Xenon Pharmaceuticals Inc. · NASDAQ:XENE
Xenon Pharmaceuticals — Eilat XIV Meeting 2018
21 slides from Xenon Pharmaceuticals's conference presentation, May 15, 2018
Slide 1: XEN901: A Novel, Highly Selective NaV1.6 Inhibitor for the Treatment of Epilepsy
XEN901: A Novel, Highly Selective NaV1.6 Inhibitor for the Treatment of Epilepsy Charles Cohen, PhD 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: XEN901: A Highly Selective NaV1.6 Inhibitor
XEN901: A Highly Selective NaV1.6 Inhibitor • Potent and highly selective NaV1.6 inhibitor • Avoid inhibition of NaV1.1 and NaV1.5 to improve safety profile • Novel sodium channel binding site and mechanism of action • Precision medicine to selectively address the etiology of Early Infantile Epilept
Slide 4: Rationale for Selective NaV1.6 Inhibitors
Rationale for Selective NaV1.6 Inhibitors • Low TI of currently used NaV inhibitors is generally dose limiting • Non‐selective among NaV’s in CNS (1.1, 1.2 and 1.6) and CV (1.5) • Block of NaV1.1 proconvulsant: highly expressed in GABAergic interneurons • Dravet Syndrome usually loss of function mut
Slide 5: Highly Selective Inhibitors Targeting Voltage Sensor Domain IV
Highly Selective Inhibitors Targeting Voltage Sensor Domain IV • Therapeutically used NaV inhibitors bind in pore domain Fractional Block • Promiscuous, low affinity binding site • High affinity and selectivity achieved by binding VSD4 in an extracellular site • State dependent block Ahuja et al., S
Slide 6: XEN901 is a Potent and Selective Inhibitor of NaV1.6
XEN901 is a Potent and Selective Inhibitor of NaV1.6 1.0 0.8 0.6 XEN901 0.4 Phenytoin Lamotrigine 0.2 Carbamazepine 0.0 Lacosamide 0.001 0.01 0.1 1 10 100 1000 • >100‐fold selective vs. other NaV’s • >100‐fold more potent than • Inhibition of NaV1.1 is pro‐convulsant non‐selective AEDs • Inhibition
Slide 7: XEN901 is Potent Across EIEE13 Mutations
XEN901 is Potent Across EIEE13 Mutations T767I R1617Q R850Q N1768D N984K I1327V N1466K R1872W • Mutations known to cause EIEE13 were incorporated into NaV1.6 and potency of block by XEN901 was evaluated 50 • 7 of 8 mutants are blocked with similar potency as WT channel • R1617Q in the binding site;
Slide 8: Early Infantile Epileptic Encephalopathy Type 13
Early Infantile Epileptic Encephalopathy Type 13 • Precision medicine to treat the etiology of a severe childhood epilepsy • Caused by SCN8A GOF mutations • Early genetic testing support estimates of ~15‐20% of Dravet patient numbers • ≈50 births/year in U.S. • SCN8A mouse model of EIEE13 • Use for
Slide 9: Seizure Control/Freedom in SCN8A Tg Mouse Model of EIEE13
Seizure Control/Freedom in SCN8A Tg Mouse Model of EIEE13 • XEN901 completely suppresses seizures in modified 6 Hz assay • Elicit tonic‐clonic seizure in Tg mice, no seizures in wild type mice (dotted line) • Suppress to wild type at EC70 • >100‐fold greater potency compared to current treatments fo
Slide 10: XEN901 is Potent and Efficacious in MES
XEN901 is Potent and Efficacious in MES • Therapeutically used NaV antagonists active in MES assay – good translational model • Concentration‐dependent increase in efficacy • Doses of 3‐200 mg/kg • Chronic dosing leads to ~10x increase in potency • High safety margin • Similar observations in rat ME
Slide 11: Potency in the MES Model Driven by NaV1.6
