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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04519749
Recruitment Status : Active, not recruiting
First Posted : August 20, 2020
Last Update Posted : January 31, 2023
Sponsor:
Information provided by (Responsible Party):
4D Molecular Therapeutics

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Fabry Disease Biological: 4D-310 Phase 1 Phase 2

Detailed Description:
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.
Study Design
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Study Type : Interventional
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Phase 1/2 Trial of Gene Therapy 4D-310 in Adults With Fabry Disease
Actual Study Start Date : September 1, 2020
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2027

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Arms and Interventions
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Arm Intervention/treatment
Experimental: 4D-310 Dose Level 1 - AAV Neutralizing Antibody (NAb) Group A
Single IV administration of 4D-310 Dose Level 1 - AAV NAb Titer Group A patients
 Biological: 4D-310
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).
Experimental: 4D-310 Dose Level 1 - AAV NAb Titer Group B
Single IV administration of 4D-310 Dose Level 1 - AAV NAb titer Group B patients
 Biological: 4D-310
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).
Experimental: 4D-310 Dose Level 2 - AAV NAb Titer Group A and/or B
Single IV administration of 4D-310 at Dose Level 2 in AAV NAb titer Group A and/or B patients
 Biological: 4D-310
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).
Experimental: 4D-310 Dose Expansion
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
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).


Outcome Measures
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Primary Outcome Measures :
  1. Incidence and severity of adverse events [ Time Frame: 1 year ]
    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


Secondary Outcome Measures :
  1. Change from baseline in serum AGA activity [ Time Frame: 1 year ]
    Change from baseline in serum AGA activity

  2. Change from baseline serum globotriaosylsphingosine (lysoGb3) [ Time Frame: 1 year ]
    Change from baseline serum globotriaosylsphingosine (lysoGb3)


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female ≥ 18 years of age
  2. Pathogenic GLA mutation consistent with Fabry Disease
  3. Confirmed diagnosis of classic or late-onset Fabry disease
  4. 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
  5. Agree to use highly effective contraception

Exclusion Criteria:

  1. Presence of high titer neutralizing antibody to 4D-310 capsid, or presence of high antibody titer to AGA
  2. eGFR <45 mL/min/1.73 m2
  3. Undergone kidney transplantation or currently on hemodialysis or peritoneal dialysis
  4. HIV, active or chronic hepatitis B or C,
  5. Evidence of liver disease, severe pulmonary disease or diabetes with poor glycemic control
  6. History of stroke or transient ischemic attack within the last 12 months, or other significant thromboembolic disease history (e.g. pulmonary embolism)
  7. Contraindication to systemic corticosteroid therapy or immunosuppressive therapy
  8. Chronic steroid use, defined as ≥ 3 months of oral corticosteroid use within the last 12 months.
  9. Moderately severe to severe cardiovascular disease or uncontrolled hypertension
  10. Left ventricular ejection fraction of <45% on echocardiogram (ECHO)
  11. Currently receiving investigational drug, device or therapy or having ever received gene therapy
  12. History of infusion related response to ERT or any adverse reaction leading to ERT discontinuation
  13. History of cancer within 2 years (exceptions include non-melanoma skin cancer, localized prostate cancer treated with curative intent)
  14. Pregnant or breast-feeding
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04519749


Locations
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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, California
University of California at San Diego
La Jolla, California, United States, 92037
University of California at Los Angeles
Los Angeles, California, United States, 90025
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, New Jersey
Hackensack University
Hackensack, New Jersey, United States, 07601
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84108
United States, Virginia
Lysosomal & Rare Disorders Research & Treatment Center, Inc
Fairfax, Virginia, United States, 22030
Sponsors and Collaborators
4D Molecular Therapeutics
Investigators
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Study Director: Mitra Tavakkoli, MD, PharmD 4D Molecular Therapeutics
More Information
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Responsible Party: 4D Molecular Therapeutics
ClinicalTrials.gov Identifier: NCT04519749    
Other Study ID Numbers: 4D-310-C001
First Posted: August 20, 2020    Key Record Dates
Last Update Posted: January 31, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by 4D Molecular Therapeutics:
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
 Metabolic Diseases
Lipid Metabolism Disorders
Metabolic
X-Linked
Inborn
Sphingolipidoses
Metabolism
Inborn Errors
Lipodoses
Lipid Metabolism
Additional relevant MeSH terms:
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Fabry Disease
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, 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
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Sphingolipidoses
Metabolism, Inborn Errors
Lipidoses
Lipid Metabolism, Inborn Errors