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

• ClinicalTrials.gov Identifier: NCT03454893
• Recruitment Status: Terminated
• First Posted: March 6, 2018
• Last Update Posted: November 22, 2022
• Sponsor: AVROBIO
• Information provided by (Responsible Party): AVROBIO

Tracking Information

• First Submitted Date: December 20, 2017
• First Posted Date: March 6, 2018
• Last Update Posted Date: November 22, 2022
• Actual Study Start Date: February 21, 2018
• Actual Primary Completion Date: March 14, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 13, 2022)

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

Original Primary Outcome Measures (submitted: February 27, 2018)

Safety and Tolerability of AVR-RD-01 drug product [ Time Frame: baseline to 48 weeks post gene therapy ]

Incidence and severity of adverse events and serious adverse events

Current Secondary Outcome Measures (submitted: April 13, 2022)

• Change from baseline in AGA enzyme activity level in plasma and peripheral blood leukocytes (PBLs) [ Time Frame: Baseline to Week 24 and Week 48 post gene therapy ]
• Change from baseline in Globotriaosylceramide (Gb3) biomarkers for Fabry disease in plasma and urine [ Time Frame: Baseline to Week 24 and Week 48 post gene therapy ]
• Change from baseline in substrate (i.e. Gb3) in skin biopsy [ Time Frame: Baseline to Week 24 and Week 48 post gene therapy ]
• Change from baseline in renal function as assessed by measured glomerular filtration rate (mGFR) [ Time Frame: Baseline to Week 48 post gene therapy ]
• Change from baseline in renal function as assessed by estimated glomerular filtration rate (eGFR) [ Time Frame: Baseline to Week 24 and Week 48 post gene therapy ]
• Change from baseline in renal function as assessed by urine total protein levels [ Time Frame: Baseline to Week 24 and Week 48 post gene therapy ]
• Change from baseline in renal function as assessed by urine albumin levels [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Baseline to Week 24 and Week 48 post gene therapy ]
• Change from baseline in Brief Pain Inventory-Short Form (BPI-SF) questionnaire scores [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Baseline to Week 48 post gene therapy ]

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Open Label, Study Of Efficacy and Safety Of AVR-RD-01 for Treatment-Naive Subjects With Classic Fabry Disease
• Official Title: 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
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Fabry Disease

Intervention

Drug: AVR-RD-01

The subject will receive a one-time IV infusion of AVR-RD-01.

Study Arms

Experimental: Single Assignment AVR-RD-01

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

Intervention: Drug: AVR-RD-01

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 13, 2022): 11
• Original Estimated Enrollment (submitted: February 27, 2018): 12
• Actual Study Completion Date: March 14, 2022
• Actual Primary Completion Date: March 14, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subject is male, 16 years of age or older (18 years of age or older in the US), and postpubertal,(minimum age by region)
2. Subject has a confirmed diagnosis of classic Fabry disease based on deficient AGA enzyme activity (defined as < 1% of normal).

Exclusion Criteria:

1. Subject has a GLA gene mutation associated with late-onset cardiac variant Fabry disease.
2. Subject has previously received ERT and/or chaperone therapy within 3 years for treatment of Fabry disease.
3. Subject has tested positive for anti-AGA antibodies at the time of screening.
4. Subject has eGFR < 60 mL/min/1.73 m² (ie, chronic kidney disease [CKD] stage ≥ 3) at Screening.
5. Subject has a prior history of myocardial infarction (MI).
6. 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).
7. Subject has a history of moderate to severe valvular heart disease requiring valve replacement.
8. 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.

9. 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].

10. Subject has a prior history of stroke and/or transient ischemic attack (TIA).
11. Subject has aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN) at Screening.
12. Subject has a prior history of (or current) malignancy; the one exception is a prior history of resected basal cell carcinoma.
13. Subject has previously received treatment with AVR-RD-01 or any other gene therapy.

Other inclusion/exclusion criteria apply.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 16 Years to 50 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, United States
• Removed Location Countries: Canada

Administrative Information

• NCT Number: NCT03454893
• Other Study ID Numbers: AVRO-RD-01-201
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: AVROBIO
• Original Responsible Party: Same as current
• Current Study Sponsor: AVROBIO
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director, MD; AVROBIO, Inc

• PRS Account: AVROBIO
• Verification Date: April 2022