Wilson Disease
Conditions
Brief summary
The main purpose of the study was to evaluate the efficacy of ALXN1840 (formerly WTX101) for 24 weeks on non-ceruloplasmin-bound copper (NCC) concentrations adjusted for molybdenum plasma concentration in participants newly diagnosed with Wilson Disease (WD) who were aged 18 and older and who had NCC concentrations within or above the reference range at the time of enrollment in the study. The study consisted of a 24-week Treatment Period, followed by a planned 36-month Extension Period.
Interventions
DRUGALXN1840
Individualized oral doses of ALXN1840.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Able to understand and willing to comply with study procedures, restrictions, and requirements, as judged by the Investigator. * Newly established diagnosis of WD by Leipzig-Score ≥ 4 documented by testing as outlined in 2012 European Association for the Study of the Liver Wilson Disease Clinical Practice Guidelines. * NCC levels within or above the normal reference range (0.8 to 2.3 micromole). * Willing to undergo 48 hour washout from current WD treatment
Exclusion criteria
* Treatment for greater than 24 months for WD with chelation therapy (for example, penicillamine, trientine hydrochloride) or zinc therapy. * Decompensated hepatic cirrhosis. * Model for End-Stage Liver Disease score \> 11. * Modified Nazer score \> 6. * Gastrointestinal bleed within past 6 months. * Alanine aminotransferase \> 5 x upper limit of normal. * Marked neurological disease requiring either nasogastric feeding or intensive in-patient medical care. * Severe anemia with a hemoglobin \< 9 grams/deciliter.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Of Participants With Normalized Concentrations Of NCC | Week 24 | Normalized concentrations of NCC was defined as who achieving or maintaining normalized levels of NCC (0.8 to 2.3 micromole \[μmol\]l/liter \[L\]\]) adjusted for Mo plasma concentration or reaching a reduction of at least 25% in NCC corrected for Mo if above the normal reference range at the time of enrollment. NCC was calculated by subtracting the amount of copper (Cu) bound to ceruloplasmin (CP) from the total plasma Cu concentration. Post-baseline NCC values were adjusted (corrected) to account for Cu bound in tripartite complexes with ALXN1840 and albumin. Descriptive statistics are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In NCC Concentrations Adjusted For Mo Plasma Concentration At Week 24 | Baseline, Week 24 | The change from Baseline in NCC adjusted for Mo plasma concentration over 24 weeks were analyzed and descriptive statistics are reported. Change from Baseline = (Week 24 NCC concentrations adjusted for Mo plasma concentration) - (Baseline NCC concentrations). Least square means and their 95% confidence intervals (CIs) were calculated using a restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. |
| Time To Normalization Of NCC Adjusted For Mo Plasma Concentration In Participants With Elevated Baseline NCC | Up to last assessment (up to Week 176) | For time to normalization of NCC adjusted for Mo plasma concentration, a Kaplan-Meier approach was used where participants not normalized were censored at the latest observed time point. To achieve a normalized NCC concentration, participants must have demonstrated 2 consecutive measures within the normal range (0.8 to 2.3 μmol/L). Analyses includes all data up to the last assessment in the extension period for participants who reached the event of normalization of NCC corrected concentrations. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period; up to Week 176. |
| Change From Baseline In Neurological Status Using The Unified Wilson's Disease Rating Scale (UWDRS) (Neurological Subscore; Part I) At Week 24 | Baseline, Week 24 | The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD. Change from Baseline in the UWDRS I for consciousness is presented. * UWDRS I: range 0 to 3, maximum score of 3 * UWDRS I was assessed by a Neurologist * Change from Baseline was calculated as: Week 24 score - Baseline score. A decrease in score from Baseline is indicative of both an improvement in condition and a better outcome. |
| Change From Baseline In Neurological Status Using The UWDRS (Neurological Subscore; Parts II, III, And Total Score) At Week 24 | Baseline, Week 24 | The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD. UWDRS comprises 3 parts: UWDRS I (consciousness), UWDRS II (disability), and UWDRS III (neurological status). Change from Baseline in the UWDRS II, III, and total score are presented. * UWDRS I: range 0 to 3, maximum score of 3 * UWDRS II: range 0 to 40, maximum score of 40 * UWDRS III: range 0 to 175, maximum score of 175 * UWDRS total score: sum of the UWDRS I, II, and III: range 0 to 218, maximum score of 218 * UWDRS I and III were assessed by a neurologist, while UWDRS II was reported by the participant or caregiver. * Change from Baseline was calculated as: Week 24 score - Baseline score. Least square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. A decrease in score from Baseline is indicative of an improvement in condition and a better outcome. |
| Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Baseline, Week 24 | The M.I.N.I. is a short structured diagnostic interview for the Diagnostic and Statistical Manual of Mental Disorders IV and the 10th revision of the International Statistical Classification of Diseases and Related Health Problems. It was used to track the severity of symptoms by using a combination of questions in 16 Psychiatric Status dimensions that are summarized using a single standardized score for each dimension, ranging from 0 (interpreted as did not occur at all) to 4 (interpreted as occurred extremely often). The standardized score is an average of these responses. Change from Baseline = Week 24 standardized score - Baseline standardized score. Least square means and 95% CIs were calculated using an REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. Decrease from Baseline (a lower score) is indicative of a decrease in symptoms and a better outcome. |
| Clinical Global Impression-Improvement Scale (CGI-I) At Week 24 | Week 24 | 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. Change from Baseline = Week 24 score - Baseline score. An increase in CGI-I score indicates improvement. |
| Change From Baseline In Clinical Global Impression Severity Scale (CGI-S) At Week 24 | Baseline, Week 24 | 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. Change from Baseline = Week 24 score - Baseline score. Decrease in CGI-S score and increase indicates improvement. |
| Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The European Quality Of Life 5 Dimensions (EQ-5D) Visual Analogue Scale (VAS) At Week 24 | Baseline, Week 24 | The EQ-5D VAS records the participant's self-rated health as indicated on a scale from 0 to 100 with 0 being the worst health you can imagine and 100 being the best health you can imagine, with higher scores for a higher quality of life. Change from Baseline = Week 24 score - Baseline score. An increase in score indicates improvement. The least-square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. |
| Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The EQ-5D Descriptive System UK Health Index Scores At Week 24 | Baseline, Week 24 | The EQ-5D-5L Descriptive System provides a simple descriptive profile and a single index value for health status (United Kingdom \[UK\] Health Index Score). The EQ-5D-5L consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each of which can have 1 of 5 responses that represent 5 levels of severity (no problems, slight problems, moderate problems, severe problems, extreme problems). The participant was asked to indicate his/her health state for each of the 5 dimensions. The 5-item index score was transformed into a utility score between 0 (worst health state) and 1 (best health state). Change from Baseline = Week 24 index score - Baseline index score. An increase in score indicates improvement. The least square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. |
| QoL/PRO Assessed By The 8-Item Medication Adherence Scale (MMAS-8) At Week 24 | Week 24 | The MMAS-8 is a scale used to evaluate adherence to medication. The MMAS-8 consists of 8 questions with a sum score ranging between 0 and 8 points, with 8 being the maximum adherence to medication. Mean adherence to medication is presented. |
| QoL/PRO Assessed By The Treatment Satisfaction Questionnaire For Medication (TSQM-9) At Week 24 | Week 24 | The TSQM-9 was used to assess the overall level of satisfaction or dissatisfaction with medication participants were taking. This composite scale is comprised of 2 items on the TSQM-9 survey: How satisfied are you that good things about this medication outweigh the bad things? Taking all things into account, how satisfied or dissatisfied are you with this medication? The TSQM-9 domain scores (effectiveness score, convenience score, global satisfaction score) range from 0 to 100 with higher scores representing greater satisfaction for the domain. |
| Change From Baseline In Hepatic Laboratory Measure Alanine Aminotransferase (ALT) At Week 24 | Baseline, Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 ALT level - Baseline ALT level. |
| Change From Baseline In Hepatic Laboratory Measure Aspartate Aminotransferase (AST) At Week 24 | Baseline, Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 AST level - Baseline AST level. |
| Change From Baseline In Hepatic Laboratory Measure International Normalized Ratio (INR) At Week 24 | Baseline, Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 INR - Baseline INR. |
| Change From Baseline In Hepatic Laboratory Measure Bilirubin At Week 24 | Baseline, Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 bilirubin level - Baseline bilirubin level. |
| Change From Baseline In Exchangeable Cu At Week 24 | Baseline, Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 Exchangeable Cu level - Baseline Exchangeable Cu level. |
| Change From Baseline In Speciation Profiling (Mo, Cu, And Protein Complex Profiling Using Size Exclusion Chromatography) At Week 24 | Baseline, Week 24 | Due to low chromatographic resolution of data, quantitative analysis for speciation profiling, as had been planned in the protocol, was not feasible. |
