The purpose of this study is to evaluate the safety, tolerability, biological activity, and initial efficacy of PM577a, an investigational Prime Editing therapy, in adults and adolescents with Wilson disease (WD). Wilson disease is caused by changes (mutations) in the ATP7B gene that prevent the body from removing excess copper normally. PM577a is designed to precisely correct one of the most common disease-causing ATP7B mutations (p.H1069Q) in liver cells with the goal of restoring normal copper metabolism. This is the first study of PM577a in people. Participants will receive a single intravenous (IV) infusion of PM577a and will be monitored closely to evaluate safety, how the body responds to treatment, whether copper metabolism improves, and whether treatment may improve signs and symptoms of Wilson disease.
This is a Phase 1/2, open-label study evaluating PM577a in adults and adolescents with Wilson disease who have specific disease-causing changes in the ATP7B gene, including at least one p.H1069Q mutation. The study will evaluate the safety of PM577a, determine an appropriate dose for future studies, and assess whether treatment restores copper metabolism and improves clinical measures of Wilson disease. Participants will receive a single IV infusion of PM577a and will undergo regular safety evaluations, laboratory testing, imaging, and clinical assessments for approximately 48 weeks after treatment. Participants will then be asked to enroll in a separate long-term follow-up study to continue monitoring safety and treatment effects.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
42
PM577a is being evaluated in participants with Wilson disease caused by biallelic pathogenic, likely pathogenic, or suspected pathogenic ATP7B variants, including at least one p.H1069Q allele.
Northwestern University Division of Gastroenterology and Hepatology
Chicago, Illinois, United States
NOT_YET_RECRUITINGARC Texas Liver Institute
San Antonio, Texas, United States
RECRUITINGNew Zealand Clinical Research (NZCR)
Grafton, Auckland, New Zealand
RECRUITINGSafety and tolerability of PM577a. Quantified by frequency and severity of treatment emergent adverse events (TEAEs).
Time frame: Post-infusion through Week 48
Frequency and severity of Dose Limiting Toxicities (DLTs)
Time frame: Infusion through the 14-day post infusion DLT observation period
Evidence of improved copper metabolism based on meeting the criteria to stop standard of care (SOC) therapy (chelation or zinc), including stable or improving non-ceruloplasmin bound copper levels and liver function tests.
Time frame: Infusion through Week 48
Percent of participants with non-ceruloplasmin bound copper (NCC)
Time frame: Weeks 12, 24, and 48 post-infusion
Percent change from baseline in ceruloplasmin levels
Time frame: From PM577a infusion to Weeks 4, 6, 9, 12, 24, and 48 post-infusion
Percent of participants with ceruloplasmin within the normal range
Time frame: Weeks 4, 6, 9, 12, 24, and 48 post-infusion
Percent of participants with improved non-ceruloplasmin bound copper measured by protein speciation (NCC-Sp)
Time frame: Weeks 12, 24, and 48 post-infusion of PM577a
Change in serum radiocopper ratio
Time frame: 24 hours/2 hours post-64Cu injection from baseline to Week 6 or later post-infusion of PM577a
Percent change in liver copper efflux
Measured by hepatic 64Cu PET standard uptake value (SUV)
Time frame: 1.5 hours and 20 hours post 64Cu injection from baseline to Week 6 or later post-infusion of PM577a
Percentage of participants off of standard of care
Time frame: Weeks 12 and 48 post-infusion of PM577a
On-target editing
Measured by liver biopsy specimen
Time frame: Weeks 24 and 48 post-infusion
Percent change in Liver Copper Concentration
Assessed by liver biopsy
Time frame: From baseline to Week 24, and to Week 48 post PM577a infusion
Change in Liver Stiffness
Measured using transient or shear wave elastography
Time frame: from baseline to Week 48 post PM577a infusion
Evaluation of health-related quality of life (HRQoL) as compared to baseline
Measured using the age-appropriate EuroQol 5 Dimension 5-Level instrument (EQ-5D-5L)
Time frame: From baseline through study completion (Week 48)
Percent of participants with stable or improved modified Unified Wilson's Disease Rating Scale (mUWDRS) score
Test is divided into 3 parts to assess for neurological and functional status in Wilson disease and divided into 3 parts. Part 1 (range 0-3), Part 2a (range 0-40), Part 2b (range 0-20) and Part 3 (range 0-147). Total cumulative range is 0-210. Higher scores indicate greater disease severity.
Time frame: Week 48 post PM577a infusion compared to baseline
Percent of participants with stable or improved score on the Clinical Global Impression Improvement Scale (CGI-I)
Scores range from 1-7. Lower scores indicate a better outcome.
Time frame: Measured over the course of the study (through Week 48) compared to baseline
Percent of participants with stable or improved score on the Clinical Global Impression Severity Scale (CGI-S)
Scores range from 1-7. Lower scores indicate a better outcome.
Time frame: Measured over the course of the study (through Week 48) compared to baseline
Percent of participants with stable or improved Model for End-Stage Liver Disease (MELD) score
Scores range from 6 and upward, with higher scores indicating a more severe liver disease and a worse prognosis.
Time frame: Measured at Week 48 post PM577a infusion compared to baseline
Percent of participants with stable or improved modified Nazer score
This score assesses prognosis in Wilson disease using total bilirubin, international normalized ratio (INR), aspartate aminotransferase (AST), white blood cell count (WBC), and serum albumin. Each component is scored from 0 to 4, producing a total score ranging from 0 to 20. Higher scores indicate a worse prognosis.
Time frame: Measured at Week 48 post PM577a infusion compared to baseline
Percent change in 24-hour urinary copper excretion (UCE)
For participants who are not on standard of care at the specified timepoint
Time frame: From baseline to Weeks 12, 24, and 48 post PM577a infusion
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