BEQVEZ Solution for infusion Ref.[109832] Active ingredients: Fidanacogene elaparvovec

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.

Table 4. Clinical Study 1: Factor IX Activity Over Time by 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).
^* Silica-based one-stage assay
^** Ellagic acid-based OSA

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 (C_max) and time to maximum vector DNA level (T_max). The maximum vector DNA concentrations were found in plasma followed by saliva, peripheral blood mononuclear cells (PBMC), semen and urine. The mean T_max was 1.2 days for plasma and saliva and 1.6 days for urine. The mean T_max 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.

Carcinogenicity, mutagenicity, reproductive toxicity, and impairment of fertility studies have not been conducted with BEQVEZ. In a 2-year vector integration study in NHPs administered 5 × 10¹² vg/kg, vector DNA was mostly detected in the form of episomal DNA that was not integrated into the host genome. The integration sites were generally random with a low frequency, and there was no indication of significant clonal expansion.

The efficacy of BEQVEZ was evaluated in clinical study 1 (NCT03861273) which is an ongoing, prospective, open-label, single-arm, multi-national study. The study enrolled 45 adult male patients with moderately severe to severe hemophilia B (factor IX activity ≤2 IU/dL). All patients completed a prospective lead-in study of at least six months for baseline data collection while they received routine factor IX prophylaxis in the usual care setting before entering clinical study 1. Enrolled patients then received a single intravenous infusion of BEQVEZ at a dose of 5 × 10¹¹ vg/kg of body weight and entered a follow-up (FU) period of 6 years. Of the 45 patients, 41 completed at least 15 months of FU. The median FU of the 45 treated patients was 2.0 years (range: 0.4 to 3.2 years) from the time of infusion.

Only patients who were negative for pre-existing neutralizing antibodies to AAVRh74var capsid were eligible. Other key exclusion criteria included history of or current inhibitor to factor IX (≥0.6 Bethesda units), active hepatitis B or C infection, HIV infection with CD4 cell count ≤200 mm³ or viral load >20 copies/mL, hypersensitivity to factor IX product, ALT/AST/ALP >2 times ULN, bilirubin >1.5 times ULN, unstable liver or biliary disease, and significant liver fibrosis.

Enrolled patients were 73% White, 16% Asian and 2.2% Black. The median age was 29 years (range: 18 to 62 years). A total of 13 (29%) and 15 (33%) patients had a history of hepatitis B and C, respectively. One (2%) patient was HIV positive.

The main efficacy outcome was a non-inferiority (NI) test of annualized bleeding rate (ABR) during the efficacy evaluation period (EEP), Week 12 (Day 82) to data cutoff following BEQVEZ treatment, compared with baseline ABR during the lead-in period. The ABR included treated and untreated bleeds, excluding procedural bleeds. The NI margin on the difference between the mean EEP ABR and the mean baseline ABR was 3.0 bleeds/year.

Table 5 summarizes the efficacy results. The model derived mean ABR was 4.5 bleeds/year (95% CI: 1.9, 7.2) during the baseline period and 2.5 bleeds/year (95% CI: 1.0, 3.9) during post-BEQVEZ EEP, resulting in a difference between the mean post-BEQVEZ EEP ABR and the baseline ABR of -2.1 bleeds/year (95% CI: -4.8, 0.7). The upper bound of the 95% CI in the difference was less than 3.0 bleeds/year, meeting the NI study success criterion. Six out of 45 patients (13%) resumed routine factor IX prophylaxis after BEQVEZ treatment, starting from 0.4 years to 1.7 years after BEQVEZ infusion. An additional patient had intermittent exogenous factor IX use and had a higher ABR post BEQVEZ (5.0 bleeds/year) compared to baseline (1.2 bleeds/year) with a factor IX activity <5% (SynthASil assay) starting at 0.4 years.

Table 5. Summary of Annualized Bleeding Rate and Bleeding Events (N=45):

ABR = Annualized Bleeding Rate for all bleeds (treated and untreated with factor IX, excluding procedural bleeds).
CI = confidence interval.
^a Post-BEQVEZ efficacy evaluation period is from Week 12 (Day 82) to data cutoff.
^b A total of 7 participants (16%) had used factor IX replacement products during the efficacy evaluation period for extended prophylaxis that confounded the treatment effect of BEQVEZ, with a median start time at 0.8 (range: 0.4 to 1.1) years. An ABR of 20 bleeds/year was imputed for the confounded periods.
^c The results presented in this table included data on a participant with a baseline ABR of 53.9 bleeds/year, which disproportionately influenced the baseline ABR estimate. A post-hoc sensitivity analysis, excluding this participant, still met the non-inferiority study success criterion.
^d Model-based ABR estimates from a repeated measures generalized linear model with negative binomial distribution and identity link function.