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

Prospective, Single-center, Open-label, Single-arm, Single-dose Clinical Study to Evaluate the Safety, Tolerability and Efficacy of LY-M003 Injection in Adult and Pediatric 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, LY-M003 Injection is a gene therapy products with rAAV8 vector. After a single intravenous infusion, LY-M003 can be transduced to the target organ of liver and express the ATP7B in hepatocytese.

This study adopts 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.

This study is designed with 4 dose groups and 2 cohorts (adult cohort and pediatric cohort), namely: Dose Group 1 (1.0 × 10¹³ vg/kg), Dose Group 2 (2.0 × 10¹³ vg/kg), Dose Group 3 (4.0 × 10¹³ vg/kg) and Dose Group 4 (6.0 × 10¹³ vg/kg). Among them, Dose Group 1 serves as the starting dose of this study. The decision to escalate to the 4th dose group shall be made by the investigators and collaborators based on the accumulated safety, efficacy and other relevant data. Based on the accumulated efficacy and safety data of enrolled adult subjects, the investigator and collaborators will determine the starting dose, subsequent enrollment doses, and the number of enrolled cases for pediatric subjects.

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. Patients diagnosed with Wilson Disease .
3. Wilson Disease (WD) patients confirmed by laboratory tests to have biallelic mutations in the ATP7B gene.
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).
8. Subjects and their partners who have no childbearing plans from the screening period to 6 months after the end of the study and are willing to adopt effective contraceptive measures (e.g., abstinence, condoms, etc.); subjects have no plans to donate sperm or ova.

Exclusion Criteria:

1. AAV8 neutralizing antibody titer > 1:10 .
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. A history of epileptic seizures or other diseases that may potentially affect compliance with study procedures within 6 months prior to the screening period.
13. Hepatitis B surface antigen (HBsAg) positive, hepatitis C virus (HCV) antibody positive, human immunodeficiency virus (HIV) antibody positive or Treponema pallidum antibody positive.
14. Subjects with end-stage renal disease receiving dialysis (chronic kidney disease stage 3 and above) or creatinine clearance < 60 mL/min.
15. Severe hyperlipidemia (triglycerides > 1000 mg/dL).
16. 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.
17. Clinically diagnosed or judged as serious cardiovascular disease by the investigator (eg, classification of heart failure ≥ 3 according to New York Heart Association [NYHA]).
18. Patients with uncontrolled concomitant diseases or infectious diseases as judged by the investigator.
19. Subjects who have hypersensitivity to any component of LY-M003 injection.
20. Subjects who have previously received gene therapy or cell therapy of any kind.
21. 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).
22. 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.
23. 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.
24. 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.
25. Pregnant women (or women planning to become pregnant) or lactating women.
26. Other circumstances in which the investigator deems the subject inappropriate for study participation.