A non-randomized, open-label, dose-escalation, phase I/II study to evaluate the safety, tolerability, kinetics and efficacy of a single intravenous infusion of ZS801 in hemophilia B subjects with endogenous FIX ≤2%.

This study will seek to determine the safety, tolerability, kinetics and efficacy of a single IV infusion of ZS801.

Hemophilia B is a genetic bleeding disorder resulting in the lack of ability to produce blood-clotting factor IX (FIX). Individuals with hemophilia B suffer repeated bleeding events, which can cause chronic joint disease and sometimes leads to death due to the inability for blood to clot efficiently. The current treatment is intravenous infusion of FIX protein products, either prophylactically or in response to bleeding.

ZS801 is an adeno-associated viral (AAV) vector designed to drive expression of the human factor IX (hFIX) transgene and raise circulating levels of endogenous FIX.

Dose-escalation phase: 16 patients will be enrolled sequentially every 3 weeks or more between cohorts and administered with single infusion of ZS801. Dose escalation may occur based on the safety and FIX activity on steady state. The dose levels are as follows: 2.0×10^12vg/kg, 5.0×10^12vg/kg, 1.0×10^13vg/kg.

Dose-expansion phase: 5 patients will be enrolled and be administrated of ZS801.

Subjects will provide informed consent and then undergo screening assessments up to 6-8 weeks prior administration of ZS801. All subjects will undergo 52 weeks safety and efficacy observation.

Inclusion Criteria:

1. Male ≥18 years of age;
2. Confirmed diagnosis of hemophilia B, and endogenous FIX ≤2%;
3. Have had ≥100 prior exposure days (EDs) to any recombinant and/or plasma-derived FIX protein products;
4. The subject had at least 3 or more bleeding events and/or chronic hemophilia arthritis in one or more joints in the previous 1 year requiring treatment with FIX;
5. Agree to use reliable barrier contraception and prohibition of sperm donation until 52 weeks after the administration of ZS801.
6. Subjects voluntarily participate and are fully informed, fully understand the research and can comply with the requirements of the research protocol, are willing to complete the research as planned, and voluntarily cooperate with the provision of biological samples for testing.

Exclusion Criteria:

1. Hypersensitivity to any component of the study drug (including immunosuppressants) or a condition that can not use;

2. Inability to tolerate immunosuppressants or steroid drugs;

3. Have FIX inhibitor as assessed by laboratory, or documented history of FIX inhibitor;

4. Who have a history or are currently suffering from any of the following serious clinical diseases:

   1. History of malignancy or current presence of any malignancy;
   2. Have active autoimmune disease;
   3. Severe heart disease, including angina pectoris, myocardial infarction, heart failure, clinically significant congenital heart disease, heart valve disease, arrhythmia and atrioventricular block, etc.;
   4. Have underlying liver disease or history of liver disease (such as portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy or hepatic fibrosis);
   5. Have active hepatitis B infection (HBsAg positive) or active hepatitis C infection (HCVAb positive), or are currently receiving hepatitis B or hepatitis C antiviral therapy;
   6. Diabetes mellitus that is poorly controlled after drug treatment;
   7. Uncontrolled hypertension or hypotension;

5. laboratory values:

   1. Hemoglobin<110g/L;
   2. Platelets<100×10^9/L;
   3. AST, ALT, alkaline phosphatase>2×ULN;
   4. Total bilirubin>1.5×ULN;
   5. Creatinine>ULN;
   6. Albumin<LLN;
   7. HIV antibody positive or Treponema pallidum antibody positive.

6. Have AAV5 capsid neutralizing antibody titers >1:5;

7. Those who have received clinical trials of gene therapy before screening, or have used FIX clinical trial drugs within 1 month, or participated in other drug/device clinical trials within 3 months, or plan to participate in other clinical trials during this study;

8. Those who have planned surgery within 52 weeks after the infusion;

9. Those who lost more than 400 mL of blood within 3 months before screening;

10. Those with epilepsy, history of mental illness (such as schizophrenia, depression, mania or anxiety) or obvious mental disorder, incapacitated or incapacitated by other reasons;

11. Patients with a history of drug abuse or alcoholism;

12. Investigators believe that subjects have poor compliance or are expected to be less likely to complete follow-up;

13. There are clinically significant diseases or other reasons that the researcher and/or collaborators consider unsuitable to participate in this researcher.

IPD will be shared with other researchers when ZS801 is fully approved

IPD will be shared with other researchers when ZS801 is fully approved

IPD will be shared with other researchers when ZS801 is fully approved