safety, pk/pd, and exploratory efficacy study of amt-191 in classic fabry disease

Conditions: Fabry Disease

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.

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).

Eligibility criteria:
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 αgal a enzyme activity \< 1% of mean normal (vardarli, 2020) 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 ≥ 40 ml/min/1.73 m2 4. participant agrees to use a condom during sexual intercourse until semen shedding samples have tested negative at 3 consecutive visits (expected not to exceed a period of 18 months) 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 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, 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 \*note: timing of 12 months is counted from the first ert treatment to the most recent ert treatment. the appropriateness of the schedule and number of doses received during that period is determined by the treating physician and is not defined by this study. however, none of the regularly scheduled doses in the patient's established dosing schedule should have been skipped in the 3 months prior to the consent, to ensure consistent assessment of chronic pain 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 with amt-191 unless allowed by study protocol exclusion criteria: 1. 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. 2. proteinuria, with random urine protein/creatinine ratio (rupcr) ≥1 mg/mg 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 migalastat (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, new york heart association (nyha) class 3 or 4 (see appendix 2); 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 (eg, pulmonary embolism); or history of thrombotic risk resulting in current use of anticoagulant/antiplatelet agents (not including prophylactic use of low-dose aspirin) 13. 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 measurements * patients 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. 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 12 months prior to screening 17. known uncontrolled allergic conditions or type i allergy/hypersensitivity to any component of the amt-191 excipients (not including infusion-related reactions to ert) 18. screening laboratory values for renal and liver function that meet or exceed any of the following: 1. alanine transaminase (alt) \> 2 x upper limit of normal for the testing laboratory (uln) 2. aspartate aminotransferase (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. hemoglobin \< lower limit of normal (lln) (as per reference laboratory ranges) 2. platelet count \< 150 x1000/μl 3. international normalized ratio (inr) \>1.1 4. soluble terminal complement complex (sc5b-9)\>uln 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 (about 0.59 inch), or presence of kidney cysts

Keywords: gla gene therapy ert fd