Clinical trial NCT03454893: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Fabry Disease
Keywords: Fabry disease
Cell therapy
Gene therapy
Lysosomal storage disorder
Lenti-viral
Lead sponsor: AVROBIO
Sponsor class: INDUSTRY
First posted: 2018-03-06
Enrollment: 15
Sex: MALE
Minimum age (years): 16
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This was a multinational, open-label study to assess the efficacy and safety of AVR-RD-01 in approximately 15 male subjects, who were 16 years of age or older and postpubertal with a confirmed diagnosis of classic Fabry disease based on deficient alpha galactosidase A (AGA) enzyme activity who were considered treatment naïve, i.e., had 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 was approximately 64 weeks (or 1 year, 12 weeks), comprised of 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) was obtained and the subject had completed other Screening procedures to confirm study eligibility. Once study eligibility was confirmed, the subjects entered the Baseline Period (up to 3 days) during which time assessments would have been performed to establish a pre-transplant baseline. Once baseline assessments were completed, the subject entered the Pre-transplant Period (approximately 6 weeks) during which time mobilization, apheresis, AVR-RD-01 investigational drug product preparation and testing for release, and conditioning regimen administration to achieve myeloablation took place. Following completion of the Pre-transplant Period, the subject entered the Transplant Period (1 day) during which time AVR-RD-01 infusion took place. After AVR-RD-01 infusion, the subject entered the Post-transplant Follow-up Period (approximately 48 weeks), during which time periodic safety and efficacy assessments were performed to assess measures of engraftment, clinical response, and safety post-transplant.

In January 2022, the study was terminated early due to a decision by the study sponsor, to deprioritize its Fabry disease development program, and therefore, some subjects (n=5) did not complete the study (i.e., Week 48). Subsequently, in August 2023, the long-term follow-up study (AVRO-RD-01-LTF01), was also terminated early due to the decision by the sponsor to terminate the development program for Fabry disease, and therefore, no subjects completed the 15-year long-term follow-up study. This decision to terminate was not based on any safety or medical reasons.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

1. Subject had a galactosidase alpha (GLA) gene mutation associated with late-onset cardiac variant Fabry disease.
2. Subject had previously received ERT and/or chaperone therapy within 3 years for treatment of Fabry disease.
3. Subject had tested positive for anti-AGA antibodies at the time of screening.
4. Subject had eGFR \< 60 mL/min/1.73 m² (ie, chronic kidney disease \[CKD\] stage ≥ 3) at Screening.
5. Subject had a prior history of myocardial infarction (MI).
6. Subject had 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 had a history of moderate to severe valvular heart disease requiring valve replacement.
8. Subject had 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 had 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 \[history of intermittent atrial fibrillation not requiring treatment was allowed\].
10. Subject had a prior history of stroke and/or transient ischemic attack (TIA).
11. Subject had aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN) at Screening.
12. Subject had a prior history of (or current) malignancy; the one exception is a prior history of resected basal cell carcinoma.
13. Subject had previously received treatment with AVR-RD-01 or any other gene therapy.

Other inclusion/exclusion criteria apply.

Primary outcomes:
measure: Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline to Week 48 post gene therapy
measure: Change From Baseline in Immunogenicity of AVR-RD-01
timeFrame: Baseline to Week 48 post gene therapy
measure: Presence of Replication Competent Lentivirus (RCL)
timeFrame: Baseline to Week 48 post gene therapy
measure: Evaluation of Aberrant Clonal Expansion
timeFrame: Baseline to Week 48 post gene therapy
measure: Change From Baseline in the Average Number of Gb3 Inclusions (ie, Myelinosomes) Per Kidney Peritubular Capillary (PTC) Per Subject
timeFrame: Baseline to Week 48 post gene therapy
Secondary outcomes:
measure: 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)
timeFrame: At Week 24 and Week 48 post gene therapy
measure: Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs)
timeFrame: Baseline to Week 24 and Week 48 post gene therapy
measure: Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma
timeFrame: Baseline to Week 24 and Week 48 post gene therapy
measure: Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine
timeFrame: Baseline to Week 24 and Week 48 post gene therapy
measure: Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy
timeFrame: Baseline to Week 24 and Week 48 post gene therapy
measure: Change From Baseline in Renal Function as Assessed by Measured Glomerular Filtration Rate (mGFR)
timeFrame: Baseline to Week 48 post gene therapy
measure: Change From Baseline in Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR)
timeFrame: Baseline to Week 24 and Week 48 post gene therapy
measure: Change From Baseline in Renal Function as Assessed by Urine Total Protein Levels
timeFrame: Baseline to Week 24 and Week 48 post gene therapy
measure: Change From Baseline in Renal Function as Assessed by Urine Albumin Levels
timeFrame: Baseline to Week 24 and Week 48 post gene therapy
measure: Change From Baseline in Left Ventricular Mass Index (LVMI) as Assessed by Cardiac Magnetic Resonance Imaging (MRI)
timeFrame: Baseline to Week 48 post gene therapy
measure: Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D)
timeFrame: Baseline to Week 24 and Week 48 post gene therapy
measure: Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores
timeFrame: Baseline to Week 24 and Week 48 post gene therapy
measure: 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
timeFrame: Baseline to Week 48 post gene therapy
measure: 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)
timeFrame: At Week 48 post gene therapy
Other outcomes:
Locations:
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Parkville VIC
city: Perth
country: Australia
facility: Royal Perth Hospital
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
state: Rio Grande Do Sul
Study officials:
affiliation: AVROBIO, Inc
name: Inderpal Panesar, MRPharmS
role: STUDY_DIRECTOR
References: