Faculty Bibliography

PURPOSE: To assess the effects of ICA-105665, an agonist of neuronal Kv7 potassium channels, on epileptiform EEG discharges, evoked by intermittent photic stimulation (IPS), the so-called photoparoxysmal responses (PPRs) in patients with epilepsy. METHODS: Male and female patients aged 18-60 years with reproducible PPRs were eligible for enrollment. The study was conducted as a single-blind, single-dose, multiple-cohort study. Four patients were enrolled in each of the first three cohorts. Six patients were enrolled in the fourth cohort and one patient was enrolled in the fifth cohort. PPR responses to 14 IPS frequencies (steps) were used to determine the standard photosensitivity range (SPR) following placebo on day 1 and ICA-105665 on day 2. The SPR was quantified for three eye conditions (eyes closing, eyes closed, and eyes open), and the most sensitive condition was used for assessment of efficacy. A partial response was defined as a reduction in the SPR of at least three units at three separate time points following ICA-105665 compared to the same time points following placebo with no time points with more than three units of increase. Complete suppression was defined by no PPRs in any eye condition at one or more time points. KEY FINDINGS: Six individual patients participated in the first three cohorts (100, 200, and 400 mg). Six patients participated in the fourth cohort (500 mg), and one patient participated in the fifth cohort (600 mg). Decreases in SPR occurred in one patient at 100 mg, two patients receiving 400 mg ICA-105665 (complete abolishment of SPR occurred in one patient at 400 mg), and in four of six patients receiving 500 mg. The most common adverse events (AEs) were those related to the nervous system, and dizziness appeared to be the first emerging AE. The single patient in the 600 mg cohort developed a brief generalized seizure within 1 h of dosing, leading to the discontinuation of additional patients at this dose, per the predefined protocol stopping rules. SIGNIFICANCE: ICA-105665 reduced the SPR in patients at single doses of 100 (one of four), 400 (two of four), and 500 mg (four of six). This is the first assessment of the effects of activation of Kv7 potassium channels in the photosensitivity proof of concept model. The reduction of SPR in this patient population provides evidence of central nervous system (CNS) penetration by ICA-105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has antiseizure effects.

Purpose of Review: Selection of the ideal antiepileptic drug (AED) for an individual patient can be a daunting process. Choice of treatment should be based on several factors, including but not limited to epilepsy classification, AED mechanism of action, AED side-effect profile, and drug interactions. Special consideration must be given to populations such as women, older adults, patients with other medical comorbidities, and patients who are newly diagnosed.Recent Findings: Head-to-head trials between AEDs in newly diagnosed patients rarely demonstrate that one AED is more or less effective. The second-generation drugs, lamotrigine, topiramate, oxcarbazepine, zonisamide, and levetiracetam, have undergone head-to-head trials confirming similar efficacy and equal or better tolerability than standard drugs in focal epilepsy.Summary: A thoughtful approach to the AED selection process must factor in data from clinical AED trials as well as a variety of patient characteristics and confounding factors. When neurologists apply an individualized approach to AED drug selection for their patients, they can find an effective and well-tolerated drug for most patients.

PURPOSE: Three suicidal ideation and suicidal behavior instruments were used to assess the prevalence of lifetime and recent suicidal ideation and suicidal behavior in patients with frequent treatment-resistant focal seizures who would be eligible for randomized clinical trials. This was done to determine which instrument was optimal for use in epilepsy. METHODS: In a cross-sectional study, we compared lifetime and recent suicidal ideation and suicide attempt on the MINI International Neuropsychiatric Interview (MINI), Columbia Suicide Severity Rating Scale (C-SSRS), and Interactive Voice Response System CSSRS (E-CSSRS). A safety algorithm determined treatment referral. Coordinators and participants evaluated experiences with the C-SSRS. The proportion of participants that baseline assessment would exclude from clinical trial enrollment was determined. KEY FINDINGS: Among 208 participants, 1.6-3.9% had recent high risk suicidal ideation and 1.0-4.7% had a recent suicide attempt across all instruments. Lifetime high-risk suicidal ideation occurred in 12.1-14.1%. Lifetime suicide attempt occurred in 10.2-13.1% of participants. Of those with recent suicide attempt, 31.1% required referral to a health professional, and 3.9% needed urgent referral. Lifetime suicidal behavior (including aborted suicide attempt, interrupted suicide attempt, suicide attempt, preparatory acts or behavior, and nonsuicidal self-injurious behavior) was found in 21.1% on the E-CSSRS and 15.5% on the C-SSRS. Agreement (Kappa) was good to excellent for comparisons of all instruments. Fifty-two percent of subjects preferred either the CSSRS or E-CSSRS, whereas the rest had no preference; of those having a preference, 87.5% favored the CSSRS. Of the 18.9% of participants who might have been excluded from trials based on suicidal ideation and suicide attempt, the CSSRS identified high-risk suicidal ideation or suicide attempt in the preceding 2 years in only 4.4%. SIGNIFICANCE: Suicidality screening is feasible in people with epilepsy. Slightly more suicidal behavior is reported with the E-CSSRS than C-SSRS, suggesting the E-CSSRS may be optimal. The proportion of patients who may be excluded from clinical trials based on worrisome suicidal ideation or suicide attempt is small, suggesting that it is possible to enroll most eligible individuals.

PURPOSE OF REVIEW: Preclinical research in epileptology has been very successful in producing effective drugs. Unfortunately, however, seizures are still not adequately controlled in a third of the affected individuals, and comorbidities still impose a major burden on the quality of life. New preclinical and clinical drug development strategies are needed to identify drugs that target these unmet medical needs. RECENT FINDINGS: Even in recent years, the antiseizure approach based on screenings has contributed to the identification of new drugs. Thus, it should not be abandoned. However, we propose that a radically new approach, specifically designed to tackle the existing gaps in care, should be developed to complement the traditional screening. This new approach will require integrated strategies for preclinical screening and experimental trial design. In this review, we will attempt to address some of the issues that must be resolved to engage this effort. Are there suitable models to tackle the unmet therapeutic needs in epilepsy? Are there ways to de-risk the transition from preclinical to clinical studies? Are there ways to improve the efficiency of clinical trials and to design ad hoc trials for the unmet therapeutic needs? SUMMARY: Development and validation of a new, integrated strategy for antiepilepsy drug development is needed to identify truly innovative drugs.