rat Nav1.2 sodium channels, a key isoform in the CNS.[28] This inhibition was quantified with a half-maximal inhibitory concentration (

IC50​) value of 68 µM.[25] A similar effect was observed in cultured rat hippocampal neurons, where Carisbamate blocked voltage-gated sodium channels with an

IC50​ of 89 µM.[28] The "use-dependent" nature of this blockade is a critical feature of many effective AEDs, as it implies that the drug preferentially binds to and inhibits channels on neurons that are firing repetitively and excessively, as occurs during a seizure, while having less effect on neurons firing at normal physiological rates.

The functional consequence of this sodium channel blockade is the inhibition of sustained repetitive firing (SRF) of action potentials in hippocampal neurons.[23] At therapeutically relevant concentrations, Carisbamate dose-dependently reduced SRF, with inhibitions of 46% at 30 µM and 87% at 100 µM.[28] This action is believed to be a primary contributor to its anticonvulsant effects by preventing the spread of seizure activity.[23] In these studies, Carisbamate had no effect on the steady-state membrane potential or on voltage-gated potassium channels, indicating a degree of selectivity in its ion channel modulation.[28]

In addition to its primary effect on sodium channels, Carisbamate has been shown to modulate T-type voltage-gated calcium channels, though this appears to be a secondary and weaker mechanism. It reduces T-type Ca2+ currents in HEK cells transfected with human recombinant Cav3.1 channels, but this effect was observed at a higher concentration of 300 µM.[3]

Despite the clear evidence for sodium channel blockade, there is a significant scientific tension regarding whether this mechanism fully accounts for Carisbamate's anticonvulsant profile. This is highlighted by a key preclinical study in a multiple-hit rat model of infantile spasms, a severe early-life epileptic encephalopathy.[29] In this model, Carisbamate at doses of 30 and 60 mg/kg acutely and dose-dependently suppressed both behavioral and electroclinical spasms. In stark contrast, phenytoin, a classic and potent sodium channel blocker, was completely ineffective at doses of 20 or 50 mg/kg.[29] The investigators of this study concluded that the suppression of spasms by Carisbamate in this model is likely not mediated via sodium channel blockade. This finding directly challenges the assumption that sodium channel inhibition is the sole driver of its anticonvulsant activity across all seizure types. It suggests a more complex MoA, where its secondary effects on T-type calcium channels—known to be implicated in generalized epilepsies—or other, yet-to-be-elucidated targets may be critically important. This mechanistic complexity could help explain both its inconsistent performance in focal epilepsy trials and its renewed potential in a generalized epileptic encephalopathy like LGS.

3.2 Preclinical Efficacy and Comparative Potency

Carisbamate has demonstrated a robust and broad-spectrum anticonvulsant profile across a wide range of preclinical seizure models, supporting its initial development as a novel AED. Its efficacy has been established in models representing different seizure types, including generalized and partial epilepsies.[23]

The drug has shown activity against seizures induced by maximal electroshock (MES), a model sensitive to sodium channel blockers, as well as against seizures induced by the chemoconvulsants pentylenetetrazole (PTZ), bicuculline, and picrotoxin.[23] It has also demonstrated efficacy in genetic models, such as the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model of absence seizures, and in the Wistar audiogenic sensitive rat model of convulsive seizures.[3] Furthermore, Carisbamate has shown efficacy in more complex models of chronic epilepsy, such as the hippocampal and corneal kindling models of partial seizures, and it substantially reduces spontaneous motor seizures in rats with kainate-induced epilepsy.[23] In vitro studies on cultured hippocampal neurons further support its antiepileptic potential, showing that it prevents the development and production of epileptiform-like discharges and exhibits neuroprotective effects following status epilepticus-like injury.[2]

A particularly informative aspect of its preclinical profile comes from a direct comparative study of its anticonvulsant potency against eight marketed AEDs in conventional mouse seizure screens.[30] The results of this comparison reveal a unique potency profile that distinguishes Carisbamate from other agents.

