Faculty Bibliography

The ideal proof-of-principle study design provides a strong efficacy signal over the shortest duration, while exposing the fewest patients possible. Data from a large database (Pfizer Inc) which studied add-on pregabalin for the treatment of partial seizures was used to model how duration of baseline, post-randomization treatment period, and number of subjects impact the likelihood of an interpretable efficacy signal. Data from four double-blind, randomized, placebo-controlled, phase III studies that had at least one 600mg/day treatment arm were combined. The common 6-week baseline period was divided into weekly intervals, as was the 12-week post-randomization period. Two methods of analysis were used: logistic regression performed on 50% responder rate and the Hodges-Lehmann estimate on percentage reduction from baseline seizure rate. A simulation-based re-sampling approach was used to determine sufficient sample size. Four weeks of baseline with 3 weeks of treatment were determined to be clinically and statistically sufficient. A reasonable sample size was estimated to be 40-50 patients per group, if a highly efficacious drug was used. These modeling results indicate that the efficacy of an antiepileptic drug can be demonstrated in a relatively short period of time with a reasonable sample size.

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.

BACKGROUND: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. RESULTS: EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. CONCLUSIONS: EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

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.

OBJECTIVE: Preapproval randomized controlled trials of antiepileptic drugs provide data in limited patient groups. We assessed the side effect and seizure reduction profile of tiagabine (TGB) in typical clinical practice. METHODS: Investigators recorded adverse effect (AE), seizure, and assessment-of-benefit data prospectively in sequential patients treated open label with TGB. RESULTS: Two hundred ninety-two patients (39 children) were enrolled to be treated long term with TGB. Seizure types were focal-onset (86%), generalized-onset (12%), both focal- and generalized-onset (0.3%), and multiple associated with Lennox-Gastaut Syndrome (2%). Two hundred thirty-one received at least one dose of TGB (median=28mg/day) and had follow-up seizure or AE data reported. Common AEs were fatigue, dizziness, psychomotor slowing, ataxia, gastrointestinal upset, weight change, insomnia, and "others" (mostly behavioral). Serious AEs occurred in 19 patients: behavioral effects (n=12), status epilepticus (n=3), others (n=3), and sudden unexplained death (n=1). No patients experienced suicidal ideation/behavior, rash, nephrolithiasis, or organ failure. Seizure outcomes were seizure freedom (5%), >/=75% reduction (12%), >/=50% reduction (23%), and increased number of seizures (17%), or new seizure type (1%). CONCLUSIONS: Behavioral AEs occurred in a larger proportion of patients compared to those reported in TGB preapproval randomized controlled trials. A moderate percentage of patients had a meaningful reduction in seizure frequency. In clinical practice, TGB remains a useful antiepileptic drug.

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.