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An Open-label, Phase 1/2 Trial of Gene Therapy 4D-310 in Adult Males With Classic 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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04519749
Recruitment Status : Not yet recruiting
First Posted : August 20, 2020
Last Update Posted : September 14, 2020
Sponsor:
Information provided by (Responsible Party):
4D Molecular Therapeutics

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 with classic 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 with classic Fabry Disease.

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Study Type : Interventional  (Clinical Trial)
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 Adult Males With Classic Fabry Disease
Estimated Study Start Date : September 15, 2020
Estimated Primary Completion Date : February 2027
Estimated Study Completion Date : April 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 4D-310 Dose Level 1 - AAV Titer Group A
Single IV administration of 4D-310 Dose Level 1 - AAV 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 Titer Group B
Single IV administration of 4D-310 Dose Level 1 - AAV 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 Titer Group A
Single IV administration of 4D-310 Dose Level 2 - AAV 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 2 - AAV Titer Group B
Single IV administration of 4D-310 at Dose Level 2 in AAV 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 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).




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 over time

  2. Change from baseline in blood leukocyte AGA activity [ Time Frame: 1 year ]
    Change from baseline in blood leukocyte AGA activity over time

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

  4. Development of antibodies to 4D-310 [ Time Frame: 1 year ]
    Quantify the development of antibodies to 4D-310 over time

  5. Development of antibodies to AGA [ Time Frame: 1 year ]
    Quantify the development of antibodies to AGA over time



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  1. Male ≥ 18 years of age
  2. Pathogenic GLA mutation consistent with Fabry Disease
  3. Confirmed diagnosis of classic Fabry Disease with one or more clinical characteristics: acroparesthesia, hypohidrosis, angiokeratoma or cornea verticillata.
  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

Exclusion Criteria:

  1. Presence of high titer NAb to 4D-310 capsid
  2. eGFR <45 mL/min/1.73 m2
  3. Undergone kidney transplantation or currently on hemodialysis or peritoneal dialysis
  4. Either history of, or a positive serology test at Screening for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCAb), or human immunodeficiency virus (HIV)
  5. Evidence of liver disease
  6. Severe pulmonary disease
  7. Diabetes with poor glycemic control
  8. History of stroke or transient ischemic attack within the last 5 years, or other significant thromboembolic disease history (e.g. pulmonary embolism)
  9. Contraindication to systemic corticosteroid therapy or immunosuppressive therapy
  10. Chronic steroid use, defined as ≥ 3 months of oral corticosteroid use within the last 12 months.
  11. Moderately severe to severe cardiovascular disease
  12. Left ventricular ejection fraction of <45% on echocardiogram (ECHO)
  13. Currently receiving investigational drug, device or therapy or having ever received gene therapy
  14. History of infusion related response to ERT or any adverse reaction leading to ERT discontinuation
  15. History of metastatic cancer
  16. Presence of intercurrent illness or other extenuating circumstance including active infection, active illicit drug or alcohol abuse; that might limit compliance with study requirements; or in the Investigator's assessment would place the subject at an unacceptable risk or confound interpretation of results

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


Contacts
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Contact: Molly Nie 510-505-2680 clinicaltrials@4DMT.com

Locations
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United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
Contact: Dawn Jacob Laney    404-778-8518    dawn.laney@emory.edu   
Principal Investigator: William Wilcox, MD, PhD         
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
Contact: Jennifer Baker    412-692-6378    jennifer.baker@chp.edu   
Principal Investigator: Gerard Vockley, MD, PhD         
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84108
Contact: Carrie Bailey       Carrie.Bailey@hsc.utah.edu   
Principal Investigator: Nicola Longo, MD, PhD         
United States, Virginia
Lysosomal & Rare Disorders Research & Treatment Center, Inc
Fairfax, Virginia, United States, 22030
Contact: Rekha Gopal    571-732-4606    rgopal@ldrtc.org   
Principal Investigator: Ozlem Goker-Alpan, MD         
Sponsors and Collaborators
4D Molecular Therapeutics
Investigators
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Study Director: Raffi Schiffman, MD, M.H.Sc 4D Molecular Therapeutics
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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: September 14, 2020
Last Verified: September 2020
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
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
Inborn
Metabolic Diseases
Lipid Metabolism Disorders
Sphingolipidoses
Metabolism
Inborn Errors
Lipodoses
Lipid Metabolism
Additional relevant MeSH terms:
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Fabry Disease
Sphingolipidoses
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
Metabolism, Inborn Errors
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders