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www.xenon-pharma.comNASDAQ: XENE Corporate Overview A U G U S T 2 0 2 5 Investor Presentation
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Forward Looking Statement/Safe Harbor This slide 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 those expressed or implied by such forward-looking statements. All statements other than statements of historical fact could be deemed forward-looking and include statements regarding the timing of and potential results from clinical trials; the potential efficacy, safety profile, future development plans in current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partners’ product candidates; the efficacy of our clinical trial designs; our ability to successfully develop and achieve milestones in our azetukalner and other pipeline and development programs, including the anticipated filing of INDs and NDAs; the timing and results of our interactions with regulators; our ability tosuccessfully develop and obtain regulatory approval of azetukalner and our other product candidates; anticipated timing of topline data readout from our clinical trials of azetukalner; and our expectation that we will have sufficient cash to fund operations into 2027. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events, or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: clinical trials may not demonstrate safety and efficacy of any of our or our collaborators’ product candidates; promising results from pre-clinical development activities or early clinical trial results may not be replicated in later clinical trials; our assumptions regarding our planned expenditures and sufficiency of our cash to fund operations may be incorrect; our ongoing discovery and pre-clinical efforts may not yield additional product candidates; any of our or our collaborators’ product candidates, including azetukalner, may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; regulatory agencies may impose additional requirements or delay the initiation or completion of clinical trials; the impact of market, industry, and regulatory conditions on clinical trial enrollment; the impact of competition; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; the impact of unstable economic conditions in the general domestic and global economic markets; adverse conditions from geopolitical events; as well as the other risks identified in our filings with the U.S. Securities and Exchange Commission and the securities commissions in British Columbia, Alberta, and Ontario. These forward-looking statements speak only as of the date hereof and we assume no obligation to update these forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements. “Xenon” and the Xenon logo are registered trademarks or trademarks of Xenon Pharmaceuticals Inc. in various jurisdictions. All other trademarks belong to their respective owner. 2
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About Xenon Pharmaceuticals ▪ Neuroscience-focused biopharmaceutical company and leader in small molecule, ion channel drug discovery and development ▪ Robust pipeline of therapeutic candidates targeting both potassium and sodium channels across various indications ▪ Our lead molecule, azetukalner, is a highly potent Kv7 channel opener in Phase 3 development in epilepsy and depression* ▪ Strong financial position • $624.8 million in cash, cash equivalents and marketable securities (as of June 30, 2025) and anticipated cash runway to fund operations into 2027 3 Azetukalner is the most advanced, clinically validated potassium channel modulator in late-stage clinical development across multiple indications and the only Kv7 program with 700+ patient-years of efficacy & safety data * Comprehensive intellectual property portfolio with patent coverage extending to at least 2040, absent any extensions of patent term
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Xenon’s Neuroscience-Focused Pipeline 4 Azetukalner (Kv7 Potassium Channel Opener) PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3 X-TOLE2: Epilepsy - Focal Onset Seizures (FOS) X-TOLE3: Epilepsy - Focal Onset Seizures (FOS) X-ACKT: Epilepsy - Primary Generalized Tonic-Clonic Seizures (PGTCS) X-NOVA2 │ X-NOVA3: Major Depressive Disorder (MDD) X-CEED: Bipolar Depression (BPD) Early-Stage Ion Channel Modulators PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3 XEN1120: Kv7 Potassium Channel Opener - Pain Indications XEN1701: Nav1.7 Inhibitor - Pain Indications Kv7 Potassium Channel Openers (Epilepsy, pain, and neuropsychiatric indications) Nav1.7 Sodium Channel Inhibitors (Pain indications) Nav1.1 Sodium Channel Openers (Dravet Syndrome) Partnered Program PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3 NBI-921355 - Nav1.2/1.6 Inhibitor (Epilepsy) – Neurocrine Biosciences Patient recruitment complete This chart displays pipeline drug candidates currently undergoing clinical and pre-clinical testing in a variety of disease indications. The safety and efficacy of these investigational drug candidates have not been fully evaluated, and they have not yet been approved for use by any regulatory authorities.
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Addressing Unmet Needs EPILEPSY 5
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6 Significant Global Epilepsy Burden Sources: Xenon-sponsored market research; Mula, et al, Effect of drug treatment changes and seizure outcomes on depression and suicidality in adults with drug-resistant focal epilepsy, Epilepsia, December 11, 2023 FOS represent the largest segment of the epilepsy population Approximately 80% of adult patients with generalized epilepsy experience PGTCS Approximately 1 million children under the age of 18 have epilepsy across the three geographic regions ▪ Epilepsy is the fourth most common neurological condition ▪ Hallmark symptoms include: • focal seizures that start in one brain hemisphere (either aware or unaware) • generalized seizures the most common of which are tonic clonic/convulsive seizures ▪ Despite the availability of multiple anti-seizure medications (ASMs), a substantial unmet medical need exists ▪ Rates of comorbid depression exist in up to 50% of epilepsy patients 0.8 M 2.6 M 3.0 M 2.6 M 0.4 M 0.1 M 0.2 M 1.6 M 0.3 M 0.8 M 1.8 M 0.3 M 0.9 M Adults with Epilepsy Adults with Focal Onset Seizures Adults with Undefined / Combination Epilepsy Adults with Generalized Seizures Patients (Millions) Estimated Diagnosed Adult Epilepsy Patient Population (2020) Key: U.S. EU4 + UK Japan
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Treatment Decisions are Highly Individualized and Complex 7 Significant opportunity remains with up to 50% of epilepsy patients requiring additional treatment options ▪ Patients continuing to experience sub-optimal response (poor efficacy, tolerability) frequently receive polypharmacy • Combinations typically involve mechanistic differentiation from early lines of therapy • Branded therapies can potentially be accessed if a patient has tried and failed 1 -2 generic ASMs ▪ Global treatment patterns are largely similar ▪ Levetiracetam and lamotrigine are commonly used in early lines of treatment ▪ Monotherapy switching in second line driven by desire for better seizure control or tolerability/AE issues Diagnosed Epilepsy Patient First Monotherapy (levetiracetam, lamotrigine) Second Monotherapy (e.g. carbamazepines, lamotrigine, lacosamide) Surgery Polypharmacy (e.g. Xcopri, Aptiom, Briviact) Cycle combinations Focal and general epilepsy have similar treatment considerations, with select ASMs (e.g. valproate) used more frequently in FOS than in generalized Treatment goal aims to optimize efficacy while managing tolerability Sources: Epilepsy Foundation; Epilepsy Currents, Englot (2018), National Association of Epilepsy Centers, National Institute of Neurological Disorders and Stroke; Company-sponsored market research
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8 Azetukalner has the Potential to Address Multiple Unmet Needs in FOS Rapid Onset of Effect Impact on Mood Novel Mechanism of Action Ease-of-Use Attributes Greater Seizure Reduction & Seizure Freedom Despite availability of numerous ASMs, up to 50% of epilepsy patients are insufficiently controlled with available ASM treatments Many ASMs require burdensome management of DDIs, and lengthy and complex titration periods to avoid serious AEs, complicating treatment for patients Despite 20+ available treatments, most ASMs fall into three main mechanisms, which limits therapeutic diversity for patients seeking improved efficacy Few marketed ASMs have positive impact on mood, with some even having negative impacts, posing challenges given high rates of depression comorbidity No marketed ASMs have demonstrated efficacy at Week 1, exacerbating challenges for patients with ongoing seizures who seek therapeutic alternatives Desirable Attributes For New Therapeutics To Treat Focal Onset Seizures Source: physician interviews; company-sponsored market research
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Compelling Azetukalner Data in Epilepsy X-TOLE, X -TOLE2, X -TOLE3, AND X -ACKT CLINICAL TRIALS 9
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X-TOLE Phase 2b Clinical Trial in Focal Onset Seizures 10 Topline results reported in October 2021 and subsequent ad hoc analyses and OLE data presented at AES meetings
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Compelling Phase 2b Efficacy Results 11 Statistically significant and dose dependent reduction in seizures Azetukalner (XEN1101) was administered as a once-daily capsule with food with no titration period. Source: “Phase 2b Efficacy and Safety of XEN1101, a Novel Potassium Channel Modulator, in Adults with Focal Epilepsy (X-TOLE).” 2022 Annual Meeting of the American Epilepsy Society (AES).