| Change From Baseline In 24-Hour Urinary Mo And Cu At Week 24 | Baseline, Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 (24-hour) urinary Mo or Cu level - Baseline 24-hour urinary Mo or Cu level. |
| Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1, Week 12, and Week 24 | PK blood sampling occurred on Day 1, Week 12, and Week 24 at the following serial PK sampling time-points: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose. |
| PK: Maximum Concentration (Cmax) Of Plasma Total Mo | 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1, Week 12, and Week 24 | PK blood sampling occurred on Day 1, Week 12, and Week 24 at the following serial PK sampling time-points: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose. |
| Extension Period: Percentage Of Participants With Normalized Concentrations Of NCC | Up to last assessment (up to Week 176) | Normalized concentrations of NCC was defined as who achieving or maintaining normalized levels of NCC (0.8-2.3 μM) adjusted for Mo plasma concentration or reaching a reduction of at least 25% in NCC corrected for Mo if above the normal reference range at the time of enrollment. NCC was calculated by subtracting the amount of Cu bound to Cp from the total plasma Cu concentration. Post-baseline NCC values were adjusted (corrected) to account for Cu bound in tripartite complexes with ALXN1840 and albumin. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period; up to Week 176. |
| Extension Period: Change From Baseline In NCC Levels Adjusted For Mo Plasma Concentration | Baseline, last assessment (up to Week 176) | The change from Baseline in NCC adjusted for Mo plasma concentration over 176 weeks were analyzed. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period, up to Week 176. Change from Baseline = (Last assessment \[up to Week 176\] NCC concentrations adjusted for Mo plasma concentration) - (Baseline NCC concentrations). Least square means and their 95% CIs were calculated using an REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. |
Countries
Austria, Germany, Poland, United Kingdom, United States
Participant flow
Pre-assignment details
Participants meeting all inclusion and no exclusion criteria were enrolled into the study and studied as outpatients. Participants enrolled as pre-treated with other de-coppering agents were required to undergo a 48-hour washout from their previous Wilson Disease (WD) treatment just prior to initiation of study treatment. Participants who completed the 24-week treatment period and had favorable safety profiles and WD control were offered the opportunity to participate in the Extension Period.
Participants by arm
| Arm | Count |
|---|---|
| ALXN1840 Treatment Period: ALXN1840 at individualized doses ranging from 15 to 60 mg per day. Dose increases or dose reductions were dependent on the individual NCC concentrations adjusted for Mo plasma concentration. ALXN1840 may have been administered every other day, once daily, or twice daily, depending on individualized dosing regimen, for 24 weeks.
Extension Period: Participants continued the same ALXN1840 daily dose maintained at Week 24 of the Treatment Period and the same dosing regimen. During the Extension Period, no up-titration was made unless NCC concentrations adjusted for Mo plasma concentration did not remain stable within (or below) the reference range. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 24-Week Treatment Period | Adverse Event | 3 |
| 24-Week Treatment Period | Participant was unable to Come | 1 |
| 24-Week Treatment Period | Physician Decision | 1 |
| 24-Week Treatment Period | Protocol Deviation | 1 |
| 24-Week Treatment Period | Withdrawal by Participant Prior to First Dose | 1 |
| Extension Period | Continued into Study WTX101-301 extension (NCT03403205). | 19 |
| Extension Period | Lost to Follow-up | 1 |
| Extension Period | Participant Withdrew for Personal Reasons | 1 |
| Extension Period | Protocol Deviation | 1 |
Baseline characteristics
| Characteristic | ALXN1840 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Age, Continuous | 34.1 years STANDARD_DEVIATION 11.86 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 28 |
| other Total, other adverse events | 26 / 28 |
| serious Total, serious adverse events | 11 / 28 |
Outcome results
Primary
Percentage Of Participants With Normalized Concentrations Of NCC
Normalized concentrations of NCC was defined as who achieving or maintaining normalized levels of NCC (0.8 to 2.3 micromole \[μmol\]l/liter \[L\]\]) adjusted for Mo plasma concentration or reaching a reduction of at least 25% in NCC corrected for Mo if above the normal reference range at the time of enrollment. NCC was calculated by subtracting the amount of copper (Cu) bound to ceruloplasmin (CP) from the total plasma Cu concentration. Post-baseline NCC values were adjusted (corrected) to account for Cu bound in tripartite complexes with ALXN1840 and albumin. Descriptive statistics are reported.
Time frame: Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALXN1840 | Percentage Of Participants With Normalized Concentrations Of NCC | 85.7 percentage of participants |
Secondary
Change From Baseline In 24-Hour Urinary Mo And Cu At Week 24
Assessed by laboratory measurements. Change from Baseline = Week 24 (24-hour) urinary Mo or Cu level - Baseline 24-hour urinary Mo or Cu level.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| ALXN1840 | Change From Baseline In 24-Hour Urinary Mo And Cu At Week 24 | Mo | 1561.1 μg/day |
| ALXN1840 | Change From Baseline In 24-Hour Urinary Mo And Cu At Week 24 | Cu | -28.1 μg/day |
Secondary
Change From Baseline In Clinical Global Impression Severity Scale (CGI-S) At Week 24
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. Change from Baseline = Week 24 score - Baseline score. Decrease in CGI-S score and increase indicates improvement.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ALXN1840 | Change From Baseline In Clinical Global Impression Severity Scale (CGI-S) At Week 24 | -0.9 score on a scale |
Secondary
Change From Baseline In Exchangeable Cu At Week 24
Assessed by laboratory measurements. Change from Baseline = Week 24 Exchangeable Cu level - Baseline Exchangeable Cu level.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALXN1840 | Change From Baseline In Exchangeable Cu At Week 24 | -25.1 ng/mL | Standard Deviation 56.64 |
Secondary
Change From Baseline In Hepatic Laboratory Measure Alanine Aminotransferase (ALT) At Week 24
Assessed by laboratory measurements. Change from Baseline = Week 24 ALT level - Baseline ALT level.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALXN1840 | Change From Baseline In Hepatic Laboratory Measure Alanine Aminotransferase (ALT) At Week 24 | -2.0 U/L | Standard Deviation 23.71 |
Secondary
Change From Baseline In Hepatic Laboratory Measure Aspartate Aminotransferase (AST) At Week 24
Assessed by laboratory measurements. Change from Baseline = Week 24 AST level - Baseline AST level.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALXN1840 | Change From Baseline In Hepatic Laboratory Measure Aspartate Aminotransferase (AST) At Week 24 | -10.3 U/L | Standard Deviation 28.18 |
Secondary
Change From Baseline In Hepatic Laboratory Measure Bilirubin At Week 24
Assessed by laboratory measurements. Change from Baseline = Week 24 bilirubin level - Baseline bilirubin level.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALXN1840 | Change From Baseline In Hepatic Laboratory Measure Bilirubin At Week 24 | -0.7 μmol/L | Standard Deviation 4.3 |
Secondary
Change From Baseline In Hepatic Laboratory Measure International Normalized Ratio (INR) At Week 24
Assessed by laboratory measurements. Change from Baseline = Week 24 INR - Baseline INR.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALXN1840 | Change From Baseline In Hepatic Laboratory Measure International Normalized Ratio (INR) At Week 24 | -0.05 ratio | Standard Deviation 0.148 |
Secondary
Change From Baseline In NCC Concentrations Adjusted For Mo Plasma Concentration At Week 24
The change from Baseline in NCC adjusted for Mo plasma concentration over 24 weeks were analyzed and descriptive statistics are reported. Change from Baseline = (Week 24 NCC concentrations adjusted for Mo plasma concentration) - (Baseline NCC concentrations). Least square means and their 95% confidence intervals (CIs) were calculated using a restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ALXN1840 | Change From Baseline In NCC Concentrations Adjusted For Mo Plasma Concentration At Week 24 | -2.56 μmol/L |
Secondary
Change From Baseline In Neurological Status Using The Unified Wilson's Disease Rating Scale (UWDRS) (Neurological Subscore; Part I) At Week 24
The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD. Change from Baseline in the UWDRS I for consciousness is presented. * UWDRS I: range 0 to 3, maximum score of 3 * UWDRS I was assessed by a Neurologist * Change from Baseline was calculated as: Week 24 score - Baseline score. A decrease in score from Baseline is indicative of both an improvement in condition and a better outcome.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALXN1840 | Change From Baseline In Neurological Status Using The Unified Wilson's Disease Rating Scale (UWDRS) (Neurological Subscore; Part I) At Week 24 | 0.0 score on a scale | Standard Deviation 0 |
Secondary
Change From Baseline In Neurological Status Using The UWDRS (Neurological Subscore; Parts II, III, And Total Score) At Week 24
The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD. UWDRS comprises 3 parts: UWDRS I (consciousness), UWDRS II (disability), and UWDRS III (neurological status). Change from Baseline in the UWDRS II, III, and total score are presented. * UWDRS I: range 0 to 3, maximum score of 3 * UWDRS II: range 0 to 40, maximum score of 40 * UWDRS III: range 0 to 175, maximum score of 175 * UWDRS total score: sum of the UWDRS I, II, and III: range 0 to 218, maximum score of 218 * UWDRS I and III were assessed by a neurologist, while UWDRS II was reported by the participant or caregiver. * Change from Baseline was calculated as: Week 24 score - Baseline score. Least square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. A decrease in score from Baseline is indicative of an improvement in condition and a better outcome.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| ALXN1840 | Change From Baseline In Neurological Status Using The UWDRS (Neurological Subscore; Parts II, III, And Total Score) At Week 24 | UWDRS Part II | -2.5 score on a scale |
