Löscher Wolfgang, Trenité Dorothée Kasteleijn-Nolst
Translational Neuropharmacology Lab, NIFE, Department of Experimental Otology of the ENT Clinics, Hannover Medical School, Hannover, Germany.
Department of Neurosurgery and Epilepsy, University Medical Center Utrecht, Utrecht, the Netherlands.
Epilepsia. 2025 May 10. doi: 10.1111/epi.18444.
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.
新型抗癫痫药物（ASMs）的临床开发将受益于早期的原理验证（POP）模型。光敏性模型利用光阵发性脑电图反应（PPR）作为癫痫发作的替代指标，是目前唯一一种在单次给药后允许对研究化合物进行POP试验的人体模型。通常，该模型中的试验作为单盲、安慰剂对照的IIa期POP研究进行，在一小群癫痫患者中评估一系列剂量。在本综述的第二部分，基于第一部分提供的背景信息，我们分析了大约50年来所有已发表试验的结果。在该模型中测试的35种药物中有许多也在癫痫患者的传统添加试验中进行了检查，从而可以分析该模型的预测性。药物被分为三组：抑制PPR的药物；对PPR无影响的药物；以及增加PPR的药物，表明有促惊厥作用。对于绝大多数药物，该模型正确预测了这些药物在不同类型癫痫患者长期研究中的活性，包括局灶性发作癫痫。对于一些研究化合物，该模型检测到了在临床前动物实验和健康志愿者的I期研究中未观察到的促惊厥活性，证明了该模型在癫痫患者不良事件评估中的价值。该模型的局限性在于，它无法预测长期给药期间患者癫痫发作的耐药程度，也无法预测新药与现有ASMs的疗效差异。光敏性POP试验是一种有用工具，可定量预测药物疗效，并有助于为随后更大规模的慢性药物给药IIb期试验选择剂量。
