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

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.

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).