• In the MES test, Carisbamate ranked fourth in potency, a respectable but not exceptional performance for a sodium channel blocker.
• However, its potency was notably higher in models involving antagonism of the GABAergic system, the brain's primary inhibitory network. It ranked first in potency against seizures evoked by both PTZ and picrotoxin (a GABAA receptor antagonist), and second against seizures evoked by bicuculline (another GABAA antagonist).[30]

This exceptional potency in models where seizures are triggered by overcoming GABAergic inhibition, relative to its more moderate potency in the sodium channel-dependent MES model, is a significant finding. While direct effects on GABA receptors have not been reported, this strong functional activity suggests that Carisbamate's mechanism is particularly effective at counteracting states of reduced neuronal inhibition, a fundamental pathophysiology in many forms of epilepsy. This provides a more nuanced understanding of its preclinical profile beyond that of a simple sodium channel blocker and may hint at downstream effects relevant to its clinical activity.

Section 4.0: Pharmacokinetics, Metabolism, and Drug Interactions

The clinical pharmacology of Carisbamate is characterized by a generally favorable pharmacokinetic profile, including linear kinetics and high oral bioavailability. However, its metabolic pathway, while avoiding the problematic cytochrome P450 system, creates a susceptibility to interactions with common AEDs that likely played a significant role in its clinical development history.

4.1 ADME Profile

Carisbamate exhibits predictable pharmacokinetic behavior following oral administration. Studies in healthy volunteers have demonstrated that it follows linear pharmacokinetics across a single and repetitive dose range of 100–750 mg.[22]

• Absorption: After oral administration, Carisbamate is well-absorbed, reaching peak plasma concentrations (Tmax​) approximately 1 to 2 hours post-dose.[31] The oral bioavailability is high, estimated to be at least 94%, as indicated by a total urinary recovery of 94% of the administered dose.[22] The presence of food does not alter its pharmacokinetics to a clinically relevant extent, allowing for dosing without regard to meals.[22]
• Distribution: The drug has an apparent volume of distribution (V/F) of approximately 62–66 L, suggesting distribution beyond the plasma volume into tissues.[22] There is no effect of age on the plasma protein binding of Carisbamate.[32]
• Metabolism: Carisbamate is extensively metabolized, with only about 2% of an administered dose being excreted as unchanged drug in the urine.[22] Its metabolism is discussed in detail in the following section.
• Excretion: The primary route of excretion is renal. The drug has a low oral clearance (CL/F) of 3.4–4.2 L/h and a mean elimination half-life (t1/2​) of approximately 10.6–12.8 hours, which supports a twice-daily (q12h) dosing regimen.[22] Renal clearance (CLr) ranges from 55–94 mL/h.[22] Studies have shown that renal clearance decreases with age, but due to the limited role of direct renal elimination for the parent drug, this decrease does not have a significant effect on the total clearance of Carisbamate.[32]

Pharmacokinetic studies comparing Japanese and Caucasian subjects found that while unadjusted plasma exposure (AUC) and Cmax​ were 20-29% higher in Japanese subjects, these differences were eliminated after normalization for body weight, indicating similar intrinsic pharmacokinetics between the two populations.[33] Furthermore, age was found to have no clinically significant effect on the pharmacokinetics of the immediate-release formulation of Carisbamate.[32]

4.2 Metabolism and Drug Interactions

A defining feature of Carisbamate's profile is its metabolic pathway, which largely bypasses the cytochrome P450 (CYP) enzyme system—a common source of drug-drug interactions (DDIs) for many CNS agents.[34] The primary routes of metabolism for Carisbamate are:

1. O-glucuronidation: Direct conjugation with glucuronic acid, mediated by UDP-glucuronosyltransferases (UGTs).
2. Carbamate ester hydrolysis: Cleavage of the carbamate group, followed by subsequent oxidation of the aliphatic side chain.[22]

Minor metabolic pathways include chiral inversion to (R)-carisbamate and hydroxylation of the aromatic ring followed by sulfation.[22] The low potential for reactive metabolite formation is suggested by the detection of only trace amounts (<0.3% of the dose) of mercapturic acid conjugates in urine.[22]

