Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial.

Importance: Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. Objective: To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs). Design, Setting, and Participants: This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe. Interventions: Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose). Main Outcomes and Measures: The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted. Results: A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, -80.4% to -16.9%) for 25 mg, 46.4% (P < .001 vs placebo; IQR, -76.7% to -14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, -61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, -37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported. Conclusions and Relevance: The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs. Trial Registration: ClinicalTrials.gov Identifier: NCT03796962.

The Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke, NIH: History and Contributions to Clinical Care in the Twentieth Century and Beyond.

The anticonvulsant screening program (ASP) of the national institute of neurological disorders and stroke (NINDS), National Institutes of Health has made substantial contributions to the drug armamentarium of the clinical neurologist. This program, originally a part of the overall Drug Development Program of the Epilepsy Branch, has been fortunate to have talented leadership, both at NINDS in Maryland and at the major contract site, the University of Utah-over a remarkable period of more than 40 years. Future discoveries by the ASP (now renamed the Epilepsy Therapy Screening) can be expected to make additional contributions to improving the health of persons with epilepsy.

The photosensitivity model is not a model for partial (focal) seizures.

New, more effective and less toxic medications are desperately needed for patients with partial (focal) epilepsy. Many hurdles prevent the appropriate study of promising compounds. One of these hurdles is the difficult gap between Phase I and Phase II-the expensive proof of concept to suggest that human trials in partial seizure patients will be successful. A short-cut, the photoparoxysmal response (PPR) model has recently been used to increase confidence in moving a compound into Phase II and III (K-N Trenite et al., 2015). This shortcut has substantial limitations. This article outlines these limitations in an effort to create full disclosure to all involved with development of drugs for partial seizures.

Mechanisms of action of anti-seizure drugs and the anticonvulsant screening program of the National Institute of Neurological Disorders and Stroke.

OBJECTIVE: To determine the efficacy of the Anticonvulsant Screening Program (ASP) of the National Institute of Neurological Disorders and Stroke (NINDS) in identifying new anti-seizure drugs with new mechanisms of action (MOA). The ASP does not itself identify the nature of the MOA, but on further basic investigation, many of these drugs prove eventually to have a wide variety of new and novel MOA. METHODS: Data were tabulated from multiple sources, including the ASP and the literature. RESULTS: Since it was established in 1975, the ASP has contributed to the identification of at least 9 new anti-seizure drugs. The effectiveness of the program was evaluated by ascertaining the number of MOA of the anti-seizure drugs discovered by the ASP screening techniques. Considering the MOA of drugs marketed after 1975 - and the MOA of investigational compounds not yet marketed - the ASP has contributed to the identification of anti-seizure drugs that possess 16 distinctly different MOA. CONCLUSION: The ever-evolving screening approach of the ASP has many characteristics of a final common pathway for anti-seizure drug discovery.

A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development.

OBJECTIVE: To obtain information on the acceptable doses of the antiepileptic drug (AED) retigabine (RTG), the maximum tolerated dose (MTD), drug interactions, safety and tolerability, and preliminary evidence of efficacy when administered as adjunctive therapy and as monotherapy. MATERIALS: Study 202 was an open-label, add-on study in patients with partial or generalized epilepsy treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or topiramate (TPM) as monotherapy. Following baseline assessments, patients entered a dose titration phase of 28 – 56 days. The initial daily RTG dose was 100 or 200 mg (2 or 3 × daily). The RTG dose was increased every 1 - 2 weeks by 50 - 200 mg to a maximum of 1,600 mg/day. Once the RTG MTD had been attained, patients entered a 14-day maintenance period. Following this, the patient's background AED dose could be reduced, with the possibility of achieving RTG monotherapy. The final dosing regimen attained was maintained for an additional 14 days. Patients who completed study 202 could choose to continue treatment with RTG (with or without other AEDs) in study 208, the long-term extension of study 202. Safety assessments included adverse event (AE) monitoring, clinical laboratory evaluations, electrocardiograms, and physical and neurologic examinations. Patients' seizure diaries to assess the frequency and type of seizures, the percentage change in seizure rate, and the responder rate (>= 50% reduction in seizure rate from baseline) were evaluated. RESULTS: 60 patients (mean age 37.2, range 16 - 64 years) were enrolled in study 202, and 47 (78%) continued treatment with RTG in the extension study (208). In study 202, the most commonly reported AEs were: dizziness (53%), asthenia (42%), somnolence (33%), nausea (27%), speech disorder (27%), and tremor (27%). In the extension study, AEs were similar and included dizziness, somnolence, diplopia, feeling "drunk", confusion, fatigue, and dysarthria. The median percent reductions in 28-day seizure rate, relative to baseline in Studies 202 and 208, were ~ 20% and 47%, respectively. RTG did not alter the pharmacokinetics of the four monotherapy AEDs investigated. CBZ and PHT increased RTG clearance by 27% and 36%, respectively, whereas TPM and VPA had no effect on RTG clearance. CONCLUSIONS: Studies 202 and 208 provided critical information on RTG safety and tolerability, and reductions in seizure rates towards the design and conduct of subsequent pivotal clinical trials. Likewise, information regarding the appropriate dosage of RTG with VPA, CBZ, PHT, or TPM was obtained, which permitted the subsequent pivotal trials to be performed appropriately. *Currently at Shire Pharmaceuticals, Behavioral Health Business Unit, Wayne, PA, USA **Currently at University of Pennsylvania, Department of Neurology, Philadelphia, PA, USA.

