An Open-Label, Non-Randomized, uncontrolled, single-dose pilot study of VGB-R04 in subjects with Hemophilia B.

Hemophilia B is a genetic bleeding disorder caused by pathogenic variants (eg, mutations, deletion) in the FIX gene. HB patients have frequent and potentially life-threatening bleeding and often develop progressive physical disability and pain from chronic haemarthropathy. Current replacement therapy needs regular treatment in the life-long time, bringing heavy economic and social burdens.

VGB-R04 is a novel AAV vector carrying a high specific activity factor IX variant. This study is intended to evaluate the safety, tolerability and kinetics of a single IV infusion of VGB-R04. All subjects in this study will provide informed consent and then undergo screening assessments up to 6 weeks before administration of VGB-R04. All subjects will undergo 52(±2) weeks of safety observation and will be encouraged to enroll in an extension study to evaluate the long-term safety of VGB-R04 for a total of five years.

Inclusion Criteria:

1. Male ≥18 years and ≤75years of age;

2. Confirmed diagnosis of hemophilia B (baseline FIX activity ≤ 2% of normal or documented history of FIX activity ≤2%);

3. At least 100 days exposure history to FIX;

4. Currently receiving FIX Prophylaxis therapy or on-demand treatment to prevent bleeding;

5. Have acceptable laboratory values:

   1. Hemoglobin ≥110 g/L;
   2. Platelets ≥100×10'9 cells/L;
   3. AST, ALT, alkaline phosphatase ≤2×upper limit of normal (ULN) at the testing laboratory;
   4. Bilirubin ≤3× ULN ;
   5. Creatinine ≤1.5× ULN.

6. No measurable factor IX inhibitor as assessed by the central laboratory and have no prior history of inhibitors to factor IX protein;

7. Agree to use reliable barrier contraception until 3 consecutive samples are negative for vector sequences;

8. Able to provide informed consent and comply with the requirements of the study.

Exclusion Criteria:

1. Have significant underlying liver disease within the past 6 months prior to or at Screening, including but not limited to:

   1. Preexisting diagnosis of portal hypertension;
   2. Splenomegaly;
   3. Encephalopathy;
   4. Reduction of serum albumin;
   5. Evidence of significant liver fibrosis;

2. Have anti-VGB-R04 neutralizing antibody titers ≥1:5;

3. Evidence of severe infection disease, i.e., human immunodeficiency virus (HIV) infection, syphilis, tuberculosis, etc.;

4. Evidence of active hepatitis B virus infection (HBV-DNA >103 IU/ml) or hepatitis C virus infection (HCV antigen and HCV-RNA positive);

5. Evidence of malignant tumours or those with a previous history of malignant tumours;

6. Have a history of chronic infection or other chronic diseases that the Investigator considers to constitute an unacceptable risk;

7. Any immunodeficiency;

8. Participated in a gene transfer trial within the last 52 weeks or in a clinical trial with an investigational drug within the last 4 weeks;

9. Have used glucocorticoids, immunosuppressive drugs, or antipsychotics within the last 3 months;

10. Previous history of hypersensitivity or allergic reaction to any FIX products or any immunoglobulin;

11. Unable or unwilling to comply with the schedule of visits and study assessments described in the clinical protocol;

12. Any concurrent clinically significant major disease or any other condition that, in the opinion of the Investigator, makes the subject unsuitable for participation in the study.

IPD will be shared with other researchers when VGB-R04 is fully approved.

IPD will be shared with other researchers when VGB-R04 is fully approved.

IPD will be shared with other researchers when VGB-R04 is fully approved.