Lentiviral Vector Gene Therapy - The Guard1 Trial of AVR-RD-02 for Subjects With Type 1 Gaucher Disease
- Registration Number
- NCT04145037
- Lead Sponsor
- AVROBIO
- Brief Summary
This was a multinational, open-label study to assess the safety and efficacy of AVR-RD-02 in approximately 8 to 16 subjects (male or female) who are ≥18 and ≤50 years of age and post pubertal at Screening with a confirmed diagnosis of Type 1 Gaucher disease (based on clinical phenotype, genotyping, and deficient GCase enzyme activity in whole blood).
- Detailed Description
Five study periods (Screening, Baseline, Pre-gene Therapy Infusion, Gene Therapy Infusion, and Post-gene Therapy Infusion Follow-up) comprised the study. During the Screening Period (approximately 60 days), written informed consent was obtained and the subject completed other Screening procedures to confirm study eligibility. Once study eligibility was confirmed, subjects entered the Baseline Period (up to 7 days) during which time assessments were performed to establish Pre-gene Therapy Infusion baseline. Once baseline assessments were completed, the subject entered the Pre-gene Therapy Infusion Period (approximately 8 to 10 weeks) during which time mobilization, apheresis, AVR-RD-02 investigational product preparation and testing for release, busulfan conditioning regimen administration took place. Enzyme replacement therapy was discontinued at least 2 weeks before the scheduled Gene Therapy Infusion Day. Following completion of the Pre-gene Therapy Infusion Period, the subject entered the Gene Therapy Infusion Period (1 day) during which AVR-RD-02 infusion took place. After AVR-RD-02 Gene Therapy Infusion, the subject entered the Post-gene Therapy Infusion Follow-up Period (approximately 52 weeks) during which time periodic safety and efficacy assessments were performed to assess measures of safety, engraftment, and clinical response following AV-RD-02 infusion.
In August 2023, the study was terminated early by the Sponsor, which was not based on any safety or medical reasons and therefore, one subject did not complete the study (i.e., Week 52). Subsequently, in August 2023, the sponsor's long-term follow-up study (AVRO-RD-02-LTF01), was also terminated early for the same reason as the AVRO-RD-02-201 study, and therefore, no subjects completed the 15-year long-term follow-up study.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 8
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Switch Stable AVR-RD-02 Switch-stable arm: Subjects who had undergone ERT ≥15 U/kg and ≤60 U/kg every other week (or equivalent; i.e., any combination of infusions resulting in a total monthly ERT dose of \>30 U/kg and \<120 U/kg) for ≥24 consecutive months for Type 1 Gaucher disease at the time of Screening. Switch-stable subjects must have discontinued ERT at least 2 weeks before the scheduled AVR-RD-02 infusion. Switch-stable subjects who had been and substrate reduction therapy (SRT) must not have received SRT within 12 months of Screening. Treatment-naïve AVR-RD-02 Treatment-naïve arm: Subjects with Type 1 Gaucher disease who had never received either ERT or SRT for Gaucher disease or had not received either ERT or SRT for Gaucher disease within 12 months of Screening (i.e., treatment-naïve subjects). Enrollment followed a similar scheme as for the switch-stable subjects. Note: No subjects enrolled in this arm.
- Primary Outcome Measures
Name Time Method Number of Clinically Significant Adverse Events (AEs) and Serious Adverse Events (SAEs) of AVR-RD-02 Baseline to 52 weeks post-AVR-RD-02 treatment follow-up 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).
AE/SAE can either be related to AVR-RD-02 infusion or attributed to the conditioning agent, mobilization agent(s), study procedures, and the underlying disease.Vector Copy Number (VCN) in Bone Marrow as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR) Baseline to 52 weeks post-AVR-RD-02 treatment follow-up VCN is defined as the average number of copies of the therapeutic gene (transgene) in a sample of cells and is a measurement of the number of copies of the vector 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. This measurement was for VCN in a sample of bone marrow progenitor cells obtained from an aspirate.
Change From Baseline in Spleen Volume Assessed by Abdominal MRI Baseline to 52 weeks post-AVR-RD-02 treatment follow-up Percent change in spleen volume = (\[spleen volume at Week 52 minus spleen volume at baseline\] divided by \[spleen volume at baseline\]) multiplied by 100. A reduction in the percent change from baseline (%CFB) in spleen volume (mL) is a positive indicator of efficacy.
Change From Baseline in Platelet Count Baseline to 52 weeks post-AVR-RD-02 treatment follow-up Ratio to baseline indicates the percent change in platelet count. The Baseline value is defined as 1 or 100%. A ratio to Baseline \<1 indicates a reduction in platelet count and a ratio to Baseline \>1 indicates an increase in platelet count.
Vector Copy Number (VCN) in Peripheral Blood as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR) Baseline to 52 weeks post-AVR-RD-02 treatment follow-up VCN, defined as the average number of copies of the therapeutic gene (transgene) in a sample of cells, is conventionally reported as the number of vector copies 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. This measurement was for VCN in a sample of progenitor cells obtained from a peripheral blood sample.