While the non-CYP metabolism is an advantage, it does not render Carisbamate free from clinically significant DDIs. Its reliance on UGT-mediated clearance creates a critical vulnerability to interactions with drugs that induce these enzymes. This is particularly relevant in the context of epilepsy treatment, where many first-line and older AEDs are potent UGT inducers. Co-administration of Carisbamate with carbamazepine or phenytoin results in a substantial increase in its clearance, leading to a 36% and 47% reduction in mean plasma concentrations, respectively.[22] This pharmacokinetic interaction is highly significant, as it can lower Carisbamate exposure to sub-therapeutic levels in patients taking these common concomitant medications. This "hidden vulnerability" likely contributed to the findings of "inconsistent efficacy" in the large partial-onset seizure trials, which enrolled highly refractory patients who were often on polypharmacy regimens that included these very inducers.[5] In such a trial, a large subset of participants in the active treatment arm would have had significantly lower-than-expected drug exposure, confounding the dose-response analysis and masking the drug's true effect.

Carisbamate can also act as a weak inducer of metabolism for other drugs. It has been shown to slightly increase the clearance of valproic acid and lamotrigine.[34]

In addition to these pharmacokinetic interactions, Carisbamate exhibits significant pharmacodynamic interactions. As a CNS-active agent, it produces additive CNS depressant effects when combined with a wide array of other drugs that act on the central nervous system. This includes an increased risk or severity of CNS depression when co-administered with benzodiazepines, opioids (e.g., alfentanil), tricyclic antidepressants (e.g., amitriptyline), antipsychotics (e.g., aripiprazole), and other sedating agents like baclofen and azelastine.[1]

Finally, there is a noted risk of an increase in methemoglobinemia when Carisbamate is combined with certain local anesthetics (e.g., articaine, bupivacaine, butacaine) and other specific drugs like ambroxol and capsaicin.[1]

Section 5.0: Clinical Development Program: Efficacy and Safety Evaluation

The clinical development of Carisbamate has been extensive, spanning multiple indications, phases, and sponsors. The program is best understood as two distinct chapters: an initial, broad exploration that ultimately failed to gain regulatory approval for common conditions, followed by a highly focused, strategic revival targeting a rare and severe epileptic encephalopathy.

5.1 Indication: Epilepsy

Epilepsy has been the central focus of Carisbamate's development, but the specific target population has changed dramatically over time.

5.1.1 Partial-Onset Seizures (Discontinued)

The initial and most extensive clinical program for Carisbamate was as an adjunctive therapy for adults with drug-resistant partial-onset seizures. This program included several Phase II and III randomized, double-blind, placebo-controlled trials.[5] A 2021 Cochrane systematic review and meta-analysis synthesized the data from four pivotal trials (NCT00228969, NCT00740623, NCT00425282, NCT00433667), which collectively enrolled 2211 participants.[5]

The meta-analysis found that, for the primary outcome of responder rate (proportion of patients achieving a 50% or greater reduction in seizure frequency), Carisbamate was statistically superior to placebo, with a risk ratio (RR) of 1.36 (95% CI 1.14 to 1.62).[39] This suggests that patients on Carisbamate were 36% more likely to be responders than those on placebo. However, the certainty of this evidence was rated as moderate, and the evidence for all other outcomes was considered low to very low.[5] This was largely due to a substantial risk of bias across the included trials, particularly a high risk of attrition bias stemming from incomplete reporting and high rates of treatment withdrawal, especially in the higher dose groups.[39] While some patients did achieve seizure freedom, the effect was not statistically significant compared to placebo (RR 2.43, 95% CI 0.84 to 7.03).[40]

The challenges faced by the program were further underscored by the Carisbamate Retention Study (CaReS), a large Phase III head-to-head trial (NCT00563459) designed to compare the long-term effectiveness, safety, and tolerability of Carisbamate against two widely prescribed AEDs, topiramate and levetiracetam.[36] This ambitious study was ultimately terminated early, with the sponsor noting that prior studies "lacked consistent efficacy data," signaling a loss of confidence in the drug's viability for this indication.[36] The combination of inconsistent efficacy, a narrow therapeutic window, and a high dropout rate in pivotal trials ultimately led to the failure to secure regulatory approval from the FDA and EMA for partial-onset seizures.[5]

