About the Investigator-Led Phase 2 XEN1101 Clinical Trial in MDD
Xenon is collaborating with the Icahn School of Medicine at Mount Sinai to conduct 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. The primary objective of the study is to investigate the effect of XEN1101 on the brain reward circuit as measured by the change in bilateral ventral striatum activity as assessed by functional MRI (fMRI). The secondary objectives are to test the effect of XEN1101 compared to placebo on clinical measures of depression and anhedonia using the MADRS and SHAPS scales.
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).