A Study to Evaluate the Safety and Efficacy of VGB-R04 in Adult Hemophilia B Patients

Study Overview
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Brief Summary
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A multicenter, open, non-randomized, phase I/II, two-phase clinical study. The dose exploration phase was phase I, and the dose extension phase was phase II.

Detailed Description
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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 efficacy 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 weeks of safety observation and will be encouraged to enroll in an Long-term follow-up study to evaluate the long-term safety of VGB-R04 for a total of five years.

Official Title
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A Phase 1/2 Study to Evaluate the Safety and Efficacy of VGB-R04 in Adult Hemophilia B Patients

Conditions
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Hemophilia B

Intervention / Treatment
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* Genetic: VGB-R04


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male ≥18 years and ≤65years of age; Confirmed diagnosis of hemophilia B (baseline FIX activity ≤ 2% of normal); At least 100 days exposure history to FIX; Currently receiving FIX Prophylaxis therapy or on-demand treatment to prevent bleeding; Have acceptable laboratory values: Hemoglobin ≥110 g/L; Platelets ≥100×109 /L; AST, ALT, alkaline phosphatase ≤2×upper limit of normal (ULN) at the testing laboratory; Bilirubin ≤3× ULN ; Creatinine ≤1.5× ULN. No measurable factor IX inhibitor as assessed by the central laboratory and have no prior history of inhibitors to factor IX protein; Agree to use reliable contraception until 2 consecutive samples are negative for vector sequences; Exclusion Criteria: Have significant underlying liver disease within the past 6 months prior to or at Screening, including but not limited to: Preexisting diagnosis of portal hypertension; Splenomegaly; Encephalopathy; Reduction of serum albumin; Evidence of significant liver fibrosis; Have anti-VGB-R04 neutralizing antibody titers ≥1:5; Evidence of severe infection disease, i.e., human immunodeficiency virus (HIV) infection, syphilis, tuberculosis, etc.; Novel coronavirus infection occurred in the 6 weeks prior to entry into the group Evidence of active hepatitis B virus infection (HBsAg positive) or hepatitis C virus infection (HCV-RNA positive); Evidence of malignant tumours or those with a previous history of malignant tumours; Have a history of chronic infection or other chronic diseases that the Investigator considers to constitute an unacceptable risk; Any immunodeficiency; planned surgery may be required within one year; Past thromboembolic events (arterial or venous thromboembolic events); Hypertensive patients with poor blood pressure control (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90mmHg after antihypertensive drug treatment);

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VGB-R04<br>Single intravenous (i.v.) infusion of VGB-R04 Intervention: Gene Therapy / Gene Transfer | Genetic: VGB-R04<br>* A novel, bioengineered adeno-associated viral (AAV) vector carrying human factor IX variant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a product; the event will not need to have a causal relationship with the treatment. | Baseline up to Week 52 | 
| Incidence of serious adverse events | A serious adverse event (SAE) is any untoward medical occurrence at any dose that resulted in death; life threatening;require inpatient hospitalization or prolongation of existing hospitalization; result in persistent or significant disability/incapacity; result in congenital anomaly/birth defect | Baseline up to Week 52 | 
| FIX:C Antigen Level at Steady State | FIX:C activity antigen levels were characterized by post-treatment population mean. | Baseline up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FIX:C activity level | FIX:C activity change from baseline during each visit. | Baseline up to Week 52 | 
| Vector- derived FIX antigen levels | The vector-derived endogenous (not affected by intercurrent FIX product infusions) FIX:C activity antigen levels will be characterized by post-treatment population mean, and its change from baseline during each visit. | Baseline up to Week 52 | 
| Annualized bleeding rate changes from baseline | The annualized numberof bleeding episodes. | Baseline up to Week 52 | 
| Annualized FIX consumption changes from baseline | The annualized use of FIX replacement therapy will be calculated. | Baseline up to Week 52 |