A Clinical Study to Evaluate the Safety and Efficacy of LY-M003 Injection in Patients with Wilson Disease

Wilson's disease (WD), also known as Wilson's disease, is a rare autosomal recessive metabolic disorder caused by a mutation of the copper transport ATPase β (ATP7B) gene located on the long arm of chromosome 13 (13q14.3). This leads to accumulation of copper ions in multiple organs such as liver, brain and kidney, resulting in organ involvement. In this study, rAAV8 as the carrier of gene therapy products. After a single intravenous infusion, ATP7B protein can be specifically transduced to the target organ liver and expressed in hepatocytes for a long time.

This study adopted a prospective, single-center, open, single-arm, single-dose clinical design to evaluate the safety, tolerability, efficacy, immunogenicity, PD and PK characteristics of LY-M003 injection in WD patients, including the main study phase and the long-term follow-up study phase.

The main study phase consisted of a screening period (weeks -8 to days -2), a baseline period (days -1), a treatment and safety observation period (days 1-28), and a short-term follow-up period (weeks 5 \[starting from days 29\] to 52). Subjects eligible for the screening period will be admitted to the study Center for a single LY-M003 treatment, and will enter the short-term follow-up period after the end of the treatment and safety observation period and complete all follow-up during the main study phase. Subjects who withdraw early from the study will be required to complete all assessments required for the End of Study (EOS) visit.

Subjects who complete the main study phase or withdraw early from the study will enter the long-term follow-up study phase to obtain long-term evaluation data. After the completion of the 5-year long-term follow-up in this study, based on the obtained safety and efficacy data of this product, it will be discussed by the investigators and partners to determine whether further extension of follow-up time is necessary.

Eligibility Criteria:
Inclusion Criteria:

1. The subject must be able to fully understood the purpose, nature, method, and possible adverse effects of the study, must be able to voluntarily participate in the study and voluntarily able to provide the written informed consent form (ICF).
2. Subjects with confirmed Wilson Disease: Leipzig scoring system assessment ≥ 4 points.
3. Subjects with confirmed WD bichromosomal ATP7B gene mutation or missing by laboratory testing.
4. Subjects must be treatment-experienced to WD who have received standard treatment (eg, D-penicillamine or zinc acetate) for at least 6 months prior to the screening period.
5. Subjects must restrict food with high copper content for at least 6 months prior to screening and continue this restriction during the entire duration of study participation.
6. Subjects must be willing to refrain from donating blood, organs, tissues or cells during study participation.
7. Negative pregnancy test in women of childbearing potential (WOCBP).

Exclusion Criteria:

1. AAV8 neutralizing antibody (NAbs) titer positive .
2. Active gastrointestinal bleeding within the past 3 months.
3. Decompensated cirrhosis or advanced hepatic disease, manifested as portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, etc.
4. Subjects with other liver diseases as determined by the investigator, such as immune hepatitis, alcoholic liver disease, primary biliary cholangitis, primary sclerosing cholangitis, and/or drug or toxic liver disease
5. Subjects considered as complicated with severe hypersplenism and requiring splenectomy as judged 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. History of noncompliance with copper chelators or zinc agents within 6 months prior to screening, as determined by the investigator.
9. Subjects with treatment-experienced WD who have ALT and/or AST 5 times greater than the upper limit of normal (ULN).
10. Severe central nervous system symptoms urgent for intensive hospitalization judged by the investigator.
11. Hemoglobin \< 90 g/L.
12. Hepatitis B surface antigen (HBsAg) positive, hepatitis C virus (HCV) antibody positive, human immunodeficiency virus (HIV) antibody positive or Treponema pallidum antibody positive.
13. Subjects with end-stage renal disease receiving dialysis (chronic kidney disease stage 3 and above) or creatinine clearance \< 60 mL/min.
14. Severe hyperlipidemia (triglycerides \> 1000 mg/dL).
15. Subject received or plans to receive bone marrow transplantation, hematopoietic stem cell transplantation and/or major organ transplantation, including but not limited to liver transplantation, kidney transplantation, etc.
16. Clinically diagnosed or judged as serious cardiovascular disease by the investigator (eg, classification of heart failure ≥ 3 according to New York Heart Association \[NYHA\]).
17. Subjects who have hypersensitivity to any component of LY-M003 injection.
18. Subjects who have previously received gene therapy or cell therapy of any kind.
19. Subjects who use systemic immunosuppressive agents or receive steroid therapy within 3 months prior to dosing (except for prophylactic immunosuppressive therapy as specified in protocol).
20. Subjects with history of cancer within 5 years prior to screening, except for completely resected non-melanoma skin cancer, non-metastatic prostate cancer and completely cured ductal carcinoma in situ.
21. Subjects who have vaccinated with attenuated live vaccine within 4 months prior to screening or plan to receive a live attenuated vaccine during the clinical trial.
22. Subjects who have received treatment or disposition with another investigational drug or investigational device within 28 days or 5 half-lives (drug only), whichever is longer, prior to screening.
23. Pregnant women (or women planning to become pregnant) or lactating women.