Xenon Pharmaceuticals Inc. · NASDAQ:XENE
Xenon Pharmaceuticals — Eilat XIV Meeting 2018
32 slides from Xenon Pharmaceuticals's conference presentation, May 15, 2018
Slide 1: XEN1101: A Novel, Next-Generation KCNQ2 Modulator for the Treatment of Epilepsy
XEN1101: A Novel, Next‐ Generation KCNQ2 Modulator for the Treatment of Epilepsy Y. Paul Goldberg, MBChB, Ph.D., FRCPC Xenon Pharmaceuticals, Inc. Eilat XIV Meeting | May 15, 2018 | Madrid, Spain NASDAQ: XENE | www.xenon‐pharma.com 1
Slide 2: Forward Looking Statement/Safe Harbor
Forward Looking Statement/Safe Harbor This presentation and the accompanying oral commentary contain forward‐looking statements that involve risks, uncertainties and assumptions. If the risks or uncertainties ever materialize or the assumptions prove incorrect, our results may differ materially from
Slide 3: XEN1101: Best-in-Class KCNQ2 Modulator
XEN1101: Best‐in‐Class KCNQ2 Modulator • Same mechanism of action as ezogabine, but with substantial improvements • More potent in vitro and in vivo • Improved PK • Once daily dosing and predict better tolerability • No predicted pigmentation liability • Does not form pigmented dimers • Modulating c
Slide 4: Presentation Overview
Presentation Overview • Background on KV7.2 and XEN1101 • Phase 1 Trial Design and Results • PK, Safety • TMS Pilot Study • Ongoing Studies and Future Development Plans • Summary 4
Slide 5: KCNQ2 is a Highly Genetically Validated Target
KCNQ2 is a Highly Genetically Validated Target M‐Current Gradient Correlates with Disease Severity 5
Slide 6: XEN1101 Based on Proven Mechanism of Action
XEN1101 Based on Proven Mechanism of Action KV7.2 Attenuates Neuronal Hyper‐Excitability 6
Slide 7: Multiple Predicted Benefits of XEN1101 over Ezogabine
Multiple Predicted Benefits of XEN1101 over Ezogabine Improvement Key Difference to Ezogabine / Predicted Impact • No dimerization or oxidative color changes Chemistry • Predict no skin and retinal pigmentation Potency • 10‐50X greater in vitro potency on Kv7.2/3 • Once daily dosing vs TID Pharmacok
Slide 8: Increased Potency of XEN1101
Increased Potency of XEN1101 40 30 Assay EC50 Function GV 0.5 Vmax (mV) KV7.2/KV7.3 27 nM CNS 20 KV7.3/KV7.5 94 nM CNS EC50 = 27nM KV7.4 113 nM Bladder 10 4 0 0.0001 0.001 0.01 0.1 1 10 100 XEN1101 (µM) 8
Slide 9: Improved Therapeutic Index of XEN1101
Improved Therapeutic Index of XEN1101 Mouse ED50 or TD50 (Mean: 95% CI) XEN1101 Tested 1h Post Dose scPTZ scPicrotoxin scBicuculline MES Ezogabine 6Hz 32mA 6Hz 44mA Rotarod 0 4 20 27 40 50 60 80 100 mg/kg 9
Slide 10: Metabolism Suggests Minimal Risk for Drug-Drug Interactions
Metabolism Suggests Minimal Risk for Drug‐Drug Interactions • Metabolism • Highly stable in liver microsomes and hepatocytes • No risk of DDI through inhibition of CYP450 enzymes • No inhibition of CYP1A2, 2C9, 2C19, 2D6 & 3A4 tested at 3µM • No significant time‐dependent inhibition of CYP1A2, 2C9,
Slide 11: Clinical Overview of XEN1101
Clinical Overview of XEN1101 • Phase 1 protocol: Adaptive integrated design • SAD/MAD/Food Effect (FE) study • Pilot TMS study (Phase 1a) • TMS Cross‐over study (Phase 1b) • Planning Phase 2 clinical trial in Adult Focal Epilepsy • Pediatric development options currently being evaluated • Focal seiz
