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

Fabry Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06270316
• Other study ID #: CT-AMT-191-01
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 31, 2024
• Est. completion date: April 29, 2027

Study information

• Verified date: May 2024
• Source: UniQure Biopharma B.V.
• Contact: Christy Quintana
• Phone: +1 781-879-6442
• Email: amt191_clinical_trials[@]uniqure.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

Fabry disease (FD) is a lysosomal storage disorder resulting from the absent or deficient activity of the lysosomal enzyme, α-galactosidase A (GLA). Despite availability of an enzyme replacement therapy (ERT) to prevent the progression of the renal, cardiac, and cerebrovascular symptoms, ERT is not curative and has variable impact on the disease progression for patients.

A recombinant serotype 5 based adeno-associated viral vector (AMT-191) for one-time intravenous (IV) administration will be investigated in this study. This recombinant AAV5-based vector contains a coding deoxyribonucleic acid (DNA) sequence for human α-galactosidase A.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: April 29, 2027
• Est. primary completion date: April 1, 2027
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

1. Male of age = 18 years and < 50 years

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

1. 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

2. Galactosidase A gene (GLA) pathogenic or likely pathogenic variant associated with classic FD phenotype identified on molecular genetic testing

3. eGFR = 45 mL/min/1.73 m2 and = 75 mL/min/1.73m2

4. Participant agrees that for a period of at least 18 months following dosing, will only have sexual intercourse with a condom.

5. 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

6. Weight = 80 kilograms (kg)

7. Able and willing to provide informed consent

8. Has received or agrees to receive a meningococcal vaccine at least 6 weeks prior to planned date of dosing with AMT-191

9. Agrees to have no vaccinations within 6 weeks prior to and 6 weeks after dosing with AMT-191

Exclusion Criteria:

1. 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)

2. Proteinuria, with urine creatinine ratio > 1 at Screening

3. Any previous treatment with investigational drug within 3 months prior to first Screening 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 miglastat (Galafold®)

7. Malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of 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 or latent infection with tuberculosis (TB) measured by QuantiFERON test

9. 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

10. 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

11. History of kidney transplantation or currently on hemodialysis or peritoneal dialysis

12. 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)

13. 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.

14. Glycated hemoglobin (HbA1c) at Screening outside the range of 4% to 7% (inclusive)

15. Contraindication to systemic corticosteroid therapy or immunosuppressive therapy

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

17. Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the AMT-191 excipients

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

1. ALT > 2 x upper limit of normal for the testing laboratory (ULN)

2. AST > 2 x ULN

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

4. Alkaline phosphatase (ALP) > 2 x ULN

5. Creatinine > 2 x ULN

19. Screening laboratory values for hematologic and coagulation function that meet any of the following:

1. Red blood cell count < 4.5 x10e6/µl

2. Platelet count < 150 x10e3/µl

3. International normalized ratio (INR) >1.1

20. 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

Related Conditions & MeSH terms

• Fabry Disease

Intervention

Drug:
• AMT-191
A recombinant serotype 5 based adeno-associated viral vector (AMT-191) for one-time intravenous (IV) administration will be investigated in this study. This recombinant AAV5-based vector contains a coding deoxyribonucleic acid (DNA) sequence for human a-galactosidase A. 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 levels in patients with FD.

Locations

Country	Name	City	State
United States	Lysosomal & Rare Disorders Research and Treatment Center, Inc	Fairfax	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
UniQure Biopharma B.V.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	• Number of Participants with Treatment-Emergent Adverse Events TEAE(n,%) by CTCAE v4.0.	26 Months
Primary	Duration of Vector deoxyribonucleic acid (DNA) shedding presented in blood, saliva, feces, semen, and urine	The duration of vector shedding DNA presented in bodily fluids such as blood, saliva, feces, semen, and urine will be followed in participants from baseline value to BLOQ.	26 Months