Fabry Disease
Conditions
Keywords
Fabry disease, Cell therapy, Gene therapy, Lysosomal storage disorder, Lenti-viral
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.
Interventions
DRUGAVR-RD-01
Single IV infusion of between 3 - 20 x 10\^6 CD34+ cells/kg.
Sponsors
AVROBIO
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
16 Years to 50 Years
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline to Week 48 post gene therapy | 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. |
| Change From Baseline in Immunogenicity of AVR-RD-01 | Baseline to Week 48 post gene therapy | 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. |
| Presence of Replication Competent Lentivirus (RCL) | Baseline to Week 48 post gene therapy | 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. |
| Evaluation of Aberrant Clonal Expansion | Baseline to Week 48 post gene therapy | 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. |
| Change From Baseline in the Average Number of Gb3 Inclusions (ie, Myelinosomes) Per Kidney Peritubular Capillary (PTC) Per Subject | Baseline to Week 48 post gene therapy | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Renal Function as Assessed by Measured Glomerular Filtration Rate (mGFR) | Baseline to Week 48 post gene therapy | mGFR is a measure of the time the kidney takes to filter products that the body does not naturally produce. |
| Change From Baseline in Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) | Baseline to Week 24 and Week 48 post gene therapy | eGFR is the measure to evaluate kidney function. It is the estimated amount of blood that is filtered through all glomeruli in a given time. |
| Change From Baseline in Renal Function as Assessed by Urine Total Protein Levels | Baseline to Week 24 and Week 48 post gene therapy | — |
| Change From Baseline in Renal Function as Assessed by Urine Albumin Levels | Baseline to Week 24 and Week 48 post gene therapy | A healthy kidney only allows very small amounts of albumin to pass from the blood into the urine. An increased level of albumin in urine (albuminuria) is a marker of renal damage. |
| 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 | 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. |
| Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D) | Baseline to Week 24 and Week 48 post gene therapy | DIBSS-D assesses bowel habits and abdominal symptoms over a period of time. It was administered daily for 14 days commencing at each study visit. Stool Consistency scale has been converted to a numeric rating scale for ease of analysis, where 1=Very hard; 2=Hard; 3=Neither too hard nor too soft; 4=Loose but not lumpy; 5=Very loose and watery. The median of each 14-day period was derived per patient, per visit before deriving the group median. Group median at Baseline (pre-treatment) was 3.540 (n=9). Change from baseline (CFB) is presented below. An increase CFB indicates softening of the stools, and a decrease CFB indicates hardening of the stools. Abdominal Pain measure asked the patient to rate the worst level of pain within the past 24hrs (0=no pain; 10=worst possible pain). A mean score was derived for each 14-day period per patient, per visit, and these means used to derive a group mean. An increase CFB indicates more abdominal pain; a decrease CFB indicates less abdominal pain. |
| Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores | Baseline to Week 24 and Week 48 post gene therapy | The short version of the BPI (Short form) includes 9 items: Q1 - Q9, Question 9 includes 7 sub-items (Q9a - Q9g). It uses a 0 to 10 numeric rating scales for item rating. The pain severity score is calculated as the average of questions answered: Q3 (worst pain), Q4 (least pain), Q5 (average pain) and Q6 (current pain). The pain interference score is calculated as the average of the answered Q9 sub-items, which represents pain interference with general activity (Q9a), mood (Q9b), walking ability (Q9c), normal work (Q9d), relations with other people (Q9e), sleep (Q9f), and enjoyment of life (Q9g). A reduction in score from baseline indicates less pain. |
| 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 | Baseline to Week 48 post gene therapy | The original version of the SF-36 was administered to the participants and consisted of eight subscales (Vitality, Physical Functioning, Bodily Pain, General Health Perceptions, Physical Role Functioning, Emotional Role Functioning, Social Role Functioning and Mental Health) each scored from 0 (worst health) to 100 (best heath). These scores were normalized (re-scaled) against mean scores obtained in the US general population (Mean=50, Standard deviation 10). The summary health components PCS and MCS are derived from the eight subscales mentioned above and summarize information from all eight subscales but with different weights. For PCS, highest weights are given to the physical subscales while some mental subscales are given negative weights. For MCS, highest weights are given to the mental subscales while some physical subscales are given negative weights. An increase in the normalized score from baseline indicates improvement in physical and mental functioning. |
| 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) | At Week 48 post gene therapy | 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 Left Ventricular Mass Index (LVMI) as Assessed by Cardiac Magnetic Resonance Imaging (MRI) | Baseline to Week 48 post gene therapy | LVMI is a surrogate of left ventricular hypertrophy. An increase in LVMI is an independent risk factor for cardiovascular morbidity and mortality. |
| 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 | 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. |
| Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma | Baseline to Week 24 and Week 48 post gene therapy | Globotriaosylceramide (Gb3) is the substrate that accumulates in the lysosomes of patients affected by Fabry Disease as a result of deficiencies in AGA enzyme activity. Treatment-naive patients are expected to have high levels of Gb3 in their lysosomes and correspondingly elevated levels in plasma. Treatment with AVR-RD-01 is intended to replace the missing AGA enzymatic activity, which allows degradation of accumulated Gb3 substrate in the lysosomes and reductions in the levels of circulating Gb3 in plasma. |
| Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine | Baseline to Week 24 and Week 48 post gene therapy | Globotriaosylceramide (Gb3) is the substrate that accumulates in the lysosomes of patients affected by Fabry Disease as a result of deficiencies in AGA enzyme activity. Treatment-naive patients are expected to have high levels of Gb3 in their lysosomes and correspondingly elevated levels in urine. Treatment with AVR-RD-01 is intended to replace the missing AGA enzymatic activity, which allows degradation of accumulated Gb3 substrate in the lysosomes and reductions in the levels of excreted Gb3 in urine. |
| Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | Baseline to Week 24 and Week 48 post gene therapy | Globotriaosylceramide (Gb3) is the substrate that accumulates in the lysosomes of patients affected by Fabry Disease as a result of deficiencies in AGA enzyme activity. Treatment-naive patients are expected to have high levels of Gb3 in their lysosomes and correspondingly elevated levels in tissue samples. Treatment with AVR-RD-01 is intended to replace the missing AGA enzymatic activity, which allows degradation of accumulated Gb3 substrate in the lysosomes and reductions in the levels of measured Gb3 in tissues. |
Countries
Australia, Brazil, United States
Participant flow
Recruitment details
Total number of subjects who signed the ICF was 16 (one subject who re-screened was not considered enrolled initially), as a result there were 15 distinct subjects who signed ICF. There were 4 participants who failed screening and were not rescreened. The Safety population consists of all 11 enrolled subjects who received any preparatory medication. The Infused population consists of all 9 enrolled subjects who received all preparatory medications and AVR-RD-01.
Participants by arm
| Arm | Count |
|---|---|
| Single Assignment AVR-RD-01 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 Single IV infusion of between 3 - 20 x 10\^6 CD34+ cells/kg. | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not pass screening | 4 |
| Overall Study | Study Terminated by the Sponsor | 5 |
Baseline characteristics
| Characteristic | Single Assignment AVR-RD-01 |
|---|---|
| Age, Continuous | 31.45 years STANDARD_DEVIATION 10.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 11 |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 8 / 11 |
Outcome results
Primary
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
Population: The infused population includes all enrolled subjects who received preparatory medications and AVR-RD-01. Four tested positive for anti-AGA antibodies post-AVR-RD-01 infusion at Week 48 or Early Termination visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Immunogenicity of AVR-RD-01 | 4 Number of positive subjects |
Primary
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.
Time frame: Baseline to Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. Of the nine subjects, only 2 subjects had baseline and Week 48 results to measure change from baseline. The remaining seven subjects either did not provide both samples or the samples provided were not evaluable.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in the Average Number of Gb3 Inclusions (ie, Myelinosomes) Per Kidney Peritubular Capillary (PTC) Per Subject | -3.555 Number of inclusions |
Primary
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.
Time frame: Baseline to Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Assignment AVR-RD-01 | Evaluation of Aberrant Clonal Expansion | 0 number of abnormal clonal proliferations |
Primary
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
Population: The Safety population consists of all enrolled subjects who received any preparatory medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single Assignment AVR-RD-01 | Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE | 354 Number of events |
| Single Assignment AVR-RD-01 | Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAE | 13 Number of events |
Primary
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
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Assignment AVR-RD-01 | Presence of Replication Competent Lentivirus (RCL) | 0 Number of positive subjects |
Secondary
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)
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.
Time frame: At Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. No analysis performed (refer to Limitations and Caveats section)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Single Assignment AVR-RD-01 | 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) | 1.14 copies/diploid genome |
Secondary
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
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | 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) | Week 24 | 0.383 copies/diploid genome | Standard Deviation 0.4628 |
| Single Assignment AVR-RD-01 | 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) | Week 48 | 0.313 copies/diploid genome | Standard Deviation 0.3447 |
Secondary
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.
Time frame: Baseline to Week 24 and Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs) | CFB Plasma W24 | 1.973 nmol/h/mg | Standard Deviation 2.585 |
| Single Assignment AVR-RD-01 | Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs) | CFB Plasma W48 | 1.548 nmol/h/mg | Standard Deviation 2.152 |
| Single Assignment AVR-RD-01 | Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs) | CFB PBL Week 24 | 29.524 nmol/h/mg | Standard Deviation 39.194 |
| Single Assignment AVR-RD-01 | Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs) | CFB PBL Week 48 | 18.973 nmol/h/mg | Standard Deviation 32.8 |
Secondary
Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D)
DIBSS-D assesses bowel habits and abdominal symptoms over a period of time. It was administered daily for 14 days commencing at each study visit. Stool Consistency scale has been converted to a numeric rating scale for ease of analysis, where 1=Very hard; 2=Hard; 3=Neither too hard nor too soft; 4=Loose but not lumpy; 5=Very loose and watery. The median of each 14-day period was derived per patient, per visit before deriving the group median. Group median at Baseline (pre-treatment) was 3.540 (n=9). Change from baseline (CFB) is presented below. An increase CFB indicates softening of the stools, and a decrease CFB indicates hardening of the stools. Abdominal Pain measure asked the patient to rate the worst level of pain within the past 24hrs (0=no pain; 10=worst possible pain). A mean score was derived for each 14-day period per patient, per visit, and these means used to derive a group mean. An increase CFB indicates more abdominal pain; a decrease CFB indicates less abdominal pain.
Time frame: Baseline to Week 24 and Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D) | Abdominal Pain Week 24 | -0.445 units on a scale | Standard Deviation 0.583 |
| Single Assignment AVR-RD-01 | Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D) | Abdominal Pain Week 48 | -0.497 units on a scale | Standard Deviation 0.626 |
| Single Assignment AVR-RD-01 | Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D) | Stool Consistency Week 24 | -0.373 units on a scale | Standard Deviation 0.216 |
| Single Assignment AVR-RD-01 | Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D) | Stool Consistency Week 48 | -0.530 units on a scale | Standard Deviation 0.104 |
Secondary
Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores
The short version of the BPI (Short form) includes 9 items: Q1 - Q9, Question 9 includes 7 sub-items (Q9a - Q9g). It uses a 0 to 10 numeric rating scales for item rating. The pain severity score is calculated as the average of questions answered: Q3 (worst pain), Q4 (least pain), Q5 (average pain) and Q6 (current pain). The pain interference score is calculated as the average of the answered Q9 sub-items, which represents pain interference with general activity (Q9a), mood (Q9b), walking ability (Q9c), normal work (Q9d), relations with other people (Q9e), sleep (Q9f), and enjoyment of life (Q9g). A reduction in score from baseline indicates less pain.
Time frame: Baseline to Week 24 and Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores | Week 24 (pain severity) | -0.188 score on a scale | Standard Deviation 0.874 |
| Single Assignment AVR-RD-01 | Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores | Week 48 (pain severity) | -0.500 score on a scale | Standard Deviation 0.612 |
| Single Assignment AVR-RD-01 | Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores | Week 24 (pain interference) | 0.073 score on a scale | Standard Deviation 1.007 |
| Single Assignment AVR-RD-01 | Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores | Week 48 (pain interference) | -0.573 score on a scale | Standard Deviation 0.996 |
Secondary
Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma
Globotriaosylceramide (Gb3) is the substrate that accumulates in the lysosomes of patients affected by Fabry Disease as a result of deficiencies in AGA enzyme activity. Treatment-naive patients are expected to have high levels of Gb3 in their lysosomes and correspondingly elevated levels in plasma. Treatment with AVR-RD-01 is intended to replace the missing AGA enzymatic activity, which allows degradation of accumulated Gb3 substrate in the lysosomes and reductions in the levels of circulating Gb3 in plasma.
Time frame: Baseline to Week 24 and Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma | Week 24 | -3334.0 nM | Standard Deviation 3846.8 |
| Single Assignment AVR-RD-01 | Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma | Week 48 | -5067.8 nM | Standard Deviation 4067 |
Secondary
Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine
Globotriaosylceramide (Gb3) is the substrate that accumulates in the lysosomes of patients affected by Fabry Disease as a result of deficiencies in AGA enzyme activity. Treatment-naive patients are expected to have high levels of Gb3 in their lysosomes and correspondingly elevated levels in urine. Treatment with AVR-RD-01 is intended to replace the missing AGA enzymatic activity, which allows degradation of accumulated Gb3 substrate in the lysosomes and reductions in the levels of excreted Gb3 in urine.
Time frame: Baseline to Week 24 and Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine | Week 24 | -11.73 nmol/mmol creatinine | Standard Deviation 309.78 |
| Single Assignment AVR-RD-01 | Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine | Week 48 | -188.73 nmol/mmol creatinine | Standard Deviation 262.9 |
Secondary
Change From Baseline in Left Ventricular Mass Index (LVMI) as Assessed by Cardiac Magnetic Resonance Imaging (MRI)
LVMI is a surrogate of left ventricular hypertrophy. An increase in LVMI is an independent risk factor for cardiovascular morbidity and mortality.
Time frame: Baseline to Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Left Ventricular Mass Index (LVMI) as Assessed by Cardiac Magnetic Resonance Imaging (MRI) | 7.270 g/m^2 | Standard Deviation 6.055 |
Secondary
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
The original version of the SF-36 was administered to the participants and consisted of eight subscales (Vitality, Physical Functioning, Bodily Pain, General Health Perceptions, Physical Role Functioning, Emotional Role Functioning, Social Role Functioning and Mental Health) each scored from 0 (worst health) to 100 (best heath). These scores were normalized (re-scaled) against mean scores obtained in the US general population (Mean=50, Standard deviation 10). The summary health components PCS and MCS are derived from the eight subscales mentioned above and summarize information from all eight subscales but with different weights. For PCS, highest weights are given to the physical subscales while some mental subscales are given negative weights. For MCS, highest weights are given to the mental subscales while some physical subscales are given negative weights. An increase in the normalized score from baseline indicates improvement in physical and mental functioning.
