A Factor IX Gene Therapy Study (FIX-GT)

NCT03369444 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: UCL/15/0552
• Study Type: interventional
• Target: 10
• Locations: 4 countries
• Sites: 11

Brief Summary

Severe haemophilia B (HB) is a bleeding disorder where a protein made by the body to help make blood clot is either partly or completely missing. This protein is called a clotting factor; with severe haemophilia B, levels of clotting factor IX (FIX) (nine) are very low and affected individuals can suffer life threatening bleeding episodes. HB mainly affects boys and men (normally one in every 30,000 males). Current treatment for HB involves intravenous infusions of factor IX as regular treatment (Prophylaxis) or 'on demand'. On demand treatment is highly effective at stopping bleeding but cannot fully reverse long-term damage that follows after a bleed. Regular treatment can prevent bleeding, however can be invasive for patients and also expensive. This research study aims to test the safety and effectiveness of a gene therapy which produces Factor IX protein in the body. The gene will be given using an inactivated virus called "the vector" ( FLT180a), in a single infusion. The vector has been developed from a virus known as an adeno- associated virus, that has been changed so that it is unable to cause a viral infection in humans. This "inactivated" virus is further altered to carry the Factor IX gene and to make its way within liver cells where Factor IX protein is normally made. Up to three different doses cohorts of FLT180a will be tested, in up to 24 patients with severe haemophilia B. Patients will be recruited from haemophilia centres in the EU and US. Patients will be in the trial for approximately 40 weeks and will undergo procedures including physical examinations, bloods tests, ECGs and liver ultrasounds.

Conditions

Hemophilia B

Outcome Measures

Primary Outcomes (2)

• Frequency and Severity of Treatment-emergent Adverse Events (TEAEs) (Safety)

  Safety as assessed by the reporting of AEs according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0

  From Day 0 (first dose of FLT180a) until week 26 post infusion (up to 26 weeks)

• Number of Participants With FIX Activity Response

  The proportion of participants at the terminal dose (1.3 x 10e\^12 vg/kg) achieving clinical FIX response and proportion of patients achieving normalised FIX response at Week 26. A clinical FIX response is defined as achieving a FIX activity of 5% to 150%. Normalised FIX response is defined as achieving FIX activity in the normal range (50-150%).

  From screening until week 26 post infusion (Up to 38 weeks)

Secondary Outcomes (7)

• Number of Participants With a Change From Baseline or Abnormal Finding From Routine Safety Assessments

  From screening until week 26 post infusion (Up to 38 weeks)

• FIX Concentrate Usage

  Baseline and Post Dose (Day15 post infusion to Week26/End of Study)

• Bleeding Frequency

  Baseline and Post-Dose (Day 15 to Week 26/EOS)

• Immune Response - Development of Inhibitors

  Week 1, week 2, week 3, week 6, week 9, week 12, week 16, week 20 and week 26/EOS post infusion

• Viral Shedding Evaluated as Time to Unquantifiable Vector Genomes

  From screening until time to unquantifiable results of vector genomes in all matrices, up to an average of 5.14 weeks

Study Arms (4)

FLT180a, 6x10e^11 vg/kg solution for infusion

EXPERIMENTAL

Participants receiving gene therapy vector at a dose of 6x10e\^11 vg/kg

Biological: FLT180a

FLT180a, 2 x 10e^12 vg/kg solution for infusion

EXPERIMENTAL

Participants receiving gene therapy vector at a dose of 2 x 10e\^12 vg/kg

Biological: FLT180a

FLT180a, 1x10e^12 vg/kg solution for infusion

EXPERIMENTAL

Participants receiving gene therapy vector at a dose of 1 x 10e\^12 vg/kg

Biological: FLT180a

FLT180a, 1.3x10e^12 vg/kg solution for infusion

EXPERIMENTAL

Participants receiving gene therapy vector at a dose of 1.3 x 10e\^12 vg/kg

Biological: FLT180a

Interventions

FLT180a BIOLOGICAL

FLT180a is a replication-incompetent adeno- associated viral vector. The vector is composed of a DNA vector genome encapsidated in an adeno-associated virus derived protein capsid. The expression cassette contains DNA encoding Factor IX.

