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Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine?

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Abstract

Lorcaserin, a selective serotonin 5-HT2C receptor agonist, was developed as an appetite suppressant with the rationale of minimizing the risk of cardiovascular toxicity associated with non-selective serotoninergic agents such as fenfluramine. Eight years after FDA approval, however, it was withdrawn from the market, when a large safety study suggested a potential cancer risk. Following in the fenfluramine footsteps and utilizing the repurposing approach coupled with the regulatory orphan drug designation, lorcaserin is currently in clinical development for the treatment of epilepsy. This potential novel indication builds on the evidence that 5-HT2C receptor stimulation can protect against seizures, and accounts at least in part for fenfluramine’s antiseizure effects in Dravet syndrome models. In animal models, lorcaserin shows a narrower range of antiseizure activity than fenfluramine. In particular, lorcaserin is inactive in classical acute seizure tests such as maximal electroshock and subcutaneous pentylenetetrazole in mice and rats, and the 6-Hz stimulation model in mice. However, it is active in the GAERS absence seizure model, and in mutant zebrafish models of Dravet syndrome. Preliminary uncontrolled studies in patients with Dravet syndrome have yielded promising results, and a phase III, double-blind, placebo-controlled, parallel group trial is currently ongoing to assess its efficacy and safety in children and adults with Dravet syndrome.

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Authors and Affiliations

  1. Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Meir Bialer

  2. David R. Bloom Center for Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel

    Meir Bialer

  3. Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia

    Emilio Perucca

  4. Department of Neuroscience, Monash University, Melbourne, VIC, Australia

    Emilio Perucca

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  1. Meir Bialer
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MB received speaker's or consultancy fees from Alkaloid, Boehringer Ingelheim, Medison, Pharma Two B, Rekah-Vitamed, USWorldMeds, and Xenon Pharma. EP received speaker and/or consultancy fees from Angelini, Arvelle, Biogen, Biopas, Eisai, GW Pharma, Sanofi group of companies, SKL Life Science, Takeda, UCB Pharma, Xenon Pharma, and Zogenix, and royalties from Wiley, Elsevier, and Wolters Kluwers.

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Bialer, M., Perucca, E. Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine?. CNS Drugs 36, 113–122 (2022). https://doi.org/10.1007/s40263-022-00896-3

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