Safety, PK/PD, and Exploratory Efficacy Study of AMT-191 in Classic Fabry Disease
Status: Not yet recruiting

This is an open-label multi-center study to evaluate safety and biomarkers of efficacy of a single dose of intravenously-administered AMT-191. The study will also include exploratory functional efficacy assessments. The plan is to investigate 2 sequential dose cohorts in 3-6 Participants per cohort. Participants will be monitored for 24 hours following AMT-191 administration then follow-up study visits will continue for 24 months, during which safety, pharmacokinetics/pharmacodynamics, biomarkers, and efficacy assessments will be performed. Participants will continue receiving their regularly scheduled enzyme replacement therapy (ERT) until they meet the criteria for withdrawal.

Eligibility:
- EligibilityCriteria: Inclusion Criteria:  Male of age ≥ 18 years and < 50 years  Confirmed clinical diagnosis of classic Fabry disease (FD) defined as:  Absent or minimal GLA enzyme activity < 1% of the testing laboratory's normal reference level measured in isolated peripheral leukocytes regardless of variant status; OR Galactosidase A gene (GLA) pathogenic or likely pathogenic variant associated with classic FD phenotype identified on molecular genetic testing eGFR ≥ 45 mL/min/1.73 m2 and ≤ 75 mL/min/1.73m2 Participant agrees that for a period of at least 18 months following dosing, will only have sexual intercourse with a condom.  Suboptimal 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 neuropathic pain (intermittent or continuous) over a period of at least 3 months defined as average pain intensity > 3 on a scale of 0-10 assessed by the Numeric Pain Rating Scale Presence 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 consent Weight ≤ 80 kilograms (kg) Able and willing to provide informed consent Has received or agrees to receive a meningococcal vaccine at least 6 weeks prior to planned date of dosing with AMT-191 Agrees to have no vaccinations within 6 weeks prior to and 6 weeks after dosing with AMT-191  Exclusion Criteria:  Any hypersensitivity reaction to ERT or infusion reaction in the 12 months prior to consent that either required medical intervention or was of severity grade 3 or above based on Common Terminology Criteria for Adverse Events (CTCAE v5.0) Proteinuria, with urine creatinine ratio > 1 at Screening Any previous treatment with investigational drug within 3 months prior to first Screening assessment Any previous treatment with gene therapy Any anticipated participation in interventional studies for the treatment of FD Current use of chaperone therapy such as miglastat (Galafold®) Malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of the skin Positive serology test at Screening for hepatitis B surface antigen (HbsAg), hepatitis C antibody (HCAb), or human immunodeficiency virus (HIV), or active or latent infection with tuberculosis (TB) measured by QuantiFERON test 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 results Evidence 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 protein History of kidney transplantation or currently on hemodialysis or peritoneal dialysis Moderately severe to severe cardiovascular disease in the opinion of the Investigator, including left ventricular ejection fraction (LVEF) < 45% on Screening CMR; history of stroke or transient ischemic attacks within the 12 months prior to Screening; history of ventricular tachycardia, history of or detection of other significant arrhythmia during screening; significant thromboembolic disease history (e.g., pulmonary embolism); or history of thrombotic risk resulting in current use of anticoagulant/antiplatelet agents (not including prophylactic use of low-dose aspirin)  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.  Patients with a known history of hypertension above these thresholds are only allowed in the study if they are taking inhibitors of renin angiotensin system (such as angiotensin-converting enzyme [ACE] inhibitors and angiotensin II receptor blockers [ARBs]), and/or beta blockers per current applicable standard of care guidelines at a dose which results in blood pressure within the allowable range as measured at Screening. Glycated hemoglobin (HbA1c) at Screening outside the range of 4% to 7% (inclusive) Contraindication to systemic corticosteroid therapy or immunosuppressive therapy Chronic steroid use, defined as ≥ 3 months of oral corticosteroid use within the 12 months prior to Screening Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the AMT-191 excipients  Screening laboratory values for renal and liver function that meet or exceed any of the following:  ALT > 2 x upper limit of normal for the testing laboratory (ULN) AST > 2 x ULN Total Bilirubin > 2 x ULN (except if this is caused by Gilbert disease) Alkaline phosphatase (ALP) > 2 x ULN Creatinine > 2 x ULN  Screening laboratory values for hematologic and coagulation function that meet any of the following:  Red blood cell count < 4.5 x10e6/μl Platelet count < 150 x10e3/μl International normalized ratio (INR) >1.1 Significant 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 [cm]), or presence of kidney cysts - HealthyVolunteers: No - Gender: Male - GenderBased: Yes - GenderDescription: Male of age ≥ 18 years and < 50 years - MinimumAge: 18 Years - MaximumAge: 50 Years - StdAgeList: Adult