Change From Baseline in Liver Volume Assessed by Abdominal MRI Baseline to 52 weeks post-AVR-RD-02 treatment follow-up Percent change in liver volume = (\[liver volume at Week 52 minus liver volume at baseline\] divided by \[liver volume at baseline\]) multiplied by 100. A reduction in the percent change from baseline (%CFB) in liver volume (mL) is a positive indicator of efficacy.
Change From Baseline in Hemoglobin Concentration Baseline to 52 weeks post-AVR-RD-02 treatment follow-up Ratio to baseline indicates the percent change in hemoglobin concentration. The baseline value is defined as 1 or 100%. A ratio to Baseline \<1 indicates a reduction in hemoglobin concentration and a ratio to Baseline \>1 indicates an increase in hemoglobin concentration.
Change From Baseline in Plasma Lyso-Gb1 Levels by Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS) Baseline to 52 weeks post-AVR-RD-02 treatment follow-up Glucosylsphingosine (lyso-Gb1) is the substrate that accumulates in the lysosomes of patients affected by Gaucher disease as a result of deficiencies in GCase enzyme activity. Treatment with AVR-RD-02 is intended to replace the missing GCase enzymatic activity, which allows degradation of accumulated lyso-Gb1 substrate in the lysosomes. Negative values (decrease from Baseline) are an indicator of efficacy.
- Secondary Outcome Measures
Name Time Method Change From Baseline in GCase Enzyme Activity Level in Plasma Weeks 13, 26, 39, and 52 Treatment-naïve Gaucher patients are deficient in glucosylcerebrosidase (GCase) enzyme activity due to mutations in the GBA gene. AVR-RD-02 is intended to increase the amount of GCase enzyme activity in the lysosomes of treated subjects. A positive value (increase from Baseline in GCase enzyme activity) is a positive indicator of efficacy.
Number of Subjects Who Restarted ERT Between Week 26 and Week 52 post-AVR-RD-02 treatment The absence of the need to re-start ERT post treatment is a positive indicator of efficacy.
Change From Baseline in Bone Mineral Density (BMD) Assessed by Bone Density Scan (DXA) Baseline to 52 weeks post-AVR-RD-02 treatment follow-up An increase in BMD is a positive indicator of efficacy. Subjects had Z-scores reported for change from baseline in Bone Mineral Density in the Femoral Neck and Lumbar Spine regions assessed by Bone Mineral Density (DXA).
A Z-score compares the subject's bone density to the average bone density of people their own age and gender. If the bones more dense than the average person their own age and gender, the bone mass will be indicated as a positive Z-score. Higher positive Z-score indicates greater bone density. If the bones are less dense than the average person their own age and gender, the bone mass will be indicated as a negative Z-score. Lower negative Z-score indicates lesser bone density.Change From Baseline in Plasma Chitotriosidase Activity Levels Measured by Fluorometric Enzyme Assay Baseline to 52 weeks post-AVR-RD-02 treatment follow-up Chitotriosidase enzyme is part of an inflammatory response originating in macrophages, which are the primary cell type affected in Gaucher disease. Gaucher disease patients typically have elevated Chitotriosidase enzyme activity in their plasma compared to healthy population. A reduction from Baseline in chitotriosidase enzyme activity is a positive indicator of efficacy.
Change From Baseline in Bone Marrow Burden (BMB) Score as Assessed by Bone Magnetic Resonance Imaging (MRI) Baseline to 52 weeks post-AVR-RD-02 treatment follow-up Bone Marrow Burden Score is a semi-quantitative MRI scoring system for assessing the extent of bone marrow involvement in Gaucher disease. A BMB score from 0 to 8 could be given for the lumbar spine, and a BMB score from 0 to 8 could be given to the femurs. Thus, a total BMB score of up to 16 is obtained by adding the lumbar and femoral BMB scores. A higher total BMB-score indicates more severe bone marrow involvement. A reduction in BMB score is a positive indicator of efficacy.
Change From Baseline in GCase Enzyme Activity Level in Peripheral Blood Leukocytes Weeks 13, 26, 39, and 52 Treatment-naïve Gaucher patients are deficient in glucosylcerebrosidase (GCase) enzyme activity due to mutations in the GBA gene. AVR-RD-02 is intended to increase the amount of GCase enzyme activity in the lysosomes of treated subjects. A positive value (increase from Baseline in GCase enzyme activity) is a positive indicator of efficacy.
Change From Baseline in Presence of Anti-GCase Total Antibodies At Weeks 5, 13, 26, 39, and 52 Number of subjects with changes in anti-GCase antibodies from Baseline to post infusion timepoints. Unit 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 compared to Baseline) indicates no immune response to the therapeutic protein.
Trial Locations
- Locations (5)
University of Iowa
🇺🇸Iowa City, Iowa, United States
UPMC Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
University Health Network
🇨🇦Toronto, Ontario, Canada
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
University of California San Diego
🇺🇸San Diego, California, United States