Xenon Pharmaceuticals (XENE) Phase 2b “X-TOLE” Clinical Trial of XEN1101 for the Treatment of Focal Epilepsy Met Primary Endpoint
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Xenon Pharmaceuticals Inc. (Nasdaq: XENE), a neurology-focused biopharmaceutical company, today announced the first positive results of the X-TOLE Phase 2b clinical trial, which evaluated clinical efficacy, safety and the tolerability of XEN1101 – a differentiated Kv7 potassium channel modulator – administered as add-on therapy in adult patients with focal epilepsy.
The trial met its primary endpoint with XEN1101, demonstrating a statistically significant and dose-dependent reduction from baseline in monthly focal seizure frequency (defined as 28 days) compared to placebo (response to monotonic dose; p
|XEN1101 25 mg(N = 112)||XEN1101 20 mg(N = 51)||XEN1101 10mg(N = 46)||Placebo(N = 114)|
|Median reduction from baseline in monthly focal seizure rate||52.8% (p||46.4% (p||33.2% (p = 0.035)||18.2||%|
|Patients with at least a 50% reduction in monthly focal seizure frequency from baseline||54.5% (p||43.1% (p||28.3% (p = 0.037)||14.9||%|
Jacqueline A. French, MD, professor in the department of neurology at NYU Langone Health and co-director of epilepsy clinical trials at the Comprehensive Epilepsy Center at NYU Langone; founder / director of the epilepsy study consortium; and Chairman of the XEN1101 X-TOLE Steering Committee, said: “Many patients today are living with the debilitating effects of focal seizures, even if they are taking several antiepileptic drugs, so there is a great need for new and effective drugs. tolerated. therapies. The X-TOLE results generated by this large-scale, multicenter controlled trial are truly exciting as they demonstrate impressive efficacy of XEN1101 for adult patients with focal epilepsy, including those with seizures considered difficult to treat. In addition, doctors and patients could benefit from the other important attributes of XEN1101, such as dosing once a day in the evening without titration. With its unique potassium channel mechanism of action, the strength of these leading data suggests that XEN1101 may play an important role in the treatment of focal epilepsy.
Dr Christopher Kenney, Medical Director of Xenon commented, “On behalf of the entire Xenon team, I would like to thank the patients, investigators and site coordinators who participated in the X-TOLE study. We have generated strong evidence that supports the efficacy, safety and tolerability of XEN1101 and describes a very favorable product profile for XEN1101. Importantly, we saw statistically significant reductions in focal seizures compared to placebo in all dose groups, suggesting that it is very active in the central nervous system. With these compelling first results, we look forward to working with the FDA to plan an accelerated development path in the future. “
Designed as a multicenter, randomized, double-blind, placebo-controlled study, the phase 2b clinical trial X-TOLE evaluated the clinical efficacy, safety and tolerability of XEN1101 given as add-on therapy once per day in adult patients with focal epilepsy. The study included a total of 325 randomized and treated subjects in the safety population and 323 subjects in the modified intention-to-treat population for efficacy analyzes. The subjects had a mean age of 40.8 ± 13.3 years, and 8.9%, 40.3%, or 50.8% of the subjects were taking and continuing to take one, two or three DMARDs (DMARDs). stable throughout the study, respectively, and failed a median of 6 previous ASMs before entry into the study. The median frequency of baseline seizures in the study groups was approximately 13.5 per month. Of the 285 subjects who completed the double-blind period, 96.5% entered the open-label extension to assess the safety, tolerability and long-term efficacy of XEN1101.
