Xenon Pharmaceuticals Announces Collaboration with Researchers at Icahn School of Medicine at Mount Sinai to Conduct a Phase 2 Study of XEN1101 for the Treatment of Major Depressive Disorder (MDD)

U.S. FDA IND acceptance and IRB approval in place for investigator-sponsored trial, expected to be initiated in the second quarter of 2021

BURNABY, British Columbia, March 08, 2021 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq:XENE), a clinical stage biopharmaceutical company, today announced a collaboration with the Icahn School of Medicine at Mount Sinai (Mount Sinai) to facilitate an investigator-sponsored Phase 2 proof-of-concept, randomized, parallel-arm, placebo-controlled clinical trial of XEN1101 for the treatment of major depressive disorder (MDD) and anhedonia, which is an inability to feel pleasure. The principal investigator and sponsor of the Investigational New Drug (IND) application for the study is Dr. James W. Murrough, MD, PhD, Associate Professor of Psychiatry and Neuroscience at Mount Sinai. Xenon will supply the study drug, XEN1101, which is a proprietary, differentiated Kv7 potassium channel modulator being developed for the treatment of epilepsy and potentially other neurological disorders. The U.S. Food and Drug Administration (FDA) has accepted the IND, and study investigators have obtained Institutional Review Board (IRB) approval of the protocol in order to proceed with the Phase 2 XEN1101 MDD clinical trial, which is expected to be initiated in the second quarter of 2021.

Dysfunction of the dopamine neurons in the ventral tegmental area (VTA) of the brain reward system is an important feature of depressive disorders and other comorbidities, including anhedonia. Evidence from preclinical studies has highlighted KCNQ-type (Kv7) neuronal potassium channels as novel targets for the treatment of depressive disorders capable of reversing the observed dysfunction in the dopamine neurons. In addition, promising results were generated from both an open-label study and a randomized, placebo-controlled clinical trial that explored the targeting of KCNQ channels as a treatment for MDD using ezogabine, an earlier-generation KCNQ potassium channel modulator that was withdrawn from the market for commercial reasons. Dr. Murrough and colleagues recently published the results from the randomized, placebo-controlled clinical trial of ezogabine in MDD and anhedonia in the American Journal of Psychiatry. For more information, refer to the news release issued by Mount Sinai on March 3, 2021: https://www.mountsinai.org/about/newsroom/2021/researchers-identify-brain-ion-channel-as-new-approach-to-treating-depression

Dr. Murrough stated, “MDD is one of the most disabling medical conditions worldwide, and new treatments are urgently needed to address this large, public health burden. Our previous clinical work using ezogabine suggests that KCNQ channel potentiation may represent a novel treatment approach for depression. Ezogabine was well-tolerated in patients with depression and resulted in a significant improvement in symptoms of depression and anhedonia. Our hope is that this new study will generate useful data that supports the utility of XEN1101 in depressive disorders such as MDD, given its common mechanism of action combined with an advantageous pharmacokinetic profile when compared to ezogabine.”

Dr. Simon Pimstone, Xenon’s Chief Executive Officer, said, “In addition to our ongoing Phase 2b X-TOLE study in adult patients with focal epilepsy, we have been exploring other neurological conditions for XEN1101. We have already completed Phase 1 and Phase 1b studies with XEN1101, establishing pharmacokinetic, toxicology, brain exposure and safety data. Dr. Murrough has generated promising, clinical results with the first generation Kv7 channel modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. This strategic collaboration allows us to further explore the potential we see for XEN1101 as a ‘next-gen’ Kv7 channel modulator in patients with depressive disorders such as MDD and also supports our ongoing epilepsy work as depression is a significant co-morbidity in many patients with focal epilepsy.”

About the Phase 2 XEN1101 MDD Clinical TrialThe Phase 2 investigator-sponsored XEN1101 MDD Study is designed as a multi-site, double-blind, randomized, parallel-arm, placebo-controlled clinical trial to test the antidepressant effect of XEN1101 compared to placebo in patients with MDD and significant anhedonia. Approximately 60 patients with a primary diagnosis of MDD according to Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) will be randomized in a 1:1 manner under double-blind conditions. Following a screening period, each subject will receive a daily dose of study drug or placebo for 8 weeks. The primary objective of the study is to investigate the effect of XEN1101 on brain measures of reward 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 a variety of clinical scales including the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS). This Phase 2 Study is expected to initiate in the second quarter of 2021.

Scientific Rationale and Pre-Clinical Support for Studying XEN1101 in MDDPre-clinical work demonstrates a regulatory role for the KCNQ-type potassium channels in reversing depressive phenotypes following 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 VTA, 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 KCNQ channel openers, or (c) systemic injection of KCNQ channel openers. Repeated peripheral daily administration of the KCNQ channel opener ezogabine completely reversed the depressive/anhedonic phenotype in the susceptible mice. XEN1101, a next-generation, more potent KCNQ channel opener, has been shown to have activity in several in vivo rodent models of electrically and chemically induced seizures and exhibits a selectivity for Kv7 channels over other ion channels and receptors. Moreover, XEN1101 was found to be relatively more selective for Kv7.2/7.3 over Kv7.3/7.5 and Kv7.4 channels, which may be relevant for the clinical profile of the drug. In vitro studies suggested a low potential for drug-drug interactions through the inhibition of the cytochrome isoenzymes, and data from Phase 1 clinical studies showed a favorable pharmacokinetic profile.

Clinical Validation for Studying XEN1101 in MDD Based on Completed Studies with EzogabineDr. Murrough conducted two clinical studies using the first-generation Kv7 potassium channel modulator, ezogabine, in order to test the hypothesis that increasing KCNQ channel signaling can be beneficial for patients with depression and anhedonia. An open-label, proof-of-concept study was conducted with eighteen individuals with MDD in a major depressive episode (MDE) who received ezogabine up to 900 mg/day orally (within the approved range for seizure disorder) over the course of ten weeks. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms MADRS score change: −13.7±9.7, p