XEN1101 / Xenon - LARVOL DELTA

Long-Term Safety and Efficacy of Azetukalner (XEN1101), a Novel, Potent KV7 Potassium Channel Opener in Adults With Focal Epilepsy: Update From the Ongoing 7-Year Open-Label Extension of X-TOLE (AAN 2025) - "In the ongoing X-TOLE OLE, azetukalner was generally well tolerated with no new safety signals. These promising interim data continue to suggest long-term safety and efficacy of azetukalner in a difficult-to-treat population."

Clinical • Alzheimer's Disease • CNS Disorders • Epilepsy • Infectious Disease • Novel Coronavirus Disease • Pain • Respiratory Diseases

X-NOVA2: A Randomized Study of Azetukalner Versus Placebo in Major Depressive Disorder (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc.

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

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 (AES 2024) - "Rationale: Azetukalner (XEN1101) is in development as a treatment for epilepsy and major depressive disorder... In the ongoing X-TOLE OLE, azetukalner was generally well tolerated with no new safety signals. These promising interim data continue to suggest long-term safety and efficacy of azetukalner in a difficult-to-treat population."

Clinical • Alzheimer's Disease • CNS Disorders • Depression • Epilepsy • Infectious Disease • Major Depressive Disorder • Mood Disorders • Novel Coronavirus Disease • Pain • Psychiatry • Respiratory Diseases

New kv7 Channel Opener Chemistry for Treatment of Seizures (AES 2024) - "Kv7 channel opening is a validated target for epilepsy with the approval of ezogabine (EZG) in 2011 as a first-in-class molecule; it was removed from the market in 2017. Kv7 openers BHV7000 and azetukalner (XEN1101) are currently in clinical development... In vivo, PO efficacy in rodent MES is >10-fold over aztukalner (ED50 > 4 mg/kg) and BHV7000 (full protection at 3 mg/kg). It is anticipated that the lead molecule, based on an in vivo minimum effective brain concentration of >20 nM for MES in mice and rats, a half maximal voltage shift of ~7 mV at 0.7 in rodents, may be effective at a plasma conc. of 30 nM, as a threshold conc., for clinical seizure protection in humans."

CNS Disorders • Depression • Epilepsy • Mood Disorders • Psychiatry

XEN1101 for Major Depressive Disorder (clinicaltrials.gov) - P2 | N=44 | Completed | Sponsor: James Murrough | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

XEN1101 for Major Depressive Disorder (clinicaltrials.gov) - P2 | N=44 | Active, not recruiting | Sponsor: James Murrough | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development. (PubMed, Epilepsia) - "These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, -2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve..."

Journal • Metastases • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Psychiatry • NAV1

XEN1101, a novel potassium channel opener: hope or hype for adults with focal seizure. (PubMed, Ann Med Surg (Lond)) - No abstract available

Journal • CNS Disorders • Epilepsy

Efficacy and Safety of XEN1101, a Novel, Kv7 Potassium Channel Opener in Adults With Moderate to Severe Major Depressive Disorder: Results From the Phase 2 X-NOVA Study (ASCP 2024) - "Despite not achieving statistical significance in its primary endpoint, XEN1101 demonstrated a clinically meaningful reduction of depression measured by the MADRS, a significant reduction in HAMD-17, an early onset of action, a significant reduction in anhedonia, and a potentially differentiated safety profile compared to other ADs. The X-NOVA results are particularly meaningful given that there was a 2 in 3 chance of receiving active treatment, which has been previously shown to increase the placebo response (Papakostos GI, et al. 2009)."

Clinical • P2 data • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Psychiatry

X-TOLE: A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (clinicaltrials.gov) - P2 | N=325 | Active, not recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Oct 2026 ➔ Oct 2028

Trial completion date • CNS Disorders • Epilepsy

A profile of azetukalner for the treatment of epilepsy: from pharmacology to potential for therapy. (PubMed, Expert Rev Clin Pharmacol) - "A literature review on the pharmacology, efficacy, tolerability, and safety of azetukalner (XEN1101), a second-generation opener of neuronal potassium channels currently in Phase 3 development as ASM...The upcoming Phase 3 clinical trials are expected to provide further insight into the efficacy, tolerability, and safety of azetukalner in treating focal-onset and primary generalized tonic-clonic seizures. Structurally distinct from currently marketed ASMs, azetukalner has the potential to be the only-in-class Kv7.2/7.3 opener on the market upon regulatory approval."

Journal • Review • CNS Disorders • Epilepsy • CYP3A4

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 (AAN 2024) - "XEN1101 was generally well tolerated and demonstrated an OLE safety profile similar to that seen in the DBP and other antiseizure medications used in FOS treatment. No new safety signals emerged. These promising data suggest long-term efficacy of XEN1101 in a difficult-to-treat population."

Clinical • P2b data • CNS Disorders • Epilepsy • Infectious Disease • Novel Coronavirus Disease • Pain • Respiratory Diseases

The Impact of Disease Severity on Responder Rates in a Phase 2b Study of XEN1101, a Potent, Selective Potassium Channel Opener, in Adults with Focal Epilepsy (X-TOLE) (AAN 2024) - "Consistent with the significant MPC seizure reduction, 54.5% of patients in the 25-mg XEN1101 group achieved RR50. XEN1101 was relatively more effective in patients with indicators of less-severe disease. XEN1101 may be appropriate for patients with focal epilepsy across the spectrum of disease severity."

Clinical • P2b data • CNS Disorders • Epilepsy

X-NOVA: A Study to Evaluate the Safety, Tolerability and Efficacy of XEN1101 in Major Depressive Disorder (clinicaltrials.gov) - P2 | N=168 | Completed | Sponsor: Xenon Pharmaceuticals Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

X-TOLE4: An Open-label Study of XEN1101 in Epilepsy (clinicaltrials.gov) - P3 | N=880 | Enrolling by invitation | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Jun 2027 ➔ Sep 2028 | Trial primary completion date: Jun 2026 ➔ Jul 2028

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

XEN1101 for Major Depressive Disorder (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: James Murrough | Trial completion date: Jan 2024 ➔ Dec 2024 | Trial primary completion date: Jan 2024 ➔ Nov 2024

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

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 (AES 2023) - "In the X-TOLE OLE, XEN1101 was generally well tolerated and demonstrated a safety profile similar to that seen in the DBP and with other ASMs used in the treatment of FOS. No new safety signals emerged. This promising interim data suggests long-term efficacy of XEN1101 in a difficult-to-treat population."

Clinical • P2b data • CNS Disorders • Epilepsy • Infectious Disease • Novel Coronavirus Disease • Pain • Respiratory Diseases

PRAX-628 Is a Next Generation Functionally Selective Small Molecule with Potent Anti-Seizure Activity and Potential as Best-in-Class Treatment for Focal Epilepsy (AES 2023) - "This study explores the in vivo anti-seizure efficacy of PRAX-628 in mice, comparing it to standard-of-care NaV channel blockers, carbamazepine, lamotrigine and cenobamate that exhibit less activity-dependence, as well as the Kv7 opener, XEN1101. The anticonvulsant activity of PRAX-628 was assessed across multiple acute seizure models in outbred male CD-1 mice: maximal electroshock (MES), 6 Hz and pentylenetetrazole (PTZ)... PRAX-628 exhibited potent anticonvulsant activity in various acute seizure models. Importantly it displayed anticonvulsant activity at doses lower than standard-of-care ASMs in the MES acute seizure model. PRAX-628 is currently being developed as a once daily, oral treatment for adult focal onset epilepsy."

CNS Disorders • Epilepsy

Long-Term Quality-of-Life Improvements in Adults with Focal Onset Seizures Treated with XEN1101 in an Ongoing Open-Label Extension of a Phase 2b Study (X-TOLE) (AES 2023) - "The overall group achieved important QoL improvements following long-term XEN1101 treatment, including overall QoL, seizure worry, and social functioning. Seizure worry and social functioning are meaningful QoL domains because they are associated with seizure severity (Harden et al. Epilepsy Behav 2007;11:208-11)."

Clinical • HEOR • P2b data • CNS Disorders • Epilepsy • Fatigue

The Impact of Disease Severity on Responder Rates in a Phase 2b Study of XEN1101, a Potent, Selective Potassium Channel Opener, in Adults with Focal Epilepsy (X-TOLE) (AES 2023) - "Consistent with the significant median percentage seizure reduction in X-TOLE, 54.5% of the patients in the 25-mg XEN1101 group achieved the benchmark of RR50. This effect was observed in a population with characteristics of severe disease. XEN1101 was relatively more effective in patients with indicators of less-severe disease in the trial population."

Clinical • P2b data • CNS Disorders • Epilepsy

Scientific Exhibit | XEN1101, a Novel Potassium Channel Opener: Clinical Program Updates (AES 2023) - "Sponsored by Xenon Pharmaceuticals"

Clinical

Xenon Pharmaceuticals Announces Topline Results from Phase 2 Proof-of-Concept X-NOVA Clinical Trial of XEN1101 in Major Depressive Disorder (MDD) (GlobeNewswire) - P2 | N=150 | X-NOVA (NCT05376150) | Sponsor: Xenon Pharmaceuticals Inc. | "The primary endpoint of the study was a change in the Montgomery-Åsberg Depression Rating Scale, or MADRS, at week 6. The mean reduction was 13.90 in the placebo group, 15.61 in the XEN1101 10 mg group and 16.94 in the XEN1101 20 mg group. A clear dose response and a clinically meaningful, but not statistically significant, 3.04 difference between placebo and the XEN1101 20 mg group (p=0.135) was observed. Statistical significance was achieved on the pre-specified endpoint of the Hamilton Depression Rating Scale, or HAM-D17, at week 6 with a mean reduction of 10.18 in the placebo group and 13.26 in the XEN1101 20 mg group (p=0.042)....XEN1101 was well tolerated with similar rates of adverse events reported across all treatment arms."

P2 data • CNS Disorders • Major Depressive Disorder

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial. (PubMed, JAMA Neurol) - P2 | "The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs. ClinicalTrials.gov Identifier: NCT03796962."

Clinical • Journal • P2b data • CNS Disorders • Epilepsy

Xenon Pharmaceuticals Announces Publication of Results from XEN1101 Phase 2b 'X-TOLE' Clinical Trial in Peer-Reviewed Journal Article in JAMA Neurology (GlobeNewswire) - P2 | N=325 | X-TOLE (NCT03796962) | Sponsor: Xenon Pharmaceuticals Inc. | "We look forward to presenting additional longer-term data from the X-TOLE open-label extension study at AES 2023, the upcoming annual meeting of the American Epilepsy Society in December.'...The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, −80.4% to −16.9%) for 25 mg, 46.4% (P < .001 vs placebo; IQR, −76.7% to −14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, −61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, −37.3% to 7.0%) for placebo."

P2b data • CNS Disorders • Epilepsy

Xenon Pharmaceuticals Announces Upcoming Investor Webinar with Leading Key Opinion Leaders to Discuss XEN1101 and Major Depressive Disorder (GlobeNewswire) - "Xenon Pharmaceuticals...today announced that the company will host an investor webinar with two leading key opinion leaders (KOLs) focused on major depressive disorder....A live webcast of the company presentation will be available on the 'Investors' section of Xenon's website and posted for replay following the event."

Clinical • CNS Disorders • Depression • Major Depressive Disorder