XEN1701, a Phase 2-Ready NaV1.7 Inhibitor: Advancing a Novel Non-Opioid Strategy for Pain

XEN1701, a Phase 2-Ready NaV1.7 Inhibitor: Advancing a Novel Non-Opioid Strategy for Pain JP Gilbert1, JP Johnson1, Noam Butterfield1, Jeff Bechard1, Emily Casavant1, Rostam Namdari1, Michael Clark1, Mike Boyd1, Dejan Pavlovic1, Bo Vanecko1, Mike Grimwood1, Alison Cutts1, Selvana Emad1, Samrat Thouta1, Girish Bankar1, Luis Bettio1, Nina Weishaupt1, Ariel Le Huquet1, Puneet Mann1, Joe McIntosh1, Jim Empfield1, Matt Ronsheim1, Chris Kenney1 1Xenon Pharmaceuticals Inc., Vancouver, BC, Canada INTRODUCTION • NaV1.7 (SCN9A) is a compelling target for the treatment of pain with excellent human genetic validation • Loss of function mutations identified in the SCN9A gene have been shown to cause congenital indifference to pain (CIP).1,2 These are otherwise healthy individuals whose normal sensory functions are intact; however, they cannot feel any pain regardless of the noxious stimuli. Gain-of-function mutations in SCN9A cause severe pain disorders, including inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD), demonstrating that increased NaV1.7 activity can directly drive pain • Recent genetic research has better informed the potential level of NaV1.7 inhibition required for efficacy in pain. Individuals have recently been identified in 2 different families, by 2 independent research groups, with an incomplete loss of NaV1.7 and CIP .3,4 The subjects in these families have SCN9A mutations in both alleles, consisting of one null allele and one hypomorphic allele. Functional characterization demonstrated that these mutations resulted in approximately 75% and 85% reductions in NaV1.7 activity, respectively, yet both families exhibited a complete loss of pain sensation. In-house functional characterization of these variants has confirmed the published electrophysiological findings and reductions in NaV1.7 activity • Collectively, this human genetic data establishes that approximately >75% NaV1.7 inhibition is associated with a pain free clinical phenotype, indicating that robust therapeutic efficacy may be achieved without requiring near-complete channel blockade METHODS • Immunohistochemistry of human tissue: Human tissue cryosections were immunolabeled with primary antibodies against NaV1.7, NaV1.8, NaV1.9 or TRPV1, followed by fluorescent secondary antibodies. Sections were imaged by fluorescence microscopy to assess target localization and expression • IEM mouse line and aconitine assay: Humanized NaV1.7-I848T inherited erythromelalgia (IEM) mice and the aconitine-induced flinching assay were used as previously described by Bankar et al.8 • Cynomolgus monkey capsaicin allodynia model: Six animals were tested in a two- period crossover design. Following baseline assessments, animals received a single oral dose of vehicle or test article and crossed over to the alternate treatment. Heat pain responses at 42°C were measured 0.5 h after topical application of a 4 mM capsaicin solution • Cynomolgus monkey cardiovascular telemetry: Cardiovascular parameters were assessed in conscious telemetry-implanted cynomolgus monkeys. Arterial blood pressure and heart rate were continuously monitored from at least 2 h pre-dose to 24 h post-dose and compared with pre-dose baseline values • Phase 1 first-in-human study: Healthy participants were enrolled in SAD, MAD, food- effect, and CSF cohorts to assess the safety, tolerability, pharmacokinetics, food effect, and CNS penetration of XEN1701. CSF sampling was performed in open-label cohorts to measure central drug exposure RESULTS DISCLOSURES:

FUNDING:

This work was funded by Xenon Pharmaceuticals Inc.

All authors are current or former employees who may own securities of Xenon Pharmaceuticals Inc. (Vancouver, BC, Canada).

• Quantification of sodium channel expression demonstrated that 94.8% of DRG neurons were positive for NaV1.7 protein, compared with 72.9% and 86.3% for NaV1.8 and NaV1.9, respectively • Approximately 85% of TRPV1-positive neurons co-expressed NaV1.7 and TRPV1 in human DRG neurons • NaV1.7 expression is enriched in laminae I and II of the human spinal cord, corresponding to the primary termination site of afferent nociceptive fibers References 1. Cox et al. Nature. 2006 Dec 14;444(7121):894–898 2. Goldberg et al. Clin Genet. 2007;71(4):311–319.