Slide 12: XEN1101 Phase 1 Trial Design
XEN1101 Phase 1 Trial Design SAD TMS Pilot TMS Cross‐over placebo n=6 5 mg, n=3 Cohort 1 15 mg, n=3 Cohort 2 Cohort 1 Drug Placebo 20 mg, n=6 Cohort 3 10 mg, n=2 X 30 mg, n=6 Cohort 4 Cohort 2 15 mg, n=3 Placebo Drug food effect, 20 mg, n=10 Cohort 5 Cohort 3 20 mg, n=3 20 mg, n=15‐20 Cohort 6 Cohor
Slide 13: XEN1101 Single Ascending Dose
XEN1101 Single Ascending Dose 100 XEN1101 Conc. (ng/mL) 10 1 0 8 16 24 32 40 48 56 64 72 Time (hours) 5 mg 15 mg 20 mg 30 mg Long Half‐Life Consistent with Once Daily Dosing 13
Slide 14: XEN1101 Repeat Dosing for 7 Days
XEN1101 Repeat Dosing for 7 Days Achieve Steady State Plasma Levels at Approximately 7 days 14
Slide 15: Food Enhances XEN1101 Exposure
Food Enhances XEN1101 Exposure 100 XEN1101 Conc. (ng/mL) 10 FDA Breakfast, 20 mg FDA Fasted, 20 mg 1 0 12 24 36 48 Time (hours) Cross‐Over Design Food Effect 15
Slide 16: Chronic Low Daily Dosing Achieves Exposures Required for TMS and Pre-Clinical Efficacy
Chronic Low Daily Dosing Achieves Exposures Required for TMS and Pre‐ Clinical Efficacy Mouse MES EC50 TMS Pilot Exposure Range n=3, 20 mg 16
Slide 17: No Signal of Urinary Retention in Clinic to Date
No Signal of Urinary Retention in Clinic to Date • Single doses of XEN1101: 5‐30 mg • No urinary retention or hesitation AEs noted in 28 volunteers • Cmax range up to 104 ng/mL • Multiple doses of XEN1101: 15 mg QD for 7 days • No urinary retention or hesitation AEs noted in 6 volunteers • Cmax rang
Slide 18: Interim Preliminary Safety Summary
Interim Preliminary Safety Summary • Ongoing study, evaluated SAD: 5, 15, 20, 30 mg, MAD: 15 mg • No SAEs or deaths • No clinically significant ECG or Laboratory findings • Majority of AEs were mild and resolved spontaneously • Most common AEs were headache, dizziness, and drowsiness • One severe AE
Slide 19: Transcranial Magnetic Stimulation (TMS)
Transcranial Magnetic Stimulation (TMS) • TMS uses a magnetic pulse to stimulate human motor cortex • Response can be measured with • EMG (motor threshold for finger twitch) • EEG (characteristic response pattern) • TMS is used to assess cortical excitability in response to AEDs in both volunteers a
Slide 20: TMS EMG TMS EEG
TMS EMG TMS EEG TMS‐evoked Motor Potentials (MEPs) TMS‐evoked EEG Potentials (TEPs) Rogasch et al, 2013 Schiz Bull Premoli et al., 2014 Journal of Neuroscience 20
Slide 21: Prior TMS-EMG Cross-Over Study Using Ezogabine
Prior TMS‐EMG Cross‐Over Study Using Ezogabine • Double‐blind, placebo‐controlled cross‐over study • 15 healthy subjects • Single 400 mg dose of ezogabine • TMS‐EMG performed at Cmax of 2 hours • No TMS‐EEG performed • Resting Motor Threshold (RMT) increased • 2.4 ± 3.6 % Ossemann et al, Epilepsy Re
Slide 22: TMS Strategy for XEN1101
TMS Strategy for XEN1101 Goal: • Seeking a marker of early target engagement in humans Objectives: • Compare magnitude of effects of XEN1101 vs ezogabine • Provide preliminary evidence for CNS target engagement • Determine dose and sample size for robust double‐blind, placebo‐controlled, TMS‐EMG/EEG
