Safety, PK/PD, and Exploratory Efficacy Study of AMT-191 in Classic Fabry Disease

Inclusion Criteria:

1. Male of age ≥ 18 years and ≤50 years

2. Confirmed clinical diagnosis of classic Fabry disease (FD) defined as:

3. Absent or minimal αGAL A enzyme activity < 1% of mean normal (Vardarli, 2020)measured in isolated peripheral leukocytes regardless of variant status; OR

4. Galactosidase A gene (GLA) pathogenic or likely pathogenic variant associatedwith classic FD phenotype identified on molecular genetic testing

5. eGFR ≥ 40 mL/min/1.73 m2

6. Participant agrees to use a condom during sexual intercourse until semen sheddingsamples have tested negative at 3 consecutive visits (expected not to exceed aperiod of 18 months)

7. Suboptimal response after at least 12 months* of enzyme replacement therapy (ERT)treatment. Suboptimal response is defined as plasma lyso-Gb3 ≥ 2.3 nanograms permilliliter (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 consent

• Presence of gastrointestinal symptoms (abdominal cramping, constipation, ordiarrhea), reported by the Participant as moderate or severe and that areeither persistent or occurring two or more times over the 12 weeks prior toconsent *Note: Timing of 12 months is counted from the first ERT treatment tothe most recent ERT treatment. The appropriateness of the schedule and numberof doses received during that period is determined by the treating physicianand is not defined by this study. However, none of the regularly scheduleddoses in the patient's established dosing schedule should have been skipped inthe 3 months prior to the consent, to ensure consistent assessment of chronicpain and GI symptoms for eligibility.

6. Weight ≤ 120 kilograms (kg)

7. Able and willing to provide informed consent

8. Agrees to have no vaccinations within 6 weeks prior to and 6 weeks after dosing withAMT-191 unless allowed by study protocol

Exclusion Criteria:

1. Any allergic hypersensitivity reaction to ERT or infusion reaction in the 12 monthsprior to consent that was of severity grade 3 or above based on Common TerminologyCriteria for Adverse Events (CTCAE v5.0) and required emergency intervention forhypertension/hypotension to stabilize blood pressure or hypoxia OR any otherlife-threatening complication.

2. Proteinuria, with random urine protein/creatinine ratio (rUPCR) ≥1 mg/mg atScreening

3. Any previous treatment with investigational drug within 3 months prior to firstScreening assessment

4. Any previous treatment with gene therapy

5. Any anticipated participation in interventional studies for the treatment of FD

6. Current use of chaperone therapy such as migalastat (Galafold®)

7. Malignancy within 5 years of Screening, except for basal or squamous cell carcinomaof the skin

8. Positive serology test at Screening for hepatitis B surface antigen (HbsAg),hepatitis C antibody (HCAb), or human immunodeficiency virus (HIV), or active orlatent infection with tuberculosis (TB) measured by QuantiFERON test

9. Active or ongoing infection or any other significant concurrent, uncontrolledmedical 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, drugdependency, or any other psychological disorder that could, in the opinion of theInvestigator, risk the safety of the Participant, or interfere with adherence to theprotocol procedures or interpretation of results

10. Evidence of any liver disease, including hepatitis, fibrosis, cirrhosis of theliver, neoplastic lesion, or any known medical condition that could impact theintended transduction of the vector and/or expression and activity of the protein

11. History of kidney transplantation or currently on hemodialysis or peritonealdialysis

12. Moderately severe to severe cardiovascular disease in the opinion of theInvestigator, New York Heart Association (NYHA) class 3 or 4 (see Appendix 2);history of stroke or transient ischemic attacks within the 12 months prior toScreening; history of ventricular tachycardia, history of or detection of othersignificant arrhythmia during Screening; significant thromboembolic disease history (eg, pulmonary embolism); or history of thrombotic risk resulting in current use ofanticoagulant/antiplatelet agents (not including prophylactic use of low-doseaspirin)

13. Uncontrolled hypertension, defined as systolic blood pressure >140 millimeters ofmercury (mmHg) (inclusive) and/or diastolic blood pressure outside the range of 60to 85 mmHg (inclusive) at Screening, confirmed on at least 2 repeated measurements

• Patients taking blood pressure medication to control blood pressure orproteinuria (eg, angiotensin-converting enzyme [ACE] inhibitors and angiotensinII receptor blockers [ARBs]) and have been titrated to a stable dose for atleast 3 months prior to Screening are allowed in the study.

14. Glycated hemoglobin (HbA1c) at Screening ≥7%

15. Contraindication to systemic corticosteroid therapy or immunosuppressive therapy

16. Chronic steroid use, defined as ≥ 3 months of oral corticosteroid use within the 12months prior to Screening

17. Known uncontrolled allergic conditions or Type I allergy/hypersensitivity to anycomponent of the AMT-191 excipients (not including infusion-related reactions toERT)

18. Screening laboratory values for renal and liver function that meet or exceed any ofthe following:

19. Alanine transaminase (ALT) > 2 x upper limit of normal for the testinglaboratory (ULN)

20. Aspartate aminotransferase (AST) > 2 x ULN

21. Total Bilirubin > 2 x ULN (except if this is caused by Gilbert disease)

22. Alkaline phosphatase (ALP) > 2 x ULN

23. Creatinine > 2 x ULN

24. Screening laboratory values for hematologic and coagulation function that meet anyof the following:

25. Hemoglobin < lower limit of normal (LLN) (as per reference laboratory ranges)

26. Platelet count < 150 x1000/μl

27. International normalized ratio (INR) >1.1

28. Soluble terminal complement complex (sC5b-9)>ULN

29. Significant anatomical abnormalities on renal ultrasound such as the presence ofonly 1 kidney, significant differences in kidney sizes between the right and leftkidneys >1.5 centimeters (about 0.59 inch), or presence of kidney cysts