Efficacy and Safety of ALXN1840 Administered for 48 Weeks Versus Standard of Care in Participants With Wilson Disease

Study Overview
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Brief Summary
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The study will evaluate the efficacy and safety of ALXN1840 (formerly called WTX101) administered for 48 weeks compared to standard of care (SoC) in Wilson Disease (WD) participants aged 12 and older in the Primary Evaluation Period. In addition, efficacy and safety will be evaluated during an optional 60-month Extension Period.

Detailed Description
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The study consists of 2 cohorts. Cohort 1: Participants who have received SoC therapy for > 28 days and Cohort 2: Participants who are treatment-naïve or who have received SoC therapy for ≤ 28 days. All enrolled participants were randomized by cohort in a 2:1 ratio to treatment with ALXN1840 or SoC (either as continued therapy in Cohort 1 or as continued or initial therapy in Cohort 2).

Official Title
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A Phase 3, Randomized, Rater-Blinded, Multi-Center Study To Evaluate the Efficacy and Safety of ALXN1840 Administered For 48 Weeks Versus Standard of Care in Patients With Wilson Disease Aged 12 Years and Older

Conditions
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Wilson Disease

Intervention / Treatment
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* Drug: ALXN1840
* Drug: SoC Therapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Established diagnosis of WD by Leipzig-Score ≥ 4 Female participants of childbearing potential, if heterosexually active, must be willing to follow protocol-specified guidance for highly effective contraception starting at least 6 weeks before the Day 1 visit and continuing through 28 days after the last dose of either ALXN1840 or SoC Male participants, if heterosexually active, must be willing to follow protocol-specified guidance for highly effective contraception beginning at Day 1 visit and continuing through 90 days after last dose of either ALXN1840 or SoC Key Exclusion Criteria: Decompensated hepatic cirrhosis MELD score > 13 Modified Nazer score > 7 Clinically significant gastrointestinal bleed within past 3 months Alanine aminotransferase > 2 X upper limit of normal (ULN) for participants treated for > 28 days with WD therapy (Cohort 1) Alanine aminotransferase > 5 X ULN for treatment-naïve participants or participants who have been treated for ≤ 28 days (Cohort 2) Marked neurological disease requiring either nasogastric feeding or intensive inpatient medical care Hemoglobin < 9 grams/deciliter History of seizure activity within 6 months prior to informed consent Pregnant (or women who are planning to become pregnant) or breastfeeding women Active infection with hepatitis B virus (positive hepatitis B surface antigen) or C virus or seropositivity for human immunodeficiency virus (HIV) Previous treatment with tetrathiomolybdate Participants with end-stage renal disease on dialysis (chronic kidney disease stage 5) or creatinine clearance < 30 milliliter/minute

