An Open-label, Phase 1/2 Trial of Gene Therapy 4D-310 in Adults With Fabry Disease

Study Overview
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Brief Summary
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This is a prospective multicenter, open-label, dose-escalation trial to assess the safety, tolerability, and pharmacodynamics of 4D-310 following a single IV administration. The study population is comprised of adult males and females with Fabry Disease.

Detailed Description
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This is a prospective multicenter, open-label, dose-escalation trial to assess the safety, tolerability, and pharmacodynamics of 4D-310 following a single IV administration. The study population is comprised of adult males and females with Fabry Disease.

Official Title
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An Open-label, Phase 1/2 Trial of Gene Therapy 4D-310 in Adults With Fabry Disease

Conditions
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Fabry Disease

Intervention / Treatment
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* Biological: 4D-310


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 18 years of age Pathogenic GLA mutation consistent with Fabry Disease Confirmed diagnosis of classic or late-onset Fabry disease Individuals on ERT must be on a stable dose for at least 6 months (and a minimum of 12 months total exposure) prior to study enrollment Agree to use highly effective contraception Exclusion Criteria: Presence of high titer neutralizing antibody to 4D-310 capsid, or presence of high antibody titer to AGA eGFR <45 mL/min/1.73 m2 Undergone kidney transplantation or currently on hemodialysis or peritoneal dialysis HIV, active or chronic hepatitis B or C, Evidence of liver disease, severe pulmonary disease or diabetes with poor glycemic control History of stroke or transient ischemic attack within the last 12 months, or other significant thromboembolic disease history (e.g. pulmonary embolism) Contraindication to systemic corticosteroid therapy or immunosuppressive therapy Chronic steroid use, defined as ≥ 3 months of oral corticosteroid use within the last 12 months. Moderately severe to severe cardiovascular disease or uncontrolled hypertension Left ventricular ejection fraction of <45% on echocardiogram (ECHO) Currently receiving investigational drug, device or therapy or having ever received gene therapy History of infusion related response to ERT or any adverse reaction leading to ERT discontinuation History of cancer within 2 years (exceptions include non-melanoma skin cancer, localized prostate cancer treated with curative intent) Pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4D-310 Dose Level 1 - AAV Neutralizing Antibody (NAb) Group A<br>Single IV administration of 4D-310 Dose Level 1 - AAV NAb Titer Group A patients | Biological: 4D-310<br>* 4D-310 is a novel adeno-associated virus (AAV) gene therapy comprised of two active components: the capsid (4D-C102) and the transgene cassette, which encodes a codon-optimized full length human GLA transgene driven by the CAG promoter. 4D-310 has been engineered so that it cannot replicate (replication incompetent).<br>|
| Experimental: 4D-310 Dose Level 1 - AAV NAb Titer Group B<br>Single IV administration of 4D-310 Dose Level 1 - AAV NAb titer Group B patients | Biological: 4D-310<br>* 4D-310 is a novel adeno-associated virus (AAV) gene therapy comprised of two active components: the capsid (4D-C102) and the transgene cassette, which encodes a codon-optimized full length human GLA transgene driven by the CAG promoter. 4D-310 has been engineered so that it cannot replicate (replication incompetent).<br>|
| Experimental: 4D-310 Dose Level 2 - AAV NAb Titer Group A and/or B<br>Single IV administration of 4D-310 at Dose Level 2 in AAV NAb titer Group A and/or B patients | Biological: 4D-310<br>* 4D-310 is a novel adeno-associated virus (AAV) gene therapy comprised of two active components: the capsid (4D-C102) and the transgene cassette, which encodes a codon-optimized full length human GLA transgene driven by the CAG promoter. 4D-310 has been engineered so that it cannot replicate (replication incompetent).<br>|
| Experimental: 4D-310 Dose Expansion<br>Dose expansion cohort of single IV administration of 4D-310 at the selected dose and selected AAV Nab titer group(s) patients | Biological: 4D-310<br>* 4D-310 is a novel adeno-associated virus (AAV) gene therapy comprised of two active components: the capsid (4D-C102) and the transgene cassette, which encodes a codon-optimized full length human GLA transgene driven by the CAG promoter. 4D-310 has been engineered so that it cannot replicate (replication incompetent).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events | Safety and tolerability of 4D-310 following a single IV dose, as assessed by incidence and severity of adverse events, serious adverse events and dose limiting toxicities, including clinically significant changes from baseline to scheduled time points in safety parameters | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in serum AGA activity | Change from baseline in serum AGA activity | 1 year | 
| Change from baseline serum globotriaosylsphingosine (lysoGb3) | Change from baseline serum globotriaosylsphingosine (lysoGb3) | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolic, Lysosomal Storage Diseases, Nervous System Brain Diseases, Inborn Brain Diseases, Metabolic Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Cerebral Small Vessel Diseases, Cerebrovascular Disorders, Vascular Diseases, Cardiovascular Diseases, Genetic Diseases, X-Linked, Inborn, Metabolic Diseases, Lipid Metabolism Disorders, Sphingolipidoses, Metabolism, Inborn Errors, Lipodoses, Lipid Metabolism