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

Phase 2TerminatedNCT03454893

AVROBIO15 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Fabry Disease

Interventions

AVR-RD-01DRUG

Single IV infusion of between 3 - 20 x 10\^6 CD34+ cells/kg.

Eligibility

Sex: MALEMin age: 16 YearsMax age: 50 Years

Medical Language ↔ Plain English

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.

Locations (5)

Hackensack University Medical Center

Hackensack, New Jersey, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Royal Melbourne Hospital

Melbourne, Parkville VIC, Australia

Royal Perth Hospital

Perth, Australia

Outcomes

Primary Outcomes

Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The AE/SAE are also inclusive of any abnormalities in Clinical Laboratory Tests, Vital Signs and in Electrocardiographs (ECGs). Of the 13 serious adverse events, no SAEs reported were considered related to AVR RD 01. Of the 354 adverse events, no AEs were considered related to AVR RD 01. The SAEs and AEs reported in the study were attributed to the conditioning agent used, the underlying disease, comorbid conditions, study procedures and concomitant medications.

Time frame: Baseline to Week 48 post gene therapy

Change From Baseline in Immunogenicity of AVR-RD-01

Number of subjects with changes in anti-AGA antibodies from Baseline to post infusion timepoints. Unite of measure: Number of subjects negative at baseline but positive at post-treatment timepoints. A negative or zero result (titer lower or unchanged at post-infusion timepoints compare to Baseline) indicates no immune response to the therapeutic protein.

Time frame: Baseline to Week 48 post gene therapy

Presence of Replication Competent Lentivirus (RCL)

The "Presence of RCL" is a theoretical risk of lentiviral gene therapy treatment based on the theory that it may be possible for inadvertent generation of RCL caused either by recombination of the lentiviral vector plasmids during the vector production process or by mobilization of proviral DNA in vivo by infectious retroviruses (HIV). The absence of RCL is a positive indicator of safety.

Time frame: Baseline to Week 48 post gene therapy

Evaluation of Aberrant Clonal Expansion

Integration Site Analysis (ISA) uses next generation sequencing to identify junction sites between the integrated therapeutic transgene and the host genome. Samples are analyzed for the emergence of clonality (defined as (a single clone accounting for greater than 20% of the population) and whether any integration site is within or near a known oncogene.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

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)

Vector Copy Number (VCN) is a measurement of the number of copies of the therapeutic transgene found in a sample, relative to copies of a reference gene in the human genome. This is an estimate of the number of integration sites per cell (on average). A VCN of 1 would signify that a sample of cells evaluated contains on average at least one \[working\] copy of the therapeutic transgene per cell.

Time frame: At Week 24 and Week 48 post gene therapy

Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs)

Treatment-naïve Fabry patients are deficient in alpha-galactosidase A (AGA) enzyme activity due to mutations in the GLA gene. Any therapeutic option offered should aim to increase the amount of available AGA enzyme. This assay measured the AGA enzyme activity levels in plasma and PBLs. It should be noted that the measurement in plasma reflects the amount of "free" AGA enzyme that has been released from cells into the extracellular space and is therefore considered a more indirect measure of AGA enzyme activity, compared to the result in PBLs which is more of a direct measure of enzyme within cells. In both cases, enzyme activity is expected to increase from Baseline to the post-infusion timepoints.