Slide 1: Rapidly Improved Copper Balance in Wilson Disease Patients on Tiomolybdate Choline
Rapidly Improved Copper Balance in Wilson Disease Patients on Tiomolybdate Choline Aftab Ala, MBBS,MD, FRCP, PhD Institute of Liver Studies, King’s College Hospital, London, UK Thomas Damgaard Sandahl, MD, PhD Aarhus University Hospital, Aarhus, DK Anna Członkowska, MD, PhD Second Department of Neur
Slide 2: Disclosures
Disclosures • Research grants from Orphalan, Univar, Ultragenyx, Vivet, Takeda, NIHR, MRC • Writing: The Lancet • Advisory Boards: Orphalan, Univar, Arbomed, Prime Medicine, Ultragenyx • Travel grants from Orphalan, Univar, Monopar Therapeutics, WDA • Speaker Fees: Orphalan, Univar, Ipsen 2
Slide 3: Wilson Disease (WD)
Wilson Disease (WD) Wilson disease is a rare genetic disorder of impaired copper (Cu) transport Cu accumulates in the liver and brain, causing organ damage Standard-of-care (SoC) therapies have numerous limitations: - paradoxical neurological worsening - complex, multi-per-day dosing - slow onset of
Slide 4: ALXN1840 is a Once Daily Oral Small Molecule Therapy for WD
ALXN1840 is a Once Daily Oral Small Molecule Therapy for WD ALXN1840 Tightly Binds Cu ALXN1840-Cu-albumin Forms a Tripartite Complex Cu binding affinity (Kd) CuCu D-penicillamine 2.4 x 10-16 Trientine 1.7 x 10-17 Cu ALXN1840 ALXN1840 ALXN1840 2.3 x 10-20 ALXN1840 (MoS42-, tiomolybdate choline) Cu-AL
Slide 5: Recap of Recently Presented ALXN1840 Clinical Data
Recap of Recently Presented ALXN1840 Clinical Data 5
Slide 6: Sustained Long-term Clinical Improvement Over 6 Years
Sustained Long-term Clinical Improvement Over 6 Years 6 Source: Weiss KH et al. Poster presented at: EASL 2025; May, 2025; Amsterdam, NL.
Slide 7: Sustained Long-term Neurologic and Psychiatric Benefit
Sustained Long-term Neurologic and Psychiatric Benefit 7 Source: Lorincz M et al. Poster presented at: ANA 2025; September, 2025; Baltimore, MD.
Slide 8: Copper Balance in Patients with Wilson Disease
Copper Balance in Patients with Wison Disease Efficacy End Point: Mean Daily Cu balance = Cu intake (food and drink) – Cu output (feces + urine) 8
Slide 9: Copper Balance Study Baseline Demographics and Characteristics
Copper Balance Study Baseline Demographics and Characteristics Enrolled Wilson Disease Subjects (n=9)† Demographics Clinical site location United Kingdom (Richmond Pharmacology Ltd) 6 (66.7%) New Zealand (University of Auckland) 3 (33.3%) Male sex 7 (77.8%) Race White 8 (88.9%) Asian 1 (11.1%) Age,
Slide 10: Cu Balance Study Design (ALXN1840-WD-204) in Wilson Disease Patients
Cu Balance Study Design (ALXN1840-WD-204) IN WILSON DISEASE PATIENTS Baseline Input / Output 15mg 15mg Days 25 – 28, Days -4 Assessment Periods Days 1 - 8 15mg QOD / 30mg Days 31 - 39 to -1 Pre-Study Washout Discharged Days -21 to -5 home 15mg Treatment Begins 10 Source: ALXN1840-WD-204 – Copper bal
Slide 11: Encouraging Patient-Level Improvement in Copper Balance
Encouraging Patient-Level Improvement in Copper Balance Cu Balance Cumulative Change from Baseline per Subject Cumulative change from baseline in Cu balance by subject (mg) Study Day 11 Source: Ala A et al. J Hepatol. 2025;S0168-8278(25)02483-3.
Slide 12: Rapid Significant, Sustained Improvement in Copper Balance on ALXN1840
Rapid Significant, Sustained Improvement in Copper Balance on ALXN1840 Cu Balance Cumulative Change from Baseline Cumulative Cu balance change from baseline (mg) Increased fecal Cu excretion results in statistically significantly improved Cu balance on ALXN1840 p = 0.005 p = 0.023 Study Day 12 Sourc
Slide 13: ALXN1840 Statistically Significantly Increases Human Fecal Copper Excretion
ALXN1840 Statistically Significantly Increases Human Fecal Copper Excretion Fecal Cu Output Relative to Cu Intake ALXN1840 treatment significantly increased fecal Cu excretion by ~50% vs. pre-treatment baseline (red line) Study Day Data presented as a rolling average and error bars represent standar
Slide 14: ALXN1840 Strongly Blocks Dietary Copper Uptake in Humans
ALXN1840 Strongly Blocks Dietary Copper Uptake in Humans 15 hours post oral 64Cu ingestion Pre-Treatment Post-Treatment Trientine Penicillamine ALXN1840 Placebo 14 Source: Kirk et al. J Hepatol. 2024;80(4):586-595; Sandahl 2022 Aarhus University Hospital
Slide 15: Marked Decrease in Total Body Copper in WD Mice on ALXN1840 at 8 weeks
Marked Decrease in Total Body Copper in WD Mice on ALXN1840 at 8 weeks 800 * p < 0.05 vs control 700 600 Total body Cu is significantly Mean Total Body Cu (μg) 500 lower after 8 weeks in WD mice treated with ALXN1840 400 (n = 5 mice per group) 300 200 100 Water ALXN1840 ALXN1840 ALXN1840 D-penicilla
Slide 16: MoA: Oral ALXN1840 Induces 1:1 Biliary Excretion with Cu in WD Rats
MoA: Oral ALXN1840 Induces 1:1 Biliary Excretion with Cu in WD Rats Cu and Mo (nmol/ml) Correlation in Bile1 Fecal Cu (ng/g)1 Cu concentration (nmol/ml) 400 50,000 Cu concentration (ng/g) 300 40,000 30,000 200 20,000 100 10,000 0 100 200 300 400 Mo concentration (nmol/ml) Study Day Once bound, Cu-AL
Slide 17: Supportive New ALXN1840 Data
Supportive New ALXN1840 Data 17
Slide 18: Cu Transits Through Sites of Albumin Processing – Does Not Accumulate
Cu Transits Through Sites of Albumin Processing – Does Not Accumulate Total Body Cu (ug) at Week 81 Sites of albumin 700 processing 600 Cu transits with albumin 500 (as ALXN1840-Cu-albumin complex) through sites of Cu (μg) albumin processing before 400 excretion in WD mice 300 200 100 Albumin proces
Slide 19: Mo Transits Thru Sites of Albumin Processing – Does Not Accumulate
Mo Transits Thru Sites of Albumin Processing – Does Not Accumulate Sites of albumin Total Body Cu Total Body Mo processing 600 600 500 500 400 400 Mo (μg) Cu (μg) 300 300 < 2 daily doses of ALXN1840 200 200 100 100 2 wks 2 wks 8 wks 16 wks 2 wks 2 wks 8 wks 16 wks Control ALXN1840 (15 mg/kg) Control
Slide 20: Cu and Mo (ALXN1840) Transit Thru Tissue is Non-toxic and Reversible
Cu and Mo (ALXN1840) Transit Thru Tissue is Non-toxic and Reversible Kidney Cu Kidney Mo 20 15 After a 2-week withdrawal Total (μg) period in WD mice, kidney 10 Cu and Mo levels decrease in parallel 5 2 wks on 2 wks on, 2 wks on 2 wks on, 2 wks off 2 wks off ALXN1840 (15 mg/kg) treatment ALXN1840 (1
Slide 21: Clinical Data Corroborate Nonclinical Findings; TPC Transit Appears Safe
Clinical Data Corroborate Nonclinical Findings; TPC Transit Appears Safe Before ALXN1840 After ALXN1840 Hepatic Kidney ↓ Hepatic ↑ Kidney Cu Cu Cu Cu ALXN1840 blocks Cu uptake in liver1; transits through the kidney in a manner that appears safe Drug-related Adverse Events2 Number of patients 266 Pat
Slide 22: No Impact on Kidney Function in Humans Across 6 Years of Treatment
No Impact on Kidney Function in Humans Across 6 Years of Treatment Serum Creatinine Mean serum creatinine (top) and mean 24-hour urine creatinine (bottom) were within normal limits across 6 years on ALXN1840 24-hr Urine Creatinine 22 Source: Pooled Phase 2/3 Safety Analysis
Slide 23: Clean SAE Profile at Sites of Albumin Processing
Clean SAE Profile at Sites of Albumin Processing SAEs from Phase 3 Clinical Trial (48-weeks) All SAEs Related only ALXN1840 SoC ALXN1840 SoC System Organ Class (n=137) (n=70) (n=137) (n=70) Gastrointestinal disorders 1 (0.7%) 2 (2.9%) 0 0 Musculoskeletal and connective tissue disorders 1 (0.7%) 2 (2
Slide 24: Key Take-aways
Key Take-aways ALXN1840 improves copper balance in Wilson disease patients through increased fecal copper excretion Demonstrated in humans a potent blocking of dietary copper uptake Pre-clinical studies demonstrate reduction in total body Cu and biliary co-excretion of Cu-ALXN1840 (Mo) complex New S
Slide 25: Acknowledgements
Acknowledgements We would like to thank the patients and their families for their participation in the studies, as well as all participating sites
Slide 26: Thank You !
Thank You ! Email aftab.ala1@nhs.net