safety and tolerability of vgb-r04 in patients with haemophilia b

Conditions: Hemophilia B

Summary: 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.

Eligibility criteria:
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.

Keywords: hemophilia aav safety gene therapy