Efficacy and Safety Study of WTX101 (ALXN1840) in Adult Wilson Disease Patients

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Assessed by laboratory measurements. Change from Baseline = Week 24 ALT level - Baseline ALT level.

Assessed by laboratory measurements. Change from Baseline = Week 24 AST level - Baseline AST level.

Assessed by laboratory measurements. Change from Baseline = Week 24 INR - Baseline INR.

Assessed by laboratory measurements. Change from Baseline = Week 24 bilirubin level - Baseline bilirubin level.

Assessed by laboratory measurements. Change from Baseline = Week 24 Exchangeable Cu level - Baseline Exchangeable Cu level.

Due to low chromatographic resolution of data, quantitative analysis for speciation profiling, as had been planned in the protocol, was not feasible.

Assessed by laboratory measurements. Change from Baseline = Week 24 (24-hour) urinary Mo or Cu level - Baseline 24-hour urinary Mo or Cu level.

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 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.

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.

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.