BEQVEZ (fidanacogene elaparvovec-dzkt) is a gene therapy designed to introduce in the transduced cells a functional copy of the factor IX gene encoding a high-activity FIX variant (FIX-R338L, hFIX Padua).
The AAVRh74var capsid is able to transduce hepatocytes, the natural site of factor IX synthesis. Single intravenous infusion of BEQVEZ results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B.
BEQVEZ therapy results in continuous endogenous coagulation factor IX expression.
The pharmacodynamic effect of BEQVEZ was assessed by measuring circulating factor IX activity level following administration of 5 × 1011 vg/kg of BEQVEZ. Factor IX activity level over time obtained from clinical study 1 is presented in Table 4. At Month 15, 86% (30 out of 35) patients had FIX activity ≥5% based on one-stage SynthASil assay and 68% (23 out of 34) and 71% (25 out of 35) based on one-stage Actin-FSL assay and chromogenic assay, respectively. At Month 24, 82% (18 out of 22) patients had FIX activity ≥5% based on one-stage SynthASil assay, and 64% (14 out of 22) based on one-stage Actin-FSL assay and chromogenic assay.
| Any samples taken within 7 days (14 days if extended half-life product is used) of exogenous FIX replacement therapy were not included in the analysis. | |||
| If a patient withdrew consent, dropped out early from the study or resumed FIX prophylaxis, then the assessments at the visits following withdrawal/dropout/resumption were imputed as 1.9%. Of the 6 participants needing imputation the following timepoints were imputed: Month 6 (1), Month 15 (5) and Month 24 (3). | |||
One-Stage Assay (SynthASil Reagent)* (N=45) | One-Stage Assay (Actin-FSL Reagent)† (N=45) | Chromogenic Assay (N=45) | |
Week 4 | |||
N | 42 | 42 | 43 |
Mean (SD) | 19 (7.5) | 9 (4.4) | 9 (4.5) |
Median (min, max) | 18 (4, 32) | 9 (1, 22) | 8 (2, 22) |
Week 12 | |||
N | 44 | 43 | 44 |
Mean (SD) | 28 (15.2) | 14 (8.1) | 14 (9.3) |
Median (min, max) | 26 (3, 69) | 13 (2, 35) | 12 (1, 36) |
Month 6 | |||
N | 39 | 41 | 40 |
Mean (SD) | 28 (21.3) | 13 (11.1) | 15 (13.0) |
Median (min, max) | 23 (2, 100) | 10 (1, 55) | 10 (1, 58) |
Month 15 | |||
N | 35 | 34 | 35 |
Mean (SD) | 27 (25.7) | 13 (12.8) | 16 (17.0) |
Median (min, max) | 23 (2, 119) | 10 (2, 62) | 10 (2, 74) |
Month 24 | |||
N | 22 | 22 | 22 |
Mean (SD) | 25 (22.6) | 13 (11.9) | 15 (18.8) |
Median (min, max) | 23 (2, 95) | 9 (1, 47) | 10 (1, 80) |
Up to 6 years of follow-up FIX activity data is available from patients receiving the recommended dose of 5 × 1011 vg/kg in clinical study 2 (NCT02484092/NCT03307980). FIX activity remained stable over time, with mean factor IX activity (one-stage assay with Actin-FSL reagent) at 27.9% at Month 15 (n=9), 24.9% at Month 24 (n=14), 21.5% at Month 48 (Year 4, n=11) and 21.5% at Month 72 (Year 6, n=5).
Specific Populations
There is a trend of higher mean FIX activity (Week 12 to Month 15) with age, higher BMI, as well as in White race. Patients ≥35 years old (n=17) had 1.9-fold higher mean FIX activity as compared to patients 18 to <35 years old (n=28). Patients with BMI ≥25 kg/m2 (n=29) had 1.5-fold higher mean FIX activity as compared to patients with <25 kg/m2 (n=16). Patients in White race group (n=29) had 1.6-fold higher mean FIX activity as compared to patients in Non-white race group (n=12).
Biodistribution (Within the Body) and Vector Shedding (Excretion/Secretion)
BEQVEZ vector DNA levels were measured and quantified in blood and various shedding matrices using a quantitative polymerase chain reaction (qPCR) assay. This assay is sensitive and specific to BEQVEZ vector DNA, but could also detect DNA fragments. Saliva, semen, and urine samples from a subset of patients in the clinical study 1 were further characterized by measuring encapsidated vector DNA by a modified assay.
Nonclinical Biodistribution
Biodistribution of BEQVEZ was evaluated approximately 92 days after intravenous administration in healthy male non-human primates (NHPs) at dose levels up to 5 × 1012 vg/kg. Vector DNA was detected in all tissues assessed, including the testes. The highest levels of vector DNA were detected in the liver, spleen, and inguinal lymph nodes.
