A Fabry Disease Gene Therapy Study

• Register: EUCTR
• Last refreshed on: 5 January 2021
• Main ID: EUCTR2018-002097-51-DK
• Date of registration: 08/07/2019
• Prospective Registration: Yes
• Primary sponsor: Freeline Therapeutics Ltd
• Public title: A Fabry Disease Gene Therapy Study
• Scientific title: A Phase 1/2, Baseline-controlled, Non-randomised, Open-label, Single-ascending Dose Study of a Novel Adeno-associated Viral Vector (FLT190) in Patients With Fabry disease - MARVEL1
• Date of first enrolment: 04/12/2020
• Target sample size: 12
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-002097-51
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Denmark, France, Germany, Italy, Norway, Spain, United Kingdom, United States

Contacts

• Name: Clinical Operations
• Affiliation: Freeline Therapeutics Ltd

• Name: Clinical Operations
• Affiliation: Freeline Therapeutics Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
1. Adult males, = 18 years of age with classic Fabry disease.
2. Confirmed diagnosis of classic Fabry disease (including historical documentation of a classic pathological GLA mutation).
3. Plasma and/or leucocyte alpha galactosidase activity at screening (measured by central laboratory activity assay at trough) less than 5% of normal according to the central laboratory reference ranges.
4. One or more of the characteristic features of classic Fabry disease: neuropathic pain, corneal verticillata, clustered skin angiokeratoma.
5. Plasma LysoGb3 levels > 83ng/ml at screening (Part 2 only)
6. Estimated glomerular filtration rate (eGFR) =60mL/min/1.73m2.
7. <1gm/24 hours of urinary protein, determined by urine spot analysis and 24-hour urine analysis (required if urine spot analysis >500mg of urinary protein) at screening.
8. Able to give full informed consent and able to comply with all requirements of the trial including 5-year long-term follow-up.
9. Willing to practice barrier contraception until at least 2 consecutive semen samples (as specified in the study schedule of assessments) after vector administration are negative for vector sequences.
10. Lack of neutralising anti-AAVS3 antibodies using an in vitro transduction inhibition assay within 6 weeks prior to vector administration.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 2

Exclusion criteria:
1. Presence of either R118C, A143T, or other GLA mutations leading to non-classical Fabry disease manifestation and any mutations that have not yet been classified.
2. Presence of antibodies to aGLA, Replagal, or Fabrazyme as defined by a positive result in the screening assay.
3. Patients with chronic kidney disease, stages 3-5 Kidney Disease: Improving Global Outcomes (KDIGO 2012 classification).
4. Patients with severe myocardial fibrosis (=3 segments) identified by magnetic resonance imaging (MRI).
5. Use of investigational therapy for Fabry disease within 60 days before enrolment. In addition, participation in any other clinical trial of an investigational medicinal product, and/or receiving any other IMP during the course of the study.
6. Evidence of liver dysfunction (persistently elevated ALT, aspartate aminotransferase (AST), bilirubin >1.5 x upper limit of normal).
7. Platelet count < 100 x 109/L.
8. Patients receiving warfarin or other anticoagulants interfering with the ability to perform renal or skin biopsies, or patients with a clinically significant bleeding disorder.
9. Either history of, or a positive serology test at screening for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCAb), or human immunodeficiency virus (HIV).
10. Uncontrolled glaucoma, diabetes mellitus, or hypertension.
11. Malignancy requiring treatment.
12. Patients with uncontrolled cardiac failure, unstable angina, or myocardial infarction in the past 6 months.
13. Prior treatment with any gene transfer medicinal product.
14. Known or suspected intolerance, hypersensitivity or contraindication to the investigational medicinal product (IMP) and non-investigational medicinal products (NIMPs) or their excipients.
15. Patients who are assessed as having any contraindications to MRI. Including patients with ferromagnetic metallic implants, including pacing and defibrillator devices, nerve stimulators and cochlear implants.
16. Patients who have had a renal transplant.


Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Fabry disease
MedDRA version: 20.0 Level: PT Classification code 10016016 Term: Fabry's disease System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: FLT190
Product Code: FLT190
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: NA
Current Sponsor code: FLT190
Other descriptive name: FLT190
Concentration unit: vector genomes (vg)/mL
Concentration type: range
Concentration number: 1.5-4.5

Primary Outcome(s)

Secondary Objective: - To investigate endogenous production of aGLA (plasma) following systemic administration of FLT190 in adult males with Fabry disease at up to 3 different dose cohorts.
-To investigate the clearance of Gb3 and LysoGb3 measured in plasma and urine.
-To investigate the clearance of cellular Gb3 inclusions in skin and renal biopsies.
-To assess viral shedding in various body fluids after systemic administration of FLT190.
-To describe the immune responses to the aGLA transgene product following systemic administration of FLT190.

Main Objective: To investigate the safety of systemic administration of FLT190 in adult males with Fabry disease at up to 3 different dose cohorts.

Timepoint(s) of evaluation of this end point: throughout the study

Primary end point(s): Safety as assessed by the reporting of AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Efficacy: change from baseline towards end of the study
Immune Response: throughout the study
Shedding: throughout the study
Pharmacokinetic:
• Change from baseline in mean plasma aGLA activity at week 12, 24, and 38.
• Overall aGLA activity area under curve from baseline to week 38.

Secondary end point(s): Efficacy
-Change from baseline in Gb3 and LysoGb3 in plasma and urine up to 9 months post treatment.
Immune Response
- Immune response to the human aGLA transgene product will be assessed by measurement of antibodies.
Shedding
-Clearance of vg in blood, urine, saliva, stool, and semen.

Secondary ID(s)

2018-002097-51-DE

FLT190-01

Source(s) of Monetary Support

Freeline Therapeutics Ltd

Ethics review

Status: Approved
Approval date: 04/12/2020
Contact: