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

A Multicenter, Open, Single-arm, Single-dose, Phase I/II Study Evaluating 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).

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:

1. 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).
2. Patients with confirmed diagnosis of Wilson's disease (WD).
3. Subjects with Wilson's disease (WD) confirmed by laboratory testing to have biallelic ATP7B gene mutation or deletion.
4. 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.
5. 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.
6. Subjects must agree to refrain from donating blood, organs, tissues or cells at any time after treatment.
7. Female subjects of childbearing potential (WOCBP) must have a negative pregnancy test.
8. 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:

1. AAV8 neutralizing antibody titer > 1:10 .
2. History of active gastrointestinal bleeding within the past 3 months.
3. Decompensated liver cirrhosis or advanced liver disease presenting with portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, etc.
4. 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.
5. Subjects with severe hypersplenism complicated and requiring splenectomy as assessed by the investigator.
6. Model for End-Stage Liver Disease (MELD) score > 13.
7. Other disorders of copper metabolism, such as chronic cholestatic liver diseases, disorders of glycosylation, copper metabolism disorders, etc.
8. A history of non-compliance with copper chelators or zinc agents as assessed by the investigator within 6 months prior to screening.
9. Previously treated WD subjects with ALT and/or AST levels more than 5 times the upper limit of normal (ULN).
10. Subjects with severe neurological deficits or impairments that, in the investigator's judgment, compromise their safety and/or ability to participate in the study.
11. Hemoglobin < 90g/L.
12. 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.
13. Subjects with end-stage renal disease on dialysis (Chronic Kidney Disease Stage 3 and above), or creatinine clearance < 60 mL/min.
14. Severe hyperlipidemia (triglycerides >1000 mg/dL);
15. 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.
16. 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).
17. Subjects with uncontrolled concomitant diseases or infectious diseases as assessed by the investigator.
18. Subjects who are allergic to any ingredient of LY-M003 Injection.
19. Prior receipt of any type of gene therapy or cell therapy.
20. Use of systemic immunosuppressants or steroids within 3 months prior to administration (except for prophylactic immunosuppressive therapy specified in the protocol).
21. 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.
22. Received live attenuated vaccines within 4 months prior to screening, or planned to receive such vaccines during the clinical trial.
23. 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.
24. Pregnant women (or women planning pregnancy) or breastfeeding women.
25. Other conditions that, in the investigator's opinion, render the subject ineligible for study participation.