Gene Therapy for Chinese Hemophilia B

Gene Therapy for Chinese Hemophilia B With Adeno-associated Virus (AAV) Vector

GT2019001 is a Phase 1, open- label, non- randomized, uncontrolled, single dose pilot study to evaluate the safety, tolerability and kinetics of a single intravenous infusion of BBM-H901 in hemophilia B subjects with ≤2IU/dl residual FIX levels. BBM-H901 is an adeno-associated viral (AAV) vector designed to drive expression of the human factor IX (hFIX) transgene and raise circulating levels of endogenous FIX.

Study Overview

• Status: Completed
• Conditions: Hemophilia B
• Intervention / Treatment: Genetic: Single dose intravenous injection of BBM-H901

Detailed Description

GT2019001 is a Phase 1, open- label, non- randomized, uncontrolled, single dose pilot study to evaluate the safety, tolerability and kinetics of a single intravenous infusion of BBM-H901 in hemophilia B subjects with ≤2IU/dl residual FIX levels. Three subjects will be enrolled and administered with single infusion of BBM-H901, an AAV at one dose level of 5x1012 vg/Kg.Subjects will provide informed consent and then undergo screening assessments up to 4-8weeks prior administration of BBM-H901. All subjects will undergo 52(+- 2) weeks safety observation and will be encouraged to enroll in an extension study to evaluate long- term safety of BBM-H901 for a total 5 years.The first subject will be dosed at 5x1012 vg/Kg and undergo 2 months safety observation of which the data will undergo review by an independent safety committee. The dosing to the second subject will not be performed until acquiring the approve from independent safety committee.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Institute of Hematology & Blood Diseases Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Be able to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local privacy regulations;
2. Be male and ≥18 years of age;
3. Have hemophilia B with ≤2 IU/dL (≤2 %) endogenous FIX activity levels as documented by a certified clinical laboratory at the time of screening. If the screening result is >2% due to insufficient washout from FIX protein product, then the severity of hemophilia B may be confirmed by documented historical evidence from a certified clinical laboratory demonstrating ≤2% FIX coagulant activity (FIX:C) ;
4. Have had ≥100 prior exposure days (EDs) to any recombinant and/or plasma-derived FIX protein products based on historical data from the subject's record/history;
5. a. Prophylaxis subjects: have had bleeding events and/or infusions with FIX protein products during the last 12 weeks documented in the subjects' medical records; OR b. On-demand subjects: have had ≥4 bleeding events in the last 52 weeks and/or chronic hemophilic arthropathy (pain, joint destruction, and loss of range of motion) in one or more joints;
6. Have no prior history of hypersensitivity or anaphylaxis associated with any FIX or IV immunoglobulin administration;
7. Have no measurable FIX inhibitor as assessed by laboratory; or documented no prior history of FIX inhibitor after 50 EDs (family history of inhibitors will not exclude the subject) and no clinical signs or symptoms of decreased response to FIX administration;

8. Have acceptable laboratory values:

   1. Hemoglobin ≥11 g/dL;
   2. Platelets ≥100,000 cells/μL;
   3. AST, ALT, alkaline phosphatase ≤2x upper limit of normal at the testing laboratory;
   4. Bilirubin ≤3x ULN ;
   5. Creatinine ≤2.0 mg/dL.
9. Agree to use reliable barrier contraception until 52 weeks and semen samples after the administration of BBM- H901 are negative for vector sequences.

Exclusion Criteria:

