Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Pharmacotherapeutic group: Blood coagulation factors
ATC code: not yet assigned
Fidanacogene elaparvovec is a gene therapy designed to introduce a functional copy of the high activity Padua variant of the factor IX gene (FIX-R338L) in the transduced cells to address the monogenic root cause of haemophilia B.
Fidanacogene elaparvovec is a non-replicating recombinant AAV vector that utilises AAVRh74var capsid to deliver a stable human factor IX transgene. AAVRh74var capsid is able to transduce hepatocytes, the natural site of factor IX synthesis. The factor IX gene present in fidanacogene elaparvovec is designed to reside predominately as episomal DNA within transduced cells and expression of the transgene is driven by a liver specific promoter, which results in tissue specific, continuous and sustained factor IX protein expression.
Fidanacogene elaparvovec therapy results in measurable vector-derived coagulation factor IX activity.
The efficacy of fidanacogene elaparvovec was evaluated in an open-label, multi-site Phase 3 study (C0371002, N=45). The study enrolled adult male patients aged 18-62 years with moderately severe to severe haemophilia B (factor IX activity ≤2%) that were negative for neutralising antibody (nAb) to AAVRh74var and who received a single intravenous infusion dose of fidanacogene elaparvovec at 5 × 1011 vg/kg of body weight. The patients will continue follow-up post-infusion for a total of 6 years per patient. All patients completed a lead-in study of at least 6 months to capture baseline bleed and infusion data, where the patients were receiving prophylaxis as usual care. These data served as the control for comparison with post-fidanacogene elaparvovec infusion efficacy data.
The study excluded patients with active hepatitis B or C infection, ALT/AST/ALP >2 × ULN, bilirubin >1.5 × ULN, unstable liver or biliary disease, and significant liver fibrosis. Thirty-three of 45 (73.3%) patients were White, 7 (15.6%) were Asian, 1 (2.2%) was Black or African American and 4 (8.9%) were not reported.
The primary efficacy endpoint was annualised bleeding rate (ABR) for total bleeds (treated and untreated) from week 12 to month 15 versus usual care factor IX prophylaxis replacement regimen, comparing pre- and post-fidanacogene elaparvovec infusion.
The secondary endpoints included ABR for treated bleeds, annualised infusion rate (AIR) of exogenous factor IX, and annualised FIX consumption, all from week 12 to month 15. Vector-derived factor IX activity level is presented up to 36 months.
ABRtotal collected in the lead-in period prior to vector infusion while receiving routine care prophylaxis regimen was 4.50 (95% CI: 1.84, 7.16) and ABRtotal from week 12 to month 15 post-fidanacogene elaparvovec infusion was 1.44 (95% CI: 0.57, 2.31). Fidanacogene elaparvovec resulted in statistically significant decrease of ABRtotal (treatment difference and 95% CI: -3.06 [-5.34, -0.78], two-sided p=0.0084) compared with factor IX prophylaxis.
Six out of 45 (13.3%) patients have resumed factor IX prophylaxis post-fidanacogene elaparvovec infusion (primary reason: 5 due to low FIX:C and 1 due to bleed frequency), with time to resumption ranging from 5.1 months to 20.5 months.
The efficacy results of fidanacogene elaparvovec with respect to ABRtotal, ABRtreat, ABRtotal of specific types (spontaneous, joint, target joint), AIR and annualised FIX consumption are shown in Table 7.
Table 7. C0371002 study: annualised bleed rate, annualised factor infusions and annualised factor IX consumption:
| Factor IX prophylaxis (N=45) | BEQVEZ (N=45) | |
|---|---|---|
| ABRtotal* | ||
| Model based estimate (95% CI) | 4.50 (1.84, 7.16) | 1.44 (0.57, 2.31) |
| Treatment difference (95% CI) | −3.06 (−5.34, −0.78) | |
| p-value for treatment difference | 0.0084 | |
| Percent reduction (95% CI) | 68.0% (44.3%, 81.7%) | |
| n (%) of patients without any bleeds | 13 (28.9) | 28 (62.2) |
| ABRtreat | ||
| Model based estimate (95% CI) | 3.34 (1.70, 4.98) | 0.73 (0.23, 1.23) |
| Treatment difference (95% CI) | -2.61 (-4.27, -0.96) | |
| p-value for treatment difference | 0.0020 | |
| Percent reduction (95% CI) | 78.2% (51.6%, 90.1%) | |
| n (%) of patients without any bleeds | 16 (35.6) | 33 (73.3) |
| ABRtotal of spontaneous bleeding | ||
| Model based estimate (95% CI) | 3.23 (0.91, 5.56) | 0.68 (0.19, 1.18) |
| p-value for treatment difference | 0.0191 | |
| Percent reduction (95% CI) | 78.9% (56.0%, 89.9%) | |
| n (%) of patients without any bleeds | 18 (40.0) | 35 (77.8) |
| ABRtotal of joint bleeding | ||
| Model based estimate (95% CI) | 3.73 (1.32, 6.14) | 0.85 (0.33, 1.38) |
| p-value for treatment difference | 0.0100 | |
| Percent reduction (95% CI) | 77.2% (57.4%, 87.8%) | |
| n (%) of patients without any bleeds | 20 (44.4) | 31 (68.9) |
| ABRtotal of target joint bleeding | ||
| Model based estimate (95% CI) | 2.54 (0.28, 4.80) | 0.39 (0.02, 0.75) |
| p-value for treatment difference | 0.0372 | |
| Percent reduction (95% CI) | 84.8% (68.8%, 92.6%) | |
| n (%) of patients without any bleeds | 37 (82.2) | 39 (86.7) |
| AIR | ||
| Mean (SD) | 58.83 (29.056) | 4.54 (10.026) |
| Median (Q1, Q3) | 52.58 (46.81, 71.22) | 0.00 (0.00, 3.77) |
| Percent reduction | 92.3% | |
| n (%) of patients without any infusions | 0 | 29 (64.4) |
| Annualised factor IX consumption (IU/kg) | ||
| Mean (SD) | 3 168.56 (1 635.545) | 239.39 (539.617) |
| Median (Q1, Q3) | 2 350.07 (2 010.78, 4 353.49) | 0.00 (0.00, 177.09) |
| Percent reduction | 92.4% | |
* Bleeding events that occurred post-resumption of prophylaxis were included in the analysis from week 12 to month 15.
Analysis period was from week 12 to month 15 post-infusion of BEQVEZ. No participant withdrew from the study prior to month 15.
Model based ABR estimates and two-sided p-value for treatment difference from a repeated measures generalised linear model (GLM) with negative binomial distribution and identity link function.
Percent reduction for ABR from a repeated measures GLM with negative binomial distribution and log link function.
ABRtotal = Annualised Bleed Rate for all bleeds (treated and untreated with factor IX, excluding procedural bleeds).
ABRtreat = Annualised Bleed Rate for treated bleeds (treated with factor IX, excluding procedural bleeds). CI = confidence interval.
AIR = Annualised Infusion Rate (for any reason, including perioperative infusions).
From week 12 onward, the levels of factor IX remained stable. Factor IX activity level over time by assay is presented in Table 8.