Clinical Data
Vector shedding after infusion with BEQVEZ was assessed in 60 patients at multiple time points in clinical studies (clinical study 1 and clinical study 2). In clinical study 1 a subset of patients (n=17) provided optional samples at early timepoints (2, 24 and 72 hours post-infusion) to better define parameters such as maximum vector DNA level (Cmax) and time to maximum vector DNA level (Tmax). The maximum vector DNA concentrations were found in plasma followed by saliva, peripheral blood mononuclear cells (PBMC), semen and urine. The mean Tmax was 1.2 days for plasma and saliva and 1.6 days for urine. The mean Tmax was 3.8 days and 7.4 days for semen and PBMC, respectively. For pooled analysis of clinical data (N=60 patients), full clearance of vector DNA was defined as having 3 consecutive negative results (i.e., below quantification limit). Vector DNA fully cleared from plasma, saliva, and semen within a mean of 1 to 4 months after infusion and PBMC was the slowest fluid to full clearance within a mean of 12 months. In semen, the maximum observed time for vector DNA full clearance was 154 days. In urine, the peak vector DNA concentration was very low relative to plasma and declined to full clearance within a mean of 4 weeks after infusion.
The administration of BEQVEZ has the potential to generate immunity in the form of neutralizing antibodies against the vector capsid, the transgene (virus-derived factor IX) and as a cellular response against the transduced cells producing factor IX.
In clinical studies, all patients receiving treatment were required to screen negative for anti-AAVRh74var neutralizing antibodies and negative (<0.6 BU) for factor IX inhibitors in a Nijmegen modified Bethesda assay following a lifetime minimum of 50 exposure days to factor IX replacement therapy. No patients developed factor IX inhibitors during the clinical studies using BEQVEZ.
A sustained increase in neutralizing anti-AAVRh74var antibodies has been observed after administration of BEQVEZ in all patients who participated in clinical studies and had neutralizing antibody (nAb) assessment.
In clinical study 1, anti-AAVRh74var antibody titers were assessed annually following BEQVEZ administration. Mean (SD) titer at Week 52 was 101,230.98 (118,479.743) and at the last time point tested, Week 156, mean (SD) titer was 132,527.56 (121,891.612).
BEQVEZ-treated patients were tested for cellular immune responses to overall capsid pool and overall factor IX pool using an IFN-γ enzyme-linked immunosorbent spot (ELISpot) assay.
ELISpot results did not show a trend of presumed T-cell response (based on limited positive ELISpot) as a function of time during the 1-year post-infusion period in either clinical study 1 or clinical study 2.
BEQVEZ (fidanacogene elaparvovec-dzkt) is a gene therapy designed to introduce in the transduced cells a functional copy of the factor IX gene encoding a high-activity FIX variant (FIX-R338L, hFIX Padua).
The AAVRh74var capsid is able to transduce hepatocytes, the natural site of factor IX synthesis. Single intravenous infusion of BEQVEZ results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B.
BEQVEZ therapy results in continuous endogenous coagulation factor IX expression.
The pharmacodynamic effect of BEQVEZ was assessed by measuring circulating factor IX activity level following administration of 5 × 1011 vg/kg of BEQVEZ. Factor IX activity level over time obtained from clinical study 1 is presented in Table 4. At Month 15, 86% (30 out of 35) patients had FIX activity ≥5% based on one-stage SynthASil assay and 68% (23 out of 34) and 71% (25 out of 35) based on one-stage Actin-FSL assay and chromogenic assay, respectively. At Month 24, 82% (18 out of 22) patients had FIX activity ≥5% based on one-stage SynthASil assay, and 64% (14 out of 22) based on one-stage Actin-FSL assay and chromogenic assay.
| Any samples taken within 7 days (14 days if extended half-life product is used) of exogenous FIX replacement therapy were not included in the analysis. | |||
| If a patient withdrew consent, dropped out early from the study or resumed FIX prophylaxis, then the assessments at the visits following withdrawal/dropout/resumption were imputed as 1.9%. Of the 6 participants needing imputation the following timepoints were imputed: Month 6 (1), Month 15 (5) and Month 24 (3). | |||
One-Stage Assay (SynthASil Reagent)* (N=45) | One-Stage Assay (Actin-FSL Reagent)† (N=45) | Chromogenic Assay (N=45) | |
Week 4 | |||
N | 42 | 42 | 43 |
Mean (SD) | 19 (7.5) | 9 (4.4) | 9 (4.5) |
Median (min, max) | 18 (4, 32) | 9 (1, 22) | 8 (2, 22) |
Week 12 | |||
N | 44 | 43 | 44 |
Mean (SD) | 28 (15.2) | 14 (8.1) | 14 (9.3) |
Median (min, max) | 26 (3, 69) | 13 (2, 35) | 12 (1, 36) |
Month 6 | |||
N | 39 | 41 | 40 |
Mean (SD) | 28 (21.3) | 13 (11.1) | 15 (13.0) |
Median (min, max) | 23 (2, 100) | 10 (1, 55) | 10 (1, 58) |
Month 15 | |||
N | 35 | 34 | 35 |
Mean (SD) | 27 (25.7) | 13 (12.8) | 16 (17.0) |
Median (min, max) | 23 (2, 119) | 10 (2, 62) | 10 (2, 74) |
Month 24 | |||
N | 22 | 22 | 22 |
Mean (SD) | 25 (22.6) | 13 (11.9) | 15 (18.8) |
Median (min, max) | 23 (2, 95) | 9 (1, 47) | 10 (1, 80) |
Up to 6 years of follow-up FIX activity data is available from patients receiving the recommended dose of 5 × 1011 vg/kg in clinical study 2 (NCT02484092/NCT03307980). FIX activity remained stable over time, with mean factor IX activity (one-stage assay with Actin-FSL reagent) at 27.9% at Month 15 (n=9), 24.9% at Month 24 (n=14), 21.5% at Month 48 (Year 4, n=11) and 21.5% at Month 72 (Year 6, n=5).
