Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: CSL Behring GmbH, D-35041 Marburg, Germany
Pharmacotherapeutic group: not yet assigned
ATC code: not yet assigned
Etranacogene dezaparvovec is a gene therapy product designed to introduce a copy of the human Factor IX coding DNA sequence into hepatocytes to address the root cause of the Haemophilia B disease. Etranacogene dezaparvovec consists of a codon-optimised coding DNA sequence of the gain-of-function Padua variant of the human Factor IX (hFIXco-Padua), under control of the liver-specific LP1 promoter, encapsulated in a non-replicating recombinant adeno-associated viral vector of serotype 5 (AAV5) (see section 2.1).
Following single intravenous infusion, etranacogene dezaparvovec preferentially targets liver cells, where the vector DNA resides almost exclusively in episomal form (see section 5.3 below). After transduction, etranacogene dezaparvovec directs long-term liver-specific expression of Factor IX-Padua protein. As a result, etranacogene dezaparvovec partially or completely ameliorates the deficiency of circulating Factor IX procoagulant activity in patients with Haemophilia B.
The safety and efficacy of etranacogene dezaparvovec was evaluated in 2 prospective, open-label, single-dose, single-arm studies, a phase 2b study performed in US and a phase 3 multi-national study performed in US, UK and EU. Both studies enrolled adult male patients (body weight range: 58 to 169 kg) with moderately severe or severe Haemophilia B (≤2% of Factor IX activity; N=3 in phase 2b and N=54 in phase 3), who received a single intravenous dose of 2 × 1013 gc/kg body weight of etranacogene dezaparvovec and entered a follow-up period of 5 years.
In the pivotal phase 3 study, a total of N=54 male patients, aged 19 to 75 at enrollment (n=47 ≥18 and <65 years; n=7 ≥65 years) with moderately severe or severe Haemophilia B completed a ≥6-month observational lead-in phase with standard of care routine Factor IX prophylaxis after which the patients received a single intravenous dose of etranacogene dezaparvovec. Post-treatment follow-up visits occurred regularly, with 53/54 patients completing at least 18 months of follow-up. One patient, aged 75 at screening, died of cardiogenic shock at month 15 post-dose, an event confirmed not treatment-related. The remaining 53/54 patients continue follow-up for a total of 5 years post-dose. Of these, 1 patient received a partial dose (10%) of etranacogene dezaparvovec due to an infusion reaction during infusion. All patients were on prophylactic Factor IX replacement therapy prior to dosing with etranacogene dezaparvovec. Preexisting neutralising anti-AAV5 antibodies were present in 21/54 (38.9%) patients at baseline.
The primary efficacy objective for the phase 3 study was to assess the annualised bleeding rate (ABR) reduction between month 7 and 18 post-dose, i.e., after establishment of stable Factor IX expression by month 6 post-dose, compared to the observational lead-in period. For this purpose, all bleeding episodes, regardless of investigator assessment, were considered. The efficacy results showed superiority of etranacogene dezaparvovec to continuous routine Factor IX prophylaxis (see Table 5).
Table 5. Bleeding events and Annualised Bleeding Rates:
| Number | ≥6-month lead-in period FAS (N=54) | 7-18 months post-dose FAS (N=54) | ≥6-month lead-in period (N=53)*** | 7-18 months post-dose (N=53)*** |
|---|---|---|---|---|
| Number of patients with bleeds | 40 (74.1%) | 20 (37.0%) | 40 (75.5%) | 19 (35.8%) |
| Number of patients with zero bleeds | 14 (25.9%) | 34 (63.0%) | 13 (24.5%) | 34 (64.2%) |
| Number of any bleeds | 136 | 54 | 136 | 49 |
| Number of person years for bleeding events | 33.12 | 49.78 | ||
| Adjusted* ABR** (95% CI) for any bleeds | 4.19 (3.22, 5.45) | 1.51 (0.81, 2.82) | 3.89 (2.93, 5.16) | 1.07 (0.63, 1.82) |
| ABR reduction (lead-in to post-treatment) 2-sided 95% Wald CI 1-sided p-value**** | - | 64% (36%, 80%) 0.0002 | 72% (57%, 83%) p<0.0001 | |
| Number of patients with severe bleeds | 10 (18.5%) | 7 (13%) | - | - |
| Number of patients with very severe bleeds | 3 (5.6%) | 2 (3.7%) | - | - |
| Adjusted ABR for spontaneous bleeds 1-sided p-value | 1.52 | 0.44 p=0.0034 | - | - |
| Adjusted ABR for joint bleeds 1-sided p-value | 2.35 | 0.51 p<0.0001 | - | - |
| Adjusted ABR for traumatic bleeds 1-sided p-value | 2.09 | 0.62 p<0.0001 | - | - |
Abbreviations: ABR = annualised bleeding rate; FAS = Full Analysis Set including all 54 patients dosed; CI = confidence interval
* Adjusted ABR: Adjusted ABR rate and comparison of ABR between lead-in and post-treatment period was estimated from a statistical modelling (i.e., from a repeated measures generalised estimating equations negative binomial regression model accounting for the paired design of the study with an offset parameter to account for the differential collection periods. Treatment period was included as a categorical covariate.)