Table 8. C0371002 study: factor IX activity over time by assay:
| Change from baseline$ | ||||||
|---|---|---|---|---|---|---|
| Visit | n | Mean (SD) | Median (min, max) | LS mean (SE)^ | 95% CI^ | One-sided p-value^ |
| One-stage assay (SynthASil reagent)* | ||||||
| Week 12 | 44 | 27.79 (15.226) | 26.45 (3.2, 68.6) | 26.63 (2.671) | (21.39, 31.87) | <0.0001 |
| Month 6 | 39 | 27.64 (21.373) | 23.20 (0.9, 99.7) | 26.25 (2.679) | (21.00, 31.51) | <0.0001 |
| Month 15 | 39 | 26.17 (25.100) | 22.50 (0.9, 119.0) | 24.70 (2.678) | (19.44, 29.95) | <0.0001 |
| Month 24 | 39 | 26.47 (25.092) | 22.90 (0.9, 123.4) | 24.66 (2.688) | (19.38, 29.93) | <0.0001 |
| Month 36 | 13 | 23.83 (19.165) | 21.80 (0.9, 74.8) | 25.47 (3.021) | (19.54, 31.40) | <0.0001 |
| One-stage assay (Actin FSL reagent) | ||||||
| Week 12 | 44 | 13.58 (8.047) | 13.58 (1.7, 35.1) | 12.53 (1.806) | (8.99, 16.08) | <0.0001 |
| Month 6 | 41 | 13.08 (11.170) | 10.10 (0.6, 55.0) | 11.93 (1.808) | (8.38, 15.47) | <0.0001 |
| Month 15 | 39 | 13.96 (15.403) | 10.20 (0.9, 69.8) | 12.57 (1.810) | (9.02, 16.12) | <0.0001 |
| Month 24 | 38 | 15.70 (16.392) | 12.85 (0.9, 87.3) | 13.81 (1.818) | (10.24, 17.37) | <0.0001 |
| Month 36 | 13 | 14.57 (12.473) | 12.50 (0.9, 47.6) | 16.88 (2.049) | (12.86, 20.90) | <0.0001 |
| Chromogenic assay | ||||||
| Week 12 | 44 | 13.91 (9.302) | 12.05 (1.4, 36.3) | 12.78 (1.561) | (9.71, 15.84) | <0.0001 |
| Month 6 | 40 | 14.81 (12.988) | 10.30 (0.9, 57.7) | 13.04 (1.569) | (9.96, 16.12) | <0.0001 |
| Month 15 | 38 | 15.19 (16.647) | 10.00 (0.9, 74.2) | 13.60 (1.571) | (10.52, 16.69) | <0.0001 |
| Month 24 | 39 | 14.61 (16.648) | 9.60 (0.9, 80.3) | 13.07 (1.582) | (9.96, 16.17) | <0.0001 |
| Month 36 | 13 | 11.62 (10.549) | 10.10 (0.9, 40.8) | 10.45 (1.958) | (6.61, 14.29) | <0.0001 |
Any samples taken within 7 days (14 days if extended half-life product was used) of exogeneous FIX replacement therapy were not eligible.
If a participant 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% based on their baseline disease severity (0.9% if severe and 1.9% if moderately severe).
* Silica-based one-stage assay
$ Baseline FIX:C was imputed based on the reported baseline disease severity level. If the participant was in severe category (FIX:C <1%), the baseline FIX:C was imputed as 0.9%. If the participant was in the moderately severe category (FIX:C 1 to ≤2%), the baseline FIX:C was imputed as 1.9%.
^ Least square (LS) mean, standard error (SE), 95% CI, and one-sided p-value were from repeated measures linear mixed effect model (MMRM) with participant as the random effect, and study visit as a fixed effect.
Study visits with n ≥10 were included in the model
The proportions of Study C0371002 participants achieving specific factor IX activity level thresholds over time by assay are presented in Table 9.
At month 15, 85% (33 out of 39) patients were in or above mild range (FIX activity ≥5%) based on one-stage SynthASil assay, and 67% and 71% based on one-stage Actin FSL assay and chromogenic assay, respectively. At month 24, 82% (32 out of 39) patients were in or above mild range (FIX activity ≥5%) based on one-stage SynthASil assay, and 71% and 69% based on one-stage Actin FSL assay and chromogenic assay, respectively.
