Phase 1 Pharmacokinetic Data Supports Potential for Once Daily Dosing
Today, Xenon presented interim data from its ongoing XEN1101 Phase 1 clinical trial, which is evaluating the safety, tolerability and pharmacokinetics of both single ascending doses (SAD) and multiple ascending doses (MAD) of XEN1101 in healthy subjects, along with results from the completed Phase 1a pilot transcranial magnetic stimulation (TMS) study in 8 healthy subjects. The pilot TMS study was designed to assess XEN1101’s ability to inhibit cortical excitability, an important CNS effect observed with anti-epileptic drugs (AEDs). Based on this pilot Phase 1a TMS study, Xenon has initiated a double-blind, placebo-controlled, randomized cross-over Phase 1b TMS study, which is expected to include approximately 15 to 20 healthy subjects and be completed by mid-year, with data expected in the second half of 2018.
Dr. Simon Pimstone, Xenon’s Chief Executive Officer, said, “The interim XEN1101 Phase 1 clinical data presented today are very exciting. We believe that the pre-clinical and interim clinical data presented, demonstrate a number of significant benefits of XEN1101 when compared to historical data for ezogabine, an earlier generation potassium channel modulator. These benefits include both pharmacokinetic (PK) and apparent safety benefits as well as achievement of a key pharmacodynamic (PD) readout at a 20 mg dose, which approximately 1/20th of that reported in historical data for ezogabine. The XEN1101 PK profile from the current Phase 1 clinical trial, supports the potential for once daily dosing with XEN1101 versus ezogabine’s three-times daily dosing. From a safety perspective, the majority of adverse events were mild and resolved spontaneously, with an overall profile showing XEN1101 as safe and well tolerated. Importantly, this safety has been observed at drug exposures where we have now shown XEN1101 having an inhibitory effect on cortical excitation in humans.”
Dr. Pimstone added, “In order to obtain an early PD read-out, we used the TMS assay as a measure of cortical excitability and indicator of drug activity in the target CNS tissue. We are pleased to see a robust PD effect in the TMS assay in healthy human volunteers. When compared with the historical data generated with ezogabine, XEN1101 had approximately twice the effect at significantly lower doses.”
Dr. Premoli continued, “Our work with Xenon underscores our belief that the TMS assay has the potential to be used more broadly during the early stages of AED development to potentially provide early read-outs of a pharmacodynamic effect. I am looking forward to further validating these positive results from the XEN1101 Phase 1a TMS pilot study with the data generated from the XEN1101 Phase 1b TMS placebo-controlled cross-over study, which we expect to complete later this quarter.”
Summary of XEN1101 Interim Phase 1 Clinical Data / Phase 1a Pilot TMS Study
- The XEN1101 interim Phase 1 results include data from five SAD cohorts (n=28, placebo=6) ranging in dose from 5 to 30 mg, and one MAD cohort at a 15 mg dose (n=6, placebo=2).
- Pharmacokinetic data confirms a half-life consistent with once daily dosing. Based on data generated from the MAD cohort, it is anticipated that steady state could be achieved at approximately seven days, and food enhances the exposure of XEN1101. Drug exposure levels in the Phase 1 clinical trial were observed above the EC50 in preclinical models.
- The preliminary XEN1101 interim Phase 1 data suggest that overall XEN1101 is safe and well tolerated, with no serious adverse events, and no clinically significant laboratory findings. The majority of adverse events were mild and resolved spontaneously. The most common adverse events were headache, dizziness and drowsiness. One severe adverse event, a vasovagal reaction, was observed following a blood draw and standing. Importantly, no urinary retention or hesitation adverse events were noted, which was one of the adverse events observed in historical clinical trials with ezogabine.
- The TMS Phase 1a pilot study included 8 male subjects where three doses were tested (10 mg, n=2; 15 mg, n=3; 20 mg, n=3). When measuring the resting motor threshold (RMT) in the TMS-EMG assay, the mean change (standard deviation) in RMT was 1.5% (±2.1), 1.33% (±0.58) and 4.33% (±0.58) for the 10 mg, 15 mg and 20 mg doses, respectively. 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, all three subjects at the 20 mg dose showed statistically significant (p<0.01) modulating activity at 4 hours post dose when compared to baseline. The effects of ezogabine within a TMS-EEG have not been tested.
- Based on pre-clinical in vitro metabolism studies, it is anticipated that there is a low risk of drug-drug interactions with XEN1101.
The release of the complete Phase 1 results, including the Phase 1b TMS data from approximately 15 to 20 subjects, is anticipated in the second half of 2018. Xenon anticipates initiating a Phase 2 clinical trial evaluating XEN1101 as a treatment for adult focal seizures by year end. Xenon also intends to explore a parallel plan to advance XEN1101 into rare, pediatric forms of epilepsy as soon as feasible thereafter.
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 Information
Xenon will host a conference call and webcast today at 8:00 a.m. Eastern Time (5:00 a.m. Pacific Time) to provide a corporate update and discuss the XEN1101 and XEN901 Eilat presentations. To participate in the call, please dial (855) 779-9075, or (631) 485-4866 for international callers and provide conference ID number 5249928. The webcast will be broadcast live on the “Investors” section of Xenon’s website at www.xenon-pharma.com and will be available for replay following the call for 30 days.
About Xenon Pharmaceuticals Inc.
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Xenon Pharmaceuticals Inc.