Clinical trial NCT05709288: Gene Therapy for Hemophilia B Patients Aged 12-18 Years Old
Official title: A Pilot Study Evaluating the Safety, Tolerability and Efficacy of Gene Therapy With BBM-H901 in Hemophilia B Patients Aged 12-18 Years Old
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Hemophilia B
Keywords: gene therapy
AAV
Lead sponsor: Institute of Hematology & Blood Diseases Hospital, China
Sponsor class: OTHER
First posted: 2023-02-02
Enrollment: 9
Sex: MALE
Minimum age (years): 12
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Hemophilia B patients
Primary purpose: TREATMENT

Brief summary: This is a Phase 1, open- label, non- randomized, uncontrolled, single dose pilot study to evaluate the safety, tolerability and efficacy of a single intravenous infusion of BBM-H901 in hemophilia B subjects with ≤2IU/dl residual FIX levels and aged 12-18 years old. 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.

Detailed description: This is a Phase 1, open- label, non- randomized, uncontrolled, single dose pilot study to evaluate the safety, tolerability and efficacy of a single intravenous infusion of BBM-H901 in hemophilia B subjects with ≤2IU/dl residual FIX levels and aged 12-18 years old. 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. Nine subjects will be enrolled and administered with single infusion of BBM-H901, an AAV at one dose level of 5x10'12 vg/Kg. Subjects and statutory guardian must 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 continuously followed up to evaluate long- term safety and efficacy of BBM-H901 up to ten years. The first subject will be dosed at 5x10'12 vg/Kg and undergo 8 weeks safety observation of which the data will undergo review by an independent safety committee.

Eligibility criteria: Inclusion Criteria:

1. Subjects and statutory guardian must be able to understand the purpose and risks of the study and provide signed and dated informed consent;
2. Be male and 12≤ age \<18 years of age, body wight ≥ 50kg;
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. Had had ≥75 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. With ≤ 1:4 neutralizing antibodies and ≤1:200 binding antibodies against BBM-H901 capsid;
6. Subjects with bleeding episode and/ or FIX agents infusion events within 12 weeks prior to screening;
7. Have no prior history of hypersensitivity or anaphylaxis associated with any FIX or IV immunoglobulin administration;
8. Have no measurable FIX inhibitor as assessed by laboratory; or documented no prior history of FIX inhibitor (family history of inhibitors will not exclude the subject) and no clinical signs or symptoms of decreased response to FIX administration;
9. Have acceptable laboratory values:

   1. Hemoglobin ≥11 g/dL ;
   2. Platelets ≥100,000 cells/μL;
   3. AST, ALT ≤1.5x upper limit of normal at the testing laboratory;
   4. Bilirubin ≤1.5x ULN ;
   5. glomerular filtration rate eGFR ≥ 60ml/min.
10. For those subjects with sexual maturity, subject and statutory guardian must know that subjects must agree to use reliable barrier contraception until 52 weeks;
11. with good compliance to the schedule of visit and fill in the subject diary.

Exclusion Criteria:

1. Hepatitis B surface antigen antibody (HBSAg-Ab) or HBV-DNA positive; hepatitis C antibody or HCV-RNA positive;
2. Currently on antiviral therapy for hepatitis B or C;
3. With coagulation disorders other than hemophilia B;
4. Had immunosuppressive therapy other than steroid and other suggested IST agents within 30 days prior to screening;
5. Had vaccine 30 days prior to screening or have scheduled vaccination plan during the study (up to 52 weeks);
6. Have significant underlying liver disease, as defined by a preexisting diagnosis of portal hypertension, splenomegaly, encephalopathy, etc; other liver conditions unsuitable to gene therapy judged by investigator;
7. Have surgery plan within 52 weeks after gene therapy;
8. Have history of chronic infection or high rish of infection that the Investigator considers to constitute an unacceptable risk;
9. Had 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;
10. Had any herb that may affect the liver function within 4 weeks prior to screening;
11. Have history of fatal bleeding episode, eg intracranial hemorrhage, etc;
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;

Primary outcomes:
measure: The incidence of treatment related adverse events deemed related to BBM-H901 within 10 weeks after vector administration
timeFrame: infusion to 10 weeks after vector infusion.
measure: The incidence of adverse events and serious adverse events within 52 weeks after BBM-H901 administration
timeFrame: Vector infusion to 52 weeks after gene therapy.
measure: Change from baseline aspartate amino transferase
timeFrame: At multiple timepoints from pre-dose through up to 1 years post-dose
measure: Change from baseline alanine aminotransferase
timeFrame: At multiple timepoints from pre-dose through up to 1 years post-dose
Secondary outcomes:
measure: Vector shedding after BBM-H901 infusion
timeFrame: multiple timepoints until 2 consecutive negative results achieved usually within 52 weeks
measure: Vector derived Factor IX(FIX) activity
timeFrame: infusion to 52 weeks after gene therapy
measure: Annualized bleeding rate(ABR) after gene therapy
timeFrame: vector infusion to 52 weeks after gene therapy
measure: Times of infusion of factor IX agents
timeFrame: vector infusion to 52 weeks after gene therapy
measure: number of target joint
timeFrame: vector infusion to 52 weeks after gene therapy
measure: factor IX inhibitor
timeFrame: vector infusion to 52 weeks after gene therapy
Other outcomes:
measure: Long term factor IX activity
timeFrame: 52 weeks after gene therapy to up to 10 years
measure: Long term Annualized bleeding rate
timeFrame: 52 weeks after gene therapy to up to 10 years
Locations:
city: Tianjin
country: China
facility: Institute of haematology and Blood diseases hospital
state: Tianjin
Study officials:
affiliation: Insitute of haematology and blood diseases hospital, chinese academy of medical sciences
name: Lei Zhang, MD
role: PRINCIPAL_INVESTIGATOR
References: