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

Primary Purpose

Fabry Disease

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
4D-310
Sponsored by
4D Molecular Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fabry Disease focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham
  • University of California at San Diego
  • University of California at Los Angeles
  • Emory University
  • Hackensack University
  • Children's Hospital of Pittsburgh of UPMC
  • University of Utah
  • Lysosomal & Rare Disorders Research & Treatment Center, Inc

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

4D-310 Dose Level 1 - AAV Neutralizing Antibody (NAb) Group A

4D-310 Dose Level 1 - AAV NAb Titer Group B

4D-310 Dose Level 2 - AAV NAb Titer Group A and/or B

4D-310 Dose Expansion

Arm Description

Single IV administration of 4D-310 Dose Level 1 - AAV NAb Titer Group A patients

Single IV administration of 4D-310 Dose Level 1 - AAV NAb titer Group B patients

Single IV administration of 4D-310 at Dose Level 2 in AAV NAb titer Group A and/or B patients

Dose expansion cohort of single IV administration of 4D-310 at the selected dose and selected AAV Nab titer group(s) patients

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Change from baseline in serum AGA activity
Change from baseline in serum AGA activity
Change from baseline serum globotriaosylsphingosine (lysoGb3)
Change from baseline serum globotriaosylsphingosine (lysoGb3)

Full Information

First Posted
August 14, 2020
Last Updated
January 30, 2023
Sponsor
4D Molecular Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT04519749
Brief Title
An Open-label, Phase 1/2 Trial of Gene Therapy 4D-310 in Adults With Fabry Disease
Official Title
An Open-label, Phase 1/2 Trial of Gene Therapy 4D-310 in Adults With Fabry Disease
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 1, 2020 (Actual)
Primary Completion Date
June 2023 (Anticipated)
Study Completion Date
June 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
4D Molecular Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fabry Disease
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
4D-310 Dose Level 1 - AAV Neutralizing Antibody (NAb) Group A
Arm Type
Experimental
Arm Description
Single IV administration of 4D-310 Dose Level 1 - AAV NAb Titer Group A patients
Arm Title
4D-310 Dose Level 1 - AAV NAb Titer Group B
Arm Type
Experimental
Arm Description
Single IV administration of 4D-310 Dose Level 1 - AAV NAb titer Group B patients
Arm Title
4D-310 Dose Level 2 - AAV NAb Titer Group A and/or B
Arm Type
Experimental
Arm Description
Single IV administration of 4D-310 at Dose Level 2 in AAV NAb titer Group A and/or B patients
Arm Title
4D-310 Dose Expansion
Arm Type
Experimental
Arm Description
Dose expansion cohort of single IV administration of 4D-310 at the selected dose and selected AAV Nab titer group(s) patients
Intervention Type
Biological
Intervention Name(s)
4D-310
Intervention Description
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 Measure Information:
Title
Incidence and severity of adverse events
Description
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
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Change from baseline in serum AGA activity
Description
Change from baseline in serum AGA activity
Time Frame
1 year
Title
Change from baseline serum globotriaosylsphingosine (lysoGb3)
Description
Change from baseline serum globotriaosylsphingosine (lysoGb3)
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mitra Tavakkoli, MD, PharmD
Organizational Affiliation
4D Molecular Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
University of California at San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Facility Name
University of California at Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90025
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Hackensack University
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84108
Country
United States
Facility Name
Lysosomal & Rare Disorders Research & Treatment Center, Inc
City
Fairfax
State/Province
Virginia
ZIP/Postal Code
22030
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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