rwj-333369 and Epilepsies--Partial

Epilepsy is a common neurological condition, affecting over 70 million individuals worldwide.. The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies.. Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.

Topics: Adult; Animals; Anticonvulsants; Cannabidiol; Epilepsies, Partial; Epilepsy; Humans; Lennox Gastaut Syndrome; Spasms, Infantile; Tuberous Sclerosis

Epilepsy is one of the most common neurological disorders. Many people with epilepsy are drug-resistant and require add-on therapy, meaning that they concomitantly take multiple antiepileptic drugs. Carisbamate is a drug which is taken orally and inhibits voltage-gated sodium channels. Carisbamate may be useful for drug-resistant focal epilepsy.. To evaluate the efficacy and tolerability of carisbamate when used as an add-on therapy for drug-resistant focal epilepsy.. We searched the following databases on 8 April 2021: Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) 1946 to April 07, 2021. CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, WHO ICTRP, the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane review groups including Epilepsy. We also searched ongoing trials registers, checked reference lists, and contacted authors of the included trials.. Double-blind randomised controlled trials (RCTs) comparing carisbamate versus placebo or another antiepileptic drug, as add-on therapy for drug-resistant focal epilepsy. Trials could have a parallel-group or cross-over design.. Two review authors independently selected the trials for inclusion, assessed trial quality, and extracted data. The primary outcome was 50% or greater reduction in seizure frequency (responder rate). The secondary outcomes were: seizure freedom, treatment withdrawal (for any reason and due to adverse events); adverse events, and quality of life. We analysed data using the Mantel-Haenszel statistical method and according to the intention-to-treat population. We presented results as risk ratios (RRs) with 95% confidence intervals (CIs).. We included four RCTs involving a total of 2211 participants. All four trials compared carisbamate with placebo for drug-resistant focal epilepsy. Participants in all trials were over 16 years of age and received at least one other antiepileptic drug concomitantly. We detected substantial risk of bias across the included trials. All four trials were at high risk of attrition bias due to the incomplete reporting of attrition and the high treatment withdrawal rates noted, especially with higher doses. All four trials also had unclear risk of detection bias, as they did not specify whether outcome assessors were blinded. Meta-analysis suggested that carisbamate produced a higher responder rate compared to placebo (RR 1.36, 95% CI 1.14 to 1.62; 4 studies; moderate-certainty evidence). More participants in the carsibamate group achieved seizure freedom (RR 2.43, 95% CI 0.84 to 7.03; 1 study); withdrew from treatment for any reason (RR 1.32, 95% CI 0.82 to 2.12; 4 studies); and withdrew from treatment due to adverse events (RR 1.80, 95% CI 0.78 to 4.17; 4 studies) than in the placebo group. However, the evidence for the three outcomes was very low-certainty. There was no difference between treatment groups for the proportion of participants experiencing at least one adverse event (RR 1.10, 95% CI 0.93 to 1.30; 2 studies; low-certainty evidence). More participants in the carisbamate group than in the placebo group developed dizziness (RR 2.06, 95% CI 1.23 to 3.44; 4 studies; very low-certainty evidence) and somnolence (RR 1.82, 95% CI 1.28 to 2.58; 4 studies; low-certainty evidence), but not fatigue (RR 1.11, 95% CI 0.73 to 1.68; 3 studies); headache (RR 1.13, 95% CI 0.92 to 1.38; 4 studies); or nausea (RR 1.19, 95% CI 0.81 to 1.75; 3 studies). None of the included trials reported quality of life.. The results suggest that carisbamate may demonstrate efficacy and tolerability as an add-on therapy for drug-resistant focal epilepsy. Importantly, the evidence for all outcomes except responder rate was of low to very low certainty, therefore we are uncertain of the accuracy of the reported effects. The certainty of the evidence is limited by the significant risk of bias associated with the included studies, as well as the statistical heterogeneity detected for some outcomes. Consequently, it is difficult for these findings to inform clinical practice. The studies were all of short duration and only included adult study populations. There is a need for further RCTs with more clear methodology, long-term follow-up, more clinical outcomes, more seizure types, and a broader range of participants.

Topics: Adult; Anticonvulsants; Carbamates; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Humans; Pharmaceutical Preparations; Randomized Controlled Trials as Topic

To assess the efficacy, safety, and tolerability of adjunctive carisbamate treatment at 800 mg/day and 1,200 mg/day in patients with partial-onset seizures (POS).. Patients ≥ 16 years of age with an established diagnosis of POS for ≥ 1 year and uncontrolled on one to three antiepileptic drugs were enrolled. Eligible patients remained on stable doses of prescribed antiepileptic drugs for an 8-week pretreatment baseline phase and were then randomized (1:1:1) to receive carisbamate (800 mg/day or 1,200 mg/day), or placebo, for a 14-week double-blind phase. Primary efficacy endpoints were percentage reduction in POS frequency and responder rate (patients with ≥ 50% reduction in POS frequency) during the double-blind versus baseline phase.. Five hundred forty-seven patients were randomized; 540 composed the intent-to-treat (ITT) analysis. Four hundred thirty-four patients (79%) completed the study. The median percent reduction from baseline to treatment phase in POS frequency was: 21% (placebo); 30% (carisbamate 800 mg); 36% (carisbamate 1,200 mg), and 32% (combined carisbamate doses). The combined carisbamate dose group was not significantly different from placebo for the median percent reduction of POS frequency (p = 0.20) or responder rate (p = 0.18). Therefore, the difference from placebo for the individual carisbamate dose groups was also considered nonsignificant, based on a prespecified step-down analysis. Dizziness was the most common treatment-emergent adverse event, with a higher incidence (≥ 5% difference) in the combined carisbamate group (31%) than placebo (9%); the incidence was higher with carisbamate 1,200 mg (32%, n = 58) than with carisbamate 800 mg (30%, n = 53).. Adjunctive carisbamate therapy in patients with POS did not demonstrate efficacy across the dose range assessed versus placebo. No new safety findings were observed.