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X-TOLE Sub-Group Analyses (Double-Blind Period) Baseline Seizure Sub-Group Analysis ▪ Seizure reduction was 70.6% for subjects with ≤ 8.5 seizures/month at baseline compared to 50.8% for those with > 8.5 seizures/month 12 Prior Failed ASMs Sub-Group Analysis ▪ Median monthly FOS reduction was 58.0% in subjects who failed ≤ 6 ASMs at baseline and 43.0% in subjects who failed > 6 ASMs Concomitant ASMs Sub-Group Analysis ▪ Median monthly FOS reduction was 60.9% for subjects with 1-2 concomitant ASMs and 50.8% for subjects with 3 concomitant ASMs Notes: Azetukalner (XEN1101) was administered as a once-daily capsule with food. The post hoc analysis was categorized by ≤ 8.5 and > 8.5* seizures per month for baseline seizure burden, ≤ 6 and > 6 prior failed ASMs (median), and = 3 or ≤ 2 concomitant ASMs (pre -specified). Source: “The Impact of Disease Severity on Efficacy From a Phase 2b Study of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy (X-TOLE).” 2022 Annual Meeting of the American Epilepsy Society (AES).
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Rapid Onset of Efficacy (Double-Blind Period) Median Percent Change from Baseline in Weekly Focal Onset Seizure (FOS) Frequency in DBP 13 Responders (RR50) Based on Percent Change from Baseline for Week 1 in Weekly FOS Frequency in DBP Marked reduction in median FOS frequency at Week 1 for all doses compared with placebo Azetukalner (XEN1101) was administered as a once-daily capsule with food with no titration period. Source: “Rapid Onset of Efficacy of XEN1101, a Novel Potassium Channel Opener, in Adults with Focal Epilepsy: Results from a Phase 2b Study (X-TOLE).” 2022 Annual Meeting of the American Epilepsy Society (AES).
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Robust Long-Term Efficacy Results in X-TOLE OLE 14 Sustained monthly reduction in seizure frequency in OLE from DBP baseline with even greater improvements inpatients on fewer baseline ASMs Source: French J, Porter R, Perucca E, et al. Long-term safety and efficacy of azetukalner, a novel, potent Kv7 potassium channel opener in adults with focal epilepsy: Update from the ongoing 7-year open-label extension of X-TOLE. American Epilepsy Society Annual Meeting, December 6-10, 2024, Los Angeles, CA; Interim data cut October 7, 2024; OLE: open-label extension; MPC: median percent change; QD: once daily MPC in Monthly FOS Frequency During DBP and OLE Patients receiving 1–2 ASMs at baseline experienced higher monthly MPC reductions in FOS frequency from baseline at OLE study month 36 (100% seizure reduction, n=67), compared to those receiving 3 ASMs (80.6% seizure reduction, n=80) OLE Dose: 20 mg QD Azetukalner (XEN1101) was administered as a once-daily capsule with food with no titration period.
