Copper Concentration & Histopathologic Changes in Liver Biopsy in Participants With Wilson Disease Treated With ALXN1840

Study Overview
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Brief Summary
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The main objective of the study is to evaluate the change in liver copper (Cu) concentration following 48 weeks of treatment with ALXN1840 in adult participants with Wilson Disease (WD) who have been previously treated for at least 1 year with standard of care (that is, trientine, penicillamine, or zinc). In the Treatment Period, efficacy and safety of ALXN1840 will be assessed at Week 48.

Detailed Description
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Participants who complete the 48-week Treatment Period will be offered the opportunity to continue their treatment in a 48-week Extension Period that will offer additional time for evaluation of long-term efficacy and safety of ALXN1840. There will be no liver biopsies during the Extension Period.

Official Title
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A Phase 2, Single-arm Pathologist-blinded 48-week Study Using Liver Biopsy Specimens to Assess Copper Concentration and Histopathologic Changes in ALXN1840-treated Patients With Wilson Disease Followed by an up to 48-weeks Extension Period

Conditions
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Wilson Disease

Intervention / Treatment
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* Drug: Bis-Choline Tetrathiomolybdate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of WD by Leipzig Criteria ≥ 4 or by historical test results. Continuous treatment for WD with penicillamine, trientine or zinc for at least 1 year prior to screening. Body mass index < 30 kilograms/meter squared. Able to cooperate with a percutaneous liver biopsy. Willing and able to follow protocol-specified contraception requirements. Capable of giving signed informed consent. Exclusion Criteria: Decompensated cirrhosis or Model for End Stage Liver Disease score > 13. Modified Nazer score > 7. Clinically significant gastrointestinal bleed within past 3 months. Alanine aminotransferase > 2 × upper limit of normal. History of bleeding abnormality or known coagulopathy, including platelet count < 100,000, and international normalized ratio for prothrombin time ≥ 1.5. Participant unwilling to accept blood products, if required. Marked neurological disease requiring either nasogastric feeding tube or intensive inpatient medical care. Hemoglobin less than lower limit of the reference range for age and sex. Participants in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney disease 5) or creatinine clearance < 30 milliliters/minute. Lymphoma, leukemia, or any malignancy within the past 5 years. Current or chronic history of liver disease not associated with WD.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALXN1840<br>Participants will receive ALXN1840. | Drug: Bis-Choline Tetrathiomolybdate<br>* Participants will be initiated at 15 milligrams once daily, then the dose will be increased to 30 milligrams once daily at Week 6.<br>* Other names: ALXN1840;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Liver Cu Concentration at Week 48 (Treatment Period) | Liver biopsy samples were taken for the assessment of liver Cu concentration. Multiple imputation was used to impute missing data at Week 48 due to any reason based on Baseline values. | Baseline, Week 48 (Treatment Period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Change From Baseline in Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Fibrosis Stage at Week 48 (Treatment Period) | Fibrosis from histology was evaluated by NASH CRN Fibrosis Stage, which was scaled from 0 to 4 stages where Score 0: None; Score 1: Perisinusoidal or periportal - 1a - mild, zone 3, perisinusoidal; Score 1: Perisinusoidal or periportal - 1b - moderate, zone 3, perisinusoidal; Score 1: Perisinusoidal or periportal - 1c - portal/periportal; Score 2: Both perisinusoidal and portal/periportal; Score 3: Bridging fibrosis; and Score 4: Cirrhosis. Higher scores indicated greater fibrosis. | Baseline, Week 48 (Treatment Period) | 
| Number of Participants With Change From Baseline in Metavir Fibrosis Score at Week 48 (Treatment Period) | Fibrosis from histology was evaluated by Metavir Fibrosis Score, which was ranged from 0 to 4 where Score 0: No fibrosis; Score 1: Stellate enlargement of portal tract but without septa formation; Score 2: Enlargement of portal tract with rare septa formation; Score 3: Numerous septa without cirrhosis; and Score 4: Cirrhosis. Higher scores indicated greater fibrosis. | Baseline, Week 48 (Treatment Period) | 
| Number of Participants With Change From Baseline in Ishak Fibrosis Score at Week 48 (Treatment Period) | Fibrosis from histology was evaluated by Ishak Fibrosis Score, which was ranged from 0 to 6 where Score 0: No fibrosis; Score 1: Fibrous expansion of some portal areas, with or without short fibrous septa; Score 2: Fibrous expansion of most portal areas, with or without short fibrous septa; Score 3: Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; and Score 4: Fibrous expansion of portal areas with marked bridging (P-P) as well as portal central (P-C); Score 5: Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); and Score 6: Cirrhosis, probable or definite. Higher scores indicated greater fibrosis. | Baseline, Week 48 (Treatment Period) | 
| Change From Baseline in Hepatic Collagen Content at Week 48 (Treatment Period) | Fibrosis from histology was evaluated by morphometric quantification of hepatic collagen content. | Baseline, Week 48 (Treatment Period) | 
| Change From Baseline in a-SMA Content at Week 48 (Treatment Period) | Fibrosis from histology was evaluated by morphometric quantification of hepatic a-SMA content. | Baseline, Week 48 (Treatment Period) | 
| Number of Participants With Change From Baseline in NAS Steatosis Grading Score at Week 48 (Treatment Period) | Steatosis from histology was evaluated by the steatosis component of the NAS, which was ranged from 0 to 3 where Score 0: < 5% (minimal); Score 1: 5 - 33% (mild); Score 2: 34 - 66% (moderate); and Score 3: > 66% (severe). Higher scores indicated greater steatosis. | Baseline, Week 48 (Treatment Period) | 
| Change From Baseline in Hepatic Fat Content at Week 48 (Treatment Period) | Steatosis from histology was evaluated by morphometric quantification of hepatic fat content. | Baseline, Week 48 (Treatment Period) | 
| Change From Baseline in NAS Total Score at Week 48 (Treatment Period) | Inflammation was quantified by the NAS total score. The score is defined as the unweighted sum of the scores for steatosis (0 [minimal] to 3 [severe]), lobular inflammation (0 [none] to 3 [>4 foci / 200x field]), and hepatocellular ballooning (0 [none] to 2 [many]), thus ranging from 0 (no inflammation) to 8 (severe inflammation), with higher scores indicating more severe disease. | Baseline, Week 48 (Treatment Period) | 
| Treatment Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The TEAEs were AEs with onset on or after the first study drug dose. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. | Day 1 (Treatment Period) up to Week 48 (Treatment Period) | 
| Extension Period: Number of Participants With TEAEs | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The TEAEs were AEs with onset on or after the first study drug dose. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. | Day 1 (Extension Period) up data cutoff date of 29 Jul 2022 (up to Week 86) | 
| Treatment Period: Predose Trough Plasma Total Mo Concentration |  | Predose up to 4 hours postdose at Week 6 (Day 43) and Week 36 (Day 253) | 
| Treatment Period: Predose Trough Plasma Total PUF Mo Concentration |  | Predose up to 4 hours postdose at Week 6 (Day 43) and Week 36 (Day 253) | 
| Change From Baseline in Mo in Liver Biopsy Specimen at Week 48 (Treatment Period) |  | Baseline, Week 48 (Treatment Period) | 
| Clinical Global Impression-Improvement (CGI-I) Scale Score at Week 48 (Treatment Period) | The CGI-I is a 7-point scale clinician assessment where 1= very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much worse. Higher scores indicated worsening of disease. | Week 48 (Treatment Period) | 
| Change From Baseline in CGI-S Scale Score at Week 48 (Treatment Period) | The CGI-S is a 7-point scale clinician assessment. Participants were assessed on severity of illness at the time of rating/assessment as follows: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; or 7 = extremely ill. Higher scores indicated worsening of disease. | Baseline, Week 48 (Treatment Period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Copper, ALXN1840, Histology, Liver Biopsy