Table 9. Participants achieving factor IX activity category in study C0371002 over time:
| BEQVEZ (N=45) | ||||
|---|---|---|---|---|
| Visit | FIX:C category | One-stage assay (SynthASil reagent)* n (%) | One-stage assay (Actin FSL reagent) n (%) | Chromogenic assay n (%) |
| Week 12 | Total | 44 | 44 | 44 |
| 0 - <5% | 1 (2.3) | 8 (18.2) | 9 (20.5) | |
| 5 - <15% | 8 (18.2) | 19 (43.2) | 19 (43.2) | |
| 15 - <40% | 25 (56.8) | 17 (38.6) | 16 (36.4) | |
| 40 - <150% | 10 (22.7) | 0 | 0 | |
| <> ≥150% | 0 | 0 | 0 | |
| Month 6 | Total | 39 | 41 | 40 |
| 0 - <5% | 4 (10.3) | 9 (22.0) | 8 (20.0) | |
| 5 - <15% | 4 (10.3) | 22 (53.7) | 19 (47.5) | |
| 15 - <40% | 25 (64.1) | 8 (19.5) | 10 (25.0) | |
| 40 - <150% | 6 (15.4) | 2 (4.9) | 3 (7.5) | |
| <> ≥150% | 0 | 0 | 0 | |
| Month 15 | Total | 39 | 39 | 38 |
| 0 - <5% | 6 (15.4) | 13 (33.3) | 11 (28.9) | |
| 5 - <15% | 9 (23.1) | 12 (30.8) | 14 (36.8) | |
| 15 - <40% | 15 (38.5) | 12 (30.8) | 10 (26.3) | |
| 40 - <150% | 9 (23.1) | 2 (5.1) | 3 (7.9) | |
| ≥150% | 0 | 0 | 0 | |
| Month 24 | Total | 39 | 38 | 39 |
| 0 - <5% | 7 (17.9) | 11 (28.9) | 12 (30.8) | |
| 5 - <15% | 7 (17.9) | 12 (31.6) | 14 (35.9) | |
| 15 - <40% | 18 (46.2) | 13 (34.2) | 10 (25.6) | |
| 40 - <150% | 7 (17.9) | 2 (5.3) | 3 (7.7) | |
| ≥150% | 0 | 0 | 0 | |
| Month 36 | Total | 13 | 13 | 13 |
| 0 - <5% | 2 (15.4) | 2 (15.4) | 4 (30.8) | |
| 5 - <15% | 3 (23.1) | 6 (46.2) | 6 (46.2) | |
| 15 - <40% | 7 (53.8) | 4 (30.8) | 2 (15.4) | |
| 40 - <150% | 1 (7.7) | 1 (7.7) | 1 (7.7) | |
| ≥150% | 0 | 0 | 0 | |
Any samples taken within 7 days (14 days if extended half-life product is used) of exogeneous FIX replacement therapy were not eligible.
If a participant withdrew consent, dropped out early from the study or resumed FIX prophylaxis, then the assessments at the visits following withdrawal/dropout/resumption were imputed based on their baseline disease severity (0.9% if severe and 1.9% if moderately severe).
* Silica-based one-stage assay
In Study C0371002, efficacy remained stable during year 2 to year 4 post-fidanacogene elaparvovec infusion (Table 10).
Table 10. Summary of ABRtotal, AIR, and annualised factor IX consumption over time*:
| Year 2 (month 15 to month 24) (N=44) | Year 3 (month 24 to month 36) (N=40) | Year 4 (month 36 to month 48) (N=15) | Overall follow-up# (N=45) | |
|---|---|---|---|---|
| ABRtotal | ||||
| Number (%) of patients without any bleeds | 33 (84.6) | 27 (79.4) | 13 (86.7) | 27 (60.0) |
| Mean (SD) | 0.39 (1.110) | 0.61 (1.624) | 0.29 (0.776) | 1.09 (2.208) |
| Median (min, max) | 0.00 (0.0, 5.6) | 0.00 (0.0, 8.2) | 0.00 (0.0, 2.6) | 0.00 (0.0, 9.9) |
| AIR | ||||
| Number (%) of patients without any infusions | 33 (75.0) | 29 (72.5) | 12 (80.0) | 25 (55.6) |
| Mean (SD) | 6.52 (18.697) | 4.90 (14.871) | 1.40 (4.691) | 4.84 (11.085) |
| Median (min, max) | 0.00 (0.0, 92.4) | 0.00 (0.0, 81.2) | 0.00 (0.0, 18.3) | 0.00 (0.0, 53.3) |
| Annualised FIX consumption (IU/kg) | ||||
| Mean (SD) | 301.34 (852.206) | 219.01 (570.946) | 56.28 (186.122) | 230.51 (498.669) |
| Median (min, max) | 0.00 (0.0, 4402.7) | 0.00 (0.0, 2752.5) | 0.00 (0.0, 724.7) | 0.00 (0.0, 2304.8) |
| Number of participants resumed FIX prophylaxis (n) | 1 | 0 | 0 | 6$ |
* Patients had varying length of follow-up post-infusion of fidanacogene elaparvovec, and bleeding and infusion rates were annualised within each time period.