3. Emery et al. J Neurosci. 2015 May 20;35(20):7674–7681.

4. Sun et al. Mol Pain. 2020 Apr 3; 16: 1744806920917528.

5. Rothenberg et al. Clin Drug Investig. 2019 Aug;39(8):787– 807.

6. Mulcahy et al. Br J Pharmacol. 2024;1–12.

7. Regan et al. Circulation. 2024 Apr 23;149:1394–1396.

8. Bankar et al. Cell Rep. 2018 Sep 18;24(12):3133–3145.

CONCLUSIONS • Human genetic and protein expression data strongly support NaV1.7 as a non-opioid therapeutic target for pain • Selective NaV1.7 inhibition produced robust analgesic activity across mouse and non- human primate pain models at central and peripheral receptor occupancies consistent with human genetic data, without observed effects on blood pressure or heart rate in these preclinical models • In the preclinical studies conducted to date, XEN1701 did not show a consistent dose- or exposure-related pattern of autonomic cardiovascular effects at exposures greater than predicted therapeutic levels, and the human safety data to date (Table 3) likewise showed no consistent dose- or exposure-related pattern of TEAEs potentially related to autonomic function • Phase 1 PK and CSF data demonstrated that XEN1701 and its active metabolite 1701- AM rapidly achieved and maintained ≥75% NaV1.7 receptor occupancy at proposed therapeutic dose levels • XEN1701 was generally well tolerated in the Phase 1 first-in-human study, with no dose limiting or serious TEAEs and no consistent dose- or exposure-related pattern of TEAEs- potentially related to autonomic function • Collectively, these findings position XEN1701 as an exciting potential non-opioid therapy ready to advance into Phase 2 proof-of-concept studies in pain NaV1.7 NaV1.8 NaV1.9 Human DRG: NaV subtypes Human DRG: NaV1.7 + TRPV1 co-localization MergeNaV1.7 TRPV1 Nav1.7 Nav1.8 Nav1.9 0 20 40 60 80 100 % Total Neuronal Population (NeuN+) ✱✱✱✱ ✱✱✱✱ ✱✱✱ n = 3 donors. One-way ANOVA with Tukey's multiple comparisons test; ***p < 0.001, ****p < 0.0001.

Nav1.7 + TRPV1 85.47% Nav1.7 3.63% TRPV1 10.90% • CNS exposure: engagement of NaV1.7 in the spinal cord: best mimics the genetics • Improved free drug exposure and tissue distribution • Comprehensive selectivity over NaV subtypes Target Compound Profile XEN1701 Did Not Show a Pattern of Autonomic Cardiovascular Effects • Selected TEAEs potentially related to autonomic function (Table 3) were infrequent, 5/76 (6.6%) XEN1701-treated subjects and 1/24 (4.2%) placebo-treated subjects, with no consistent dose- or exposure-related pattern, and none occurred at the highest SAD or MAD dose levels • All but one of these TEAEs were mild • One event, a brief (~2 min) severe syncope, was reported in a subject with pre-existing low blood pressure and a heart rate variability (postural increase) at baseline. The event occurred prior to morning dose on day 3 (~10.5 hours after previous dose). The subject remained on study and completed the remaining dosing (7 days) without recurrence Preferred Term 10 mg QD Fasted (N=6) n 20 mg QD Fed (N=6) n 20 mg BID Fed (N=6) n 30 mg BID Fed (N=6) n 40 mg BID Fed (N=6) n XEN1701 Overall (N=30) n (%) Pooled Placebo (N=10) n (%) Nervous System Disorders Headache 0 0 3 0 0 3 (10.0%) 1 (10.0%) Dizziness 0 0 1 0 1 2 (6.7%) 1 (10.0%) Dizziness postural 1 0 1 0 0 2 (6.7%) 0 Summary of FIH Phase 1 SAD and MAD TEAEs • No dose-limiting TEAEs • No TEAEs leading to study-drug or study discontinuation SAD:

• No serious or severe TEAEs; all TEAEs were mild • TEAEs considered related to study treatment in >1 XEN1701 participant shown in Table 1 MAD:

• No serious TEAEs, most events were mild • TEAEs considered related to study treatment in >1 XEN1701 participant shown in Table 2 Figure 7. Proposed Phase 2 Doses Achieve High Levels of NaV1.7 Receptor Occupancy in the Peripheral and Central Nervous System Mean Predicted Receptor Occupancy Time (h) 20 mg BID 40 mg BID Peripheral Central Peripheral Central 0 0 0 0 0 0.5 0 0 9 5 1 54 41 94 88 1.5 94 88 96 89 2 96 89 97 93 3 97 90 98 95 4 97 90 99 95 6 97 88 99 94 8 96 83 98 90 10 94 74 97 85 12 95 86 96 86 14 97 90 99 96 24 94 73 96 82 0 4 8 12 16 20 24 0 10 20 30 40 50 60 70 80 90 100 Predicted Central Receptor Occupancy Time (h) Receptor Occupancy (%) 20 mg BID 40 mg BID 75% RO 0 4 8 12 16 20 24 0 10 20 30 40 50 60 70 80 90 100 Predicted Peripheral Receptor Occupancy Time (h) Receptor Occupancy (%) 20 mg BID 40 mg BID 75% RO • Predicted receptor occupancy modeling indicates that the proposed Phase 2 doses achieve and sustain ≥75% NaV1.7 receptor occupancy in the peripheral and central nervous systems, with peripheral receptor occupancy approaching 99% and >90% central occupancy maintained for the majority of the dosing interval • CSF sampling confirmed central exposures of XEN1701 and its active metabolite, supporting the predicted central receptor occupancy estimates. At the high dose, target occupancy is achieved within approximately 1 hour in both compartments • Collectively, this data supports rapid and sustained NaV1.7 target engagement in both the peripheral and central nervous systems at the dose levels proposed for Phase 2 evaluation Figure 6. Pharmacokinetic Profile of XEN1701 and Active Metabolite 1701-AM 0 4 8 12 16 20 24 0.1 1 10 100 1000 1701-AM SAD Cohorts Time (h) Plasma (ng/ml) 1701-AM 4 mg Fasted 1701-AM 8 mg Fasted 1701-AM 16 mg Fasted 1701-AM 20 mg Fed 1701-AM 30 mg Fed 1701-AM 40 mg Fed 0 4 8 12 16 20 24 0.1 1 10 100 1000 XEN1701 SAD Cohorts Time (h) Plasma (ng/ml) XEN1701 4 mg Fasted XEN1701 8 mg Fasted XEN1701 20 mg Fed XEN1701 16 mg Fasted XEN1701 30 mg Fed XEN1701 40 mg Fed • XEN1701 exhibited dose-dependent increases in plasma exposure across the evaluated dose range • The active metabolite, 1701-AM, was detected in all cohorts and demonstrated a consistent metabolite-to-parent exposure ratio across all doses • The combined exposure profile of XEN1701 and the active metabolite 1701-AM, support the potential for achieving clinically relevant NaV1.7 inhibition 0.01 0.1 1 10 100 1000 0.0 0.5 1.0 Plasma (μM) IEM Aconitine Flinching (Fraction in Pain) 2nd Gen (PF-771) XEN1701 2nd Gen (GDC-0310) 0.01 0.1 1 10 100 0.0 0.5 1.0 [Free Brain]/NaV1.7 EP IC50 IEM Aconitine Flinching (Fraction in Pain) XPC-1 XEN1701 XPC-2 XPC-3 75-90% receptor occupancy XEN1701 Demonstrates Target Engagement at Low Total Plasma Concentrations In vivo Activity Correlates to Free Brain Concentrations Across Xenon’s Lead Compounds 0-5 5-10 10-15 15-20 0 50 100 150 200 Time after Aconitine Injection IEM Aconitine Nociceptive Events IEM WT IEM Aconitine Assay (Flinching) Figure 4. XPC-4 Reduces Capsaicin-Evoked Pain in Monkeys without Observed Cardiovascular Effects at the Doses Tested XPC-4 Predicted Receptor Occupancies (at Cmax) Dose (mg/kg) Peripheral Central 0.15 70% 57% 0.5 88% 80% 1.5 96% 93% 5 99% 98% 0.1 1 10 100 1000 10000 0.00 0.25 0.50 0.75 1.00 1.25 Unbound Plasma (ng/mL) Fraction in Pain Cyno Capsaicin Mouse IEM Model Correlation of Cynomolgus Capsaicin and Mouse IEM Models Vehicle 0.15 0.5 1.5 5 0.00 0.25 0.50 0.75 1.00 1.25 1.50 XPC-4 Dose (mg/kg) Fraction in Pain More Pain Less Pain Cynomolgus Capsaicin Allodynia Model * ** -60 0 60120180240300360420480540600660720780840900960 1020 1080 1140 1200 1260 1320 1380 1440 80 100 120 140 160 180 Systolic Blood Pressure Cynomolgous Monkey Time (minutes) SAP (mmHg) Vehicle 1.5 mg/kg 5 mg/kg -60 0 60120180240300360420480540600660720780840900960 1020 1080 1140 1200 1260 1320 1380 1440 80 100 120 140 160 180 200 220 240 260 280 300 Heart Rate Cynomolgous Monkey Time (minutes) HR (bpm) Vehicle 1.5 mg/kg 5 mg/kg Figure 5. XEN1701 Achieves Predicted Therapeutic Exposures without Observed Effects on Heart Rate or Blood Pressure in Cynomolgus Monkey Predose 2 4 6 8 10 12 14 16 18 20 22 24 50 60 70 80 90 100 110 120 130 Mean Arterial Pressure Time (h) mmHg Vehicle Low Dose Mid Dose High Dose Dark Cycle XEN1701 Mean Arterial Pressure in Cynomolgus Monkey Predose 2 4 6 8 10 12 14 16 18 20 22 24 50 75 100 125 150 175 200 225 250 Heart Rate Time (h) Beats per Minute Vehicle Low Dose Mid Dose High Dose Dark Cycle XEN1701 Heart Rate in Cynomolgus Monkey • Prior published reports have demonstrated autonomic effects after pharmacological inhibition of NaV1.7, however these compounds differ from Xenon’s target compound profile5,6,7 • In the preclinical studies conducted to date, XEN1701 did not show a consistent pattern of autonomic cardiovascular effects at exposures greater than predicted therapeutic levels • No change in heart rate or mean arterial pressure was observed in cynomolgus monkeys across the range of doses tested (high dose predicted at 97% peripheral receptor occupancy) Human spinal cord: NaV1.7 NaV1.7 DAPI I II III/IV V Adverse Event XEN1701 Single Doses (N=6/group) XEN1701 Multiple Dosing (7 days) (N=6/group) Total XEN1701 N=76 n (%) Total Placebo N=24 n (%) 4 mg Fasted n 8 mg Fasted n 8 mg FE (N=10) n 16 mg Fasted n 20 mg Fed n 30 mg Fed n 40 mg Fed n 10 mg QD Fasted n 20 mg QD Fed n 20 mg BID Fed n 30 mg BID Fed n 40 mg BID Fed n Hypotension 0 0 0 1 0 0 0 0 0 0 0 0 1 0 Dizziness postural 0 0 0 0 1 0 0 1 0 1 0 0 3 0 Orthostatic hypotension 0 0 0 0 1 0 0 0 1 1 0 0 3 1 Postural orthostatic tachycardia 0 0 0 0 0 0 0 0 0 1 0 0 1 0 Syncope 0 0 0 0 0 0 0 0 0 1 0 0 1 0 Total Subjects 0 0 0 1 1* 0 0 1 1 1* 0 0 5 (6.6%) 1 (4.2%) Preferred Term 4 mg Fasted (N=6) n 8 mg Fasted (N=6) n 16 mg Fasted (N=6) n 20 mg Fed (N=6) n 30 mg Fed (N=6) n 40 mg Fed (N=6) n XEN1701 Overall (N=36) n (%) Pooled Placebo (N=12) n (%) Nervous System Disorders Dizziness 0 1 1 0 0 0 2 (5.6%) 0 Headache 0 1 0 0 1 0 2 (5.6%) 1 (8.3%) 75-85% Reduction in NaV1.7 Function Congenital Insensitivity to Pain (CIP) XPC-4 Reduces Capsaicin-Evoked Pain in Monkeys without Observed Cardiovascular Effects at the Doses Tested (Figure 4) • Representative Xenon NaV1.7 inhibitor, XPC-4, produced dose-dependent reductions in capsaicin-evoked heat allodynia in the cynomolgus monkey, with target engagement observed at doses ≥0.5 mg/kg • Efficacious exposures in the cynomolgus capsaicin model closely correlated with the mouse IEM model • Doses achieving >75% NaV1.7 predicted central and peripheral receptor occupancy were associated with reductions in capsaicin-evoked allodynia in the monkey capsaicin model • No clinically meaningful change in systolic arterial blood pressure, heart rate or the cardiovascular response to technician room entry and handling (t = 240 min) was observed with XPC-4 at the two highest efficacious doses evaluated in the cynomolgus capsaicin model Figure 1. NaV1.7 is Highly Enriched in Human Nociceptive Pathways DAPI, 4’,6-diamidino-2-phenylindole; DRG, dorsal root ganglion; TPRV1, transient receptor potential vanilloid 1.

