A Phase 1/2, Single Dose, Dose Ranging Study of Intravenous AAV5-GLA (AMT-191) in Adult Males With Classic Fabry Disease

To evaluate safety and biomarkers of efficacy of a single dose of intravenously-administered AMT-191. To assess the safety, tolerability and early signs of efficacy of AMT-191 in individuals with Fabry disease. The trial will explore the safety, tolerability, and early signs of efficacy by measuring the expression of lysosomal enzyme aGLA-A. This is an open-label, multi-center study to evaluate safety, tolerability, and exploratory efficacy of a single dose of intravenously-administered AMT-191. The plan is to investigate 2 sequential dose cohorts with 3-6 Participants per cohort. Participants will continue receiving regularly scheduled enzyme replacement therapy (ERT) until they meet the criteria for withdrawal. To assess the safety, tolerability and early signs of efficacy of AMT-191 in individuals with Fabry disease. The trial will explore the safety, tolerability, and early signs of efficacy by measuring the expression of lysosomal enzyme aGLA-A. The main goals of this clinical study are to characterize safety and PK/PD of AMT-191 i.e. if drug doses used in the study are safe and tolerable and to understand how it acts in the body of people with Fabry disease. The trial will explore the safety, tolerability, and early signs of efficacy by measuring the expression of lysosomal enzyme α-Gal A.

CT.gov Identifier

NCT06270316

EudraCT Identifier

N/A

CTIS:

N/A

Collaborator

N/A

Study Contact Information

+31 20 240 6000

Recruiting

Study Details

Diseases

Fabry Disease

Study Drug

Ifezuntirgene inilparvovec

AMT-191

Enzyme replacement therapy, unspecified

Genes

GLA

Study Dates

May 2024 - Dec 2027

Sex

Male

Age

18 - 65 Years

Inclusion and Exclusion Criteria

Inclusion Criteria:

Male of age ≥ 18 years and ≤65 yearsConfirmed clinical diagnosis of classic Fabry disease (FD) defined as:Absent or minimal αGAL A enzyme activity < 1% of mean normal measured in plasma regardless of variant status; ORα-galactosidase A (GLA) pathogenic or likely pathogenic variant associated with classic FD phenotype identified on molecular genetic testing with plasma αGLA A enzyme activity below lower bound of the reference range (as measured at trough enzyme replacement therapy [ERT] levels).eGFR ≥ 40 mL/min/1.73 m2Participant agrees to use a condom during sexual intercourse with any female partner who could become pregnantSuboptimal response after at least 12 months of enzyme replacement therapy (ERT) treatment. Suboptimal response is defined as plasma lyso-Gb3 ≥ 2.3 nanograms per milliliter (ng/mL) at Screening and one or both of the following:Persistent moderate or severe neuropathic pain (intermittent or continuous) over a period of at least 3 months prior to consentPresence of gastrointestinal symptoms (abdominal cramping, constipation, or diarrhea), reported by the Participant as moderate or severe and that are either persistent or occurring two or more times over the 12 weeks prior to consentWeight ≤ 120 kilograms (kg) and ≥ 45 kgAble and willing to provide informed consentAgrees to have no vaccinations within 6 weeks prior to and 6 weeks after dosing with AMT-191 unless allowed by stud protocol

Exclusion Criteria:

Any allergic hypersensitivity reaction to ERT or infusion reaction in the 12 months prior to consent that was of severity grade 3 or above based on Common Terminology Criteria for Adverse Events (CTCAE v5.0) and required emergency intervention for hypertension/hypotension to stabilize blood pressure or hypoxia OR any other life-threatening complication.Proteinuria, with random urine protein/creatinine ratio (rUPCR) ≥1 mg/mg at ScreeningAny previous treatment with investigational drug within 3 months prior to first Screening assessmentAny previous treatment with gene therapyAny anticipated participation in interventional studies for the treatment of FDCurrent use of chaperone therapy such as migalastat (Galafold®)Malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of the skinPresence of chronic, active, or latent infection with hepatitis B or C, human immunodeficiency virus (HIV), or tuberculosis (TB) as assessed at the screening visit.Active or ongoing infection or any other significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, cardiovascular, hematological, GI, endocrine (such as diabetes mellitus with poor glycemic control), pulmonary, neurological, cerebral, or psychiatric disease, alcoholism, drug dependency, or any other psychological disorder that could, in the opinion of the Investigator, risk the safety of the Participant, or interfere with adherence to the protocol procedures or interpretation of resultsEvidence of any liver disease, including hepatitis, fibrosis, cirrhosis of the liver, neoplastic lesion, or any known medical condition that could impact the intended transduction of the vector and/or expression and activity of the proteinHistory of kidney transplantation or currently on hemodialysis or peritoneal dialysisModerately severe to severe cardiovascular disease, history of stroke or transient ischemic attacks within 12 months prior to Screening, history of ventricular tachycardia, history of or detection of other significant arrhythmia during Screening; significant thromboembolic disease history; or history of thrombotic risk resulting in current use of anticoagulant/antiplatelet agents.Uncontrolled hypertension, defined as systolic blood pressure >140 millimeters of mercury (mmHg) (inclusive) and/or diastolic blood pressure outside the range of 60 to 85 mmHg (inclusive) at Screening, confirmed on at least 2 repeated measurementsPatients taking blood pressure medication to control blood pressure or proteinuria (eg, angiotensin-converting enzyme [ACE] inhibitors and angiotensin II receptor blockers [ARBs]) and have been titrated to a stable dose for at least 3 months prior to Screening are allowed in the study.Glycated hemoglobin (HbA1c) at Screening ≥7%Contraindication to systemic corticosteroid therapy or immunosuppressive therapyChronic steroid use, defined as ≥ 3 months of oral corticosteroid use within 12 months prior to ScreeningScreening laboratory values for renal and liver function that meet or exceed any of the following:Alanine transaminase (ALT) > 1.5 x upper limit of normal for the testing laboratory (ULN)Aspartate aminotransferase (AST) > 1.5 x ULNTotal Bilirubin > ULN (except if this is caused by Gilbert disease)Alkaline phosphatase (ALP) > ULNCreatinine > 2 x ULNDirect bilirubin > ULNAlbumin < 30 g/LGamma-glutamyl transferase (GGT) > ULNAlpha-fetoprotein > 20 ng/mL unless cause is known and does not meet any other exclusion criteriaScreening laboratory values for hematologic and coagulation function that meet any of the following:Hemoglobin < lower limit of normal (LLN) (as per reference laboratory ranges)Platelet count < 150 x1000/μlInternational normalized ratio (INR) >1.1Soluble terminal complement complex (sC5b-9)>ULNSignificant anatomical abnormalities on renal ultrasound such as the presence of only 1 kidney, significant differences in kidney sizes between the right and left kidneys >1.5 centimeters (about 0.59 inch), or presence of kidney cystsPre-existing ocular disease and/or intraocular pressure >21 mmHg at Screening unless referred for formal ophthalmology review and cleared b ophthalmologist to commence prednisoneTo be (re)-assessed on Day 0 prior to planned infusion:Active systemic bacterial, viral, or fungal infectionALT or AST ≥ 1.5 x ULN

Protocol Summary

To assess the safety, tolerability and early signs of efficacy of AMT-191 in individuals with Fabry disease.

The trial will explore the safety, tolerability, and early signs of efficacy by measuring the expression of lysosomal enzyme aGLA-A.

The main goals of this clinical study are to characterize safety and PK/PD of AMT-191 i.e. if drug doses used in the study are safe and tolerable and to understand how it acts in the body of people with Fabry disease.

The trial will explore the safety, tolerability, and early signs of efficacy by measuring the expression of lysosomal enzyme α-Gal A.

Study Locations

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