Safety and Tolerability of VGB-R04 in Patients With Haemophilia B

Safety and Tolerability of VGB-R04 in Patients With Haemophilia B

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.