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

NCT03454893 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: AVRO-RD-01-201
• Study Type: interventional
• Target: 15
• Locations: 3 countries
• Sites: 5

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.

Conditions

Fabry Disease

Keywords

Fabry disease; Cell therapy; Gene therapy; Lysosomal storage disorder; Lenti-viral

Outcome Measures

Primary Outcomes (5)

• 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.

  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.

  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.

  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.

  Baseline to Week 48 post gene therapy

• Change From Baseline in the Average Number of Gb3 Inclusions (ie, Myelinosomes) Per Kidney Peritubular Capillary (PTC) Per Subject

  Globotriaosylceramide (Gb3) Inclusions in Peritubular Capillaries (PTC) on Kidney Biopsy. Electron microscopic images of kidney biopsy samples were taken and read centrally by two independent renal pathologists, each of whom scored the average number of Gb3 inclusions per kidney PTC per subject using a quantification method. Healthy renal tissue would have no Gb3 inclusions. A reduction from baseline is desirable.

  Baseline to Week 48 post gene therapy

Secondary Outcomes (14)

• 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)

  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)

  Baseline to Week 24 and Week 48 post gene therapy

• Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma

  Baseline to Week 24 and Week 48 post gene therapy

• Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine

  Baseline to Week 24 and Week 48 post gene therapy

• Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy

  Baseline to Week 24 and Week 48 post gene therapy

Study Arms (1)

Single Assignment AVR-RD-01

EXPERIMENTAL

AVR-RD-01 is an autologous CD34+-enriched cell fraction transduced with LV/AGA containing an RNA transcript that, after reverse transcription, results in codon-optimized cDNA that, upon its integration into the human genome, encodes for functional human AGA.

Drug: AVR-RD-01

Interventions

AVR-RD-01 DRUG

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

Single Assignment AVR-RD-01

Eligibility Criteria

• Age: 16 Years - 50 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)
• Subject had a confirmed diagnosis of classic Fabry disease based on deficient AGA enzyme activity (defined as \< 1% of normal).

You may not qualify if:

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

Sponsors & Collaborators

• AVROBIO: lead

Study Sites (5)

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Royal Melbourne Hospital

Melbourne, Parkville VIC, Australia

Location

Royal Perth Hospital

Perth, Australia

Location

Hospital de Clinicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, Brazil

Location

MeSH Terms

Conditions

Fabry Disease; Lysosomal Storage Diseases

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Limitations and Caveats

SF-36 data at W24 was inadvertently not collected due to omission in the Protocol Schedule of Assessments. Invasive sampling, such as bone marrow aspirate, was only provided by one subject at Week 48. Central laboratory only reported albumin levels in urine and not urine total protein data.

Results Point of Contact

• Title: AVROBIO MedInfo
• Organization: AVROBIO, Inc

medinfo@avrobio.com

617-914-8419

Study Officials

• Inderpal Panesar, MRPharmS

  AVROBIO, Inc

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2017
• First Posted: March 6, 2018
• Study Start: February 21, 2018
• Primary Completion: March 14, 2022
• Study Completion: March 14, 2022
• Last Updated: January 5, 2024
• Results First Posted: January 5, 2024

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2); US (2); BR (1)