XEN1120, a Phase 2-Ready KV7 Channel Opener: Advancing a Novel Non- Opioid Strategy for Pain

KV7 Channel Modulation Produces Robust Analgesic Efficacy in the Mouse Formalin Model (Figure 3) • Formalin injection produces a biphasic pain response consisting of an acute nociceptive phase (0-5 min), followed by a longer lasting inflammatory phase (30-45 min). Most analgesics only work in the inflammatory phase, whereas only opioids typically show efficacy in the acute nociceptive phase • Diclofenac, a non-steroidal anti-inflammatory drug, is not effective in the acute nociceptive phase, but does reduce the inflammatory response. The opioid buprenorphine reduces both the nociceptive and inflammatory pain responses • Flupirtine, a compound previously approved for the treatment of pain with a mechanism of action that involves potassium channel opening, reduces both the acute nociceptive and inflammatory responses, as do Xenon KV7 potentiators • Across a broad range of exemplary Xenon KV7 modulators, in vivo free plasma EC50 values in the formalin acute phase strongly correlate with KV7.2/7.3 in vitro potency, supporting KV7 channel modulation as the primary driver of analgesic efficacy.

Although flupirtine also demonstrates GABAA activity, its in vivo efficacy correlates with KV7.2/7.3 potency, suggesting KV7 as the main driver of its analgesic efficacy • Flupirtine demonstrated efficacy in the formalin acute nociceptive phase but required free plasma exposures ~7x higher than those used for post-operative pain clinically. In contrast, XEN1120 demonstrated efficacy at substantially lower exposures, with predicted clinical therapeutic plasma concentrations overlapping the efficacious exposure range defined in the acute phase of the mouse formalin model5 • Dose-dependent reductions in the acute phase of the formalin model were observed for both XEN1120 and XPC-B • Exposure-response modeling identified plasma EC50 values for XEN1120 and XPC-B, supporting a quantitative relationship between exposure and analgesic efficacy 30 40 50 60 70 80 90 100 110 0 10 20 30 Size (μm) % of Total Neurons Kv7.2 + Kv7.3 Kv7.2 Only Kv7.3 Only C-fiber + Aδ Aαβ XEN1120, a Phase 2-Ready KV7 Channel Opener: Advancing a Novel Non- Opioid Strategy for Pain JP Gilbert1, Richard Dean1, JP Johnson1, Noam Butterfield1, Jeff Bechard1, Emily Casavant1, Rostam Namdari1, Christoph Dehnhardt1, Michael Clark1, Charles Bernard1, Dejan Pavlovic1, Ariel Le Huquet1, Alison Cutts1, Kate Shepard1, Selvana Emad1, Samrat Thouta1, Girish Bankar1, Luis Bettio1, Nina Weishaupt1, Joe McIntosh1, Jim Empfield1, Matt Ronsheim1, Chris Kenney1 1Xenon Pharmaceuticals Inc., Vancouver, BC, Canada INTRODUCTION • Voltage-gated potassium (KV7; KCNQ) channels regulate neuronal excitability by stabilizing membrane potential and limiting repetitive action potential firing. Multiple lines of evidence support KV7 channels as therapeutic targets for pain. KV7 channels are broadly expressed throughout the peripheral and central pain pathways, including primary sensory neurons, where they act as key regulators of nociceptive signaling¹ • KV7 plays a significant role in the initial transduction of pain stimuli into pain signals, the transmission of those pain signals along nociceptive neurons, and the relay from peripheral sensory neurons to spinal cord neurons in the central nervous system • Dysfunction or downregulation of KV7 channel activity has been observed in altered pain states2,3 • Additionally, flupirtine, a compound previously approved for the treatment of pain has a mechanism of action that involves potassium channel opening4 • Lead KV7 compound, XEN1120, is a novel KV7 channel opener being developed for pain. In Phase 1 studies, XEN1120 was generally well tolerated and achieved plasma exposures within the predicted therapeutic range established in rodent and non- human primate pain models • Together, these findings support XEN1120 as a promising non-opioid approach to treat a range of pain conditions, including neuropathic and inflammatory pain METHODS • Immunohistochemistry of human tissue: Human tissue cryosections were immunolabeled with primary antibodies against KV7.2, KV7.3 or NaV1.7, followed by fluorescent secondary antibodies and imaged by fluorescence microscopy • Electrophysiology recordings in human DRGs: Whole-cell current clamp recordings were conducted on dissociated human DRGs. Rheobase, resting membrane potential and number of action potentials were measured at baseline and after compound application • Mouse Formalin Assay: Licking behavior during the acute nociceptive (0-5 min) and inflammatory (30-45 min) phases following formalin administration in male CD-1 mice was quantified from video recordings using automated analysis software developed at Xenon • Voltage clamp automated electrophysiology was used to assess potency of KV7 openers in HEK cell lines stably expressing KV7.2/7.3 • 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 • Phase 1 first-in-human study: Healthy participants were enrolled in SAD, MAD, food- effect cohorts to assess the safety, tolerability, pharmacokinetics and food effect of XEN1120 RESULTS Poster: 51 | IASP World Congress on Pain | October 26-30, 2026 | Bangkok, Thailand ACKNOWLEDGEMENTS:

Human DRG electrophysiology studies were conducted in collaboration with Anabios Corporation (San Diego, US).