1. Have active hepatitis B or C, and HBsAg, hepatitis B core antibody, hepatitis B virus-DNA positivity or hepatitis C virus-RNA viral load positivity, respectively. Negative viral assays in two samples, collected at least six months apart, will be required to be considered negative. Both natural clearers and those who have cleared hepatitis C virus on antiviral therapy are eligible;
2. Currently on antiviral therapy for hepatitis B or C;
3. Have significant underlying liver disease, as defined by a preexisting diagnosis of portal hypertension, splenomegaly, encephalopathy, reduction below normal limits of serum albumin or evidence of significant liver fibrosis (fibrosis stage ≥ 3) within the past 6 months prior to or at Screening as determined by any of the following diagnostic modalities: AST-to-Platelet Ratio Index (APRI) >1;
4. Have serological evidence of HIV-1 or HIV-2 with CD4 counts ≤200/mm3. Subjects who are HIV-positive and stable, with an adequate CD4 count (>200/mm3) and undetectable viral load (<50 gc/mL) measured twice in the six months prior to enrollment, on an antiretroviral drug regimen are eligible to enroll;
5. Have anti-BBM-H901 neutralizing antibody titers ≥1:5;
6. Have history of chronic infection or other chronic disease that the Investigator considers to constitute an unacceptable risk;
7. Have participated in a previous gene therapy research trial within the last 52 weeks or in a clinical study with an investigational drug within the last 12 weeks;
8. 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;
9. Unable or unwilling to comply with the schedule of visits and study assessments described in the clinical protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm of BBM-H901; Subjects will be dosed with single dose of BBM-H901 at 5x10·12 vg/kg via intravenous infusion.	Genetic: Single dose intravenous injection of BBM-H901; Single dose intravenous infusion of BBM-H901, an adeno-associated viral (AAV) vector designed to drive expression of the human factor IX (hFIX) transgene in liver. The dose of BBM-H901 will be 5x10'12 vg/Kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment- related adverse events	Number of patients experiencing treatment-related adverse events. Including inhibitor development.	Infusion to the end of study, average 1 year.
Change from baseline alanine aminotransferase ans aspartate amino transferase	liver function tests include ALT, AST.	At multiple timepoints from pre-dose through up to 1 years post-dose
Antibody against AAV capsid protein	Immune response against AAV capsid will be evaluated by measurement of the total antibody and neutralizing antibody against AAV capsid protein in plasma samples collected at multiple timepoints after dosing up to 1 year.	from screening through up to 1 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vector- derived FIX:C and FIX antigen levels.	Vector- derived FIX:C and FIX antigen levels will be measured after dosing.	At multiple timepoints from pre-dose through up to 1 years post-dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vector shedding of BBM-H901	Serum and semen will be collected to assess clearance of vector genomes	From date of infusion until the date of 3 consecutive documented negative results, assessed up to 1 year
annualized bleeding rate changes from baseline	annualized bleeding rate changes from baseline	through study completion, an average of 1 year
Long- term vector derived factor IX activity level	mesure factor IX activity using on- stage method at least annually to explore the long- term efficacy of gene therapy	Up to twenty years after gene transfer
Long- term annualized bleeding rate	assess annualized bleeding rate annually by collecting bleeding number of subjects	Up to twenty years after gene transfer

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Collaborators: East China University of Science and Technology
• Investigators: Principal Investigator: Lei Zhang, MD, Institute of Hematology & Blood Diseases Hospital, China

Publications and helpful links

General Publications

• Xue F, Li H, Wu X, Liu W, Zhang F, Tang D, Chen Y, Wang W, Chi Y, Zheng J, Du Z, Jiang W, Zhong C, Wei J, Zhu P, Fu R, Liu X, Chen L, Pei X, Sun J, Cheng T, Yang R, Xiao X, Zhang L. Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial. Lancet Haematol. 2022 Jul;9(7):e504-e513. doi: 10.1016/S2352-3026(22)00113-2. Epub 2022 May 19.

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2019
• Primary Completion (Actual): January 7, 2022
• Study Completion (Actual): January 7, 2022

Study Registration Dates

• First Submitted: October 8, 2019
• First Submitted That Met QC Criteria: October 20, 2019
• First Posted (Actual): October 22, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 20, 2025
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Hemophilia B; gene therapy; ADENO-ASSOCIATED VIRUSES
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Genetic Diseases, X-Linked; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: GT2019001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Researchers qualified can request the dataset, including de-identified individual subject data. Data may be requested from PI from 12 months 36 months after study completion.
• IPD Sharing Time Frame: From 12 months 36 months after study completion.
• IPD Sharing Access Criteria: Upon request to PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No