Ages Eligible for Study
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Minimum Age: 12 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALXN1840<br>ALXN1840 was administered orally for 48 weeks at doses ranging from 15 milligrams (mg) every other day (QOD) up to a titrated dose of 60 mg daily. Participants who completed the Primary Evaluation Period had the option to participate in the up to 60-month Extension Period. | Drug: ALXN1840<br>* ALXN1840 administered orally in 15 mg tablets<br>* Other names: Bis-choline tetrathiomolybdate;|
| Active Comparator: Standard of Care (SoC) Medication<br>SoC medication was administered for 48 weeks. Participants who completed the Primary Evaluation Period had the option to participate in the up to 60-month Extension Period. | Drug: SoC Therapy<br>* Depending on the site/region, participants randomized to receive SoC treatment will receive trientine, penicillamine, Zinc, or a combination of these medicines, administered according to standard regimens.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily Mean Area Under The Effect-time Curve (AUEC) of Directly Measured Non-ceruloplasmin-bound Copper (dNCC) From 0 to 48 Weeks (dNCC AUEC0-48W) | dNCC is the directly quantified copper not bound to ceruloplasmin, obtained by inductively coupled plasma mass spectrometry after immunocapture and removal of ceruloplasmin. Baseline was defined as last non-missing value on or before first study drug administration. Least square (LS) mean and standard error (SE) was calculated using analysis of covariance (ANCOVA). | Baseline to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An AE was any untoward medical occurrence in a participant administered the study drug and which did not necessarily have a causal relationship with this treatment. TEAEs were defined as those AEs with onset after the first dose of randomized treatment or existing events that worsened in severity after the first dose of randomized treatment. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. | Baseline up to Week 48 | 
| Change From Baseline in the Unified Wilson Disease Rating Scale (UWDRS) Part II Total Score at Week 48 | The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of Wilson Disease (WD). The UWDRS comprises 3 parts: UWDRS Part I (level of consciousness, item 1), UWDRS Part II (a patient-reported review of daily activity items [disability], items 2 to 11 [10 items in total]), and UWDRS Part III (a detailed neurological examination, items 12 to 34 [23 items in total]). The UWDRS Part II may be reported to a non-blinded member of the study team, by the participant, family member or caregiver. The UWDRS Part II total score was calculated as the sum of Question 2 to Question 11 (each question has range 0 [none] to 4 [severe]). The UWDRS Part II total score ranges from 0 (no disability) to 40 (severe disability), with lower score indicating improvement in condition and a better outcome. Change from baseline was calculated as: postbaseline assessment value - baseline assessment value when both values were not missing. | Baseline, Week 48 | 
| Change From Baseline in UWDRS Part III Total Score at Week 48 | The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of Wilson Disease (WD). The UWDRS comprises 3 parts: UWDRS Part I (level of consciousness, item 1), UWDRS Part II (a patient-reported review of daily activity items [disability], items 2 to 11 [10 items in total]), and UWDRS Part III (a detailed neurological examination, items 12 to 34 [23 items in total]). The UWDRS Part I and III was assessed by a neurologist who was blinded to the treatment randomization. The UWDRS Part III total score was calculated as the sum of Question 12 to Question 34. The UWDRS Part III total score ranges from 0 (normal) to 175 (severe disease), with lower score indicating improvement in condition and a better outcome. Change from baseline was calculated as: postbaseline assessment value - baseline assessment value when both values were not missing. | Baseline, Week 48 | 
| Change From Baseline in UWDRS Part III Functional Subscale Score at Week 48 | UWDRS Part III Functional Subscale consists of speech, handwriting, arising from chair, and gait from UWDRS Part III. The standardized score of the first 3 items ranges from 0 (normal) to 10 (worst), and standardized transformed score of gait ranges from 0 (normal) to 10 (worst). The average of these scores was used to create the Part III Functional Subscale with a range of 0 (normal) - 10 (worst) with higher scores indicating more functional disability. | Baseline, Week 48 | 
| Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | UWDRS Part III individual items speech, handwriting, arising from chair, and gait are reported here. For speech (Question 12), original score ranges from 0 (normal) to 4 (unintelligible). For handwriting (Question 20), original score ranges from 0 (normal) to 4 (cannot hold a pen). For arising from chair (Question 27), original score ranges from 0 (normal) to 4 (unable to arise without help). For gait (Question 29), the original score (range: 0 [normal] to 10 [severe condition]) was calculated by summing subscores (0 [normal] to 4 [severe]) of Part A (Right and Left Leg dystonia), B (Ataxia), and C (Parkinsonism). | Baseline, Week 48 | 