Figure 2. Xenon’s Lead NaV1.7 Compounds have a Differentiated Profile Figure 3. Xenon NaV1.7 Compounds Achieve Robust Analgesic Activity at Receptor Occupancies Consistent with Human Genetics • The IEM model utilizes transgenic mice expressing a human gain-of-function NaV1.7 mutation identified in patients with IEM. Following intraplantar administration of the sodium channel activator aconitine, IEM mice exhibit robust pain-related flinching behaviors that are absent in wild-type animals, enabling assessment of human NaV1.7 target engagement and analgesic efficacy in vivo • XEN1701 reduced pain-related behaviors in the mouse IEM model at substantially lower plasma exposures than second-generation NaV1.7 inhibitors. Relative to GDC- 0310 and PF-771, XEN1701 demonstrated in vivo efficacy at approximately 10-fold and 100-fold lower total plasma concentrations, respectively • Across Xenon's lead NaV1.7 compounds, in vivo efficacy was observed to strongly correlate with free brain exposure normalized to NaV1.7 electrophysiological potency • Robust analgesic activity was observed when compounds achieved approximately 75- 90% CNS receptor occupancy, with similar or greater levels of peripheral target engagement • This receptor occupancy range aligns with human genetic data suggesting that >75% NaV1.7 inhibition is required for analgesia3,4 IEM, inherited erythromelalgia; SAP , systolic arterial pressure.

BID, twice daily; RO, receptor occupancy.

AM, active metabolite; SAD, single ascending dose.

Table 1. SAD: TEAEs Considered Related in >1 XEN1701-Treated Participant Participant counts shown; more than one event per participant is possible.

BID, twice daily; N, number of participants; n, number of participants with >1 related TEAE; MAD, multiple ascending dose; QD, once daily; TEAE, treatment-emergent adverse event.

Participant counts shown; more than one event per participant is possible.

N, number of participants; n, number of participants with >1 related TEAE; SAD, single ascending dose; TEAE, treatment- emergent adverse event.

Table 2. MAD: TEAEs Considered Related in >1 XEN1701-Treated Participant *1 subject experienced all TEAEs shown within the respective dose group.

BID, twice daily; FE, food effect; N, number of participants; n, number of participants with >1 related TEAE; QD, once daily; TEAE, treatment-emergent adverse event.

Table 3. Selected TEAEs Potentially Related to Autonomic Function Poster: 718 | IASP World Congress on Pain | October 26-30, 2026 | Bangkok, Thailand EP: electrophysiology; IEM, inherited erythromelalgia.