Wilson Disease
Conditions
Keywords
Wilson Disease, ALXN1840, Copper
Brief summary
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
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).
Interventions
DRUGALXN1840
ALXN1840 administered orally in 15 mg tablets
DRUGSoC Therapy
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.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
This study is rater-blinded for the Unified Wilson Disease Rating Scale (UWDRS) assessment only.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Baseline to Week 48 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Unified Wilson Disease Rating Scale (UWDRS) Part II Total Score at Week 48 | Baseline, Week 48 | 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 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. |
| Change From Baseline in UWDRS Part III Total Score at Week 48 | Baseline, Week 48 | 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. |
| Change From Baseline in UWDRS Part III Functional Subscale Score at Week 48 | Baseline, 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. |
| Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Baseline, 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). |
| Clinical Global Impression-Improvement Scale (CGI-I) Score at Week 48 | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Baseline up to Week 48 | 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. |
| Change From Baseline in Model for End-Stage Liver Disease (MELD) Score at Week 48 | Baseline, Week 48 | 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. |
| Absolute Change From Baseline in Calculated Non-Ceruloplasmin Bound Copper (cNCC) or Calculated Non-Ceruloplasmin Bound Copper Corrected (cNCCcorrected) in Plasma at Week 48 | Baseline, Week 48 | cNCC = Plasma Total Copper (Cu) \[micrograms (µg)/L\]-(3.15\*ceruloplasmin \[milligrams (mg)/L\])/63.5 \[µg/µmol\] For ALXN1840-treated participants, cNCC in plasma corrected for amount of Cu bound to ALXN1840 tripartite complex (TPC) cNCCcorrected = (√cNCC- 0.993)2√Mo, (Mo= molybdenum). In calculation of cNCC and cNCCcorrected following rules apply: - For plasma total Cu concentration \<lower limit of quantification (LLOQ), cNCC was considered missing (LLOQ = 20 nanograms \[ng\]/mL); - Serum ceruloplasmin concentration values \<LLOQ are set to 0 (LLOQ = 22.5 mg/L); - Plasma total Mo concentration values \<LLOQ are set to 0 (LLOQ = 1 ng/L); - If 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. |
| Percent Change From Baseline in cNCC or cNCCcorrected in Plasma at Week 48 | Baseline, Week 48 | cNCC \[µmol/L\] = Plasma Total Cu \[µg/L\]-(3.15\*ceruloplasmin \[mg/L\])/63.5 \[µg/µmol\] For ALXN1840-treated participants, cNCC in plasma was corrected for amount of Cu bound to the ALXN1840 TPC using square root-based cNCC correction method: cNCCcorrected = (√cNCC- 0.993)2√Mo, where Mo = molybdenum. In calculation of cNCC and cNCCcorrected following rules apply: - For plasma total Cu concentration values \<LLOQ, cNCC was considered missing (LLOQ = 20 ng/mL); - Serum ceruloplasmin concentration values \<LLOQ are set to 0 (LLOQ = 22.5 mg/L); - Plasma total Mo concentration values \<LLOQ are set to 0 (LLOQ = 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. |
| cNCC/cNCCcorrected Responder at Week 48 | 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. |
| Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 48 | Baseline, 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. |
Countries
Australia, Austria, Canada, Czechia, Denmark, France, Germany, Hong Kong, Hungary, Israel, Japan, New Zealand, Poland, Russia, Serbia, Singapore, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The study consisted of 2 periods: Primary Evaluation Period (PEP) and Open-label Extension (OLE) Period. Participants who completed the 48-week PEP were offered the opportunity to continue treatment in an up to 60-month Extension. A total of 214 participants were randomized; 207 participants were treated in the PEP.