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Impressive Seizure Freedom in the X-TOLE OLE 15 Participants (n=147) Treated for >36 Months in the OLE Source: French J, Porter R, Perucca E, et al. Long-term safety and efficacy of azetukalner, a novel, potent Kv7 potassium channel opener in adults with focal epilepsy: Update from the ongoing 7-year open-label extension of X-TOLE. American Epilepsy Society Annual Meeting, December 6-10, 2024, Los Angeles, CA; Interim data cut October 7, 2024; All doses taken with food no titration; OLE: open-label extension Nearly 1 in 3 patients treated for >36 months in the OLE experienced ≥12 consecutive months of seizure freedom 32.7% 20.4% 10.2% 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% Participants, n 48 30 15 Responders (%) >12 Months >24 Months >36 Months Any Consecutive Months of 100% Seizure Reduction
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X-TOLE: Safety and Tolerability Data ▪ X-TOLE Double-Blind Period • Azetukalner was generally well-tolerated in this study with adverse events consistent with commonly prescribed ASMs • The most common reported treatment emergent adverse events (TEAEs) across all azetukalner dose groups were dizziness (24.6%), somnolence (15.6%) and fatigue (10.9%), as compared to the placebo group which reported dizziness (7.0%), somnolence (7.0%) and fatigue (5.3%) • The most common TEAEs leading to discontinuation across all azetukalner dose groups were dizziness (4.7%), balance disorder (2.4%), dysarthria (1.9%) and gait disturbance (1.9%) • Serious adverse events (SAE) incidence was low and balanced across groups (3.3% across all azetukalner dose groups as compared to 2.6% in the placebo group) ▪ X-TOLE Open-Label Extension* • Azetukalner 20 mg QD was generally well tolerated in OLE, and the safety profile observed was similar to that of the DBP; no new safety signals were identified 16 Sources: “Phase 2b Efficacy and Safety of XEN1101, a Novel Potassium Channel Modulator, in Adults with Focal Epilepsy (X-TOLE).” 2022 Annual Meeting of the American Epilepsy Society (AES). “Interim Long-Term Safety and Efficacy of XEN1101, a Potent, Selective Potassium Channel Opener: Update From an Ongoing, Open-Label Extension of a Phase 2b Study (X-TOLE) in Adults With Focal Epilepsy.” 2023 Annual Meeting of the American Epilepsy Society (AES). * Results are from interim data from the open-label extension of X-TOLE (cutoff date September 5, 2023).
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X-TOLE2 and X-TOLE3 Phase 3 Clinical Trials in FOS 17 X-TOLE2 Phase 3 FOS topline data anticipated early 2026 ▪ Xenon’s Phase 3 epilepsy program in focal onset seizures and primary generalized tonic-clonic seizures is underway ▪ Plan to submit NDA supported by efficacy data from Phase 2b study (X-TOLE) and first Phase 3 study (X-TOLE2) ▪ Conducting two identical multi-center, placebo-controlled Phase 3 FOS trials (N = ~360 in each study) ▪ Primary Objective: assess effect of azetukalner vs placebo on reducing focal onset seizure frequency ▪ Secondary Objectives include assessing the effect on azetukalner vs placebo on RR50, early treatment effect as measured at Week 1, and PGI-C Up to 9.5 weeks 12-week double-blind period (DBP) 3-year open-label extension (OLE) *Administered as once-daily capsule with food with no titration period. Open-Label Extension (25 mg QD*) Final 8-Week Follow-up (if not entering OLE) azetukalner 25 mg QD* azetukalner 15 mg QD* placebo QD* Randomization 1:1:1 Screening and Baseline
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X-ACKT Phase 3 Clinical Trial in PGTCS 18 ▪ Significant unmet need remains in PGTCS despite available treatment options and an opportunity remains for a broad- spectrum agent with activity across seizure types ▪ Conducting a single, multi-center, placebo-controlled Phase 3 trial to support registration (N = ~160) ▪ Primary Objective: assess effect of azetukalner vs placebo on reducing frequency of primary generalized tonic clonic seizures ▪ Secondary Objectives include assessing the effect on azetukalner vs placebo on RR50, seizure freedom and PGI-C Up to 9.5 weeks 12-week double-blind period (DBP) 3-year open-label extension (OLE) *Administered as once-daily capsule with food with no titration period. Subjects aged ≥12 years and <18 years will receive either azetukalner 15mg, azetukalner 25 mg, or placebo; subjects aged ≥18 years will receive either azetukalner 25 mg or placebo. There is no placebo dose in the OLE. Open-Label Extension (25 mg QD*) Final 8-Week Follow-up (if not entering OLE) azetukalner 25 mg QD* placebo QD* Randomization 1:1 Screening and Baseline
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Expanding Azetukalner in Neuropsychiatry 19
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MDD is a Highly Prevalent Mental Health Disorder 20 ▪ In 2022, the MDD diagnosed prevalent population in the U.S. was approximately 21 million adults • ~55% treated with pharmacotherapy • 1 in 3 patients are inadequately managed on pharmacotherapy ▪ Anhedonia is a common comorbidity of MDD • Associated with poorer treatment outcomes Depression Accounts for Greatest Disability Among All Central Nervous System Disorders Sources: Whiteford et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013; Kern et al. Treatment patterns and sequences of pharmacotherapy for patients diagnosed with depression in the United States: 2014 through 2019. BMC Psychiatry. 2020; Fava, M. Definition and epidemiology of treatment-resistant depression. Psychiatry Clin North Am. 1996.