FLT180a, 1.3x10e^12 vg/kg solution for infusion; FLT180a, 1x10e^12 vg/kg solution for infusion; FLT180a, 2 x 10e^12 vg/kg solution for infusion; FLT180a, 6x10e^11 vg/kg solution for infusion

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults males, ≥ 18 years of age.
• Confirmed diagnosis of HB defined as one of the following:
• Documented severe FIX deficiency with plasma FIX activity of \<1% of normal, or
• moderately severe FIX deficiency with plasma FIX activity level between ≥1% and ≤2% and a severe bleeding phenotype defined by one of the following: i. On prophylaxis for a history of bleeding, or ii. On demand therapy with a history of 4 or more bleeding episodes/year on average over the past 3 years, or iii. evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion).
• Able to give full informed consent and able to comply with all requirements of the trial including 15-year long-term follow-up.
• Willing to practice barrier contraception until at least 3 consecutive semen samples after vector administration are negative for vector sequences.
• Lack of neutralising anti-AAV-S3 antibodies using an in vivo transduction inhibition assay within 4 weeks of vector administration.
• At least 150 exposure days to FIX concentrates.

You may not qualify if:

• Presence of neutralising anti-human FIX antibodies (inhibitor, determined by the Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX inhibitor;
• Patients at high risk of thromboembolic events (high risk patients would include those with a history of arterial or venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism, non-haemorrhagic stroke, arterial embolus) and those with acquired thrombophilia including conditions such as atrial fibrilation);
• Use of investigational therapy for haemophilia within 30 days before enrolment;
• Patients with active hepatitis B or C, and hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) Ribonucleic acid (RNA) viral load positivity, respectively, or currently on antiviral therapy for hepatitis B or C. Negative viral assays in 2 samples, collected at least 6 months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible.;
• Serological evidence of human immunodeficiency virus (HIV-1);
• Evidence of liver dysfunction (persistently elevated alanine aminotransaminase, aspartate aminotransferase, bilirubin \>1.5 x upper limit of normal);
• Platelet count \<50 x 109/L;
• Uncontrolled glaucoma, diabetes mellitus, or hypertension;
• Malignancy requiring treatment;
• Patients with uncontrolled cardiac failure, unstable angina or myocardial infarction in the past 6 months;
• Poor performance status (World Health Organization score \>1);
• Prior treatment with any gene transfer medicinal product;
• Known or suspected intolerance, hypersensitivity or contraindication to the investigational product and non-investigational medicinal products or their excipients;
• Planned major elective surgery prior to the end of trial.
• Current or relevant history of a physical or psychiatric illness or any medical condition that in the opinion of the investigator could affect the patients safety or interfere with the study assessments.

Sponsors & Collaborators

• University College, London: lead

Study Sites (11)

St Jude Children's Research Hospital

Memphis, Tennessee, 38119, United States

Location

St James's Hospital

Dublin, Ireland

Location

University of Milan

Milan, Italy

Location

Basingstoke Haemostasis and Thrombosis Centre

Basingstoke, United Kingdom

Location

East Kent Hospitals University

Canterbury, United Kingdom

Location

Guy's and St Thomas's NHS Foundation Trust

London, United Kingdom

Location

Royal Free Hospital

London, United Kingdom

Location

Newcastle Hospitals NHS Trust

Newcastle upon Tyne, United Kingdom

Location

Oxford University Hospital

Oxford, United Kingdom

Location

University of Sheffield

Sheffield, United Kingdom

Location

University Hospital Southampton

Southampton, United Kingdom

Location

Related Publications (1)

• Chowdary P, Shapiro S, Makris M, Evans G, Boyce S, Talks K, Dolan G, Reiss U, Phillips M, Riddell A, Peralta MR, Quaye M, Patch DW, Tuddenham E, Dane A, Watissee M, Long A, Nathwani A. Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med. 2022 Jul 21;387(3):237-247. doi: 10.1056/NEJMoa2119913.

  PMID: 35857660 DERIVED

MeSH Terms

Conditions

Hemophilia B

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, X-Linked

Limitations and Caveats

Protocol defined number of participants (n=24) was not met, the terminal dose as specified in the protocol was not identified prior to early study termination. The primary efficacy endpoints (FIX response at the terminal dose) could therefore not be detailed established. However the FIX response data (efficacy endpoint) for the 4 patients treated at the last studied dose level 1.3×10e\^12 vg/kg, have been presented instead.

Results Point of Contact

• Title: Pratima Chowdary
• Organization: University College London

p.chowdary@ucl.ac.uk

+44(0)20 7472 6835

Study Officials

• Pratima Chowdary

  University College London / Royal Free London NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2017
• First Posted: December 12, 2017
• Study Start: December 5, 2017
• Primary Completion: October 20, 2020
• Study Completion: October 20, 2020
• Last Updated: December 2, 2022
• Results First Posted: December 2, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); GB (8); IE (1); IT (1)