The human photosensitive epilepsy model for clinical proof-of-principle trials of novel antiseizure medications: 2. Analysis of drug trials and predictive value of the model

Abstract

Clinical development of novel antiseizure medications (ASMs) would benefit from an early proof of principle (POP) model. The photosensitivity model, which uses the photoparoxysmal electroencephalographic response (PPR) as a surrogate of seizures, is currently the only human model that allows POP trials of investigational compounds after a single drug administration. Typically, trials in this model are performed as single-blinded, placebo-controlled phase IIa POP studies, evaluating a range of doses in small groups of epilepsy patients. In the second part of this review, based on the background information provided in Part 1, we analyze the outcome of all published trials performed over roughly 50 years. Many of the 35 drugs tested in the model were also examined in traditional add-on trials in patients with epilepsy, thus allowing analysis of the predictivity of the model. Drugs were categorized into three groups: drugs that suppressed PPR; drugs that exerted no effect on PPR; and drugs that increased PPR, indicating a proconvulsant effect. For the vast majority of drugs, the model correctly predicted the drugs' activity during long-term studies in patients with different types of epilepsy, including focal onset epilepsies. For some investigational compounds, the model detected proconvulsant activity that had not been observed in preclinical animal experiments and phase I studies in healthy volunteers, demonstrating the value of the model for adverse event assessment in patients with epilepsy. Limitations of the model are that it does not predict the extent of drug resistance of patients' seizures during chronic administration or efficacy differentiation of the novel drug from existing ASMs. Photosensitive POP trials are a useful tool to quantitatively predict drug efficacy and in aiding dose selection for subsequent larger phase IIb trials with chronic drug administration.

Keywords: animal models; intermittent photic stimulation; mechanism of action; pharmacodynamics; pharmacokinetics; photoparoxysmal EEG response; proof of concept.

FIGURE 1

Correlation between the average effective single doses of 14 approved antiseizure medications (ASMs) that suppress photoparoxysmal electroencephalographic responses (PPRs) in photosensitive epilepsy patients and the average effective maintenance dose administered during chronic treatment of patients with epilepsy. Note that during maintenance treatment, these doses are typically administered twice or three times per day, depending on the pharmacokinetics of the respective drug. For six of the ASMs shown, the efficacy in the photosensitivity model was determined long before clinical maintenance doses were established in patients with epilepsy. See Table 3 for the doses that were used for the correlation analysis. Spearman rank correlation was used to calculate the correlation coefficient r. Linear regression analysis was used to construct the solid line through the data and the standard errors as indicated by the stippled lines. BRV, brivaracetam; CBZ, carbamazepine; CNB, cenobamate; DZP, diazepam; ESM, ethosuximide; LEV, levetiracetam; LTG, lamotrigine; LZP, lorazepam; MPHT, mephenytoin; PRG, progabide; PRM, primidone; VGB, vigabatrin; VPA, valproate; VPM, valpromide.

FIGURE 2

Correlation between preclinical antiseizure doses of drugs in animal models and the average effective dose to suppress the photoparoxysmal electroencephalographic response (PPR) in photosensitive epilepsy patients. Preclinical doses are given as median effective dose (ED₅₀; or ED in baboons) in mg/kg intraperitoneally (or intravenously in baboons), whereas clinical doses are in mg orally (except for diazepam, which was administered intravenously). Spearman rank correlation was used to calculate the correlation coefficient r. Nonlinear regression analysis was used to construct the lines through the data. (A) Approved antiseizure medications (ASMs): correlation between anticonvulsant ED₅₀s for suppression of clonic audiogenic seizures in the DBA/2 mouse model of reflex epilepsy and the average dose of ASMs suppressing PPR in patients with photosensitive epilepsy. Note that doses at both axes are shown on a log scale. The relative drug potencies were significantly correlated. (B) Investigational drugs: correlation between anticonvulsant ED₅₀s for suppression of clonic audiogenic seizures in the DBA/2 mouse model of reflex epilepsy and the average dose of ASMs suppressing PPR in patients with photosensitive epilepsy. Note that doses at both axes are shown on a log scale. The relative drug potencies were significantly correlated. (C) ASMs: lack of significant correlation between anticonvulsant ED₅₀s for suppression of clonic audiogenic seizures in the audiogenic seizure‐prone rat model of reflex epilepsy and the average dose of ASMs suppressing PPR in patients with photosensitive epilepsy. (D) ASMs: correlation between anticonvulsant EDs for suppression of photosensitive seizures in the epileptic baboon model of reflex epilepsy and the average dose of ASMs suppressing PPR in patients with photosensitive epilepsy. Note that two ASMs (ethosuximide and primidone) that were effective in photosensitive patients were ineffective in baboons and are therefore not included in the graph; thus, the correlation shown in panel D is false positive. See Tables 3, 4, 5 for individual values. BRV, brivaracetam; CBZ, carbamazepine; CNB, cenobamate; DZP, diazepam; ESM, ethosuximide; LEV, levetiracetam; LTG, lamotrigine; PRG, progabide; PRM, primidone; VGB, vigabatrin; VPA, valproate; VPM, valpromide.