XEN1101 (FOS)

XEN1101, A Differentiated K_V7 Potassium Channel Opener for the Treatment of Epilepsy

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 continues to execute on its comprehensive strategy to protect and expand the intellectual property portfolio that covers XEN1101. Importantly, two additional U.S. patents were granted in 2021 with claims related to: (1) compositions-of-matter covering four distinct crystalline forms of XEN1101 drug substance (including the forms used in current and future clinical development); and (2) methods of enhancing the bioavailability of XEN1101 by administration with or close to a meal (consistent with the dosing of XEN1101 in clinical studies). These U.S. patents are expected to expire in 2040 and 2039, respectively, absent any extensions of patent term.

About the XEN1101 Phase 3 Program in Focal Onset Seizures (FOS)

Xenon has initiated its XEN1101 Phase 3 development program, which includes two identical Phase 3 clinical trials called X-TOLE2 and X-TOLE3, which are designed closely after the Phase 2b X-TOLE clinical trial. X-TOLE2 is expected to be initiated in the second half of 2022 followed by the initiation of X-TOLE3 and both studies will run in parallel. These multicenter, randomized, double-blind, placebo-controlled trials will evaluate the clinical efficacy and safety of XEN1101 administered as adjunctive treatment in patients with FOS. Approximately 360 patients will be randomized 1:1:1 for once-daily dosing of XEN1101 (15 mg), XEN1101 (25 mg) or placebo in each trial. Eligibility criteria include adults aged 18 to 75 years old taking one to three anti-seizure medications (ASMs) with a seizure frequency of ≥4 seizures per month at baseline.

Patients will undergo an 8-week baseline period to assess seizure frequency and eligibility for randomization, followed by a 12-week double blind period (DBP). There is no titration period. The primary efficacy endpoint is the median percent change (MPC) in monthly seizure frequency from baseline through the DBP of XEN1101 compared to placebo. Key secondary endpoints include the proportion of patients experiencing ≥50% reduction in seizure frequency from baseline for XEN1101 versus placebo, MPC at Week 1 compared to baseline to assess the rapidity of seizure reduction and the Patient Global Impression of Change (PGI-C) at Week 12. On completion of the DBP in X-TOLE2 and X-TOLE3, eligible patients may enter an open-label extension study for up to three years. In addition, the ongoing X-TOLE open-label extension also continues to generate important long-term data for XEN1101 in FOS.

Clinical Development of XEN1101

On June 21, 2022, Xenon announced completion of an End-of-Phase 2 (EOP2) meeting with the U.S. FDA. The outcome of the EOP2 meeting supports the advancement of XEN1101 into Phase 3 clinical development, and Xenon remains on track to initiate the Phase 3 program in the second half of 2022

Based on the EOP2 meeting, Xenon and the FDA aligned on key elements of the Phase 3 program to support a New Drug Application (NDA) submission. Xenon plans to submit an NDA upon completion of the first XEN1101 Phase 3 clinical trial ‘X-TOLE2’, if successful, and use the existing data package from the Phase 2b X-TOLE clinical trial along with additional safety data from other clinical trials to meet regulatory requirements. Additionally, alignment was obtained with the FDA on key elements of a single Phase 3 clinical trial to pursue an additional epilepsy indication of primary generalized tonic clonic seizures (PGTCS).

Previously, in May 2022, Xenon announced its plans to evaluate XEN1101 as a treatment for Major Depressive Disorder (MDD). A Phase 2 proof-of-concept trial called “X-NOVA” is currently underway, along with an investigator led study with collaborators at the Icahn School of Medicine at Mount Sinai.

About the Phase 2b X-TOLE Clinical Trial

On October 4, 2021, Xenon reported positive topline results from the Phase 2b X-TOLE clinical trial, which evaluated the clinical efficacy, safety, and tolerability of XEN1101 administered as adjunctive treatment in adult patients with focal epilepsy.

The trial met its primary efficacy endpoint with XEN1101 demonstrating a statistically significant and dose-dependent reduction from baseline in monthly (defined as 28 days) focal seizure frequency when compared to placebo (monotonic dose response; p<0.001). Additional primary and secondary measures included a pairwise comparison of each active dose to placebo and a responder analysis with the proportion of patients who achieved a 50% or greater reduction in monthly focal seizure frequency from baseline.