Pre-assignment details
Participants were randomized, stratified by cohort, in a 2:1 ratio to treatment with ALXN1840 or continued treatment with Standard of Care (SoC). Two cohorts were defined. Cohort 1: participants previously treated with SoC for \>28 days; Cohort 2: participants who were treatment naïve or previously treated with SoC for ≤28 days. Participants who completed participation in Study WTX101-201 (NCT02273596) were offered the opportunity to participate in the Study WTX101-301 OLE Period.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: ALXN1840 Participants in Cohort 1 (who received SoC therapy, that is, chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc therapy for \>28 days) received titrated doses of ALXN1840 orally for up to 48 weeks. | 104 |
| Cohort 1: SoC Therapy Participants in Cohort 1 (who received SoC therapy, that is, chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc therapy for \>28 days) continued to receive SoC therapy for up to 48 weeks according to the local package label. | 56 |
| Cohort 2: ALXN1840 Participants in Cohort 2 (who were treatment naïve or who received SoC therapy for ≤28 days) received titrated doses of ALXN1840 orally for up to 48 weeks. | 33 |
| Cohort 2: SoC Therapy Participants in Cohort 2 (who were treatment naïve or who received SoC therapy for ≤28 days) received/continued to receive SoC therapy for up to 48 weeks according to the local package label. | 14 |
| Cohort 1: WTX101-201- ALXN1840 Participants who received ALXN1840 during Study WTX101-201 (NCT02273596) continued to receive ALXN1840 for up to 60 months. | 8 |
| Cohort 2: WTX101-201- ALXN1840 Participants who received ALXN1840 during Study WTX101-201 (NCT02273596) continued to receive ALXN1840 for up to 60 months. | 11 |
| Total | 226 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Extension Period (Up to 60 Months) | Adverse Event | 6 | 3 | 1 | 1 | 0 | 0 |
| Extension Period (Up to 60 Months) | Death | 1 | 0 | 0 | 0 | 0 | 0 |
| Extension Period (Up to 60 Months) | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 |
| Extension Period (Up to 60 Months) | Other than specified | 5 | 5 | 3 | 0 | 1 | 0 |
| Extension Period (Up to 60 Months) | Physician Decision | 2 | 1 | 1 | 0 | 0 | 0 |
| Extension Period (Up to 60 Months) | Pregnancy | 1 | 1 | 0 | 0 | 0 | 0 |
| Extension Period (Up to 60 Months) | Protocol Deviation | 1 | 0 | 0 | 0 | 0 | 0 |
| Extension Period (Up to 60 Months) | Study Terminated by Sponsor | 66 | 32 | 21 | 10 | 7 | 8 |
| Extension Period (Up to 60 Months) | Withdrawal by Subject | 6 | 7 | 2 | 1 | 0 | 2 |
| Primary Evaluation Period (48 Weeks) | Adverse Event | 4 | 0 | 1 | 0 | 0 | 0 |
| Primary Evaluation Period (48 Weeks) | Death | 1 | 0 | 1 | 0 | 0 | 0 |
| Primary Evaluation Period (48 Weeks) | Lost to Follow-up | 1 | 1 | 0 | 0 | 0 | 0 |
| Primary Evaluation Period (48 Weeks) | Pregnancy | 1 | 0 | 0 | 0 | 0 | 0 |
| Primary Evaluation Period (48 Weeks) | Protocol Deviation | 0 | 1 | 0 | 0 | 0 | 0 |
| Primary Evaluation Period (48 Weeks) | Randomized but not treated | 1 | 0 | 4 | 2 | 0 | 0 |
| Primary Evaluation Period (48 Weeks) | Withdrawal by Subject | 4 | 2 | 2 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: SoC Therapy | Cohort 2: ALXN1840 | Cohort 2: SoC Therapy | Cohort 1: ALXN1840 | Cohort 1: WTX101-201- ALXN1840 | Cohort 2: WTX101-201- ALXN1840 | Total |
|---|---|---|---|---|---|---|---|
| Age, Customized ≥12 years - <18 years | 4 Participants | 2 Participants | 2 Participants | 10 Participants | 0 Participants | 0 Participants | 18 Participants |
| Age, Customized ≥18 years - <65 years | 50 Participants | 31 Participants | 12 Participants | 92 Participants | 7 Participants | 11 Participants | 203 Participants |
| Age, Customized ≥65 years | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 32 Participants | 11 Participants | 101 Participants | 7 Participants | 11 Participants | 216 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Asian | 13 Participants | 5 Participants | 0 Participants | 19 Participants | 1 Participants | 1 Participants | 39 Participants |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Unknown | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 41 Participants | 27 Participants | 12 Participants | 80 Participants | 7 Participants | 9 Participants | 176 Participants |
| Sex: Female, Male Female | 30 Participants | 9 Participants | 3 Participants | 46 Participants | 3 Participants | 7 Participants | 98 Participants |
| Sex: Female, Male Male | 26 Participants | 24 Participants | 11 Participants | 58 Participants | 5 Participants | 4 Participants | 128 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 104 | 0 / 56 | 1 / 33 | 0 / 14 | 1 / 89 | 0 / 49 | 0 / 28 | 0 / 12 | 0 / 8 | 0 / 11 |
| other Total, other adverse events | 46 / 104 | 18 / 56 | 16 / 33 | 7 / 14 | 45 / 89 | 32 / 49 | 10 / 28 | 4 / 12 | 6 / 8 | 7 / 11 |
| serious Total, serious adverse events | 14 / 104 | 6 / 56 | 4 / 33 | 0 / 14 | 20 / 89 | 10 / 49 | 6 / 28 | 3 / 12 | 2 / 8 | 3 / 11 |
Outcome results
Primary
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).
