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
试验速览
- 阶段
- 早期 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Incidence of adverse events (AEs) and serious adverse events (SAEs) within 52 weeks after the injection of LY-M003
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 10 Years 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
- •Patients diagnosed with Wilson Disease .
- •Wilson Disease (WD) patients confirmed by laboratory tests to have biallelic mutations in the ATP7B gene.
- •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.
- •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.
- •Subjects must be willing to refrain from donating blood, organs, tissues or cells during study participation.
- •Negative pregnancy test in women of childbearing potential (WOCBP).
- •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.
排除标准
- •AAV8 neutralizing antibody titer > 1:10 .
- •Active gastrointestinal bleeding within the past 3 months.
- •Decompensated cirrhosis or advanced hepatic disease, manifested as portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, etc.
- •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
- •Subjects considered as complicated with severe hypersplenism and requiring splenectomy as judged by the investigator.
- •Model for End-Stage Liver Disease (MELD) Score >
- •Other disorders of copper metabolism, such as chronic cholestatic liver diseases, disorders of glycosylation, copper metabolism disorders, etc.
- •History of noncompliance with copper chelators or zinc agents within 6 months prior to screening, as determined by the investigator.
- •Subjects with treatment-experienced WD who have ALT and/or AST 5 times greater than the upper limit of normal (ULN).
- •Severe central nervous system symptoms urgent for intensive hospitalization judged by the investigator.
- •Hemoglobin < 90 g/L.
- •A history of epileptic seizures or other diseases that may potentially affect compliance with study procedures within 6 months prior to the screening period.
- •Hepatitis B surface antigen (HBsAg) positive, hepatitis C virus (HCV) antibody positive, human immunodeficiency virus (HIV) antibody positive or Treponema pallidum antibody positive.
- •Subjects with end-stage renal disease receiving dialysis (chronic kidney disease stage 3 and above) or creatinine clearance < 60 mL/min.
- •Severe hyperlipidemia (triglycerides > 1000 mg/dL).
- •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.
- •Clinically diagnosed or judged as serious cardiovascular disease by the investigator (eg, classification of heart failure ≥ 3 according to New York Heart Association [NYHA]).
- •Patients with uncontrolled concomitant diseases or infectious diseases as judged by the investigator.
- •Subjects who have hypersensitivity to any component of LY-M003 injection.
- •Subjects who have previously received gene therapy or cell therapy of any kind.
- •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).
- •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.
- •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.
- •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.
- •Pregnant women (or women planning to become pregnant) or lactating women.
- •Other circumstances in which the investigator deems the subject inappropriate for study participation.
研究组 & 干预措施
LY-M003 Dose group 1-Adult Cohort
Adult participants receive a single, peripheral intravenous (IV) infusion of LY-M003 at dose group 1.
干预措施: LY-M003 (Genetic)
LY-M003 Dose group 2-Adult Cohort
Adult participants receive a single, peripheral intravenous (IV) infusion of LY-M003 at dose group 2.
干预措施: LY-M003 (Genetic)
LY-M003 Dose group 3-Adult Cohort
Adult participants receive a single, peripheral intravenous (IV) infusion of LY-M003 at dose group 3.
干预措施: LY-M003 (Genetic)
LY-M003 Dose group 4-Adult Cohort
Adult participants receive a single, peripheral intravenous (IV) infusion of LY-M003 at dose group 4.
干预措施: LY-M003 (Genetic)
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.
干预措施: LY-M003 (Genetic)
结局指标
主要结局
Incidence of adverse events (AEs) and serious adverse events (SAEs) within 52 weeks after the injection of LY-M003
时间窗: From enrollment to 52 weeks after administration
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
Incidence of dose-limiting toxicity (DLT) events assessed within at least 28 days following LY-M003 infusion
时间窗: From enrollment to 52 weeks after administration
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.
次要结局
- Percentage decrease in standard of care (SoC) medication use within 52 weeks after administration(From enrollment to 52 weeks after administration)
- Number and proportion of subjects who discontinue standard of care medication within 52 weeks after administration(From enrollment to 52 weeks after administration)
- Change from baseline in serum ceruloplasmin content level through 52 weeks after administration(From enrollment to 52 weeks after administration)
- Change from baseline in total serum copper level through 52 weeks after administrationfrom(From enrollment to 52 weeks after administration)
- Change from baseline in serum non-ceruloplasmin-bound copper (NCC) through 52 weeks after administration(From enrollment to 52 weeks after administration)
- Change from baseline in 24-hour urinary copper Concentration through 52 weeks after administration(From enrollment to 52 weeks after administration)
- Change from baseline in serum ceruloplasmin activity level through 52 weeks after administration(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.(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(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(From enrollment to 52 weeks after administration)
- Change from baseline in liver elasticity through 52 weeks after administration(From enrollment to 52 weeks after administration)
- Change from baseline in Kayser-Fleischer (K-F) rings through 52 weeks after administration(From enrollment to 52 weeks after administration)
研究者
Chaohui Yu
Chief physician
First Affiliated Hospital of Zhejiang University