XEN1101, a Differentiated KV7 Potassium Channel Modulator, Impacts Depression and Anhedonia
Abstract number :
3.26
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2021
Submission ID :
1826227
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:53 AM
Authors :
Alison Cutts, PhD - Xenon Pharmaceuticals; Rostam Namdari - Xenon Pharmaceuticals; Greg Beatch - Xenon Pharmaceuticals; Nina Weishaupt - Xenon Pharmaceuticals; Richard Dean - Xenon Pharmaceuticals; Jeff Bechard - Xenon Pharmaceuticals; JP Johnson - Xenon Pharmaceuticals; James Empfield - Xenon Pharmaceuticals; Robin Sherrington - Xenon Pharmaceuticals
Rationale: XEN1101 is being developed for the treatment of epilepsy and potentially other indications, including Major Depressive Disorder (MDD). Depression is a common co-morbidity in epilepsy, with a lifetime prevalence of 30-50%, that impacts patient Quality of Life (QOL) and limits anti-seizure medication (ASM) treatment options and response. A first generation Kv7 potentiator (ezogabine) has demonstrated significant improvement of depression and anhedonia both pre-clinically and clinically. We tested XEN1101 for similar activities.
Methods: The progressive ratio test (PRT) is a translational animal model of motivational performance and anhedonia, the latter being a core feature of MDD. Trained rats followed a progressive schedule of reinforcement in which the number of lever presses required to obtain a food reward increased for successive reinforcers. The break point was defined as the point at which a rat failed to earn a food pellet in 20 minutes. Rats received a single dose of 1, 3, or 8 mg/kg XEN1101 or vehicle. The 32 rats in the PRT were also ranked based on their performance measured over 5 days prior to dosing. In a sub-group analysis, animals were classified as either low performers (n=11), exhibiting lowered motivation and greater anhedonia, or high performers (n=11) at baseline. To compare plasma exposures for efficacy across anti-seizure models with efficacy in the PRT, XEN1101 was also evaluated in the mouse Direct Current Maximal Electroshock Seizure (DC-MES) model at 1, 3, 5, 7.5 or 10 mg/kg.
Results: In the PRT, XEN1101 significantly increased the breakpoint at 3 mg/kg (n=12.5 ± 0.4) and 8 mg/kg (n=12.8 ±0.5) compared to n=11.5 ± 0.5 for vehicle (p< 0.05 and p< 0.01, respectively). Further, XEN1101 significantly increased the number of lever presses at the same doses (n=439 ± 40 at 3 mg/kg, n=480 ± 57 at 8 mg/kg, compared to n=334 ± 38 for vehicle; p< 0.05 and p< 0.001, respectively). In the sub-group analysis, the XEN1101 effect on breakpoint and total lever presses was only significant in the low performing sub-group. Based on pharmacokinetic data, significant effects of XEN1101 in the PRT occurred at and above the EC
Anti-seizure Medications