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).

• Immunohistochemistry of KV7.2 and KV7.3 in human DRG neurons demonstrated extensive co-localization within individual sensory neurons • Quantification of KV7.2 and KV7.3 expression across DRG neuron size distributions demonstrates a high level of KV7 expression within the small- to medium-diameter neurons, corresponding to C and Aδ fibers • 85% of DRG neurons co-expressed KV7.2 and KV7.3, while only a small proportion expressed KV7.2 alone (6%) or KV7.3 alone (9%) • Quantification of KV7.2 and NaV1.7 expression across neuronal size distributions showed the greatest overlap within small- to medium-diameter neurons, corresponding to C and Aδ fibers • Among KV7.2- and/or NaV1.7-positive neurons, 72% co-expressed both KV7.2 and NaV1.7, while 24% expressed NaV1.7 alone and 4% expressed KV7.2 alone, demonstrating substantial overlap between KV7.2 and NaV1.7 expression in nociceptive sensory neurons References 1. Passmore et al., J Neurosci. 2003;23:7227-7236 2. Kim et al. Brain Res Mol Brain Res. 2002 Sep 30;105(1-2):146–152.

3. Yuan et al. Brain Commun. 2021 Sep 8;3(3):fcab212.

4. Korsgaard et al. J Pharmacol Exp Ther. 2005;315(1):282-292.

5. Devulder J. CNS Drugs. 2010;24(10):867-881.

CONCLUSIONS • KV7.2 and KV7.3 are highly expressed in human DRG neurons, including nociceptive populations that co-express NaV1.7, supporting KV7 as a compelling non-opioid target to modulate pain signaling • Xenon’s lead KV7 pain compound, XEN1120, decreased excitability in human DRG neurons and demonstrated robust efficacy in the acute nociceptive phase of the mouse formalin model • In vivo efficacy across structurally distinct KV7 potentiators correlated with KV7.2/7.3 potency, supporting KV7 channel modulation as a primary driver of analgesic effects • Predicted clinical therapeutic exposures of XEN1120 align with efficacious exposures in the mouse formalin acute model, whereas flupirtine required substantially higher (~7- fold) exposures than those associated with clinical efficacy in post-operative pain • Representative Xenon KV7 potentiator, XPC-B, demonstrated dose-dependent efficacy in the cynomolgus monkey capsaicin allodynia model at lower plasma exposures than those required for efficacy in the mouse formalin model • XEN1120 was generally well tolerated in the Phase 1 first-in-human study, with no dose limiting or serious TEAEs, and achieved plasma exposures in line with the predicted efficacious range established from rodent and non-rodent models • Collectively, these findings position XEN1120 as an exciting potential non-opioid therapy ready to advance into Phase 2 proof-of-concept studies in pain Figure 5. XEN1120 Clinical PK Achieves Target Therapeutic Exposures Based on Preclinical Efficacy Models Figure 4. XPC-B Demonstrates Analgesic Efficacy in a Cynomolgus Monkey Capsaicin Allodynia Model • PK data from healthy volunteers demonstrated that XEN1120 achieved plasma levels consistent with the predicted efficacious exposure range derived from preclinical rodent and non-rodent efficacy models (target exposure range shaded in blue). Food increased Cmax (93% ) and AUC0-48 (30%) • A loading dose rapidly achieves target exposures, while maintenance dosing sustains plasma concentrations within the predicted efficacious range for the duration required for an acute pain study Figure 2. XEN1120 Reduces Excitability of Human Dorsal Root Ganglion Neurons • Human DRG neurons were evaluated using whole-cell current-clamp electrophysiology to assess the effects of XEN1120 on neuronal excitability • Treatment with XEN1120 (600 nM) reduced action potential firing across a range of depolarizing current injections relative to rheobase compared with vehicle-treated neurons, indicating a reduction in neuronal excitability and an increase in the current required to elicit repetitive firing • Representative current-clamp recordings acquired at baseline and following application of XEN1120 (600 nM) demonstrate a marked reduction in evoked action potential firing • XEN1120 had a significant effect on rheobase, resting membrane potential and action potential firing compared to baseline • These findings demonstrate that XEN1120 suppresses excitability in human dorsal root ganglion neurons, consistent with enhanced KV7 channel activity and reduced nociceptor firing • In cynomolgus monkeys, XPC-B produced dose-dependent reductions in capsaicin- evoked thermal allodynia • Exposure-response analysis identified an unbound plasma EC₅₀ of 1.36 ng/mL in the cynomolgus capsaicin model, compared with 3.15 ng/mL in the mouse formalin acute phase, indicating that analgesic efficacy was achieved at approximately 2.3-fold lower exposures in the cynomolgus model • These data suggest the mouse formalin acute nociceptive model is a stringent efficacy model that may provide a conservative foundation for clinical dose selection Kv7.3 10X Kv7.2 Merge Merge Naᵥ1.7 Kᵥ7.2 Kv7.2 + Kv7.3 85% Kv7.2 Only 9% 6% Kv7.3 Only Nav1.7+ + Kv7.2+ 72% Nav1.7+ only 24% Kv7.2+ only 4% 1.0x 1.5x 2.0x 2.5x 3.0x 0 2 4 6 8 10 12 Human DRGs Current injection (x rheobase) #APs/2s Vehicle ( n = 5) 600 nM XEN1120 ( n = 5) XEN1120 600 nM Participant counts shown; more than one event per participant is possible. *Includes at least 1 moderate event.