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1st Line 4th Line 2nd Line 3rd Line Opportunity to Improve MDD Treatment Paradigm 21 Physicians typically use multiple SSRIs/SNRIs, prior to progressing to branded therapy Poorly managed patients may seek alternative MOAs in 3L+ Opportunity exists for novel mechanisms that offer efficacy in anhedonia with a differentiated safety profile MDD Lines of Therapy SSRI Switch SSRI SNRI + NDRI + Anticonvulsants + Atypical Antipsychotics + Tricyclics + 5HT Partial Agonist + Somatic Therapies + Ketamine Used less frequently in clinical practice Treatment Considerations Source: Xenon-sponsored market research
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X-NOVA Phase 2 Proof-of-Concept Clinical Trial in MDD 22 ▪ Conducted a Phase 2 proof-of-concept, randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety, tolerability, and efficacy of azetukalner in major depressive disorder (MDD) ▪ Primary Objective: Montgomery- Åsberg Depression Rating Scale (MADRS) score change through Week 6 ▪ Key Secondary Objective: Snaith- Hamilton Pleasure Scale (SHAPS) score change through Week 6 Topline data from Phase 2 X-NOVA study announced in November 2023 4 weeks 6-week double-blind period (DBP) 4 weeks *Administered as once-daily capsule with food with no titration period. 4-week follow-up azetukalner 20 mg QD* azetukalner 10 mg QD* placebo QD* Randomization 1:1:1 Screening
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23 X-NOVA Primary Efficacy Endpoint: Change in MADRS Total Scores at Week 6 (mITT) A clear dose response and a clinically meaningful 3.04 difference in MADRS at Week 6 in the 20 mg group *p<0.05 Placebo (N=54) Azetukalner 20 mg (N=53) ΔMADRS from BL at Wk 6 (LS mean) -13.90 -16.94 Diff. vs Pbo -3.04 p-value 0.135 MADRS: Montgomery-Åsberg Depression Rating Scale; LSMean (SEM) shown; mITT: modified intent to treat; population included all randomized subjects who received at least 1 dose of study treatment and at least 1 post randomization MADRS score Azetukalner (XEN1101) was administered as a once-daily capsule with food with no titration period.
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X-NOVA Pre-Specified Endpoint Improvement in Depressive Symptoms: Change in HAM-D17 T otal Score at Week 6 (mITT) 24 Improvement in depressive symptoms assessed by HAM-D17 total scores was significantly different at Week 6 Placebo (N=54) Azetukalner 20 mg (N=53) HAM-D17 total score change from baseline at Week 6 (LS mean) -10.18 -13.26 Difference vs. placebo -3.08 p-value 0.042 HAM-D17: Hamilton Depression Rating Scale was assessed at screening, baseline, and Week 6; mITT: modified intent to treat; population included all randomized subjects who received at least 1 dose of study treatment and at least 1 post randomization MADRS score Azetukalner (XEN1101) was administered as a once-daily capsule with food with no titration period.
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X-NOVA Secondary Efficacy Endpoint: Change in SHAPS Total Score at Week 6 (mITT) 25 Placebo (N=54) Azetukalner 20 mg (N=53) SHAPS total score change from baseline at Week 6 (LSMean) -5.30 -7.77 Difference vs. placebo -2.46 p-value 0.046 Anhedonia symptom improvement: significantly different change in SHAPS at Week 6in 20 mg group SHAPS: Snaith-Hamilton Pleasure Scale; LSMean (SEM) shown Azetukalner (XEN1101) was administered as a once-daily capsule with food with no titration period.
