Xenon Announces Positive XEN1101 Pharmacodynamic Data from Phase 1b TMS Study
XEN1101 Demonstrates Statistically Significant Reduction in Corticospinal and Cortical Excitability as Measured by TMS-EMG and TMS-EEG
XEN1101 Demonstrates Greater Effect on TMS-EMG Resting Motor Threshold at Significantly Lower Dose When Compared to Historical Ezogabine Data
XEN1101 Phase 2 Clinical Trial in Adult Focal Seizures Expected to be Initiated in Fourth Quarter of 2018
Conference Call Today at
The completed Phase 1b TMS study was a double-blind, placebo-controlled, randomized cross-over study in 20 healthy male subjects and was initiated based on positive results from a Phase 1a pilot TMS study in 8 healthy subjects, which suggested XEN1101 has an ability to inhibit cortical excitability, an important CNS effect observed with approved anti-epileptic drugs (AEDs).
Summary of XEN1101 Phase 1b TMS Study Results
- The TMS Phase 1b double-blind, placebo-controlled, randomized cross-over study included 20 healthy male subjects. TMS measurements were taken at 2 and 4 hours for all subjects and, due to a prolonged absorption phase displayed by XEN1101 pharmacokinetics, an additional TMS assessment time-point was added at 6 hours for a subset of subjects. Subjects were randomized initially to either a 20 mg dose of XEN1101 or placebo and then, after a wash-out period, crossed over to the other treatment arm.
- Consistent with the Phase 1a TMS pilot study, XEN1101 reduced corticospinal excitability, as demonstrated by a concentration dependent elevation in RMT, the key TMS-EMG measure. Single 20 mg doses of XEN1101 resulted in plasma levels of 15.7 ng/mL, 30.2 ng/mL and 44.4 ng/mL at 2, 4 and 6 hours, respectively and elevated RMT (as a percentage of maximum stimulator output) by 1.5±0.4% (p<0.05), 3.0±0.7% (p<0.01) and 4.3±0.8% (p<0.01) compared to time matched placebo changes of 0.4±0.3%, 0.7±0.4% and 0.9±0.3%. This compares to a literature publication of ezogabine (Ossemann et. al) where in a double-blind, placebo-controlled, cross-over study in 15 healthy subjects at a single dose of 400 mg, ezogabine increased the RMT by 2.4±3.6%.
- In the TMS-EEG portion of the study, a 20 mg XEN1101 dose statistically significantly modulated TMS-evoked potentials (TEPs) in a manner consistent with reductions in cortical excitability, potentially showing a unique “fingerprint” of activity as anticipated based on studies with other AEDs. Relative to time-matched placebo, at peak plasma levels, XEN1101 decreased the amplitude of TEPs measured at 25 ms (N15-P25: 4.5 vs 6.0 µV, p<0.05), 45 ms (N45: -2.3 vs -3.0 µV, p<0.01) and 180 ms (P180: 2.2 vs 3.0 µV, p<0.01) after the TMS pulse. Additional measures of cortical excitability including
Global Mean Field Powerwere similarly impacted by XEN1101.
- XEN1101 was well tolerated with all adverse events (AEs) reported as mild or moderate and reversible. The most common AEs were dizziness and drowsiness, similar to marketed antiepileptic drugs. There were no withdrawals, serious AEs, or deaths.
Update on XEN1101 Phase 1 Clinical Trial and XEN901 Phase 1 Clinical Trial
In addition to completing both the Phase 1a pilot and Phase 1b TMS studies, Xenon has now completed enrollment in the XEN1101 Phase 1 clinical trial using a powder-in-capsule formulation, which is evaluating the safety, tolerability and pharmacokinetics of both single ascending doses (SAD) and multiple ascending doses (MAD) of XEN1101. The XEN1101 Phase 1 clinical trial included 5 SAD cohorts, a food effect cohort and 3 MAD cohorts of 66 healthy subjects. Interim results presented in
Xenon is also developing XEN901, a potent, highly selective Nav1.6 sodium channel inhibitor, for the treatment of epilepsy. A randomized, double-blind, placebo-controlled Phase 1 clinical trial to evaluate XEN901’s safety, tolerability and pharmacokinetics in both SAD and MAD cohorts is ongoing, with 6 SAD cohorts, a food effect cohort and 3 MAD cohorts completed and 74 subjects enrolled in the study to date. Interim results presented in
Comparisons of XEN1101 and ezogabine are not based on data resulting from head-to-head trials and are not direct comparisons of safety or efficacy. Different protocol designs, trial designs, patient selection and populations, number of patients, trial endpoints, trial objectives and other parameters that are not the same between the relevant trials may cause any comparisons of results from different trials to be unreliable.
Conference Call and Webcast Information
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We are a clinical stage, neurology-focused biopharmaceutical company focused on developing innovative therapeutics to improve the lives of patients with neurological disorders. Building upon our extensive knowledge of human genetics and diseases caused by mutations in ion channels, known as channelopathies, we are advancing – both independently and with our collaborators – a novel product pipeline of central nervous system, or CNS, therapies to address areas of high unmet medical need, such as epilepsy, migraine and pain. For more information, please visit www.xenon-pharma.com.
Safe Harbor Statement
This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995 and Canadian securities laws. These forward-looking statements are not based on historical fact, and include statements regarding our expectations regarding the timing of and results from clinical trials and pre-clinical development activities, including those related to XEN901, XEN1101 and our other product candidates, the potential efficacy, safety profile, future development plans, addressable market, regulatory success and commercial potential of XEN901, XEN1101 and our other product candidates, the anticipated timing of IND, or IND equivalent, submissions and the initiation of future clinical trials for XEN901, XEN1101 and our other product candidates, the efficacy of our clinical trial designs, our ability to successfully develop and achieve milestones in the XEN901, XEN1101 and other development programs, the anticipated benefits of the unique mechanisms of action of XEN901 and XEN1101, the design of our clinical trials and anticipated enrollment, the potential for XEN1101 to support once daily dosing, the potential for XEN901 to support twice daily or better dosing, the progress and potential of our other ongoing development programs, and the timing of our public presentation and potential publication of future clinical data. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: promising results in preclinical and early clinical trials may not be replicated in subsequent clinical trials; clinical trials may not demonstrate safety and efficacy of any of our or our collaborators' product candidates; any of our or our collaborators' product candidates may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; the impact of competition; adverse conditions in the general domestic and global economic markets; as well as the other risks identified in our filings with the
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