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

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.

Study Overview

• Status: Recruiting
• Conditions: Wilson Disease
• Intervention / Treatment: Genetic: LY-M003

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Chaohui Yu, PhD; Phone Number: 86+13957161659; Email: ych623@sina.com
• Study Contact Backup: Name: Yi Chen, PhD; Phone Number: 86+13735536389; Email: yiiic@126.com

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 312000
      • Recruiting
      • First affiliated Hospital of Zhejiang University
      • Contact: Chaohui Yu, PhD; Phone Number: 86+13957161659; Email: ych623@sina.com
      • Contact: Yi Chen, PhD; Phone Number: 86+13735536389; Email: yiiic@126.com
      • Principal Investigator: Chaohui Yu, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LY-M003 Dose group 1-Adult Cohort; Adult participants receive a single, peripheral intravenous (IV) infusion of LY-M003 at dose group 1.	Genetic: LY-M003; A single peripheral intravenous (IV) infusion of LY-M003
Experimental: LY-M003 Dose group 2-Adult Cohort; Adult participants receive a single, peripheral intravenous (IV) infusion of LY-M003 at dose group 2.	Genetic: LY-M003; A single peripheral intravenous (IV) infusion of LY-M003
Experimental: LY-M003 Dose group 3-Adult Cohort; Adult participants receive a single, peripheral intravenous (IV) infusion of LY-M003 at dose group 3.	Genetic: LY-M003; A single peripheral intravenous (IV) infusion of LY-M003
Experimental: LY-M003 Dose group 4-Adult Cohort; Adult participants receive a single, peripheral intravenous (IV) infusion of LY-M003 at dose group 4.	Genetic: LY-M003; A single peripheral intravenous (IV) infusion of LY-M003
Experimental: LY-M003-Pediatric Cohort; Based on the accumulated efficacy and safety data of enrolled adult subjects, the investigator and collaborators will determine the starting dose, subsequent enrollment doses for pediatric participants.	Genetic: LY-M003; A single peripheral intravenous (IV) infusion of LY-M003

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events (AEs) and serious adverse events (SAEs) within 52 weeks after the injection of LY-M003	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.	From enrollment to 52 weeks after administration
Incidence of dose-limiting toxicity (DLT) events assessed within at least 28 days following LY-M003 infusion	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.The adverse events defined as dose-limiting toxicity (DLT) have been clearly specified in the protocol.	From enrollment to 52 weeks after administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage decrease in standard of care (SoC) medication use within 52 weeks after administration	To assess the reduction in standard of care (SoC) medication use in subjects who completed administration of LY-M003 injection.	From enrollment to 52 weeks after administration
Number and proportion of subjects who discontinue standard of care medication within 52 weeks after administration	To evaluate the number and proportion of subjects who complete the administration of LY-M003 injection and discontinued standard of care (SOC) drugs.	From enrollment to 52 weeks after administration
Change from baseline in serum ceruloplasmin content level through 52 weeks after administration	To assess from baseline in serum ceruloplasmin content level through 52 weeks afterinjection of LY-M003.	From enrollment to 52 weeks after administration
Change from baseline in total serum copper level through 52 weeks after administrationfrom	To assess change from baseline in total serum copper level through 52 weeks after injection of LY-M003.	From enrollment to 52 weeks after administration
Change from baseline in serum non-ceruloplasmin-bound copper (NCC) through 52 weeks after administration	To assess change from baseline in serum non-ceruloplasmin-bound copper (NCC) through 52 weeks after injection of LY-M003.	From enrollment to 52 weeks after administration
Change from baseline in 24-hour urinary copper Concentration through 52 weeks after administration	To assess change from baseline in 24-hour urinary copper Concentration through 52 weeks after injection of LY-M003.	From enrollment to 52 weeks after administration
Change from baseline in serum ceruloplasmin activity level through 52 weeks after administration	To assess change from baseline in serum ceruloplasmin activity level through 52 weeks after injection of LY-M003.	From enrollment to 52 weeks after administration
Assessment of the change from baseline in neurological subscale of the Unified Wilson Disease Rating Scale (UWDRS) through 52 weeks after administration.	Assessment of the score change from baseline via the evaluation of neurological subscale of the Unified Wilson Disease Rating Scale (UWDRS).	From enrollment to 52 weeks after administration
Assessment of the change from baseline in hepatic subscale of the Unified Wilson Disease Rating Scale (UWDRS) through 52 weeks after administration	Assessment of the score change from baseline via the evaluation of hepatic subscale of the Unified Wilson Disease Rating Scale (UWDRS).	From enrollment to 52 weeks after administration
Assessment of the change from baseline in psychiatric subscale of the Unified Wilson Disease Rating Scale (UWDRS) through 52 weeks after administration	Assessment of the score change from baseline via the evaluation of psychiatric subscale of the Unified Wilson Disease Rating Scale (UWDRS).	From enrollment to 52 weeks after administration
Change from baseline in liver elasticity through 52 weeks after administration	Assessment of the change in liver elasticity from baseline in subjects via detection with hepatobiliary color Doppler ultrasound combined with ultrasound elastography.	From enrollment to 52 weeks after administration
Change from baseline in Kayser-Fleischer (K-F) rings through 52 weeks after administration	Evaluation of the change in Kayser-Fleischer (K-F) ring grade from baseline via slit-lamp examination of the eye.	From enrollment to 52 weeks after administration

Collaborators and Investigators

• Sponsor: Chaohui Yu
• Investigators: Principal Investigator: Chaohui Yu, PhD, First affiliated Hospital of Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2024
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): March 30, 2030

Study Registration Dates

• First Submitted: October 15, 2024
• First Submitted That Met QC Criteria: October 18, 2024
• First Posted (Actual): October 21, 2024

Study Record Updates

• Last Update Posted (Actual): January 23, 2026
• Last Update Submitted That Met QC Criteria: January 21, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Gene therapy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Digestive System Diseases; Neurodegenerative Diseases; Liver Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Metal Metabolism, Inborn Errors; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hepatolenticular Degeneration
• Other Study ID Numbers: LY-M003-WD-IIT-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The study is in its early stages and will consider releasing data and related information when detailed and sufficient safety and efficacy data are available in subjects.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No