5.1.2 Lennox-Gastaut Syndrome (LGS) (Active)

Following the discontinuation of the partial-onset seizure program, development was strategically pivoted to Lennox-Gastaut Syndrome (LGS), a severe epileptic encephalopathy with high unmet medical need. This shift was formalized when Carisbamate received Orphan Drug Designation for the treatment of LGS from the U.S. FDA on August 2, 2017.[12]

The new program began with a Phase I, open-label, dose-escalation study (NCT03731715, NCT04062981) to assess the pharmacokinetics, safety, and tolerability of single and multiple doses of Carisbamate in pediatric and adult patients with LGS (ages ≥2 years).[31] This study was crucial for establishing a safe and effective dosing strategy in a pediatric population. The results demonstrated that Carisbamate exhibited linear, dose-proportional pharmacokinetics after both single and multiple doses. Population PK modeling based on these results indicated that adult dosing regimens were appropriate for patients aged 12 and older, whereas weight-based dosing was necessary for patients aged 4 to <12 years.[31]

These foundational data paved the way for the ongoing pivotal Phase III trial, known as the "LGS DISCOVER Study" (NCT05219617; YKP509C003).[7] This is a global, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of Carisbamate as an adjunctive treatment for seizures associated with LGS. The trial aims to enroll over 250 patients aged 4 to 55 years who are currently taking one to four concomitant ASMs.[7] Participants are randomized to one of three arms: two different doses of Carisbamate (or their pediatric weight-based equivalents) or a matched placebo, administered as an oral suspension twice daily.[46] The primary efficacy endpoint of the study is the percentage change from baseline in the frequency of drop seizures (defined as tonic, atonic, and tonic-clonic seizures that could lead to a fall) during the double-blind treatment period.[46] The successful outcome of this trial is critical for the future of Carisbamate.

Table 2: Summary of Major Clinical Trials for Carisbamate in Epilepsy

NCT Identifier	Study Name/Title	Phase	Indication	Design	Comparators	Status	Key Findings/Relevance
Partial-Onset Seizures
NCT00433667	Efficacy and Safety of RWJ-333369 as Add-on Therapy	3	Partial-Onset Seizures	RCT	Placebo	Completed	Part of the meta-analysis showing modest efficacy but high attrition.
NCT00425282	Efficacy and Safety of RWJ-333369 as Add-on Therapy	3	Partial-Onset Seizures	RCT	Placebo	Completed	Contributed to the NDA submission and subsequent Cochrane review.
NCT00740623	Efficacy and Safety of RWJ-333369 as Add-on Therapy	3	Partial-Onset Seizures	RCT	Placebo	Completed	Another pivotal trial included in the failed regulatory submissions.
NCT00563459	Carisbamate Retention Study (CaReS)	3	Partial-Onset Seizures	RCT	Topiramate, Levetiracetam	Terminated	Head-to-head trial terminated due to lack of consistent efficacy in prior studies.
Lennox-Gastaut Syndrome
NCT03731715	Carisbamate in Adult & Pediatric Subjects With LGS	1	Lennox-Gastaut Syndrome	Open-Label	N/A	Completed	Established PK, safety, and dosing for pediatric and adult LGS patients.
NCT05219617	LGS DISCOVER Study	3	Lennox-Gastaut Syndrome	RCT	Placebo	Recruiting	Pivotal trial to evaluate efficacy in reducing drop seizures.

5.2 Discontinued Indications

In parallel with its early epilepsy program, Carisbamate was investigated for several other CNS disorders, primarily neuropathic pain. However, these explorations did not yield positive results and were subsequently discontinued.[6]

5.2.1 Neuropathic Pain

A series of three proof-of-concept, randomized, double-blind, placebo-controlled trials were conducted to evaluate Carisbamate's efficacy in treating pain associated with postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN).[48]

• Two studies used a crossover design with Carisbamate 400 mg/day versus placebo in patients with PHN (n=91) and DPN (n=137).[50]
• A third, larger study in DPN (n=386) used a parallel-group design to test higher doses of Carisbamate (800 mg/day and 1200 mg/day) against both placebo and an active comparator, pregabalin (300 mg/day).[48]