# From Week 12 to 30 Aug 2023
$ Five (5) participants resumed FIX prophylaxis between month 5 and month 15.
If prophylaxis FIX regimen was resumed for a patient, then the time period following the resumption of the prophylaxis regimen was excluded from ABR endpoint calculation, but still included in the AIR calculation.
The European Medicines Agency has deferred the obligation to submit the results of studies with BEQVEZ in one or more subsets of the paediatric population in the treatment of congenital factor IX deficiency (haemophilia B). See section 4.2 for information on paediatric use.
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Fidanacogene elaparvovec 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 fidanacogene elaparvovec vector DNA, but could also detect DNA fragments.
Vector shedding after infusion with fidanacogene elaparvovec was assessed in 60 patients at multiple time points in clinical studies (C0371005/C0371003 and C0371002). Vector DNA was shed in peripheral blood mononuclear cells (PBMC), saliva, urine, semen, and serum/plasma. In general, peak levels of vector DNA occurred within the first two weeks after infusion. Highest peak vector DNA concentrations were found in serum/plasma compared to the other liquid matrices (saliva, urine, semen). In plasma (measured only in C0371002), mean peak vector DNA concentration of 2.008 × 109 vg/mL was observed. The mean peak vector DNA concentration in any shedding matrix was 6.261 × 106 vg/mL.
Full clearance of vector DNA was defined as having 3 consecutive negative results (i.e., below quantification limit; BQL). Vector DNA fully cleared in serum, plasma, saliva, and semen within a mean of 1-4 months after infusion and PBMC was slowest fluid to full clearance within a mean of 12 months. 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. Across studies, the maximum observed time for vector DNA full clearance in saliva, urine and semen were 105 days, 87 days and 154 days, respectively.
To further characterise the shed material, saliva, semen, and urine samples from a subset of 17 patients in Study C0371002 were tested using nuclease treatment (MNase) prior to DNA extraction. Nuclease treatment digests the free floating vector DNA so it cannot be quantified, ensuring the material being quantified following digestion is only encapsulated viral DNA. After nuclease treatment and subsequent DNA extraction, the amount of fidanacogene elaparvovec was measured by qPCR. In saliva, mean concentrations were similar up to week 2 between the MNase treatment and without MNase treatment subgroups, while all participants had concentrations BQL by week 9. In semen, mean concentrations were approximately 33% lower in the MNase treatment subgroup until week 3, and BQL for all participants by week 11. In urine, mean concentrations were approximately 30% lower in the MNase treatment subgroup until 72 h post-infusion and were BQL for all participants by week 2.
No adverse findings were observed in a 90-day single-dose intravenous general toxicity study in cynomolgus monkeys at doses up to 5 × 1012 vg/kg (10 times the recommended human dose). In a monkey biodistribution study, 22 tissues were collected 30 and 92 days following treatment. The highest levels of vector DNA were found in liver with levels approximately 20-fold higher than spleen, the organ with second most abundant levels of genomic DNA. There was very little biodistribution to testes.
In a 2-year vector integration study in cynomolgus monkeys administered 5 × 1012 vg/kg (10 times the recommended human dose), there was no indication that integration of vector DNA into host cell DNA resulted in altered liver function, or hepatocellular hyperplasia and carcinoma up to 2 years. The integration profile was considered benign as the integrations were generally random with a low frequency that was below published spontaneous mutation rate estimates for the liver and due to the absence of significant clonal expansion. Nonclinical safety data available beyond 2 years has not been established.
Carcinogenicity studies have not been conducted. The results of the integration site analysis conducted in cynomolgus monkeys and haemophilia B dogs indicated a benign profile and there was no evidence of clonal expansion. There was no evidence of hepatocellular hyperplasia in monkeys at the 92-day or 2-year necropsied, nor in mice in the 1-year study.
No dedicated reproductive and developmental toxicity studies, including embryofoetal and fertility assessments, were performed with fidanacogene elaparvovec, as males comprise the majority of the patient population to be treated with fidanacogene elaparvovec. The potential for germline transmission has been evaluated in male rabbits and vector was no longer detectable in semen at 5 months post-administration.
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