| ALXN1840 | Change From Baseline In Neurological Status Using The UWDRS (Neurological Subscore; Parts II, III, And Total Score) At Week 24 | UWDRS Part III | -5.75 score on a scale |
| ALXN1840 | Change From Baseline In Neurological Status Using The UWDRS (Neurological Subscore; Parts II, III, And Total Score) At Week 24 | Total Score | -8.23 score on a scale |
Secondary
Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24
The M.I.N.I. is a short structured diagnostic interview for the Diagnostic and Statistical Manual of Mental Disorders IV and the 10th revision of the International Statistical Classification of Diseases and Related Health Problems. It was used to track the severity of symptoms by using a combination of questions in 16 Psychiatric Status dimensions that are summarized using a single standardized score for each dimension, ranging from 0 (interpreted as did not occur at all) to 4 (interpreted as occurred extremely often). The standardized score is an average of these responses. Change from Baseline = Week 24 standardized score - Baseline standardized score. Least square means and 95% CIs were calculated using an REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. Decrease from Baseline (a lower score) is indicative of a decrease in symptoms and a better outcome.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Major Depressive Episode Standardized | -0.39 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Suicidality Tracking Scale Standardized | -0.07 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Manic/Hypomanic Episode Standardized | -0.09 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Panic Disorder Standardized | -0.28 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Agoraphobia Standardized | -0.58 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Social Anxiety Disorder Standardized | -0.35 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Obsessive Compulsive Disorder Standardized | -0.04 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Post Traumatic Stress Disorder Standardized | -0.24 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Alcohol Use Disorder Standardized | 0.00 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Substance Use Disorder Standardized | -0.02 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Psychotic Disorders Standardized | 0.00 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Anorexia Nervosa Standardized | 0.04 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Bulimia Nervosa Standardized | 0.0 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Binge Eating Disorder Standardized | 0.04 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Generalized Anxiety Disorder Standardized | -0.37 score on a scale |
| ALXN1840 | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | Antisocial Personality Disorder Standardized | -0.06 score on a scale |
Secondary
Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The EQ-5D Descriptive System UK Health Index Scores At Week 24
The EQ-5D-5L Descriptive System provides a simple descriptive profile and a single index value for health status (United Kingdom \[UK\] Health Index Score). The EQ-5D-5L consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each of which can have 1 of 5 responses that represent 5 levels of severity (no problems, slight problems, moderate problems, severe problems, extreme problems). The participant was asked to indicate his/her health state for each of the 5 dimensions. The 5-item index score was transformed into a utility score between 0 (worst health state) and 1 (best health state). Change from Baseline = Week 24 index score - Baseline index score. An increase in score indicates improvement. The least square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ALXN1840 | Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The EQ-5D Descriptive System UK Health Index Scores At Week 24 | 0.0439 EQ-5D-5L index score |
Secondary
Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The European Quality Of Life 5 Dimensions (EQ-5D) Visual Analogue Scale (VAS) At Week 24
The EQ-5D VAS records the participant's self-rated health as indicated on a scale from 0 to 100 with 0 being the worst health you can imagine and 100 being the best health you can imagine, with higher scores for a higher quality of life. Change from Baseline = Week 24 score - Baseline score. An increase in score indicates improvement. The least-square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ALXN1840 | Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The European Quality Of Life 5 Dimensions (EQ-5D) Visual Analogue Scale (VAS) At Week 24 | 11.3 score on a scale |
Secondary
Change From Baseline In Speciation Profiling (Mo, Cu, And Protein Complex Profiling Using Size Exclusion Chromatography) At Week 24
Due to low chromatographic resolution of data, quantitative analysis for speciation profiling, as had been planned in the protocol, was not feasible.