The results were consistently negative across all three trials. For the primary efficacy endpoint—the mean of the last seven average daily pain scores—neither Carisbamate at any dose nor the active comparator pregabalin demonstrated a statistically significant difference from placebo.[50] While the drug was generally well-tolerated in these populations, the lack of efficacy led to the discontinuation of development for neuropathic pain indications.[6]

5.2.2 Other CNS Disorders

Development has also been discontinued for other indications following early-phase trials. A Phase II proof-of-concept study (NCT00524056) was completed to assess the effectiveness of Carisbamate in the treatment of Essential Tremor.[51] Additionally, a double-blind, placebo-controlled trial in 323 patients with migraine failed to demonstrate that Carisbamate was sufficiently more effective than placebo for migraine prophylaxis, despite being well-tolerated at doses up to 600 mg/day.[21] These negative findings resulted in the cessation of development for these conditions.[6]

Section 6.0: Safety and Tolerability Profile

The safety and tolerability profile of Carisbamate has been extensively characterized across numerous clinical trials involving thousands of patients. The data consistently show a profile dominated by dose-dependent CNS-related adverse events, which ultimately define the drug's therapeutic window and played a pivotal role in its development history.

The most frequently reported treatment-emergent adverse events (TEAEs) across the clinical program are headache, dizziness, and somnolence.[5] These events are typically mild to moderate in severity and exhibit a clear dose-dependent relationship, with a higher incidence observed at doses of 1000 mg/day or more.[38] The Cochrane meta-analysis of the partial-onset seizure trials provided quantitative estimates of these risks. Compared to placebo, patients receiving Carisbamate were approximately twice as likely to experience dizziness (RR 2.06, 95% CI 1.23 to 3.44) and somnolence (RR 1.82, 95% CI 1.28 to 2.58).[39] Subgroup analyses within this review confirmed that the risk for these AEs, as well as for headache and treatment withdrawal, was driven primarily by the higher doses tested (e.g., 800-1600 mg/day).[54]

This dose-limiting CNS toxicity is central to understanding the drug's initial failure. The effective dose range appeared to overlap significantly with the poorly tolerated dose range. This created a clinical development paradox where the doses required to achieve robust efficacy in a broad, refractory population were the same doses that led to intolerable side effects and high rates of study discontinuation. For example, in the partial seizure trials, the rate of discontinuation due to adverse events was significantly higher in high-dose groups (RR 2.71) but not in low-dose groups (RR 0.94).[54] This narrow therapeutic index—the ratio of efficacy to toxicity—is a classic reason for drug development failure and explains the regulatory conclusion of an unfavorable risk-benefit profile for the broad indication of partial-onset seizures. The current LGS trial, which utilizes a maximum dose of 600 mg/day (or pediatric equivalent), appears to be designed to operate within a more tolerable dosage window.[46]

While generally considered to have a good safety profile outside of these CNS effects, rare instances of other safety signals have been noted. In two large studies involving 752 Carisbamate-treated patients, two individuals (0.3%) experienced clinically significant elevations of alanine aminotransferase (ALT), one of whom was diagnosed with an acute hepatitis B infection.[55] This suggests a need for monitoring liver function, although the overall incidence of hepatotoxicity appears to be low. The most common adverse events and key drug interactions are summarized in Table 3.

Table 3: Common Adverse Events and Clinically Significant Drug-Drug Interactions

Part A: Common Adverse Events (from Partial Seizure Trials)
Adverse Event
Dizziness
Somnolence
Headache
Fatigue
Nausea
Part B: Clinically Significant Drug-Drug Interactions
Interacting Drug/Class
Carbamazepine, Phenytoin
Valproic Acid, Lamotrigine
Benzodiazepines, Opioids, Antidepressants, other CNS Depressants
Articaine, Bupivacaine, Ambroxol

Data synthesized from.[1]

Section 7.0: Regulatory Trajectory and Current Development Status

The regulatory history of Carisbamate is a tale of two distinct eras, defined by different corporate sponsors, target indications, and ultimate outcomes. This journey reflects the immense challenges of drug development and the strategic necessity of adapting to clinical and regulatory feedback.

