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

Alexion Pharmaceuticals, Inc.31 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Wilson Disease

Interventions

Bis-Choline TetrathiomolybdateDRUG

Participants will be initiated at 15 milligrams once daily, then the dose will be increased to 30 milligrams once daily at Week 6.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Diagnosis of WD by Leipzig Criteria ≥ 4 or by historical test results. 2. Continuous treatment for WD with penicillamine, trientine or zinc for at least 1 year prior to screening. 3. Body mass index \< 30 kilograms/meter squared. 4. Able to cooperate with a percutaneous liver biopsy. 5. Willing and able to follow protocol-specified contraception requirements. 6. Capable of giving signed informed consent. Exclusion Criteria: 1. Decompensated cirrhosis or Model for End Stage Liver Disease score \> 13. 2. Modified Nazer score \> 7. 3. Clinically significant gastrointestinal bleed within past 3 months. 4. Alanine aminotransferase \> 2 × upper limit of normal. 5. History of bleeding abnormality or known coagulopathy, including platelet count \< 100,000, and international normalized ratio for prothrombin time ≥ 1.5. 6. Participant unwilling to accept blood products, if required. 7. Marked neurological disease requiring either nasogastric feeding tube or intensive inpatient medical care. 8. Hemoglobin less than lower limit of the reference range for age and sex. 9. Participants in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney disease 5) or creatinine clearance \< 30 milliliters/minute. 10. Lymphoma, leukemia, or any malignancy within the past 5 years. 11. Current or chronic history of liver disease not associated with WD.

Locations (12)

Research Site

Sacramento, California, United States

Research Site

Ann Arbor, Michigan, United States

Research Site

Dallas, Texas, United States

Research Site

Outcomes

Primary Outcomes

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.

Time frame: Baseline, Week 48 (Treatment Period)

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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Toronto, Ontario, Canada

Research Site

Århus N, Denmark

Research Site

Grafton, New Zealand

Research Site

Moscow, Russia

Research Site

Saint Petersburg, Russia

Research Site

Singapore, Singapore

Research Site

Barcelona, Spain

...and 2 more locations

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Day 1 (Extension Period) up Week 52 (Extension Period)

Treatment Period: Predose Trough Plasma Total Mo Concentration

Time frame: 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

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Week 48 (Treatment Period)