Time frame: Baseline to Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. For Week 24 data, please see comment in Limitations and Caveats section.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | 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 | Physical Functioning Week 48 | 3.235 score on a scale | Standard Deviation 4.81 |
| Single Assignment AVR-RD-01 | 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 | Mental Functioning Week 48 | -1.580 score on a scale | Standard Deviation 4.652 |
Secondary
Change From Baseline in Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR)
eGFR is the measure to evaluate kidney function. It is the estimated amount of blood that is filtered through all glomeruli in a given time.
Time frame: Baseline to Week 24 and Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) | Week 24 | -6.386 mL/min/1.73 m^2 | Standard Deviation 9.699 |
| Single Assignment AVR-RD-01 | Change From Baseline in Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) | Week 48 | -3.561 mL/min/1.73 m^2 | Standard Deviation 7.332 |
Secondary
Change From Baseline in Renal Function as Assessed by Measured Glomerular Filtration Rate (mGFR)
mGFR is a measure of the time the kidney takes to filter products that the body does not naturally produce.
Time frame: Baseline to Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Renal Function as Assessed by Measured Glomerular Filtration Rate (mGFR) | -2.358 mL/min/1.73m^2 | Standard Deviation 14.502 |
Secondary
Change From Baseline in Renal Function as Assessed by Urine Albumin Levels
A healthy kidney only allows very small amounts of albumin to pass from the blood into the urine. An increased level of albumin in urine (albuminuria) is a marker of renal damage.
Time frame: Baseline to Week 24 and Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Renal Function as Assessed by Urine Albumin Levels | Week 24 | 0.915 mg/dL | Standard Deviation 6.704 |
| Single Assignment AVR-RD-01 | Change From Baseline in Renal Function as Assessed by Urine Albumin Levels | Week 48 | 0.643 mg/dL | Standard Deviation 5.789 |
Secondary
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
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01. No data were collected for any subjects since samples were not analyzed in order to produce data (Refer to Limitations and Caveat section.)
Secondary
Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy
Globotriaosylceramide (Gb3) is the substrate that accumulates in the lysosomes of patients affected by Fabry Disease as a result of deficiencies in AGA enzyme activity. Treatment-naive patients are expected to have high levels of Gb3 in their lysosomes and correspondingly elevated levels in tissue samples. Treatment with AVR-RD-01 is intended to replace the missing AGA enzymatic activity, which allows degradation of accumulated Gb3 substrate in the lysosomes and reductions in the levels of measured Gb3 in tissues.
Time frame: Baseline to Week 24 and Week 48 post gene therapy
Population: The Infused population consists of all enrolled subjects who received all preparatory medications and AVR-RD-01.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Assignment AVR-RD-01 | Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | Myelinosomes in superficial dermal capillary endothelial cells (Week 24) | -0.4 number of myelinosomes | Standard Deviation 1.3 |
| Single Assignment AVR-RD-01 | Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | Myelinosomes in superficial dermal capillary endothelial cells (Week 48) | -0.5 number of myelinosomes | Standard Deviation 1 |
| Single Assignment AVR-RD-01 | Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | Myelinosomes in deep dermal capillary endothelial cells (Week 24) | 0 number of myelinosomes | Standard Deviation 1.3 |
| Single Assignment AVR-RD-01 | Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | Myelinosomes in deep dermal capillary endothelial cells (Week 48) | -0.5 number of myelinosomes | Standard Deviation 1 |
| Single Assignment AVR-RD-01 | Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | Myelinosomes in vascular smooth muscle cells (Week 24) | 0.1 number of myelinosomes | Standard Deviation 1.2 |
| Single Assignment AVR-RD-01 | Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | Myelinosomes in vascular smooth muscle cells (Week 48) | -0.5 number of myelinosomes | Standard Deviation 1 |
| Single Assignment AVR-RD-01 | Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | Myelinosomes in perineurium (Week 24) | 0 number of myelinosomes | Standard Deviation 1.4 |
| Single Assignment AVR-RD-01 | Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy | Myelinosomes in perineurium (Week 48) | -0.5 number of myelinosomes | Standard Deviation 1 |