Abstracts

Rationale: Epileptiform discharges evoked by IPS (photoparoxysmal EEG responses, PPR) can be used as biomarker for determination of efficacy of a potential antiseizure drug (ASD). An international community-driven and standardized stimulation protocol of repeated photic stimulation over a three-day period (a baseline placebo IPS day #1, an investigational ASD, single dose, on Day #2, followed by a third IPS day to determine the ASD’s duration of effect) has been accepted by the scientific community as a valid method for determining an ASD’s pharmacologic effect in epilepsy. This Phase IIa, Proof of Principle (PoP) Study procedure has been designated the ‘Photosensitivity Model’. Determination of potential -within patient- reduction of PPR flash-frequency ranges combined with pharmacokinetic data has been used in ASD development over the past thirty years in a variety of compounds- many of them on the market for focal onset seizures with or without generalization. The question we address here is whether the results shown in the ‘Photosensitivity Model’ are in line with effects shown in Phase III/IV trials or in clinical practice. In other words: Are there to date false-positive or false-negative findings? Methods: We have analysed all available data about effect of potential ASD that have been studied in the ‘Photosensitivity Model’ in relation to effect in Phase IIb, III or IV or in clinical practice. Descriptive Statistic analysis was done. Results: A total of 36 studies (34 different chemical entities) has been traced (1978-2018), 5 of them being unpublished. Of those 34 compounds, 18 to date have not been further studied in clinical open (phase IIb) or double blind trials (Phase III): reasons were mainly toxicity (long term toxicity or new toxicity findings in animals), small therapeutic window in patients or in two studies small effect size despite high doses. The full AMPA and NMDA antagonists (3 compounds) showed especially moderate to severe CNS side-effects; in one full NMDA antagonist (ORG 637) PPR range increased significantly. Taltrimide, working on the taurine and GABA mechanisms, showed also an increase of sensitivity. Taltrimide has been tested in a DB Phase III trial in patients with focal and generalized epilepsy and in an open trial with focal epilepsy and LGS patients: there was either no effect or an increase in seizure frequency. Of the other 10 compounds tested in DB Phase III, all have shown efficacy, although in two ASDs two trials have been performed with one trial negative due to high placebo responses.Overall, 11 compounds (32%), tested in the Photosensitivity Model,  are used in daily clinical practice for treatment of focal and generalized epilepsy; all have shown a suppressive effect on the generalized PPRs.    Conclusions: The Human Photosensitivity Phase IIa Model predicted correctly clinical efficacy of a potential ASD both in focal and generalized epilepsy. Many compounds though (18/34) have not further been tested; thanks to the model increase in photosensitivity or spontaneous seizures and toxicity were detected as early as possible in a controlled safe manner. Funding: No funding has been received for this analysis.