** The ABR was measured from month 7 to month 18 after etranacogene dezaparvovec infusion, ensuring this period represented steady-state Factor IX expression from the transgene.
*** The population data includes all patients dosed except for one patient with the preexisting neutralising anti-AAV5 antibody titre of 1:3212 who did not respond to treatment, i.e., did not show Factor IX expression and activity post-dose.
**** 1-sided p-value ≤0.025 for post-treatment/lead-in <1 was regarded as statistically significant.
After single-dose of etranacogene dezaparvovec, clinically relevant increases in Factor IX activity were observed, as measured by the one-stage (aPTT-based) assay (see Table 6). Factor IX activity was also measured with chromogenic assay and the results were lower compared to the results of the one-stage (aPTT-based) assay with the mean chromogenic to one-stage Factor IX activity ratio ranging from 0.408 to 0.547 from month 6 to month 24 post-dose.
Table 6. Uncontaminated2 Factor IX activity at 6, 12, 18 and 24 months (FAS; one-stage (aPTTbased) assay):
| Baseline1 (N=54)2 | 6 months post-dose (N=51)2 | 12 months post-dose (N=50)2 | 18 months post-dose (N=50)2 | 24 months post-dose5 (N=50)2 | |
|---|---|---|---|---|---|
| Mean % (SD) | 1.19 (0.39) | 38.95 (18.72) | 41.48 (21.71) | 36.90 (21.40) | 36.66 (18.96) |
| Median % (min, max) | 1.0 (1.0, 2.0) | 37.30 (8.2, 97.1) | 39.90 (5.9, 113.0) | 33.55 (4.5, 122.9) | 33.85 (4.7, 99.2) |
| Change from baseline Least Squares (LS) mean (SE)3 95% CI 1-sided p-value4 | n.a. | 36.18 (2.432) 31.41, 40.95 p<0.0001 | 38.81 (2.442) 34.01, 43.60 p<0.0001 | 34.31 (2.444) 29.52, 39.11 p<0.0001 | 34.13 (2.325) 29.57, 38.69 p<0.0001 |
Abbreviations: aPTT = activated Partial Thromboplastin Time; CI = confidence interval; FAS = Full Analysis Set including all 54 patients dosed; LS = least squares; max = maximum; min = minimum; n.a. = not applicable; SD = standard deviation; SE = standard error.
1 Baseline: baseline Factor IX activity was imputed based on subject’s historical Haemophilia B severity documented on the case report form. If the subject had documented severe Factor IX deficiency (Factor IX plasma level <1%), their baseline Factor IX activity level was imputed as 1%. If the subject had documented moderately severe Factor IX deficiency (Factor IX plasma level ≥1% and ≤2%) their baseline Factor IX activity level was imputed as 2%.
2 Uncontaminated: the blood samples collected within 5 half-lives of exogenous Factor IX use were excluded. Both the date and time of exogenous Factor IX use and blood sampling were considered in determining contamination. Patients with zero uncontaminated central laboratory post-treatment values had their change from baseline assigned to zero for this analysis, and had their post-baseline values set equal to their baseline value. Baseline Factor IX was imputed based on patients' historical Haemophilia B severity documented on the case report form. The FAS included 1 patient who received only 10% of the planned dose, 1 patient who died at month 15 post-dose due to unrelated concomitant disease, 1 patient with 1:3212 titre of preexisting neutralising anti-AAV5 antibodies who did not respond to treatment, and 1 patient with contamination with exogenous Factor IX. Accordingly, the population data included 54 to 50 patients with uncontaminated sampling.
3 Least Squares Mean (SE): mean from repeated measures linear mixed model with visit as a categorical covariate.
4 1-sided p-value ≤0.025 for post-treatment above baseline was regarded as statistically significant.
5 For month 24, data was based on an ad-hoc analysis and the p-value was not adjusted for multiplicity.
The onset of Factor IX protein expression post-dose was detectable from the first uncontaminated measurement at week 3. In general, although more variable, Factor IX protein kinetic profile during the post-treatment period followed a trend similar to Factor IX activity.
Durability analysis of Factor IX activity showed stable Factor IX levels from 6 months up to 24 months. The durability analysis showed a similar trend of post-dose Factor IX activity for etranacogene dezaparvovec as for the predecessor, the rAAV5-hFIX gene therapy encoding wild type human Factor IX in a preceding clinical study, which showed stable post-dose Factor IX activity from 6 months up to 5 years (see section 5.3).
While overall numerically lower mean Factor IX activity was observed in patients with preexisting neutralising anti-AAV5 antibodies, no clinically meaningful correlation was identified between patients' preexisting anti-AAV5 antibody titre and their Factor IX activity at 18 months post-dose (see Table 7). In 1 patient with a titre of 1:3212 for preexisting anti-AAV5 antibodies at screening, no response to etranacogene dezaparvovec treatment was observed, with no Factor IX expression and activity.
Table 7. Endogenous Factor IX activity levels post-dose in patients with and without preexisting neutralising anti-AAV5 antibodies (FAS; one-stage (aPTT-based) assay):
| Change from Baseline | ||||||
|---|---|---|---|---|---|---|
| Number of patient | Mean Factor IX activity (%) (SD) | Median Factor IX activity (%) (min, max) | Least Squares mean (SE)† | 95% CI | 1-sided p-value | |
| With preexisting neutralising anti-AAV5 antibodies | ||||||
| Baseline | 21 | 1.24 (0.44) | 1.00 (1.0, 2.0) | n.a. | n.a. | n.a. |
| Month 6 | 18 | 35.91 (19.02) | 36.60 (8.2, 90.4) | 30.79 (3.827) | 23.26, 38.32 | <0.0001 |
| Month 12 | 18 | 35.54 (17.84) | 39.95 (8.5, 73.6) | 31.59 (3.847) | 24.02, 39.16 | <0.0001 |
| Month 18 | 17 | 31.14 (13.75) | 32.00 (10.3, 57.9) | 26.83 (3.854) | 19.24, 34.41 | <0.0001 |
| Month 24 | 17 | 32.98 (18.51) | 33.50 (9.1, 88.3) | 28.35 (3.928) | 20.62, 36.08 | <0.0001 |
| Without preexisting neutralising anti-AAV5 antibodies | ||||||
| Baseline | 33 | 1.15 (0.36) | 1.00 (1.0, 2.0) | n.a. | n.a. | n.a. |
| Month 6 | 33 | 40.61 (18.64) | 37.30 (8.4, 97.1) | 39.46 (3.172) | 33.23, 45.69 | <0.0001 |
| Month 12 | 32 | 44.82 (23.21) | 38.65 (5.9, 113.0) | 43.07 (3.176) | 36.83, 49.31 | <0.0001 |
| Month 18 | 33 | 39.87 (24.08) | 35.00 (4.5, 122.9) | 38.72 (3.172) | 32.49, 44.95 | <0.0001 |
| Month 24 | 33 | 38.55 (19.19) | 35.40 (4.7, 99.2) | 37.40 (2.933) | 31.64, 43.16 | <0.0001 |
Abbreviations: FAS = Full Analysis Set including all 54 patients dosed; aPTT = activated partial thromboplastin time; CI = confidence interval; LS = least square; max = maximum; min = minimum; n.a. = not applicable; SD = standard deviation; SE = standard error.