Development of new treatment approaches for epilepsy: unmet needs and opportunities.

A working group was created to address clinical "gaps to care" as well as opportunities for development of new treatment approaches for epilepsy. The working group primarily comprised clinicians, trialists, and pharmacologists. The group identified a need for better animal models for both efficacy and tolerability, and noted that animal models for potential disease-modifying or antiepileptogenic effect should mirror conditions in human trials. For antiseizure drugs (ASDs), current animal models have not been validated with respect to their relationship to efficacy in common epilepsy syndromes. The group performed an "expert opinion" survey of perceived efficacy of the available ASDs, and identified a specific unmet need for ASDs to treat tonic-atonic and myoclonic seizures. No correlation has as yet been demonstrated between animal models of tolerability and adverse effects (AEs), versus tolerability in humans. There is a clear opportunity for improved therapies in relation to dose-related AEs. The group identified common and rare epilepsy syndromes that could represent opportunities for clinical trials. They identified opportunities for antiepileptogenic (AEG) therapies in both adults and children, acknowledging that the presence of a biomarker would substantially improve the chances of a successful trial. However, the group acknowledged that disease-modifying therapies (given after the first seizure or after the development of epilepsy) would be easier to study than AEG therapies.

Issues related to development of new antiseizure treatments.

This report represents a summary of the discussions led by the antiseizure treatment working group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Working Groups joint meeting in London (London Meeting). We review here what is currently known about the pharmacologic characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the National Institute of Neurological Disorders and Stroke (NINDS)-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacologic development. We also briefly address what we believe is necessary, going forward, to achieve the goal of stopping seizures in all patients, with a call to arms for funding agencies, the pharmaceutical industry, and basic researchers.

Retigabine as adjunctive therapy in adults with partial-onset seizures: integrated analysis of three pivotal controlled trials.

We assessed the efficacy and tolerability of retigabine (RTG; international non-proprietary name)/ezogabine (EZG; US adopted name) as adjunctive therapy in adults with partial-onset seizures in an integrated analysis of three trials. Studies 205, 301 (NCT00232596), and 302 (NCT00235755) were randomized, double-blind, placebo-controlled studies in adults having ≥4 partial-onset seizures per 28 days and receiving 1-3 antiepileptic drugs with/without vagus nerve stimulator. Patients underwent titration to RTG/EZG 600, 900, or 1200 mg/day or to placebo followed by 8 or 12 weeks maintenance. For efficacy analyses, placebo was compared with RTG/EZG 600 and 900 mg/day in Studies 205 and 302, and RTG/EZG 1200 mg/day in Studies 205 and 301. Responder rates (≥50% reduction in baseline seizure frequency) were 35% and 45% for RTG/EZG 600 and 900 mg/day, respectively (placebo=21%; p<0.001), and 50% for RTG/EZG 1200 mg/day (placebo=24%, p<0.001). Reductions in 28-day total partial-seizure frequency (medians: placebo=14%; 600 mg/day=26%, p=0.003; 900 mg/day=37%, p<0.001; placebo=15%; 1200 mg/day=39%, p<0.001) were significantly greater with all RTG/EZG doses vs. placebo from baseline to the double-blind phase, and similarly during the maintenance phase. The most commonly reported (>10%) treatment-emergent adverse events were dizziness, somnolence, headache, and fatigue. RTG/EZG demonstrated efficacy and was generally tolerated as adjunctive therapy in adults with partial-onset seizures in this integrated analysis.

Clinical development of drugs for epilepsy: a review of approaches in the United States and Europe.

The process of drug development of new anti-seizure drugs is addressed, with an emphasis on the differences between the United States and Europe. The article begins with a brief description of the companies that are responsible, in partnership with academia and clinicians, of bringing drugs to the marketplace. In considering the differences in drug development between the US and EU, it is not so much the companies that drive the differences but the regulatory processes. In fact, the only major principle on which the US and EU regulatory processes differ is on the path to monotherapy approval. The drug development process might seem to some to be a simple exercise in uncovering whether a drug is effective against a disease or a disorder and simultaneously evaluating its safety for the targeted patient population. While these issues are paramount in the minds of all involved, regulation of the industry has become extraordinarily sophisticated and complex. Most of the actions taken by a company are, at least in part, driven by the government administrations charged with drug development oversight. The similarities of the US and EU drug development processes are great; however, sufficient differences mandate close attention to obtain registration on both sides of the Atlantic.

Retigabine.

Retigabine is a novel antiseizure drug that acts through potassium channels and has activity in a broad range of animal models of epilepsy. It is also effective in several preclinical pain models. The drug has been extensively studied in phase I and II studies, with very promising results. The maximal tolerated dose for most patients is 1,200 mg/day. Adverse effects have been largely CNS-related and mild; most have occurred during the titration periods in the various studies. At present, retigabine is in two pivotal phase III studies.