XEN1101 (MDD)

XEN1101, A Differentiated KV7 Potassium Channel Opener

We are developing XEN1101, a differentiated Kv7 potassium channel opener, for the treatment of epilepsy, major depressive disorder (MDD), and potentially other neurological disorders.

Xenon’s Clinical Development Plans in MDD

In November 2023, Xenon reported topline results from the Phase 2 proof-of-concept X-NOVA clinical trial, which evaluated the clinical efficacy, safety, and tolerability of 10 mg and 20 mg of XEN1101 in 168 patients with moderate to severe MDD.

Xenon anticipates participating in an “end-of-Phase 2” meeting with the U.S. Food and Drug Administration in April to support the initiation of its late-stage XEN1101 clinical program in MDD, which will include three Phase 3 clinical trials, with the first Phase 3 study expected to initiate in the second half of 2024. Xenon is also evaluating other potential indications for the future development of XEN1101.

In addition, Xenon is collaborating with the Icahn School of Medicine at Mount Sinai to support an ongoing investigator-sponsored Phase 2 proof-of-concept, randomized, parallel-arm, placebo-controlled multi-site study of XEN1101 for the treatment of MDD in approximately 60 subjects.

Scientific Rationale for Studying XEN1101 in MDD

Pre-clinical work demonstrates that increased activity of KCNQ type potassium channels reverses depressive phenotypes following chronic social defeat stress (Krishnan et al. 2007; Friedman et al. 2014; Friedman et al. 2016). Mice resilient to depression and anhedonia exhibit increased KCNQ channel activity within the ventral tegmental area (VTA) of the reward system, dampening the hyperexcitability of the dopamine neurons that is associated with depressive/anhedonia phenotypes observed in the susceptible mice. This susceptible phenotype can be reversed through (a) overexpression of KCNQ channels in the VTA dopamine neurons, (b) direct intra-VTA injection of small molecule KCNQ channel openers, or (c) systemic injection of KCNQ channel openers. Repeated peripheral daily administration of ezogabine, an earlier-generation KCNQ potassium channel modulator, completely reversed the depressive/anhedonic phenotype in the susceptible mice.

In addition to an open label study, statistically significant clinical results were generated from a randomized, placebo-controlled clinical trial that explored the targeting of KCNQ channels as a treatment for MDD and anhedonia using ezogabine (Costi et al. 2021). XEN1101, a next-generation KCNQ channel opener, has been studied in a Phase 2b clinical trial in adult patients with focal onset seizures, and demonstrated compelling efficacy results, with a statistically significant and dose-dependent reduction from baseline in monthly focal seizure frequency when compared to placebo (monotonic dose response; p<0.001).