Time frame: Baseline to Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ALXN1840 | 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) | 2.50 micromoles (µmol)*hours (hr)/liter (L) | Standard Error 0.15 |
| Cohort 1: SoC Therapy | 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) | 0.87 micromoles (µmol)*hours (hr)/liter (L) | Standard Error 0.204 |
| Cohort 2: ALXN1840 | 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) | 4.76 micromoles (µmol)*hours (hr)/liter (L) | Standard Error 0.319 |
| Cohort 2: SoC Therapy | 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) | 0.96 micromoles (µmol)*hours (hr)/liter (L) | Standard Error 0.487 |
Comparison: Analysis was performed using ANCOVA model, which included treatment, cohort, and baseline value. Missing imputation was performed: 1) for intermediate missing, interpolation was used to fill out missing values. 2) For participants who die, baseline dNCC was carried forward from discontinuation to week 48. 3) For others, multiple imputation was used to impute missing dNCC assuming data were missing not at random.p-value: <0.000195% CI: [1.14, 2.13]ANCOVA
Comparison: Analysis was performed using ANCOVA model, which included treatment, cohort, and baseline value. Missing imputation was performed: 1) for intermediate missing, interpolation was used to fill out missing values. 2) For participants who die, baseline dNCC was carried forward from discontinuation to week 48. 3) For others, multiple imputation was used to impute missing dNCC assuming data were missing not at random.p-value: <0.000195% CI: [2.65, 4.94]ANCOVA
Secondary
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 = Plasma Total Copper (Cu) \[micrograms (µg)/L\]-(3.15\*ceruloplasmin \[milligrams (mg)/L\])/63.5 \[µg/µmol\] For ALXN1840-treated participants, cNCC in plasma corrected for amount of Cu bound to ALXN1840 tripartite complex (TPC) cNCCcorrected = (√cNCC- 0.993)2√Mo, (Mo= molybdenum). In calculation of cNCC and cNCCcorrected following rules apply: - For plasma total Cu concentration \<lower limit of quantification (LLOQ), cNCC was considered missing (LLOQ = 20 nanograms \[ng\]/mL); - Serum ceruloplasmin concentration values \<LLOQ are set to 0 (LLOQ = 22.5 mg/L); - Plasma total Mo concentration values \<LLOQ are set to 0 (LLOQ = 1 ng/L); - If 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.
Time frame: Baseline, Week 48
Population: Full analysis set: all randomized participants who received at least 1 dose of study drug. 'Overall number of participants analyzed'= participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ALXN1840 | Absolute Change From Baseline in Calculated Non-Ceruloplasmin Bound Copper (cNCC) or Calculated Non-Ceruloplasmin Bound Copper Corrected (cNCCcorrected) in Plasma at Week 48 | -0.72 µmol/L | Standard Deviation 1.107 |
| Cohort 1: SoC Therapy | Absolute Change From Baseline in Calculated Non-Ceruloplasmin Bound Copper (cNCC) or Calculated Non-Ceruloplasmin Bound Copper Corrected (cNCCcorrected) in Plasma at Week 48 | 0.64 µmol/L | Standard Deviation 2.769 |
| Cohort 2: ALXN1840 | Absolute Change From Baseline in Calculated Non-Ceruloplasmin Bound Copper (cNCC) or Calculated Non-Ceruloplasmin Bound Copper Corrected (cNCCcorrected) in Plasma at Week 48 | -1.95 µmol/L | Standard Deviation 1.536 |
| Cohort 2: SoC Therapy | Absolute Change From Baseline in Calculated Non-Ceruloplasmin Bound Copper (cNCC) or Calculated Non-Ceruloplasmin Bound Copper Corrected (cNCCcorrected) in Plasma at Week 48 | -1.51 µmol/L | Standard Deviation 2.361 |
Secondary
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.