Slide 23: XEN1101 Open-Label Pilot TMS Study
XEN1101 Open‐Label Pilot TMS Study • 8 male subjects • Entered pilot TMS study after completing SAD cohort • Three dose levels (10, 15, 20 mg) evaluated, open label • TMS‐EMG and TMS‐EEG evaluations compared to baseline 23
Slide 24: XEN1101: Substantial RMT Response at Low Dose
XEN1101: Substantial RMT Response at Low Dose Xenon Pilot Ossemann Retigabine data from Ossemann et al., Epilepsy Research 2016; 126:78‐82 XEN1101 TMS‐pilot study data recorded at 4 hours after dose TMS‐EMG Effect of XEN1101 Observed at 20 mg vs Ezogabine at 400 mg 24
Slide 25: TMS-EEG: Provides Biomarkers of Physiological Processes
TMS‐EEG: Provides Biomarkers of Physiological Processes Premoli et al., 2014 Journal of Neuroscience 25
Slide 26: XEN1101 Shows Robust Response & Emerging EEG Signature
XEN1101 Shows Robust Response & Emerging EEG Signature TMS‐EEG of XEN1101 20 mg Dose TMS Pattern of Reduced N100 and P180 Amplitudes S4 (µV) TMS‐EEG Evoked Potentials Amplitude (µV) Pre-dose 2hr 20 mg Pre Post 2h Post 4h Amplitude 4hr N100 P180 N100 P180 N100 P180 mean ‐3.87 1.61 ‐2.23 0.54 ‐2.02 ‐0
Slide 27: Summary of Pilot TMS Results
Summary of Pilot TMS Results • EMG • Signal at 10 and 15 mg, with robust response at 20 mg • TMS‐EMG effect of XEN1101 observed at 20 mg vs ezogabine at 400 mg • EEG • 20 mg dose shows statistically significant modulating activity, with reproducible and specific pattern of response • Reduced amplitu
Slide 28: Summary of XEN1101 Interim Phase 1 / Pilot TMS Results
Summary of XEN1101 Interim Phase 1 / Pilot TMS Results • XEN1101 has a PK profile consistent with once a day dosing • Mild transient AE profile consistent with MOA (e.g., dizziness, sedation) • Majority of AEs mild except a vasovagal reaction during standing orthostatic BP test immediately after blo
Slide 29: XEN1101 Phase 1b TMS Cross-Over Study
XEN1101 Phase 1b TMS Cross‐Over Study • To evaluate the safety, tolerability, pharmacokinetics and TMS effects of XEN1101 in a double‐blind, placebo‐controlled, cross‐over study • London, UK (King’s College Hospital) • Male healthy volunteers (18‐55 years) • Single dose, 20 mg • N = 15‐20 • Placebo‐
Slide 30: XEN1101 Phase 2 Clinical Planning
XEN1101 Phase 2 Clinical Planning • Proposed plans include a Phase 2 clinical trial (H2:18 start) in adult patients with focal seizures • Pediatric development options currently being evaluated • Focal seizure population • Precision medicine in KCNQ2 population 30
Slide 31: XEN1101 Summary
XEN1101 Summary • Best‐in‐class KV7.2 modulator • Highly clinically, pharmacologically and genetically validated mechanism • Substantial improvement over ezogabine • Pigmentation issue appears resolved • More potent and predicted improved TI • Predict lower CNS‐related AEs due to QD dosing with low
Slide 32: Acknowledgements / Contributors
Acknowledgements / Contributors King’s College London Xenon Pharmaceuticals • Isabella Premoli • Greg Beatch • Mark Richardson • Catherine Leung • Pierre Rossini • Jay Cadieux • Eugenio Abela • Rostam Namdari • Kristina Posadas • Heather Kato Richmond Pharmacology Ltd. • Ying Man • Charles Cohen 1st