Open Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment-Naive Subjects With Classic Fabry Disease

Study Overview
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Brief Summary
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This is a multinational, open-label study to assess the efficacy and safety of AVR-RD-01 in approximately 8 to 12 male subjects 16 years of age or older and postpubertal with a confirmed diagnosis of classic Fabry disease based on deficient AGA enzyme activity who have not previously received treatment with enzyme replacement therapy (ERT) and/or chaperone therapy within 3 years of the time of Screening.

Detailed Description
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The duration of each subject's participation in this study will be approximately 64 weeks (or 1 year, 12 weeks), comprised of a five study periods (Screening, Baseline, Pre-transplant, Transplant, and Post-transplant Follow-up). During the Screening Period (approximately 8 weeks), written informed consent (and assent, if applicable) will be obtained and the subject will complete other Screening procedures to confirm study eligibility. Once study eligibility is confirmed, subjects will enter the Baseline Period (up to 3 days) during which time assessments will be performed to establish a pre-transplant baseline. Once baseline assessments are complete, the subject will enter the Pre-transplant Period (approximately 6 weeks) during which time mobilization, apheresis, AVR-RD-01 drug product preparation and testing for release, and conditioning regimen administration to achieve myeloablation will take place. Following completion of the Pre-transplant Period, the subject will enter the Transplant Period (1 day) during which time AVR-RD-01 infusion will take place. After AVR-RD-01 infusion, the subject will enter the Post-transplant Follow-up Period (approximately 48 weeks), during which time periodic safety and efficacy assessments will be performed to assess measures of engraftment, clinical response, and safety post-transplant. After study completion, consenting subjects will continue periodic safety and efficacy assessments for approximately 14 years (for a total of 15 years post-transplant follow-up) in a long-term follow-up study to AVRO-RD-01-201.

Official Title
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An Open-Label, Multinational Study Of The Efficacy And Safety of Ex Vivo, Lentiviral Vector-Mediated Gene Therapy AVR-RD-01 For Treatment-Naive Subjects With Classic Fabry Disease

Conditions
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Fabry Disease

Intervention / Treatment
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* Drug: AVR-RD-01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is male, 16 years of age or older (18 years of age or older in the US), and postpubertal,(minimum age by region) Subject has a confirmed diagnosis of classic Fabry disease based on deficient AGA enzyme activity (defined as < 1% of normal). Exclusion Criteria: Subject has a GLA gene mutation associated with late-onset cardiac variant Fabry disease. Subject has previously received ERT and/or chaperone therapy within 3 years for treatment of Fabry disease. Subject has tested positive for anti-AGA antibodies at the time of screening. Subject has eGFR < 60 mL/min/1.73 m² (ie, chronic kidney disease [CKD] stage ≥ 3) at Screening. Subject has a prior history of myocardial infarction (MI). Subject has a history of coronary artery disease (CAD) with angina requiring percutaneous transluminal coronary angioplasty (with or without stent placement) and/or coronary artery bypass graft (CABG). Subject has a history of moderate to severe valvular heart disease requiring valve replacement. Subject has a history of heart failure, moderate to severe diastolic dysfunction, and/or left ventricular ejection fraction (LVEF) ≤ 45% on echocardiogram (ECHO) performed at rest at Screening. Subject has a history of clinically significant cardiac arrhythmia (eg, heart block [second or third degree], atrial fibrillation requiring therapy, ventricular fibrillation, ventricular tachycardia, supraventricular tachycardia, or cardiac arrest). Note [history of intermittent atrial fibrillation not requiring treatment is allowed]. Subject has a prior history of stroke and/or transient ischemic attack (TIA). Subject has aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN) at Screening. Subject has a prior history of (or current) malignancy; the one exception is a prior history of resected basal cell carcinoma. Subject has previously received treatment with AVR-RD-01 or any other gene therapy. Other inclusion/exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Assignment AVR-RD-01<br>AVR-RD-01 Drug Product (autologous CD34+ cell-enriched fraction that contains cells transduced with Lentiviral Vector/alpha-galactosidase A (AGA) encoding for the human AGA complementary deoxyribonucleic acid (cDNA) sequence | Drug: AVR-RD-01<br>* The subject will receive a one-time IV infusion of AVR-RD-01.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of and severity of adverse events (AEs) and serious adverse events (SAEs) |  | Baseline to Week 48 post gene therapy | 
| Number of participants with clinically relevant abnormalities, as assessed by clinical laboratory tests |  | Baseline to Week 48 post gene therapy | 
| Number of participants with clinically relevant abnormalities, as assessed by vital signs |  | Baseline to Week 48 post gene therapy | 
| Number of participants with clinically relevant abnormalities as assessed by electrocardiograms (ECGs) |  | Baseline to Week 48 post gene therapy | 
| Evaluation of immunogenicity of AVR-RD-01 | Presence of anti-AGA antibodies | Baseline to Week 48 post gene therapy | 
| Presence of replication competent lentivirus (RCL) | Presence of RCL | Baseline to Week 48 post gene therapy | 
| Evaluate for the presence of aberrant clonal expansion as assessed by integration site analysis (ISA) |  | Baseline to Week 48 post gene therapy | 
| Evaluate the effect of AVR-RD-01 on substrate (ie, globotriaosylceramide [Gb3]) in kidney biopsies | Change in the average number of Gb3 inclusions (ie, myelinosomes) per kidney peritubular capillary (PTC) per subject | Baseline to Week 48 post gene therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in AGA enzyme activity level in plasma and peripheral blood leukocytes (PBLs) |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Change from baseline in Globotriaosylceramide (Gb3) biomarkers for Fabry disease in plasma and urine |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Change from baseline in substrate (i.e. Gb3) in skin biopsy |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Change from baseline in renal function as assessed by measured glomerular filtration rate (mGFR) |  | Baseline to Week 48 post gene therapy | 
| Change from baseline in renal function as assessed by estimated glomerular filtration rate (eGFR) |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Change from baseline in renal function as assessed by urine total protein levels |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Change from baseline in renal function as assessed by urine albumin levels |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Change from baseline in left ventricular mass index (LVMI) as assessed by cardiac magnetic resonance imaging (MRI) |  | Baseline to Week 48 post gene therapy | 
| Change from baseline in abdominal pain and stool consistency as assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D) |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Change from baseline in Brief Pain Inventory-Short Form (BPI-SF) questionnaire scores |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Change from baseline in physical and mental functioning as assessed by the Short Form 36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Average Vector Copy Number (VCN) in peripheral blood leukocytes as assessed by quantitative polymerase chain reaction (qPCR) and/or droplet digital polymerase chain reaction (ddPCR) |  | Baseline to Week 24 and Week 48 post gene therapy | 
| Average Vector Copy Number (VCN) in bone marrow / progenitor cells as assessed by quantitative polymerase chain reaction (qPCR) and/or droplet digital polymerase chain reaction (ddPCR) |  | Baseline to Week 48 post gene therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fabry disease, Cell therapy, Gene therapy, Lysosomal storage disorder, Lenti-viral