Evaluation of the Safety and Efficacy of Hemophilia B Gene Therapy Drug

Study Overview
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Brief Summary
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This is a multi-center, single-arm, open-label, single-dose treatment clinical study to evaluate the safety, tolerability and efficacy of BBM-H901 injection in Hemophilia B subjects with ≤2 International unit per deciliter (IU/dl) residual factor IX (FIX) levels. BBM-H901 is an adeno-associated virus (AAV) vector derived from recombinant DNA techniques to contain an expression cassette of the human factor IX (hFIX) transgene and raises circulating levels of endogenous FIX.

Official Title
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A Study to Evaluate the Safety, Tolerability and Efficacy of an Adeno-associated Virus Vector Containing an Expression Cassette of the Human Factor IX Transgene (BBM-H901) Injection in Patients With Hemophilia B

Conditions
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Hemophilia B

Intervention / Treatment
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* Genetic: Single dose intravenous injection of BBM-H901


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males ≥ 18 years of age; Have hemophilia B with ≤2 IU/dL (≤2 %) endogenous FIX activity levels; Have had ≥100 prior exposure days (EDs) to any recombinant and/or plasma-derived FIX protein products based on historical data from the subjects' records/histories; Have had bleeding events and/or injected with FIX protein products (including recombination and plasma source) during the last 12 weeks documented in the subjects' medical records; Have no prior history of hypersensitivity or anaphylaxis associated with any FIX or IV immunoglobulin administration; Agree to use a reliable barrier contraception method from the beginning of signing the informed consent to 52 weeks after administration. Exclusion Criteria: Being positive for hepatitis B surface antigen (HBsAg) or hepatitis B virus-DNA (HBV-DNA). Being positive for hepatitis C virus antibody (HCV-Ab) or hepatitis C virus RNA (HCV-RNA). Subjects with medical history of hepatitis B or C can be regarded as negative only when 2 required samplings are conducted at least 3 months apart and both test results of indicators aforementioned are negative, i.e. subjects with natural clearance and anti-viral therapy clearance for hepatitis B or C are eligible; Have potential liver diseases, such as previous diagnosis of portal hypertension, splenomegaly, hepatic encephalopathy or liver fibrosis (fibrosis stage ≥ 3); nodules or cysts were found by B ultrasound, or elevated alpha-fetoprotein was detected by laboratory tests. Subjects who are not eligible for the study if the abnormalities are clinically significant regarding to the medical judgement of the investigator; HIV positive patients; Have participated in a previous gene therapy research trial before screening, or in a clinical study with an investigational drug within 5 half-life of the investigational product, whichever is longer; Have alcohol or drug dependence, or cannot stop drinking throughout the study; Any concurrent clinically significant major disease or condition that the investigator deems unsuitable for participation in the study.

Ages Eligible for Study
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Minimum Age: 18 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: Arm of BBM-H901<br>1×10^13 vg/kg, Single-dose treatment | Genetic: Single dose intravenous injection of BBM-H901<br>* Single dose intravenous infusion of BBM-H901, an adeno-associated virus (AAV) vector derived from recombinant DNA techniques to contain an expression cassette of the human factor IX (hFIX) transgene in liver. The dose of BBM-H901 will be 1×10^13 vg/ kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicity (DLT) events. | To access the numbers of DLT events determined by the Safety Data Review Committee (SRC) within 6 or 10 weeks after administration. | 6 or 10 weeks | 
| The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) | To assess the safety of BBM-H901 Injection by TEAEs and SAEs. | 52 weeks | 
| Changes in liver function | To assess changes in liver function before and after treatment, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT). | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FIX activity | All samples collected from participants for plasma FIX activity levels were analyzed and used to determine peak and steady-state vector-derived circulating FIX activity levels. | 52 weeks | 
| FIX antigen level | To assess FIX antigen level within 52 weeks after administration. | 52 weeks | 
| The viral load of AAV vector | To assess the viral load of AAV vector within 52 weeks after administration. | 52 weeks | 
| Annualized bleeding rate (ABR) | To assess ABR, including spontaneous bleeding and traumatic bleeding after administration. | 52 weeks | 
| Improvement in patient's quality of life | To assess the proportion of subjects with life improvement from baseline through Hemophilia Joint Health Score (HJHS), Hemophilic Early Arthropathy Detection with UltraSound in China (HEAD-US-C) and the Medical Outcomes Study (MOS) item short from health survey (SF-36) at 4, 12, 26 and 52 weeks. | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophilia B;gene therapy;Adeno-Associated Virus