7.1 Era 1: Johnson & Johnson and the Pursuit of a Broad Indication (2008-2010)

The initial push for marketing approval was led by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD).[9] Following an extensive Phase III program, J&JPRD submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) on October 24, 2008.[9] The application sought approval for Carisbamate, under the provisionally approved brand name COMFYDE™, for the adjunctive treatment of partial-onset seizures in patients aged 16 years and older.[9]

However, on August 21, 2009, the development program suffered a major setback when Ortho-McNeil-Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, announced the receipt of a Complete Response Letter from the FDA.[10] This letter indicated that the FDA had declined to approve the NDA in its current form.[10] While the specific deficiencies cited in the letter were not made public by the company, the regulatory decision was widely understood to be based on the inconsistent efficacy demonstrated across the pivotal trials, coupled with the dose-limiting side effects that created an unfavorable risk-benefit profile for the proposed indication.[5]

The regulatory challenges were not confined to the United States. A parallel marketing authorisation application had been submitted to the European Medicines Agency (EMA). On January 15, 2010, the sponsor, Janssen-Cilag International NV, officially notified the EMA's Committee for Medicinal Products for Human Use (CHMP) that it was withdrawing its application.[11] The withdrawal occurred before the CHMP had rendered a final opinion, but the company's rationale was linked to the inability to consistently demonstrate efficacy.[5] Following these regulatory failures, Johnson & Johnson discontinued the development of Carisbamate for partial-onset seizures.

7.2 Era 2: SK Life Science and the Pivot to an Orphan Indication (2017-Present)

After a period of dormancy, the program was revived by its original discoverer, SK Biopharmaceuticals, through its U.S. subsidiary SK Life Science.[7] Recognizing the potential of the drug in a different context, the company initiated a new development strategy focused on a rare and severe form of epilepsy.

A critical turning point came on August 2, 2017, when the FDA granted Carisbamate Orphan Drug Designation for the treatment of Lennox-Gastaut Syndrome (LGS).[12] This designation provides incentives for the development of drugs for rare diseases and signaled a new regulatory pathway for the compound.

This was followed by a carefully planned clinical program, starting with Phase I studies to establish the appropriate dosing in the LGS population, including pediatric patients.[31] Based on these positive foundational studies, SK Life Science initiated a global, pivotal Phase III trial (the LGS DISCOVER Study) in January 2022 to definitively evaluate the efficacy and safety of Carisbamate for seizures associated with LGS.[7]

As of the current date, Carisbamate is actively in Phase III development exclusively for LGS. The development programs for all previously investigated indications—including partial-onset epilepsy, diabetic neuropathies, postherpetic neuralgia, essential tremor, and migraine—have been formally discontinued.[6] The future of Carisbamate now rests entirely on the outcome of its targeted LGS program.

Table 4: Timeline of Key Regulatory and Development Milestones

Date	Milestone Event	Company/Sponsor	Regulatory Body	Indication
1998	U.S. Investigational New Drug (IND) application activated	SK Biopharmaceuticals	FDA	Epilepsy
Oct 24, 2008	New Drug Application (NDA) submitted	Johnson & Johnson (J&JPRD)	FDA	Partial-Onset Seizures
Aug 21, 2009	Complete Response Letter (CRL) received	Johnson & Johnson (Ortho-McNeil-Janssen)	FDA	Partial-Onset Seizures
Jan 15, 2010	Marketing Authorisation Application withdrawn	Johnson & Johnson (Janssen-Cilag)	EMA	Partial-Onset Seizures
Aug 2, 2017	Orphan Drug Designation granted	SK Life Science, Inc.	FDA	Lennox-Gastaut Syndrome
Jan 6, 2022	Global Phase III clinical trial initiated	SK Life Science, Inc.	FDA / Global	Lennox-Gastaut Syndrome

Data synthesized from.[7]

Section 8.0: Strategic Analysis and Future Outlook

8.1 Synthesis and Expert Insights

The developmental saga of Carisbamate encapsulates a central paradox in modern pharmacology: a compound can possess a solid preclinical rationale, a well-defined primary mechanism of action, and a favorable metabolic profile, yet still fail in late-stage clinical development. The initial failure of Carisbamate was not due to an absence of biological activity, but rather an inability to achieve a sufficient therapeutic index—the critical balance between efficacy and toxicity—for the broad and competitive indication of adjunctive therapy for partial-onset seizures.

