Phase I/II Clinical Study to Evaluate the Safety, Tolerability and Efficacy of LY-M003 Injection in Adult Patients With Wilson's Disease

This is a multicenter, open-label, single-arm, single-dose Phase I/II clinical study. It aims to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of LY-M003 Injection in patients with Wilson's Disease (WD). The Phase I/II study consists of a main study phase and a long-term follow-up phase. The main study phase includes an 8-week screening period and a 52-week follow-up period after infusion. The long-term follow-up phase starts at Week 53 and lasts until 5 years post-infusion.

The study pre-specified two dose cohorts, consisting of one main dose cohort and one de-escalation dose cohort: Dose Cohort 1 (4.0 × 10¹³ vg/kg) and the de-escalation dose cohort (2.0 × 10¹³ vg/kg). Three subjects will be enrolled in each dose cohort.Dose Cohort 1 serves as the starting dose. After the first subject receives the study drug, a minimum 28-day DLT observation period must be completed to confirm safety before enrolling subsequent subjects.All three subjects in Dose Cohort 1 have completed the 28-day (Day 28) DLT observation period following LY-M003 infusion. The Safety Review Committee (SRC) will make a comprehensive assessment to determine whether to proceed to the dose expansion phase at the dose level of 4.0 × 10¹³ vg/kg.

Inclusion criteria

• The subject fully comprehends the purpose, design, methods and possible adverse events of the study, agrees to participate voluntarily and signs the informed consent form (ICF).
• Patients with confirmed diagnosis of Wilson's disease (WD).
• Subjects with Wilson's disease (WD) confirmed by laboratory testing to have biallelic ATP7B gene mutation or deletion.
• The subjects are treated patients with Wilson's disease (WD) who have received standard therapy (e.g., D-penicillamine or zinc acetate) continuously for at least 6 months prior to screening.
• Subjects have maintained a low-copper diet for at least 6 consecutive months prior to screening and will continue this dietary restriction throughout the study.
• Subjects must agree to refrain from donating blood, organs, tissues or cells at any time after treatment.
• Female subjects of childbearing potential (WOCBP) must have a negative pregnancy test.
• Subjects and their partners must have no plans for pregnancy from screening through 6 months after study completion, and will voluntarily use effective contraception (e.g., abstinence, condoms). Subjects shall not plan to donate sperm or ova.

Exclusion criteria

• AAV8 neutralizing antibody titer > 1:10 .
• History of active gastrointestinal bleeding within the past 3 months.
• Decompensated liver cirrhosis or advanced liver disease presenting with portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, etc.
• Subjects with other concomitant liver diseases as judged by the investigator, including autoimmune hepatitis, alcoholic liver disease, primary biliary cholangitis, primary sclerosing cholangitis, and/or drug- or toxin-induced liver disease.
• Subjects with severe hypersplenism complicated and requiring splenectomy as assessed by the investigator.
• Model for End-Stage Liver Disease (MELD) score > 13.
• Other disorders of copper metabolism, such as chronic cholestatic liver diseases, disorders of glycosylation, copper metabolism disorders, etc.
• A history of non-compliance with copper chelators or zinc agents as assessed by the investigator within 6 months prior to screening.
• Previously treated WD subjects with ALT and/or AST levels more than 5 times the upper limit of normal (ULN).
• Subjects with severe neurological deficits or impairments that, in the investigator's judgment, compromise their safety and/or ability to participate in the study.
• Hemoglobin < 90g/L.
• Subjects with positive hepatitis B surface antigen (HBsAg), positive hepatitis C virus (HCV) antibody, positive human immunodeficiency virus (HIV) antibody or positive treponema pallidum antibody.
• Subjects with end-stage renal disease on dialysis (Chronic Kidney Disease Stage 3 and above), or creatinine clearance < 60 mL/min.
• Severe hyperlipidemia (triglycerides >1000 mg/dL);
• Subjects who have received or plan to undergo bone marrow transplantation, hematopoietic stem cell transplantation and/or major organ transplantation, including but not limited to liver transplantation and renal transplantation.
• Subjects with clinically diagnosed severe cardiovascular diseases or those deemed by the investigator to have such conditions (e.g., New York Heart Association [NYHA] heart failure classification ≥ Class 3).
• Subjects with uncontrolled concomitant diseases or infectious diseases as assessed by the investigator.
• Subjects who are allergic to any ingredient of LY-M003 Injection.
• Prior receipt of any type of gene therapy or cell therapy.
• Use of systemic immunosuppressants or steroids within 3 months prior to administration (except for prophylactic immunosuppressive therapy specified in the protocol).
• History of cancer within 5 years prior to screening, excluding completely resected non-melanoma skin cancer, non-metastatic prostate cancer and fully cured ductal carcinoma in situ.
• Received live attenuated vaccines within 4 months prior to screening, or planned to receive such vaccines during the clinical trial.
• Received treatment or intervention with other investigational drugs or study devices within 28 days or 5 half-lives (for drugs only) prior to screening, whichever is longer.
• Pregnant women (or women planning pregnancy) or breastfeeding women.
• Other conditions that, in the investigator's opinion, render the subject ineligible for study participation.