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

Last updated: April 10, 2025
Sponsor: UniQure Biopharma B.V.
Overall Status: Active - Recruiting

Phase

1/2

Condition

Fabry Disease

Kidney Disease

Treatment

AMT-191

Clinical Study ID

NCT06270316
CT-AMT-191-01
  • Ages 18-50
  • Male

Study Summary

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.

Eligibility Criteria

Inclusion

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.

  1. Weight ≤ 120 kilograms (kg)

  2. Able and willing to provide informed consent

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

Exclusion

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

  2. Contraindication to systemic corticosteroid therapy or immunosuppressive therapy

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

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

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

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

  7. Aspartate aminotransferase (AST) > 2 x ULN

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

  9. Alkaline phosphatase (ALP) > 2 x ULN

  10. Creatinine > 2 x ULN

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

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

  13. Platelet count < 150 x1000/μl

  14. International normalized ratio (INR) >1.1

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

  16. 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

Study Design

Total Participants: 12
Treatment Group(s): 1
Primary Treatment: AMT-191
Phase: 1/2
Study Start date:
June 05, 2024
Estimated Completion Date:
April 29, 2027

Study Description

AMT-191 is an investigational gene therapy that encodes a recombinant serotype 5 based adeno-associated viral vector (rAAV5). AMT-191 is designed to deliver a liver-specific expression of the transgene coding for human a-galactosidase A gene (GLA) to Fabry patients via a single (one-time) IV infusion. Delivery of AMT-191 to the systemic circulation is expected to result in a therapeutic effect by promoting the liver expression of the lysosomal enzyme GLA in plasma and leukocytes levels in patients with FD Fabry disease (FD).

Connect with a study center

  • The Kirklin Clinic Of university of Alabama Birmingham Hospital

    Birmingham, Alabama 35233
    United States

    Active - Recruiting

  • Emory University School of Medicine

    Atlanta, Georgia 30322
    United States

    Active - Recruiting

  • Ann & Robert H. Lurie Children's Hospital of Chicago

    Chicago, Illinois 60611
    United States

    Active - Recruiting

  • MHealth Fairview University of Minnesota Medical Center East Bank

    Minneapolis, Minnesota 55455
    United States

    Active - Recruiting

  • NYC Health + Hospitals/Metropolitan

    New York, New York 10029
    United States

    Active - Recruiting

  • UPMC Children's Hospital of Pittsburgh

    Pittsburgh, Pennsylvania 15224
    United States

    Active - Recruiting

  • University of Utah, Clinical and Translational Sciences Institute

    Salt Lake City, Utah 84108
    United States

    Active - Recruiting

  • Lysosomal & Rare Disorders Research and Treatment Center, Inc

    Fairfax, Virginia 22030
    United States

    Active - Recruiting

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