† Least squares mean (SE): from repeated measures linear mixed model with visit as a categorical covariate.
The study also demonstrated superiority of etranacogene dezaparvovec at 18-months post-dose over the routine exogenous Factor IX prophylaxis in the lead-in period (see Table 8). The ABR for Factor IXtreated bleeding episodes during the month 7 to 18 post-dose period was reduced by 77% (see Table 5).
Table 8. Annualised Bleeding Rates for Factor IX-treated bleeding episodes:
| ≥6-month lead-in period FAS (N=54) | 7-18 months post-dose FAS (N=54) | |
|---|---|---|
| Number of patients with Factor IX-treated bleeds | 37/54 (68.5%) | 15/54 (27.8%) |
| Number of Factor IX-treated bleeds | 118 | 30 |
| Adjusted ABR (95% CI) for Factor IX-treated bleeds | 3.65 (2.82, 4.74) | 0.84 (0.41, 1.73) |
| ABR ratio for Factor IX-treated bleeds (post- treatment to lead-in) 2-sided 95% Wald CI 1-sided p-value | - | 0.23 (0.12, 0.46) p<0.0001 |
| Adjusted ABR (95% CI) for spontaneous bleeds treated with Factor IX | 1.34 (0.87, 2.06) | 0.45 (0.15, 1.39) |
| ABR ratio for spontaneous bleeds treated with Factor IX (post-treatment to lead-in) 2-sided 95% Wald CI 1-sided p-value | - | 0.34 (0.11, 1.00) p= 0.0254 |
| Adjusted ABR (95% CI) for joint bleeds treated with Factor IX | 2.13 (1.58, 2.88) | 0.44 (0.19, 1.00) |
| ABR ratio for joint bleeds treated with Factor IX (post-treatment to lead-in) 2-sided 95% Wald CI 1-sided p-value | - | 0.20 (0.09, 0.45) p<0.0001 |
Abbreviations: ABR = annualised bleeding rate; FAS = Full Analysis Set including all 54 subjects dosed; CI = confidence interval
The mean consumption of Factor IX replacement therapy significantly decreased by 248,825.0 IU/year/patient (98.42%; 1-sided p<0.0001) between month 7 and 18 and by 248.392.6 IU/year/patient (96.52%; 1-sided p<0.0001) between month 7 to 24 following treatment with etranacogene dezaparvovec compared to standard of care routine Factor IX prophylaxis during the lead-in period. From day 21 through to months 7 to 24, 52 of 54 (96.3%) treated patients remained free of continuous routine Factor IX prophylaxis.
Overall, similar results were observed at 24 months post-dose in the phase 3 study. Of note, none of the patients showed evidence of neutralising inhibitors to etranacogene dezaparvovec-derived Factor IX over 2 years post-dose. Similarly, none of the 3 patients enrolled in the phase 2b study showed evidence of neutralising inhibitors over the period of 3 years post-dose. The 3 patients demonstrated clinically relevant increases in Factor IX activity and discontinued their routine Factor IX replacement prophylaxis over the period of 3 years post-dose.
The European Medicines Agency has deferred the obligation to submit the results of studies with Hemgenix in one or more subsets of the paediatric population in the treatment of 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
The etranacogene dezaparvovec-derived Factor IX protein produced in the liver is expected to undergo similar distribution and catabolic pathways as the endogenous native Factor IX protein in people without Factor IX deficiency (see section 5.1).
The pharmacokinetics of shedding was characterised following etranacogene dezaparvovec administration, using a sensitive polymerase chain reaction (PCR) assay to detect vector DNA sequences in blood and semen samples, respectively. This assay is sensitive to transgene DNA, including fragments of degraded DNA. It does not indicate whether DNA is present in the vector capsid, in cells or in the fluid phase of the matrix (e.g. blood plasma, seminal fluid), or whether intact vector is present.