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X-NOVA: Safety and Tolerability Data ▪ Azetukalner was generally well-tolerated with similar rates of overall adverse events reported across all treatment arms • The most commonly reported TEAEs in the azetukalner 20 mg group included dizziness (17.9%), somnolence (10.7%), headache (8.9%) and disturbance in attention (8.9%), as compared to the placebo group which reported dizziness (7.3%), somnolence (1.8%), headache (12.7%) and disturbance in attention (0%) • Rates of discontinuation were similar across all treatment arms and rates of discontinuation due to TEAEs were low with three patients in the azetukalner 20 mg group (5.4%), as compared to two patients in the placebo group (3.6%) • No SAEs were reported in the two azetukalner treatment groups, and there were two patients (3.6%) in the placebo group who experienced a treatment-emergent SAE • Azetukalner was not associated with notable weight gain; patients did not report notable sexual dysfunction 26
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Phase 3 Clinical Studies in Major Depressive Disorder 27 ▪ Phase 3 MDD program consists of three multi-center, placebo-controlled clinical trials (N=~450 in each study) ▪ Plan to submit sNDA supported by efficacy data from two positive Phase 3 MDD trials ▪ Primary Objective: change from baseline in HAM-D17 score at week 6 ▪ Key Secondary Objectives include change from baseline in HAM- D17 score at week 1; change from baseline in SHAPS score at week 6; and change from baseline in CGI-S at week 6 X-NOVA2 and X-NOVA3 Phase 3 studies in MDD have been initiated and are recruiting subjects *Administered as once-daily capsule with food with no titration period. Up to 4 weeks 6-week double-blind period (DBP) Open-Label Extension (20 mg QD*) 8-Week Follow-up (if not entering OLE) azetukalner 20 mg QD* placebo QD* Randomization 1:1 Screening and Baseline
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Limited Options to Address Life-long Nature of Bipolar Depression 28CONFIDENTIAL INFORMATION 3.0 2.0 2.5 1.4 Lifetime 12-months 5.5 3.4 Bipolar I Bipolar II Estimated U.S. Bipolar disorder prevalence Millions of adults Note: 1 12-month prevalence is defined as patients who had bipolar disorder episodes in the 12 months before the clinical interview Source: Hoertel et al., J. Affect Disord. (2013); Merikangas et al., Arch. Gen. Psychiatry (2007); Merikangas et al., Arch. Gen. Psychiatry (2011); Angst et al., Am. J. Psychiatry (2010); Kessler et al., Int. J. Methods Psychiatr. Res. (2012); and corporate presentations • Bipolar disorder is a life-long disease that requires chronic management with pharmacotherapy • Lifetime prevalence is estimated at 5.5M patients • 12-month prevalent population (estimated at 3.4 million patients in the U.S.)1 excludes maintenance patients who did not have an acute bipolar episode in the last 12 months • Limited effective options (antipsychotics, mood stabilizers) results in patchwork of management options • While SSRIs are the standard-of-care in MDD, physicians must avoid agents that can induce mania and/or exacerbate psychosis (e.g. SSRIs) in BPD patients
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Bipolar Depression is Debilitating and Often Difficult to Diagnose ▪ Hallmark of bipolar disorder is its cyclical pattern, where individuals alternate between mania/hypomania and depression, often with periods of normal mood in between ▪ Depressive episodes can be longer and more frequent than manic/hypomanic episodes 29CONFIDENTIAL INFORMATION Acute mania / hypomania (5-10%) Acute depression (30-40%) Maintenance (50-60%) % of patients by disease phase Maintenance (~50-60%): stabilized patients who are not experiencing an active manic or depressed state are on maintenance therapy Acute mania / hypomania (~5-10%): acute manic patients make up a small portion of the overall patient population due to the infrequent nature of manic episodes Acute depression (~30-40%): acute depressive patients are a significant population as depressive episodes are more common in bipolar disorder
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Phase 3 Clinical Studies in Bipolar Depression 30 ▪ Phase 3 BPD program consists of two multi-center, placebo-controlled clinical trials (N=~400 in each study) in patients with bipolar I or II depression (BPD) ▪ Primary Objective: change from baseline in MADRS score at week 6 ▪ Key Secondary Objectives include change from baseline in MADRS score at week 1; change from baseline in SHAPS score at week 6; and change from baseline in CGI-S at week 6 X-CEED, first of two Phase 3 studies in BPD, has been initiated *Administered as once-daily capsule with food with no titration period. Up to 4 weeks 6-week double-blind period (DBP) Open-Label Extension (20 mg QD*) 8-Week Follow-up (if not entering OLE) azetukalner 20 mg QD* placebo QD* Randomization 1:1 Screening and Baseline 1-year open-label extension (OLE)
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Azetukalner’s Significant Potential Across Epilepsy & Neuropsychiatry 31 Novel Mechanism • Highly potent and selective Kv7.2/7.3 potassium channel opener with no activity on GABAA Rapid Onset of Effect • Statistically significant efficacy demonstrated at Week 1 in patients with FOS, and significantly different efficacy seen at Week 1 in patients with MDD Ease-of-Use Attributes • Once-daily dosing and no required titration, enabling potential for rational polypharmacy Robust Clinical Efficacy • Highly compelling double-blind efficacy data in FOS patients, durable long-term seizure freedom data as demonstrated in the ongoing OLE • Clinically meaningful activity in depression and significantly different reductions in anhedonia observed in MDD patients Sources: French, et al, AES 2021, poster 1.419; not approved for use; Butterfield, et al, ASCP 2024, poster W67; not approved for use; French J, Porter R, Perucca E, et al. Long-term safety and efficacy of azetukalner, a novel, potent Kv7 potassium channel opener in adults with focal epilepsy: Update from the ongoing 7-year open-label extension of X-TOLE. American Epilepsy Society Annual Meeting, December 6-10, 2024, Los Angeles, CA Well-Documented Safety Profile • More than 700 patient years of data in FOS patients, with some patients dosed for more than 5 years • Potentially differentiated profile in MDD patients, with no notable weight gain or sexual dysfunction observed
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Early-Stage Programs POTASSIUM & SODIUM CHANNEL SCIENCE 32
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Xenon’s Ongoing Early-Stage and Product Life Cycle Work 33 ▪ Leveraging Xenon’s deep ion channel expertise to develop promising drug candidates that target sodium and potassium channels • XEN1120, a Kv7 channel opener in development for pain: Phase 1 study underway in healthy subjects • XEN1701, a Nav1.7 channel inhibitor in development for pain: Phase 1 study underway in healthy subjects • Expect lead Nav1.1 candidate to enter IND-enabling studies in 2025 Potassium Channel Program • Strong conviction in broad applicability of Kv7 mechanism and strength of Xenon’s discovery platform • Next gen molecules to be explored in epilepsy and MDD • Further potential pipeline expansion into pain and other psychiatric indications beyond MDD Sodium Channel Program • Leveraging Xenon’s extensive knowledge and prior work to advance Nav1.7 program in pain • Xenon scientists contributed to early work linking loss of function in SCN9A gene (Nav1.7) to pain, based on strong human genetic validation • Nav1.1 channel work in epilepsy, based on genetic evidence of underlying pathophysiology of Dravet Syndrome
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Potential Value-Creating Milestone Opportunities 34 Azetukalner Epilepsy Program • Patient recruitment complete in Phase 3 azetukalner X-TOLE2 FOS study; topline data expected in early 2026 • Phase 3 azetukalner X-TOLE3 FOS study continues to enroll patients • Phase 3 clinical trial (X-ACKT) in PGTCS underway to support registration in additional epilepsy indication • NDA submission planned based on efficacy data from Phase 2b X-TOLE and Phase 3 X-TOLE2 trial Azetukalner Neuropsychiatric Programs • X-NOVA2 and X-NOVA3 studies in MDD initiated and recruiting subjects • X-CEED study in BPD initiated and recruiting subjects Partnered Program with Neurocrine Biosciences • NBI-921355, a Nav1.2/1.6 inhibitor in development as a potential treatment for certain types of epilepsy, has entered a Phase 1 clinical trial in healthy adult subjects Early-Stage Programs • Goal of filing multiple INDs, or equivalent, for potassium and sodium channel therapeutics in 2025 • XEN1120, a Kv7 channel opener in development for pain: Phase 1 study in healthy adult participants now underway • XEN1701, lead Nav1.7 candidate in development for pain: Phase 1 study in healthy adult participants now underway
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For more information INVESTORS@XENON -PHARMA.COM 35