Time frame: Baseline, Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ALXN1840 | Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 48 | -0.4 units on a scale | Standard Deviation 0.79 |
| Cohort 1: SoC Therapy | Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 48 | -0.1 units on a scale | Standard Deviation 0.73 |
| Cohort 2: ALXN1840 | Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 48 | -0.6 units on a scale | Standard Deviation 1.11 |
| Cohort 2: SoC Therapy | Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 48 | -0.5 units on a scale | Standard Deviation 1.21 |
Secondary
Change From Baseline in Model for End-Stage Liver Disease (MELD) Score at Week 48
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.
Time frame: Baseline, Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ALXN1840 | Change From Baseline in Model for End-Stage Liver Disease (MELD) Score at Week 48 | -0.1 units on a scale | Standard Deviation 1.85 |
| Cohort 1: SoC Therapy | Change From Baseline in Model for End-Stage Liver Disease (MELD) Score at Week 48 | 0.1 units on a scale | Standard Deviation 1.32 |
| Cohort 2: ALXN1840 | Change From Baseline in Model for End-Stage Liver Disease (MELD) Score at Week 48 | -0.7 units on a scale | Standard Deviation 1.61 |
| Cohort 2: SoC Therapy | Change From Baseline in Model for End-Stage Liver Disease (MELD) Score at Week 48 | 0.2 units on a scale | Standard Deviation 1.25 |
Secondary
Change From Baseline in the Unified Wilson Disease Rating Scale (UWDRS) Part II Total Score at Week 48
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 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.
Time frame: Baseline, Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ALXN1840 | Change From Baseline in the Unified Wilson Disease Rating Scale (UWDRS) Part II Total Score at Week 48 | -0.7 units on a scale | Standard Deviation 2.75 |
| Cohort 1: SoC Therapy | Change From Baseline in the Unified Wilson Disease Rating Scale (UWDRS) Part II Total Score at Week 48 | 0.0 units on a scale | Standard Deviation 2.31 |
| Cohort 2: ALXN1840 | Change From Baseline in the Unified Wilson Disease Rating Scale (UWDRS) Part II Total Score at Week 48 | -0.5 units on a scale | Standard Deviation 3.23 |
| Cohort 2: SoC Therapy | Change From Baseline in the Unified Wilson Disease Rating Scale (UWDRS) Part II Total Score at Week 48 | -1.8 units on a scale | Standard Deviation 4.63 |
Secondary
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.
Time frame: Baseline, Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ALXN1840 | Change From Baseline in UWDRS Part III Functional Subscale Score at Week 48 | -0.165 units on a scale | Standard Deviation 0.762 |
| Cohort 1: SoC Therapy | Change From Baseline in UWDRS Part III Functional Subscale Score at Week 48 | -0.102 units on a scale | Standard Deviation 0.5467 |
| Cohort 2: ALXN1840 | Change From Baseline in UWDRS Part III Functional Subscale Score at Week 48 | -0.090 units on a scale | Standard Deviation 0.8464 |
| Cohort 2: SoC Therapy | Change From Baseline in UWDRS Part III Functional Subscale Score at Week 48 | 0.227 units on a scale | Standard Deviation 0.4214 |
Secondary
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).
Time frame: Baseline, Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: ALXN1840 | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Speech | -0.1 units on a scale | Standard Deviation 0.5 |
| Cohort 1: ALXN1840 | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Handwriting | -0.2 units on a scale | Standard Deviation 0.63 |
| Cohort 1: ALXN1840 | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Arising from a chair | 0.0 units on a scale | Standard Deviation 0.45 |
| Cohort 1: ALXN1840 | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Gait | -0.03 units on a scale | Standard Deviation 1.317 |
| Cohort 1: SoC Therapy | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Handwriting | -0.1 units on a scale | Standard Deviation 0.48 |
| Cohort 1: SoC Therapy | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Arising from a chair | -0.1 units on a scale | Standard Deviation 0.56 |
| Cohort 1: SoC Therapy | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Gait | 0.00 units on a scale | Standard Deviation 1.141 |
| Cohort 1: SoC Therapy | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Speech | 0.0 units on a scale | Standard Deviation 0.35 |
| Cohort 2: ALXN1840 | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Arising from a chair | 0.0 units on a scale | Standard Deviation 0.27 |
| Cohort 2: ALXN1840 | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Handwriting | 0.1 units on a scale | Standard Deviation 0.6 |
| Cohort 2: ALXN1840 | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Gait | -0.18 units on a scale | Standard Deviation 0.945 |
| Cohort 2: ALXN1840 | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Speech | -0.1 units on a scale | Standard Deviation 0.52 |
| Cohort 2: SoC Therapy | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Gait | 0.23 units on a scale | Standard Deviation 0.754 |
| Cohort 2: SoC Therapy | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Handwriting | 0.2 units on a scale | Standard Deviation 0.4 |
| Cohort 2: SoC Therapy | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Speech | 0.1 units on a scale | Standard Deviation 0.54 |
| Cohort 2: SoC Therapy | Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 | Arising from a chair | 0.0 units on a scale | Standard Deviation 0 |
Secondary
Change From Baseline in UWDRS Part III Total Score at Week 48
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.
