A Study of the Safety and Efficacy of Prime Editing (PM577) in Participants With Wilson Disease (WD)

Official title

A Phase 1/2 Clinical Study to Evaluate Safety, Tolerability, Biological Activity, and Initial Efficacy of Prime Editing (PM577a) for the Treatment of Wilson Disease (WD) in Adult and Adolescent Participants With at Least One Allele Harboring the p.H1069Q Mutation in ATP7B

Overview

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.

Detailed description

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.

Interventions

• Drug PM577a
  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.

Primary outcome measures

• Safety and tolerability of PM577a. Quantified by frequency and severity of treatment emergent adverse events (TEAEs). [Time frame: Post-infusion through Week 48]

Secondary outcome measures (12)

• 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 [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 [Time frame: Weeks 24 and 48 post-infusion]
• Percent change in Liver Copper Concentration [Time frame: From baseline to Week 24, and to Week 48 post PM577a infusion]
• Change in Liver Stiffness [Time frame: from baseline to Week 48 post PM577a infusion]

Eligibility criteria

Inclusion criteria

• Confirmed Wilson Disease (WD) diagnosis as determined by medical history consistent with WD
• Historical genetic analysis demonstrating biallelic pathogenic, likely pathogenic, or suspected pathogenic ATP7B variants, including at least one p.H1069Q allele.
• Treated and stable on standard of care therapy for WD for the past 6 months prior to signing ICF, as documented by a history of adherence to SOC medications (i.e., penicillamine, trientine, and/or zinc) without significant medication or dose/frequency changes, per Investigator judgement.
• Demonstrated Adequate Copper Control confirmed at screening
• Willingness to maintain a stable, copper-conscious diet and avoid copper-containing supplements, from signing of the ICF until the physician determines that it is no longer necessary post-infusion.
• Willingness to abstain from alcohol use from start of the screening period through 3 months after PM577a infusion and adhere to recommendations of moderate alcohol consumption (as defined in this protocol) through primary follow-up period.
• Participants are expected to enroll in a separate long-term follow-up study for a total of approximately 15 years of follow-up following PM577a administration.

Exclusion criteria

• Known prior medically significant reactions (e.g., severe hypersensitivity, myocarditis) to an LNP-based or PEG-containing product (e.g., mRNA-based COVID vaccinations, MiraLAX) or any medication required as part of the clinical study protocol
• Receipt of any prior gene therapy for WD, including AAV-based therapy
• Receipt of any liver-directed LNP gene therapy (including siRNA or ASO therapies) or gene editing treatment.
• Unstable neurological conditions within the prior 12 months which may impact participant safety or participation in the study, including ability to complete study requirements or procedures as outlined in the clinical study protocol in the opinion of the Investigator
• In individuals with psychiatric involvement, current or fluctuant clinical instability with new or changing diagnoses or substantial medication regimen changes in the past 12 months that could limit their participation, in the opinion of the Investigator.
• Receipt of prior liver transplantation or listed for transplantation
• Body Mass Index ≥ 35 kg/m2
• Evidence of Severe Hepatic Impairment or uncontrolled liver disease within 6 months before screening.
• Evidence of Moderate or Severe Renal Impairment in the last year
• History of significant liver disease other than WD
• Clinically significant coagulopathy or disorder of platelet function
• Active infectious disease including:

• Known or suspected active systemic infection
• Receipt of systemic antimicrobial therapy within 30 days of screening.
• Positive for presence of human immunodeficiency virus (HIV)-1 or HIV-2 (evidence of infection, regardless of viral load).
• History of known autoimmune or genetic causes of myopathy or myositis
• Prior or current malignancy or myeloproliferative disorder (excluding Stage 1 or lower, fully treated/excised malignant and pre-malignant disease of the skin, cervix or colon. Additionally, any other malignant and pre-malignant disease that the Investigator in consultation with the treating oncologist and study Medical Monitor deem has been fully treated/excised for > 5 years).
• Any condition, laboratory abnormality, or reason that could adversely affect participant safety or study results, as determined by the Investigator, including, but not limited to:

• Clinical evidence of unstable coronary disease as defined by history of myocardial infarction in the past 24 months, history of unstable angina
• Any severe clinical condition of limited life expectancy
• Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile participants. Females of childbearing potential and non-sterile male participants who are or may become sexually active with female partners of childbearing potential are required to use highly effective contraception from Screening through at least 84 days after drug product infusion.
• History of moderate or severe Alcohol Use Disorder (AUD) or Drug Use Disorder (DUD) with < 3 years of continuous abstinence preceding the date of screening
• Participation in another clinical study with an investigational drug within 30 days of Screening or at least 5 times the half-life of the investigational drug (whichever is longer).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

New Zealand · 1 center

• New Zealand Clinical Research (NZCR) — Grafton

Identifiers

NCT: NCT07748403 · Prime-0201 · 2025-525034-62

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