Summary of Findings
Key Efficiency Findings:
- The main objective of the study was to assess the dose-response trend of XEN1101 in reducing the monthly frequency of focal seizures, based on a classified ANCOVA model. The median percent reduction in monthly focal seizure frequency was 52.8% in the XEN1101 25 mg group, 46.4% in the XEN1101 20 mg group, and 33.2% in the XEN1101 10 mg group compared to at 18.2% in the placebo group. The monotonic dose-response relationship between the XEN1101 active dose groups versus placebo was statistically significant (p
- In addition, XEN1101 demonstrated a statistically significant reduction from baseline in monthly focal seizure frequency in pairwise comparisons with placebo for all three doses of XEN1101. The median percent reduction in monthly focal seizure frequency was 52.8% in the XEN1101 25 mg group, 46.4% in the XEN1101 20 mg group, and 33.2% in the XEN1101 10 mg group compared to at 18.2% in the placebo group. Statistical significance was reached for all dose groups compared to placebo with two-sided p-values of p
- A key secondary endpoint of the study was a responder analysis, which compared the proportion of study subjects treated with XEN1101 who achieved a ≥ 50% reduction in monthly focal seizures compared to placebo. The percentage of subjects achieving> 50% reduction in monthly focal seizures was 54.5% in the XEN1101 25 mg group, 43.1% in the XEN1101 20 mg group and 28.3% in the XEN1101 10 mg group per compared to 14.9% in the placebo group. group. Statistical significance was reached for all dose groups compared to placebo with two-sided p-values of p
- These marked reductions in seizures were associated with statistically significant improvements in general condition, as rated by physicians using the Clinical Global Impression of Change (CGI-C) and self-report. subjects using the Patient Global Impression of Change (PGI-C) scales. in the XEN1101 25 mg group, which are shown in the table below with two-sided p-values:
|XEN1101 25 mg(N = 112)||Placebo(N = 114)|
|CGI-C (much improved or much improved portion of patients)||46.4% (p||22.8%|
|PGI-C (much improved or much improved portion of patients)||42.9% (p = 0.001)||21.9%|
In addition to the statistically significant CGI-C and PGI-C in the XEN1101 25 mg group, the XEN1101 20 mg group was statistically significant in PGI-C, while the XEN1101 20 mg group in CGI-C and the XEN1101 10 mg group for CGI-C and PGI-C both showed numerical improvements over placebo, but were not statistically significant.
Key Safety and Tolerability Findings
- XEN1101 was generally well tolerated in this study with adverse events (AEs) consistent with other ASMs. The incidence of treatment-occurring adverse events (TERs) was higher in the treatment groups than in the placebo group, with 62.3% of patients in the placebo group, 67.4% of patients in the XEN1101 10 mg group, 68.6% of patients in the XEN1101 20 mg group, and 85.1% of patients in the XEN1101 25 mg group with at least one TIA. The most common adverse reactions in all XEN1101 dose groups (n = 211) were dizziness (n = 52, 24.6%), somnolence (n = 33, 15.6%), fatigue (n = 23, 10.9%) and headaches (n = 21, 10.0%). Two urinary retention AETEs were reported in the active treatment groups, one of which required dose reduction, and both subjects remained on medication without further changes or interventions. EKG interval changes were infrequent and balanced between the placebo and active treatment groups. There have been no TIAs of pigment abnormalities reported during the double-blind phase of the study or in preliminary analysis during the ongoing open-label extension to date with approximately 70 subjects treated now. more than 12 months.
- The incidence of serious adverse events (SAEs) occurring during treatment was similar in the four arms of the study with 2.6% of patients in the placebo group, 4.3% of patients in the XEN1101 10 mg group, 3.9 % of patients in the XEN1101 20 mg group, and 2.6% of patients in the XEN1101 25 mg group experienced at least one treatment-related SAE.
- There were 3.5% of subjects in the placebo group, 2.2% of subjects in the XEN1101 10 mg group, 13.7% of subjects in the XEN1101 20 mg group, and 15.8% of subjects in the XEN1101 25 mg group who received had an AE leading to discontinuation of treatment.
Mr. Ian Mortimer, President and CEO of Xenon, said: “We believe the X-TOLE baseline data supports a very attractive clinical profile for XEN1101 with desirable attributes that help differentiate it from other ASMs and suggest that XEN1101 could be very competitive in the future adult focal seizure market. Importantly, the efficacy data for XEN1101 is particularly compelling given that approximately 50% of the subjects in X-TOLE were using three concomitant ASMs, suggesting that this was a potentially even more difficult patient population. than previous studies with other ASMs. Additionally, these data signal the activity of XEN1101 in the central nervous system, further supporting our plans for the development of XEN1101 in other indications, including major depressive disorder and other types of epilepsy.
Xenon intends to seek feedback from the United States Food and Drug Administration and other regulatory agencies to continue planning for the future clinical development of XEN1101. In addition, the open-label X-TOLE extension, which has been extended to three years, is expected to generate important long-term data for XEN1101.
Conference Call InformationXenon to host a conference call and live webcast with slides today at 7:30 a.m. EST (4:30 a.m. PT) to discuss key findings from the XEN1101 Phase 2b clinical trial X-TOLE. The webcast will be broadcast live on the Investors section of Xenon website. To join the call, please dial (855) 779-9075 or (631) 485-4866 for international callers and provide the conference ID number 4481713.