Phase 1/2 Dose Confirmation Study of FLT180a in Hemophilia B

Study Overview
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Brief Summary
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Study of FLT180a gene therapy in adults with Hemophilia B. Up to 9 patients will be enrolled to receive a single dose of FLT180a and be followed for 52 weeks. Results will confirm the dose for a future Phase 3 study.

Official Title
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A Dose Confirmation Study of FLT180a (Adeno-associated Viral Vector Containing the Padua Variant of a Codon-optimized Human Factor IX Gene) in Adult Subjects With Hemophilia B

Conditions
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Hemophilia B

Intervention / Treatment
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* Genetic: verbrinacogene setparvovec


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of Hemophilia B with known severe or moderately severe FIX deficiency (≤2% normal circulating FIX activity) for which the subject is on continuous, stable and adequate FIX prophylaxis Have acceptable laboratory values of a) Hemoglobin ≥11g/dL; b) Platelets ≥100,000 cells/µL; c) AST, ALT and alkaline phosphatase (ALP) ≤ upper limit of normal (ULN); d) Serum albumin > lower limit of normal (LLN); e) Total bilirubin ≤1.5 x ULN (except if caused by Gilbert's disease); f) Serum creatinine ≤2.0mg/dL. Level of neutralizing anti-AAV-S3 antibodies below the limit of the pre-established clinical cutoff using an in vitro transduction inhibition assay within the 4 weeks prior to FLT180a administration Has demonstrated ability to accurately, independently and in a timely manner enter bleed diary data during the lead-in study, as judged by the investigator At least 150 exposure days to FIX concentrates At least 6 months of satisfactory controlled prospective baseline data for bleeding events and FIX consumption data from the FLT-01 lead-in study (ECLIPSE) Key Exclusion Criteria: Any history of alcohol or drug dependence Presence of neutralizing anti human FIX antibodies (inhibitor; determined by the Nijmegen modified Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX inhibitor Subjects at high risk of thromboembolic events Evidence of advanced liver fibrosis Prior treatment with a gene transfer medicinal product Subjects with active hepatitis B or C Serological evidence of HIV-1, not controlled with anti-viral therapy and as evidenced by cluster of differentiation 4 (CD4)+ counts ≤200 μL Cytomegalovirus (CMV) immunoglobulin G positive subjects who are CMV polymerase chain reaction (PCR) positive at screening Known coagulation disorder other than hemophilia B High sensitivity (hs) troponin-T ≥14 pg/mL during screening History of uncontrolled cardiac failure, unstable angina, or myocardial infarction or other acute cardiac conditions requiring clinical management in the past 6 months Planned surgical procedure within the next 12 months requiring prophylactic FIX treatment Known active severe infection (including documented coronavirus (COVID)-19 infection), or any other significant concurrent, uncontrolled medical condition

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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FLT180a<br>A single dose of FLT180a will be administered. Dose will be determined by enrollment cohort. The first 3 patients will receive 7.7 x 10e11 vg/kg. The dose in subsequent cohorts will be determined by the DMC based on review of data from the prior cohort(s). | Genetic: verbrinacogene setparvovec<br>* FLT180a is a gene therapy intended to increase endogenous FIX production in adults with Hemophilia B<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of FLT180a as assessed by incidence and severity of AEs and SAEs |  | Post-dose through week 52 | 
| Assessment of FIX activity levels to allow dose confirmation for future Phase 3 study |  | Assessment at Day 21 post-dose | 
| Assessment of FIX activity levels to allow dose confirmation for future Phase 3 study |  | Assessment at Day 140 post-dose | 
| Assessment of FIX activity levels to allow dose confirmation for future Phase 3 study |  | Assessment at Day 182 post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of change in annualized bleeding rate (ABR) |  | Pre-dose and Week 52 post-dose | 
| Assessment of change in annualized FIX concentrate consumption |  | Pre-dose and Week 52 post-dose | 
| Proportion of subjects achieving FIX activity level above 40% |  | Week 26 | 
| The proportion of subjects remaining free from continuous routine FIX prophylaxis |  | Post dose through week 52 | 
| The proportion of subjects achieving a FIX activity level between 50-150% |  | Pre-dose and Week 52 | 
| Assessment of health-related Quality of Life Questionnaire (measuring physical health, feelings, sport and leisure, dealing with haemophilia treatment) (Haem-A-QoL questionnaire) |  | Pre-dose and Weeks 26, 52 post-dose | 
| Joint bleeding rates |  | Pre-dose and Week 52 | 
| Spontaneous bleeding rates |  | Pre-dose and Week 52 | 
| Number of target joints |  | Pre-dose and Week 52 | 
| Assessment of Quality of Life Questionnaire (measuring mobility, self-care, usual activities, pain/discomfort & anxiety/depression)(EQ-5D-5L questionnaire). |  | Pre-dose and Weeks 26, 52 post-dose | 
| Measurement of Anti-AAVS3 antibodies and neutralizing antibodies |  | Pre-dose, Week 4 and Week 26 | 
| Evaluation of AAVS3 capsid-specific T-cell reactions |  | Pre-dose, Week 4 and Week 26 | 
| Abnormal or change from baseline findings for liver ultrasound |  | Pre-dose and Week 52 | 
| Abnormal or change from baseline findings for serum alpha-fetoprotein (AFP) levels. |  | Pre-dose and Week 52 | 
| FIX inhibitor level |  | Pre-dose through Week 52 | 
| Use of immunosuppressants (dose and duration per participant) for the prevention and treatment of increased Liver Enzymes |  | Pre-dose through Week 52 | 
| Clearance of vector genomes in plasma and semen as assessed by PCR test |  | Pre-dose through Week 52 | 
| Assessment of Clinically significant changes in 12-lead ECG |  | Pre-dose through Week 26 |