Preclinical Safety Margins of the Potent and NaV1.6 Selective Inhibitor, XEN901, in Relation to Non-Selective Sodium Channel Blockers
Abstract number :
1.287
Submission category :
7. Antiepileptic Drugs / 7A. Animal Studies
Year :
2018
Submission ID :
502084
Source :
www.aesnet.org
Presentation date :
12/1/2018 6:00:00 PM
Published date :
Nov 5, 2018, 18:00 PM
Authors :
Celine Dube, Xenon Pharmaceuticals; JP Johnson, Xenon Pharmaceuticals; Thilo Focken, Xenon Pharmaceuticals; Rostam Namdari, Xenon Pharmaceuticals; Christoph Dehnhardt, Xenon Pharmaceuticals Inc.; Mike Grimwood, Xenon Pharmaceuticals; Kristen Burford, Xeno
Rationale: Side effects associated with currently used non-selective sodium channel anti-epileptic drugs (AEDs) may limit their therapeutic utility. These side effects may be associated with both the lack of isoform selectivity as well as weak potency of channel block. We have shown that selective inhibition of the NaV1.6 sodium channel is the major driver of efficacy in rodent seizure models including in the Maximal Electroshock (MES) assay. Given this finding, we hypothesized that side effects of currently marketed non-selective AEDs may be driven by their block of other sodium channel isoforms, particularly NaV1.1, as well as by the high exposures required for efficacy. This latter characteristic increases the chance of off target pharmacology leading to undesired side effects and toxicity. XEN901,a novel compound, that potently and selectively blocks NaV1.6 was hypothesized to exhibit improved safety margins compared to non-selective, less potent Nav blockers. Methods: To evaluate our hypothesis we determined the effective concentration in plasma for 70% reduction in seizures (EC70 values) for the rodent MES model as well as the lowest exposure leading to CNS side effects, such as ataxia, in the same animals. The MES assay was conducted as described in the accompanying abstract (Cohen et al). Safety margins were determined by comparing the plasma concentration required to achieve robust efficacy (EC70) to the lowest drug exposure leading to CNS side effects. Results: XEN901 was shown to have an enhanced safety margin (~170-fold) relative to phenytoin (1.7-fold), carbamazepine (3.8-fold), and lacosamide (5.3-fold). Conclusions: This data suggests that potent, selective NaV1.6 inhibitors may offer an improved therapeutic index and fewer side effects compared with traditional, non-selective sodium channel AEDs. The higher therapeutic index may allow greater levels of seizure freedom than was previously possible with non-selective NaV inhibitors, XEN901, is currently in clinical development and may represent an improved AED with a greater safety profile Funding: All authors are employed by Xenon Pharmaceuticals Inc.