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

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

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.

Study Overview

• Status: Terminated
• Conditions: Hemophilia B
• Intervention / Treatment: Genetic: verbrinacogene setparvovec

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Glasgow, United Kingdom
    • Glasgow Royal Infirmary
  • London, United Kingdom
    • Guys Hospital
  • London, United Kingdom
    • Royal Free London NHS Foundation Tust
  • Newcastle, United Kingdom
    • Royal Victoria Infirmary
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles
  • Florida
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• 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: FLT180a; 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; FLT180a is a gene therapy intended to increase endogenous FIX production in adults with Hemophilia B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Freeline Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2021
• Primary Completion (Actual): May 31, 2023
• Study Completion (Actual): May 31, 2023

Study Registration Dates

• First Submitted: November 22, 2021
• First Submitted That Met QC Criteria: December 7, 2021
• First Posted (Actual): December 20, 2021

Study Record Updates

• Last Update Posted (Actual): July 20, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: FLT180a-06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No