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

Summary of FIH Phase 1 SAD and MAD TEAEs • No dose-limiting treatment-emergent adverse events (TEAEs) • No serious or severe TEAEs • No TEAEs leading to discontinuations in XEN1120-treated participants Single ascending dose (SAD):

• Majority of events were mild • Moderate TEAEs included nausea in 2 participants (1 in each of 25 mg fed and 60 mg fasted groups), and vomiting in 1 participant (25 mg fed group) • TEAEs considered related to study treatment in >1 XEN1120 participant shown in Table 1 Multiple ascending dose (MAD):

• All events in XEN1120-treate participants were mild • One placebo participant experienced moderate TEAEs of headache, nausea, and vomiting; all related, and led to that participant’s discontinuation from the study • TEAEs considered related to study treatment in >1 XEN1120 participant shown in Table 2 0 4 8 12 16 20 24 28 32 36 40 44 48 0.1 1 10 100 XEN1120 SAD Cohorts Time (h) Plasma (ng/ml) 5 mg Fasted 15 mg Fasted 30 mg Fasted 60 mg Fasted Target Range 25 mg Fed 0 4 8 12 16 20 24 28 32 36 40 44 48 1 10 100 XEN1120 Doses for Ph 2 POC study Time (h) Plasma (ng/ml) 30 mg LD + 5 mg MD (extrapolated) 15 mg LD + 3 mg MD (extrapolated) Target Range Translation of flupirtine clinical therapeutic Cplasma Vehicle 0.3 1 2 0.0 0.2 0.4 0.6 0.8 XPC-B Dose (mg/kg) Fractoin in Pain More Pain Less Pain Cyno Capsaicin Allodynia Model 0.1 1 10 100 0.0 0.2 0.4 0.6 0.8 1.0 Unbound Plasma [XPC-B] (ng/mL) Fraction in Pain Cyno Capsaicin EC50 = ng/mL 1.36 EC50 = ng/mL 3.15 Mouse Formalin Acute Phase Preferred Term 15 mg QD (N=6) n 10 mg QD (N=6) n 30 mg Loading + 5 mg BID (N=6) n 30 mg Loading + 5 mg TID (N=6) n XEN1120 Overall (N=24) n (%) Pooled Placebo (N=8) n (%) Cardiac Disorders Tachycardia 0 2 2 4 8 (33.3%) 1 (12.5%) Nervous System Disorders Dizziness 4 1 0 2 7 (29.2%) 0 Somnolence 2 0 3 1 6 (25.0%) 0 Headache 0 0 1 3 4 (16.7%) 1 (12.5%)* Disturbance in attention 3 0 0 0 3 (12.5%) 1 (12.5%) Gastrointestinal Disorders Abdominal pain 1 0 0 1 2 (8.3%) 0 Gastrooesophageal reflux disease 0 0 2 0 2 (8.3%) 0 Nausea 1 0 0 1 2 (8.3%) 1 (12.5%)* General Disorders and Administration Site Conditions Fatigue 2 0 2 1 5 (20.8%) 1 (12.5%) Vascular Disorders Orthostatic hypotension 3 1 0 1 5 (20.8%) 0 Psychiatric Disorders Bradyphrenia (cognitive slowing) 2 0 0 0 2 (8.3%) 0 Vehicle XEN1120 (600 nM) 0 1000 2000 3000 Rheobase (pA) * Baseline XEN1120 (600 nM) -65 -60 -55 -50 -45 -40 RMP (mV) * Baseline XEN1120 (600 nM) 0 25 50 75 100 125 Remaining APs (%) * Figure 3. KV7 Channel Modulation Produces Robust Analgesic Efficacy in the Mouse Formalin Model XEN1120 Flupirtine 0.1 1 10 Cplasma,u EC50 (uM) XEN1120 Phase 2 Target Cplasma Flupirtine Clinical Therapeutic Cplasma ~7x below Formalin Acute Nociceptive Phase EC50 Formalin Acute Nociceptive Phase Clinical Correlation Formalin Acute Nociceptive Phase Dose Response Vehicle 0.3 1 2 0.00 0.25 0.50 0.75 1.00 1.25 Fraction in Pain XEN1120 Dose (mg/kg) * p=0.001 Formalin Acute Nociceptive Phase Exposure Response 10 100 1000 0.00 0.25 0.50 0.75 1.00 1.25 Plasma [XEN1120] (ng/mL) Fraction in Pain EC50= ng/mL 98.7 Formalin Acute Nociceptive Phase Dose Response VEH 0.5 1.5 3 6 0.00 0.25 0.50 0.75 1.00 1.25 1.50 Fraction in Pain XPC-B Dose (mg/kg) p<0.002 p<0.001 * * Formalin Acute Nociceptive Phase Exposure Response 10 100 1000 0.00 0.25 0.50 0.75 1.00 1.25 Plasma [XPC-B] (ng/mL) Fraction in Pain EC50= ng/mL 98.8 Figure 1. KV7.2 and KV7.3 are Highly Expressed in Human Dorsal Root Ganglion (DRG) Neurons and Overlap with NaV1.7 Table 1. SAD: TEAEs Considered Related in >1 XEN1120-Treated Participant Table 2. MAD: TEAEs Considered Related in >1 XEN1120-Treated Participant Participant counts shown; more than one event per participant is possible. *Includes at least 1 moderate event.

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

AP , action potential; RMP , resting membrane potential.

SAD, single ascending dose; Ph 2 POC, Phase 2 proof-of-concept; LD, loading dose; MD, maintenance dose. Dashed line indicates the predicted XEN1120 efficacious exposure, derived from preclinical-to-clinical translation of flupirtine efficacy exposures (Figure 3).

GVtail, conductance-voltage relationship derived from tail-current measurements.

30 40 50 60 70 80 90 100 110 0 10 20 30 40 Size (μm) % of Total Neurons Kv7.2 + Nav1.7 Nav1.7 Kv7.2 C-fiber + Aδ Aαβ Vehicle 10 mg/kg diclofenac 0.25 mg/kg buprenorphine 45 mg/kg flupirtine 2 mg/kg XEN1120 0.0 0.5 1.0 Fraction in Pain Formalin Acute Nociceptive Phase (0-5 min)More Pain Less Pain Formalin Acute Nociceptive Phase 0.01 0.1 1 10 0.001 0.01 0.1 1 10 KV7.2/3 Potency(GVtail) (μM) In vivo Cplasma,u EC50 (μM) XEN1120 FlupirtineFormalin Inflammatory Phase (30-45 min) Vehicle 10 mg/kg diclofenac 0.25 mg/kg buprenorphine 100 mg/kg XPC-A 0.0 0.5 1.0 Fraction in Pain Preferred Term 5 mg Fasted (N=6) n 15 mg Fasted (N=6) n 30 mg Fasted (N=6) n 60 mg Fasted (N=6) n 25 mg Fed (N=6) n XEN1120 Overall (N=30) n (%) Pooled Placebo (N=10) n (%) Nervous System Disorders Headache 1 0 2 2 1 6 (20.0%) 1 (10.0%) Dizziness 0 0 0 3 2 5 (16.7%) 1 (10.0%) Dizziness postural 0 1 0 0 1 2 (6.7%) 0 Somnolence 0 0 0 0 2 2 (6.7%) 0 Vascular Disorders Orthostatic hypotension 0 1 0 1 2 4 (13.3%) 0 Investigations HR increased 0 1 1 0 0 2 (6.7%) 1 (10.0%) Gastrointestinal Disorders Nausea 0 0 0 1* 1* 2 (6.7%) 0 Vomiting 0 0 0 1 1* 2 (6.7%) 0 Cardiac Disorders Palpitations 0 1 0 1 0 2 (6.7%) 0 Baseline