Time frame: Baseline, Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ALXN1840 | Change From Baseline in UWDRS Part III Total Score at Week 48 | -2.24 units on a scale | Standard Deviation 7.458 |
| Cohort 1: SoC Therapy | Change From Baseline in UWDRS Part III Total Score at Week 48 | -1.59 units on a scale | Standard Deviation 6.188 |
| Cohort 2: ALXN1840 | Change From Baseline in UWDRS Part III Total Score at Week 48 | -2.06 units on a scale | Standard Deviation 9.843 |
| Cohort 2: SoC Therapy | Change From Baseline in UWDRS Part III Total Score at Week 48 | 1.55 units on a scale | Standard Deviation 5.889 |
Secondary
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.
Time frame: Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ALXN1840 | Clinical Global Impression-Improvement Scale (CGI-I) Score at Week 48 | 3.4 units on a scale | Standard Deviation 0.89 |
| Cohort 1: SoC Therapy | Clinical Global Impression-Improvement Scale (CGI-I) Score at Week 48 | 3.8 units on a scale | Standard Deviation 0.8 |
| Cohort 2: ALXN1840 | Clinical Global Impression-Improvement Scale (CGI-I) Score at Week 48 | 3.1 units on a scale | Standard Deviation 1.06 |
| Cohort 2: SoC Therapy | Clinical Global Impression-Improvement Scale (CGI-I) Score at Week 48 | 3.2 units on a scale | Standard Deviation 1.34 |
Secondary
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.
Time frame: Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: ALXN1840 | cNCC/cNCCcorrected Responder at Week 48 | 101 Participants |
| Cohort 1: SoC Therapy | cNCC/cNCCcorrected Responder at Week 48 | 39 Participants |
| Cohort 2: ALXN1840 | cNCC/cNCCcorrected Responder at Week 48 | 33 Participants |
| Cohort 2: SoC Therapy | cNCC/cNCCcorrected Responder at Week 48 | 13 Participants |
Secondary
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.
Time frame: Baseline up to Week 48
Population: Safety analysis set included all participants who received at least 1 dose of randomized treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: ALXN1840 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 89 Participants |
| Cohort 1: SoC Therapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 41 Participants |
| Cohort 2: ALXN1840 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 30 Participants |
| Cohort 2: SoC Therapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 12 Participants |
Secondary
Percent Change From Baseline in cNCC or cNCCcorrected in Plasma at Week 48
cNCC \[µmol/L\] = Plasma Total Cu \[µg/L\]-(3.15\*ceruloplasmin \[mg/L\])/63.5 \[µg/µmol\] For ALXN1840-treated participants, cNCC in plasma was corrected for amount of Cu bound to the ALXN1840 TPC using square root-based cNCC correction method: cNCCcorrected = (√cNCC- 0.993)2√Mo, where Mo = molybdenum. In calculation of cNCC and cNCCcorrected following rules apply: - For plasma total Cu concentration values \<LLOQ, cNCC was considered missing (LLOQ = 20 ng/mL); - Serum ceruloplasmin concentration values \<LLOQ are set to 0 (LLOQ = 22.5 mg/L); - Plasma total Mo concentration values \<LLOQ are set to 0 (LLOQ = 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.
Time frame: Baseline, Week 48
Population: Full analysis set included all randomized participants who received at least 1 dose of randomized treatment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ALXN1840 | Percent Change From Baseline in cNCC or cNCCcorrected in Plasma at Week 48 | -7.7 percent change | Standard Deviation 263.2 |
| Cohort 1: SoC Therapy | Percent Change From Baseline in cNCC or cNCCcorrected in Plasma at Week 48 | 104.6 percent change | Standard Deviation 292.11 |
| Cohort 2: ALXN1840 | Percent Change From Baseline in cNCC or cNCCcorrected in Plasma at Week 48 | -64.0 percent change | Standard Deviation 42.88 |
| Cohort 2: SoC Therapy | Percent Change From Baseline in cNCC or cNCCcorrected in Plasma at Week 48 | -44.3 percent change | Standard Deviation 68.82 |