Potency in the MES Model Driven by NaV1.6 100 10 1 0.1 XEN901 0.01 0.01 0.1 1 10 100 WT MES EC50 (Brain, M) • Potency in both assays highly correlated with potency against NaV1.6 and brain concentration • Good correlation between SCN8A Tg mouse and MES assays • Independent of potency at NaV1.2 or ot
Slide 12: Striving for Seizure Freedom with XEN901
Striving for Seizure Freedom with XEN901 Mouse MES Assay Fraction of animals • Current NaV channel AEDs with tonic seizure require 1‐5 times the mouse MES EC50 for clinical efficacy. • Current agents lack therapeutic index needed to achieve seizure freedom for many patients Fraction of animals • Hig
Slide 13: Improved Therapeutic Index Over Other NaV Inhibitors
Improved Therapeutic Index Over Other NaV Inhibitors Toxic EC70 Plasma Plasma Safety 200 Compound (M) Levels Margin 70 acute (M) 150 XEN901 (acute) 0.264 45 170 100 10 Phenytoin 20 54 1.7 5 Carbamazepine 60 233 3.8 0 Lacosamide 12 63 5.3 • EC70 = plasma concentration where 70% of mice are protecte
Slide 14: XEN901: Favorable Motor Impairment Safety Margin
XEN901: Favorable Motor Impairment Safety Margin • Rotarod assay to assess possible motor impairment • Data expressed as function of dose (for comparison with literature values) • Safety margin based on dose in mouse MES for XEN901 : >25 • Other literature comparisons: Carbamazepine(po): 7.7 Phenyto
Slide 15: XEN901 Phase 1 Trial Design
XEN901 Phase 1 Trial Design SAD placebo n=8 5 mg, n=3 Cohort 1 10 mg, n=3 Cohort 2 food effect, 5 mg, n=9 Cohort 3 15 mg, n=6 Cohort 4 30 mg, n=6 Cohort 5 45 mg, n=6 Cohort 6 Cohort 7 MAD Cohort 1 Cohort 2 Cohort 3 Cohort 4 Optional Anticipate Complete Phase 1 Results in H2, 2018 15
Slide 16: PK in Phase 1 SAD Study with XEN901
PK in Phase 1 SAD Study with XEN901 • XEN901 shows dose proportional exposure with single doses of 5‐45 mg • PK displays low inter‐individual variability • PK profile suitable for at least BID dosing (t½ = 8‐11 hours) 16
Slide 17: Interim Preliminary Safety Summary
Interim Preliminary Safety Summary • Ongoing placebo‐controlled, randomized (3:1), double‐blind study • Single doses completed at 5, 10, 15, 30, and 45 mg • No SAEs or deaths • No clinically significant ECG, or Laboratory findings • All reported AEs to date are mild or moderate • Related AEs were mi
Slide 18: Safe Exposure in Phase 1 at or Above EC90
Safe Exposure in Phase 1 at or Above EC90 Shaded area corresponds to range between highest Cmax and C12hrs at 45 mg dose 18
Slide 19: XEN901 Proposed Phase 2 Clinical Planning
XEN901 Proposed Phase 2 Clinical Planning • Anticipate completing ongoing Phase 1 SAD and MAD in H2, 2018 • Expect regulatory filing for Phase 2 clinical trial in adult focal seizures by year‐end • Pediatric development options currently being evaluated • Focal seizure population • Explore precision
Slide 20: XEN901 Summary
XEN901 Summary • XEN901 inhibits NaV1.6 with high potency and selectivity • Novel binding site and mechanism of inhibition • Isoform selectivity enables high therapeutic index • Best in class safety margin • Demonstrated seizure freedom in rodent models • Excellent PK, safety, tolerability to date i
Slide 21: Acknowledgements / Contributors
Acknowledgements / Contributors Chemistry Biology Pharmacokinetics University of Michigan Kristen Burford Elaine Chang Gina de Boer (mouse model) Sultan Chowdhury Alison Cutts Navjot Chahal Miriam Meisler Shannon Decker Richard Dean Rainbow Kwan Jacy Wagnon Christoph Dehnhardt Celine Dube Andrea Lin