Specific Populations
There is a trend of higher mean FIX activity (Week 12 to Month 15) with age, higher BMI, as well as in White race. Patients ≥35 years old (n=17) had 1.9-fold higher mean FIX activity as compared to patients 18 to <35 years old (n=28). Patients with BMI ≥25 kg/m2 (n=29) had 1.5-fold higher mean FIX activity as compared to patients with <25 kg/m2 (n=16). Patients in White race group (n=29) had 1.6-fold higher mean FIX activity as compared to patients in Non-white race group (n=12).
Biodistribution (Within the Body) and Vector Shedding (Excretion/Secretion)
BEQVEZ vector DNA levels were measured and quantified in blood and various shedding matrices using a quantitative polymerase chain reaction (qPCR) assay. This assay is sensitive and specific to BEQVEZ vector DNA, but could also detect DNA fragments. Saliva, semen, and urine samples from a subset of patients in the clinical study 1 were further characterized by measuring encapsidated vector DNA by a modified assay.
Nonclinical Biodistribution
Biodistribution of BEQVEZ was evaluated approximately 92 days after intravenous administration in healthy male non-human primates (NHPs) at dose levels up to 5 × 1012 vg/kg. Vector DNA was detected in all tissues assessed, including the testes. The highest levels of vector DNA were detected in the liver, spleen, and inguinal lymph nodes.
Clinical Data
Vector shedding after infusion with BEQVEZ was assessed in 60 patients at multiple time points in clinical studies (clinical study 1 and clinical study 2). In clinical study 1 a subset of patients (n=17) provided optional samples at early timepoints (2, 24 and 72 hours post-infusion) to better define parameters such as maximum vector DNA level (Cmax) and time to maximum vector DNA level (Tmax). The maximum vector DNA concentrations were found in plasma followed by saliva, peripheral blood mononuclear cells (PBMC), semen and urine. The mean Tmax was 1.2 days for plasma and saliva and 1.6 days for urine. The mean Tmax was 3.8 days and 7.4 days for semen and PBMC, respectively. For pooled analysis of clinical data (N=60 patients), full clearance of vector DNA was defined as having 3 consecutive negative results (i.e., below quantification limit). Vector DNA fully cleared from plasma, saliva, and semen within a mean of 1 to 4 months after infusion and PBMC was the slowest fluid to full clearance within a mean of 12 months. In semen, the maximum observed time for vector DNA full clearance was 154 days. In urine, the peak vector DNA concentration was very low relative to plasma and declined to full clearance within a mean of 4 weeks after infusion.
The administration of BEQVEZ has the potential to generate immunity in the form of neutralizing antibodies against the vector capsid, the transgene (virus-derived factor IX) and as a cellular response against the transduced cells producing factor IX.
In clinical studies, all patients receiving treatment were required to screen negative for anti-AAVRh74var neutralizing antibodies and negative (<0.6 BU) for factor IX inhibitors in a Nijmegen modified Bethesda assay following a lifetime minimum of 50 exposure days to factor IX replacement therapy. No patients developed factor IX inhibitors during the clinical studies using BEQVEZ.
A sustained increase in neutralizing anti-AAVRh74var antibodies has been observed after administration of BEQVEZ in all patients who participated in clinical studies and had neutralizing antibody (nAb) assessment.
In clinical study 1, anti-AAVRh74var antibody titers were assessed annually following BEQVEZ administration. Mean (SD) titer at Week 52 was 101,230.98 (118,479.743) and at the last time point tested, Week 156, mean (SD) titer was 132,527.56 (121,891.612).
BEQVEZ-treated patients were tested for cellular immune responses to overall capsid pool and overall factor IX pool using an IFN-γ enzyme-linked immunosorbent spot (ELISpot) assay.
ELISpot results did not show a trend of presumed T-cell response (based on limited positive ELISpot) as a function of time during the 1-year post-infusion period in either clinical study 1 or clinical study 2.
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