| Clinical Global Impression-Improvement Scale (CGI-I) Score at Week 48 | The CGI-I is a 7-point scale where the clinician assessed how much participant's illness improved or worsened relative to a Baseline state at the beginning of the intervention and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. | Week 48 | 
| Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 48 | The CGI-S is a 7-point scale where the investigator rated severity of participant's illness at the time of assessment, relative to the investigator's past experience with participants who have the same diagnosis. Considering total clinical experience, a participant was assessed on severity of illness at time of rating as: 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. | Baseline, Week 48 | 
| Change From Baseline in Model for End-Stage Liver Disease (MELD) Score at Week 48 | The MELD is a scoring system for assessing the severity of chronic liver disease in participants 12 years and older. The MELD score uses the participant's values for bilirubin, creatinine, and the international normalized ratio (INR). The initial MELD score (MELD[i]) is calculated according to the following formula: MELD(i) = 3.78*ln[serum bilirubin (mg/dL)] + 11.2*ln[INR] + 9.57*ln[serum creatinine (mg/dL)] + 6.43. Creatinine, bilirubin, and INR values less than 1.0 are set to 1.0 and creatinine values greater than 4.0 are set to 4.0 when calculating MELD(i). Additionally, creatinine, bilirubin, and INR are rounded to the 10th decimal place prior to performing the calculation. The initial MELD score is then rounded to the nearest integer. The MELD score ranges from 6 (least sick) - 40 (most sick), with higher values indicating more advanced disease. | Baseline, Week 48 | 
| Absolute Change From Baseline in Calculated Non-Ceruloplasmin Bound Copper (cNCC) or Calculated Non-Ceruloplasmin Bound Copper Corrected (cNCCcorrected) in Plasma at Week 48 | cNCC [µmol/L] = Plasma Total Copper (Cu) [micrograms (µg)/L]-(3.15*ceruloplasmin [milligrams (mg)/L])/63.5 [µg/µmol] For ALXN1840-treated participants, cNCC in plasma was corrected for the amount of Cu bound to ALXN1840 tripartite complex (TPC) using square root-based cNCC correction method (cNCCcorrected): cNCCcorrected = (√cNCC- 0.993)2√Mo, (Mo= molybdenum). In calculation of cNCC and cNCCcorrected following rules apply: For plasma total Cu concentration values <lower limit of quantification (LLOQ), cNCC was considered missing (LLOQ value of plasma total Cu= 20 nanograms [ng]/mL); Serum ceruloplasmin concentration values <LLOQ are set to 0 (LLOQ value of serum ceruloplasmin= 22.5 mg/L); Plasma total Mo concentration values <LLOQ are set to 0 (LLOQ value of plasma total Mo= 1 ng/L); In cases where cNCC calculation produces a negative result, cNCC was considered missing and cNCCcorrected was not derived; cNCCcorrected was set to 0 when 0.993√Mo > √cNCC. | Baseline, Week 48 | 
| Percent Change From Baseline in cNCC or cNCCcorrected in Plasma at Week 48 | cNCC was calculated as follows: cNCC [µmol/L] = Plasma Total Cu [µg/L]-(3.15*ceruloplasmin [mg/L])/63.5 [µg/µmol] For ALXN1840-treated participants, the cNCC in plasma was corrected for the amount of Cu bound to the ALXN1840 TPC using the square root-based cNCC correction method (cNCCcorrected) as follows: cNCCcorrected = (√cNCC- 0.993)2√Mo, where Mo = molybdenum. In the calculation of cNCC and cNCCcorrected the following rules apply: For plasma total Cu concentration values < LLOQ, cNCC was considered missing (LLOQ value of plasma total Cu = 20 ng/mL); Serum ceruloplasmin concentration values <LLOQ are set to 0 (LLOQ value of serum ceruloplasmin = 22.5 mg/L); Plasma total Mo concentration values <LLOQ are set to 0 (LLOQ value of plasma total Mo = 1 ng/L); In cases where cNCC calculation produces a negative result, cNCC was considered missing and cNCCcorrected was not derived; cNCCcorrected was set to 0 when 0.993√Mo > √cNCC. | Baseline, Week 48 | 
| cNCC/cNCCcorrected Responder at Week 48 | cNCC/cNCCcorrected responder was defined as participants who achieved or maintained normalized cNCC/cNCCcorrected concentration (0.8-2.3 μmol) within (at or before) 48 weeks or reached a reduction of at least 25% in cNCC/cNCCcorrected within 48 weeks. Thus, a participant was considered a cNCC/cNCCcorrected responder if they met at least 1 of the following criteria: Achieved normalized cNCC/cNCCcorrected concentration for 2 consecutive measurements within 48 weeks, for participants who had elevated cNCC concentrations at baseline; Maintained normalized cNCC/cNCCcorrected concentration within 48 weeks, for participants who had normal cNCC concentrations at baseline; Reached a reduction of at least 25% in cNCC/cNCCcorrected for 2 consecutive measurements within 48 weeks. | Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALXN1840, Wilson Disease, Copper