Topics: Adult; Anticonvulsants; Carbamates; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care

To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial-onset seizures (POS).. Two identical, randomized, placebo-controlled, double-blind studies were conducted in adults with POS uncontrolled for >or=1 year. Therapy-refractory epilepsy patients (>or=16 years) remained on stable doses of prescribed antiepileptic drugs (or=50% reduction in POS frequency) during the double-blind phase compared with the prospective baseline phase.. Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16-75 years) and 36 years (study 2, range 16-74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment-emergent adverse events (>or=5% in any group), those with an incidence exceeding placebo (>or=3%) were dizziness (400 mg/day group) and somnolence.. Carisbamate 400 mg/day was effective in patients with refractory partial-onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well-tolerated in both studies.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Carbamates; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Epilepsies, Partial; Female; Glucuronosyltransferase; Humans; Male; Middle Aged; Placebos; Sleep; Treatment Outcome

To evaluate the efficacy, safety, and tolerability of carisbamate (CRS), an investigational drug, as adjunctive treatment for partial-onset seizures in adults.. A randomized, double-blind, placebo-controlled, multicenter, dose-ranging study was conducted in 12 countries. Patients counted seizures during an 8-week baseline period, and then, if eligible, entered a double-blind phase consisting of a 4-week dose-titration period (target CRS doses: 100, 300, 800, or 1,600 mg/d or placebo in two divided doses) and a 12-week maintenance period. The primary efficacy variable was percent reduction in partial-onset seizure frequency during the double-blind phase compared with pretreatment baseline. Safety data and responder rates were also assessed.. Five hundred thirty-seven patients were randomized, and 82% completed the study. In the intent-to-treat population (n = 533), CRS at doses of > or =300 mg/d (p < or = 0.006) reduced the frequency of partial-onset seizures vs placebo: 6% (placebo) vs 24% (300 mg/d), 21% (800 mg/d), and 29% (1,600 mg/d) for CRS. Adverse events consisted primarily of CNS effects, and led to discontinuation of drug in 8% of the placebo group vs 5% (100 mg/d), 6% (300 mg/d), 12% (800 mg/d), and 19% (1,600 mg/d) of the CRS groups.. Carisbamate at doses of 300, 800, and 1,600 mg/d was effective as adjunctive therapy for reducing the frequency of partial-onset seizures.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Anticonvulsants; Body Weight; Carbamates; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemispheric limbic epileptic circuit using closed-loop direct neurostimulation therapy in tandem with "on-demand'" convection-enhanced intracerebral delivery of the antiepileptic drug (AED) carisbamate. A rat model of electrically induced self-sustained focal-onset epilepsy was employed.. A 16-contact depth-recording microelectrode was implanted bilaterally in the dentate gyrus (DG) of the hippocampus of Fischer 344 rats. The right microelectrode array included an integrated microcatheter for drug delivery at the distal tip. Bihemispheric spontaneous self-sustained limbic status epilepticus (SSLSE) was induced in freely moving rats using a 90-minute stimulation paradigm delivered to the right medial perforant white matter pathway. Immediately following SSLSE induction, closed-loop right PP stimulation therapy concurrent with on-demand nanoboluses of the AED [(14)C]-carisbamate (n = 4), or on-demand [(14)C]-carisbamate alone (n = 4), was introduced for a mean of 10 hours. In addition, 2 reference groups received either closed-loop stimulation therapy alone (n = 4) or stimulation therapy with saline vehicle only (n = 4). All animals were sacrificed after completing the specified therapy regimen. In situ [(14)C]-autoradiography was used to determine AED distribution.. Closed-loop direct stimulation therapy delivered unilaterally in the right PP aborted ictal runs detected in either ipsi- or contralateral hippocampi. Freely moving rats receiving closed-loop direct stimulation therapy with ondemand intracerebral carisbamate delivery experienced a significant reduction in seizure frequency (p < 0.001) and minimized seizure frequency variability during the final 50% of the therapy/recording session compared with closed-loop stimulation therapy alone.. Unilateral closed-loop direct stimulation therapy delivered to afferent hippocampal white matter pathways concurrent with on-demand ipsilateral intracerebral delivery of nano-bolused carisbamate can rapidly decrease the frequency of electrographic seizures in an active bihemispheric epileptic network. Additionally, direct pulsatile delivery of carisbamate can stabilize seizure frequency variability compared with direct stimulation therapy alone.

Topics: Animals; Anticonvulsants; Carbamates; Combined Modality Therapy; Disease Models, Animal; Electric Stimulation Therapy; Epilepsies, Partial; Male; Rats; Rats, Inbred F344; Treatment Outcome