Read the full news release with topline data here: Xenon Pharmaceuticals Announces Positive Topline Results from Phase 2b ‘X-TOLE’ Clinical Trial of XEN1101 for the Treatment of Focal Epilepsy

Listen to replay of Management Call discussing X-TOLE topline results here: Webcast – October 4, 2021 and view the accompanying slides here: Presentation slide deck

On December 3, 2021, Xenon presented X-TOLE clinical data at the annual meeting of the American Epilepsy Society (AES2021). Our XEN1101-related presentations have been posted here.

About Epilepsy and Focal Onset Seizures

Epilepsy is a chronic neurologic disorder, the hallmark of which is recurrent, unprovoked and unpredictable seizures. Individuals are diagnosed with epilepsy if they have two unprovoked seizures (or one unprovoked seizure with the likelihood of recurrent seizures) that were not caused by a known and reversible medical condition. Seizures are generally described in two major groups: generalized seizures and focal seizures. Focal seizures are the most common type of seizure experienced by people with epilepsy. A focal seizure is localized within the brain and can either stay localized or spread to the entire brain, which is typically categorized as a secondary generalized seizure. Focal seizures account for approximately 60% of seizures in the U.S., which results in a total focal onset seizure patient population of approximately 1.8 million patients.

Numerous ASMs are available for the treatment of focal seizures in the U.S. The treatment of an individual patient with focal seizures is currently focused on reduction of seizure frequency, with seizure freedom as the ultimate goal. Early treatment typically begins with monotherapy followed by increasing use of polypharmacy to manage patients with residual seizure burden. Despite the availability of multiple treatment options, approximately 50% of patients are considered inadequately managed with initial lines of therapy warranting additional treatment options. For poorly managed patients, physicians increasingly turn to complementary mechanisms used as adjunctive therapy to control seizures. Based on our prior market research, we believe XEN1101 could offer a compelling value proposition for focal epilepsy patients with residual seizure burden if approved.

Additional Positive Data from the XEN1101 Program

In June 2022, Xenon announced new, compelling efficacy data supporting the late-stage, Phase 3 development of XEN1101:

XEN1101 rapidly reduced focal onset seizure (FOS) frequency within one week for all doses compared with placebo. At Week 1, the median percent reduction in monthly focal onset seizure frequency was 55.4% in the 25 mg group (p<0.001), 41.5% in the 20 mg group (p=0.039), and 39.1% in the 10 mg group (p=0.002) compared to 20.2% in the placebo group. Based on the strength of data from this time course to efficacy analysis, a key secondary endpoint in the Phase 3 trials will include the median percent change of weekly FOS at Week 1.
Approximately 96% of patients who completed the randomized phase of the XEN1101 Phase 2b X-TOLE study rolled over into the OLE, with 231, 193 and 54 patients having now been treated in the trial for at least 6 months, 12 months, and 2 years, respectively.
Seizure frequency continued to improve for the OLE population during the first month after the 8-week double-blind period (DBP), suggesting that the efficacy signal has the potential to persist, and may potentially improve, in the planned 12-week DBP of the XEN1101 Phase 3 trials.
Subjects remaining in the X-TOLE OLE for at least 3 months and 12 months experienced a greater than 70% and 80% reduction, respectively, in median monthly seizure frequency when compared to the DBP baseline.
54 (19.6%) and 26 (9.5%) of subjects in the OLE experienced a ≥6 and a ≥12 consecutive months of seizure freedom, respectively. This analysis uses the denominator of all patients transitioning to the OLE (N=275) even though not all patients have been in the study long enough to be treated for at least 12 months.
XEN1101 continues to be generally well-tolerated in the OLE with adverse events (AEs) consistent with other anti-seizure medicines and the X-TOLE double-blind period. There have been no treatment emergent AEs of pigmentary abnormalities reported during the DBP or OLE. As was the case in the DBP, two AEs of urinary retention occurred in the OLE possibly related to study drug; both patients continued in the study without requiring intervention. Weight changes in the OLE were 1.4 ± 4.5 kg at the 6-month visit and 0.9 ± 6.2 kg at the 12-month visit.

The full news release can be found here.