Time frame: Baseline, Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
Secondary
Clinical Global Impression-Improvement Scale (CGI-I) At Week 24
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. Change from Baseline = Week 24 score - Baseline score. An increase in CGI-I score indicates improvement.
Time frame: Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ALXN1840 | Clinical Global Impression-Improvement Scale (CGI-I) At Week 24 | -0.8 score on a scale |
Secondary
Extension Period: Change From Baseline In NCC Levels Adjusted For Mo Plasma Concentration
The change from Baseline in NCC adjusted for Mo plasma concentration over 176 weeks were analyzed. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period, up to Week 176. Change from Baseline = (Last assessment \[up to Week 176\] NCC concentrations adjusted for Mo plasma concentration) - (Baseline NCC concentrations). Least square means and their 95% CIs were calculated using an REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction.
Time frame: Baseline, last assessment (up to Week 176)
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ALXN1840 | Extension Period: Change From Baseline In NCC Levels Adjusted For Mo Plasma Concentration | -2.92 μmol/L |
Secondary
Extension Period: Percentage Of Participants With Normalized Concentrations Of NCC
Normalized concentrations of NCC was defined as who achieving or maintaining normalized levels of NCC (0.8-2.3 μM) adjusted for Mo plasma concentration or reaching a reduction of at least 25% in NCC corrected for Mo if above the normal reference range at the time of enrollment. NCC was calculated by subtracting the amount of Cu bound to Cp from the total plasma Cu concentration. Post-baseline NCC values were adjusted (corrected) to account for Cu bound in tripartite complexes with ALXN1840 and albumin. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period; up to Week 176.
Time frame: Up to last assessment (up to Week 176)
Population: Participants who were enrolled and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALXN1840 | Extension Period: Percentage Of Participants With Normalized Concentrations Of NCC | 92.9 percentage of participants |
Secondary
Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo
PK blood sampling occurred on Day 1, Week 12, and Week 24 at the following serial PK sampling time-points: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose.
Time frame: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1, Week 12, and Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had any Baseline and post-Baseline measurable concentration data reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALXN1840 | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Week 24 | 5668.7 h*ng/mL | — |
| ALXN1840 15 mg Daily | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Day 1 | 2872.6 h*ng/mL | Standard Deviation 943.4 |
| ALXN1840 15 mg Daily | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Week 24 | 4593.6 h*ng/mL | Standard Deviation 1260 |
| ALXN1840 15 mg Daily | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Week 12 | 7873.6 h*ng/mL | Standard Deviation 3361.1 |
| ALXN1840 30 mg Daily | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Week 12 | 8836.9 h*ng/mL | Standard Deviation 2675.9 |
| ALXN1840 30 mg Daily | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Day 1 | 4796.7 h*ng/mL | Standard Deviation 3464.8 |
| ALXN1840 30 mg Daily | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Week 24 | 7884.3 h*ng/mL | Standard Deviation 3157.2 |
| ALXN1840 60 mg Daily | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Week 24 | 8890.2 h*ng/mL | Standard Deviation 5801.6 |
| ALXN1840 60 mg Daily | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Day 1 | 3138.7 h*ng/mL | Standard Deviation 3090.3 |
| ALXN1840 60 mg Daily | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | Week 12 | 11342.5 h*ng/mL | Standard Deviation 4706.7 |
Secondary
PK: Maximum Concentration (Cmax) Of Plasma Total Mo
PK blood sampling occurred on Day 1, Week 12, and Week 24 at the following serial PK sampling time-points: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose.