Several key factors converged to create this outcome. First, the drug's narrow therapeutic window meant that the doses required for robust efficacy (≥800 mg/day) were precisely those that precipitated dose-limiting CNS adverse events like dizziness and somnolence, leading to high rates of patient withdrawal from clinical trials. Second, its pharmacokinetic susceptibility to metabolic induction by commonly used AEDs like carbamazepine and phenytoin created a "hidden vulnerability." In a real-world refractory epilepsy population, this interaction would lead to highly variable and often sub-therapeutic drug exposures, confounding the dose-response relationship and contributing to the regulatory finding of "inconsistent efficacy." For a market with many established and better-tolerated alternatives, this profile was untenable.

The subsequent strategic pivot to Lennox-Gastaut Syndrome represents a calculated and intelligent attempt to salvage the compound by aligning its specific attributes with a different clinical need. In the context of a devastating, life-limiting, and highly treatment-resistant condition like LGS, the tolerance for adverse events is higher, and even a modest improvement in seizure control can be considered clinically meaningful. The Orphan Drug Designation provides a more supportive regulatory pathway, acknowledging the high unmet need in this patient population.

8.2 Positioning within the LGS Treatment Landscape

Carisbamate is not entering an empty therapeutic landscape for LGS. The current standard of care is complex and multifaceted, reflecting the profound difficulty of treating this syndrome.[58] Treatment typically begins with a broad-spectrum AED, with sodium valproate often considered the first-line agent.[60] However, monotherapy is rarely sufficient, and treatment rapidly evolves to include various adjunctive therapies.

Several drugs have secured specific FDA approval for seizures associated with LGS, including lamotrigine, topiramate, felbamate, rufinamide, clobazam, cannabidiol, and fenfluramine.[61] Indirect comparative analyses suggest that clobazam, a benzodiazepine, demonstrates a particularly strong effect size in reducing drop seizures, the most debilitating seizure type in LGS.[65] More recently, highly purified cannabidiol has shown robust efficacy in large, randomized controlled trials, significantly reducing drop seizure frequency compared to placebo.[67] Non-pharmacological options, such as the ketogenic diet, vagus nerve stimulation (VNS), and corpus callosotomy surgery, are also integral parts of the treatment algorithm, especially for patients who remain refractory to multiple medications.[58]

For Carisbamate to succeed, it must demonstrate a statistically significant and, more importantly, a clinically meaningful benefit in this highly pre-treated and refractory population. Its potential niche will likely be as a later-line adjunctive therapy for patients who have failed or are intolerant to existing options. The potential for a unique mechanistic contribution—leveraging its combined effects on sodium and T-type calcium channels or other uncharacterized targets—could offer a new avenue for rational polypharmacy, providing a synergistic effect when combined with other ASMs.

8.3 Unanswered Questions and Future Directions

The ongoing LGS DISCOVER Phase III trial is the crucible in which the future of Carisbamate will be forged. The success of the program hinges on the answers to several critical questions that this trial is designed to address:

1. Magnitude of Efficacy: What is the precise magnitude of the effect on drop seizure frequency? Will the reduction be statistically significant and clinically meaningful enough to be competitive with or complementary to established LGS therapies like clobazam and cannabidiol?
2. Therapeutic Window in LGS: What is the safety and tolerability profile at the proposed LGS doses (up to 600 mg/day)? Is the therapeutic window wider and more manageable in this specific population or at these lower, weight-based doses compared to what was observed in the adult partial seizure trials?
3. Subgroup Responders: Are there specific patient subgroups within the heterogeneous LGS population (e.g., defined by seizure semiology, underlying etiology, or concomitant medications) that exhibit a preferential response to Carisbamate?

The outcome of this pivotal trial will represent the culmination of a decades-long, arduous, and strategically dynamic development journey. A positive result could finally bring a new therapeutic option to a patient population in desperate need, validating the strategic decision to reposition the drug. A negative result would likely mark the end of the road for this long-studied compound.

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