Time frame: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1, Week 12, and Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had any Baseline and post-Baseline measurable concentration data reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ALXN1840 | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Week 24 | 364.0 ng/mL | — |
| ALXN1840 15 mg Daily | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Day 1 | 202.7 ng/mL | Standard Deviation 114.5 |
| ALXN1840 15 mg Daily | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Week 24 | 359.0 ng/mL | Standard Deviation 163.7 |
| ALXN1840 15 mg Daily | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Week 12 | 393.0 ng/mL | Standard Deviation 177.3 |
| ALXN1840 30 mg Daily | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Week 12 | 488.8 ng/mL | Standard Deviation 165.5 |
| ALXN1840 30 mg Daily | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Day 1 | 304.8 ng/mL | Standard Deviation 202.9 |
| ALXN1840 30 mg Daily | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Week 24 | 447.7 ng/mL | Standard Deviation 200.4 |
| ALXN1840 60 mg Daily | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Week 24 | 489.9 ng/mL | Standard Deviation 293.4 |
| ALXN1840 60 mg Daily | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Day 1 | 167.6 ng/mL | Standard Deviation 144.6 |
| ALXN1840 60 mg Daily | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | Week 12 | 607.3 ng/mL | Standard Deviation 257.3 |
Secondary
QoL/PRO Assessed By The 8-Item Medication Adherence Scale (MMAS-8) At Week 24
The MMAS-8 is a scale used to evaluate adherence to medication. The MMAS-8 consists of 8 questions with a sum score ranging between 0 and 8 points, with 8 being the maximum adherence to medication. Mean adherence to medication is presented.
Time frame: Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ALXN1840 | QoL/PRO Assessed By The 8-Item Medication Adherence Scale (MMAS-8) At Week 24 | 7.59 score on a scale |
Secondary
QoL/PRO Assessed By The Treatment Satisfaction Questionnaire For Medication (TSQM-9) At Week 24
The TSQM-9 was used to assess the overall level of satisfaction or dissatisfaction with medication participants were taking. This composite scale is comprised of 2 items on the TSQM-9 survey: How satisfied are you that good things about this medication outweigh the bad things? Taking all things into account, how satisfied or dissatisfied are you with this medication? The TSQM-9 domain scores (effectiveness score, convenience score, global satisfaction score) range from 0 to 100 with higher scores representing greater satisfaction for the domain.
Time frame: Week 24
Population: Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| ALXN1840 | QoL/PRO Assessed By The Treatment Satisfaction Questionnaire For Medication (TSQM-9) At Week 24 | Effectiveness | 69.81 score on a scale |
| ALXN1840 | QoL/PRO Assessed By The Treatment Satisfaction Questionnaire For Medication (TSQM-9) At Week 24 | Convenience | 83.57 score on a scale |
| ALXN1840 | QoL/PRO Assessed By The Treatment Satisfaction Questionnaire For Medication (TSQM-9) At Week 24 | Global Satisfaction | 75.47 score on a scale |
Secondary
Time To Normalization Of NCC Adjusted For Mo Plasma Concentration In Participants With Elevated Baseline NCC
For time to normalization of NCC adjusted for Mo plasma concentration, a Kaplan-Meier approach was used where participants not normalized were censored at the latest observed time point. To achieve a normalized NCC concentration, participants must have demonstrated 2 consecutive measures within the normal range (0.8 to 2.3 μmol/L). Analyses includes all data up to the last assessment in the extension period for participants who reached the event of normalization of NCC corrected concentrations. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period; up to Week 176.
Time frame: Up to last assessment (up to Week 176)
Population: This analysis was only performed on the subset of participants with elevated Baseline NCC who reached the event of normalization of NCC corrected concentrations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ALXN1840 | Time To Normalization Of NCC Adjusted For Mo Plasma Concentration In Participants With Elevated Baseline NCC | 147.5 days |