In the phase 3 study, detectable vector DNA with a maximum vector DNA concentrations post-dose was observed in blood (n = 53/54) and semen (n = 42/54) at a median time (Tmax) of 4 hours and 42 days, respectively. The mean peak concentrations were 2.2 × 1010 copies/mL and 3.8 × 105 copies/mL in blood and semen, respectively. After reaching the maximum in a matrix, the transgene DNA concentration declines steadily. Shedding-negative status in patients was defined as having 3 consecutive samples at vector DNA concentration below the limit of detection (<LOD). Using this definition, a total of 56% (30/54) of patients reached absence of vector DNA from blood and 69% (37/54) from semen by month 24. The median time to absence of shedding was 52.3 weeks in blood and 45.8 weeks in semen at 24 months post-dose. Several subjects did not return the required number of blood and semen samples to assess the shedding status as per the definition. Considering shedding results obtained from the final 2 available consecutive samples, a total of 40/54 (74%) and 47/54 (87%) patients were identified to have reached absence of vector DNA from blood and semen, respectively, at 24 months post-dose.
In the phase 3 study, majority (n=45) of the patients had normal renal function (creatinine clearance (CLcr) = ≥90 mL/min defined by Cockcroft-Gault equation), 7 patients had mild renal impairment (CLcr = 60 to 89 mL/min) and 1 patient had moderate renal impairment (CLcr = 30 to 59 mL/min). No clinically relevant differences in Factor IX activity were observed between these patients.
Etranacogene dezaparvovec was not studied in patients with severe renal impairment (CLcr = 15 to 29 mL/min) or end-stage renal disease (CLCr <15 mL/min).
In the phase 3 study, patients with varying degree of liver steatosis at baseline showed no clinically relevant different Factor IX activity levels.
Patients with severe liver impairment and advanced fibrosis were not studied (see section 4.2 and 4.4).
Preclinical studies were initiated with a gene therapy product employing the recombinant adenoassociated virus serotype 5 (rAAV5) expressing the wild type of the human coagulation Factor IX (rAAV5-hFIX). Etranacogene dezaparvovec (rAAV5-hFIX-Padua) was subsequently developed from rAAV5-hFIX by introduction of a 2 nucleotide change in the transgene for human Factor IX, generating thereby the naturally occurring Padua variant of Factor IX, which exhibits significantly augmented activity (see section 5.1).
The No Observed-Adverse-Effect-Level (NOAEL) was observed at 9 × 1013 gc/kg body weight in nonhuman primates, which is approximately 5-fold above the human etranacogene dezaparvovec dose of 2 × 1013 gc/kg body weight.
Biodistribution of etranacogene dezaparvovec and its predecessor, the gene therapy of human wild type Factor IX, was assessed in mice and non-human primates following intravenous administration (see section 5.3). Dose-dependent preferential distribution to the liver was confirmed for both vectors and their transgene expression.
Genotoxic and reproductive risks were evaluated with the rAAV5-hFIX. The integration site analysis in host genomic DNA was performed on liver tissue from mice and non-human primates injected with rAAV5-hFIX up to a dose of 2.3 × 1014 gc/kg body weight, corresponding to approximately 10-fold higher than the clinical dose in human. The retrieved rAAV5-hFIX vector DNA sequences represented almost exclusively episomal forms that were non-integrated into the host DNA. The remaining low level of integrated rAAV5-hFIX DNA was distributed throughout the host genome with no preferred integration in genes associated with mediation of malignant transformation in human (see section 4.4 Risk of malignancy as a result of vector integration).
No dedicated carcinogenicity studies were performed with etranacogene dezaparvovec. Although there are no fully adequate animal models to address the tumorigenic and carcinogenic potential of etranacogene dezaparvovec in human, toxicological data do not suggest concern for tumourigenicity.
No dedicated reproductive and developmental toxicity studies, including embryo foetal and fertility assessments, were performed with etranacogene dezaparvovec, as males comprise the majority of the patient population to be treated with Hemgenix. The risk of germline transmission after administration of 2.3 × 1014 gc/kg body weight rAAV5-hFIX, i.e. a dose approximately 10-fold higher than recommended for humans, was assessed in mice. The rAAV5-hFIX administration resulted in detectable vector DNA in the reproductive organs and sperm of male animals. However, following mating of these mice with naïve female animals at 6 days after administration, the rAAV5-hFIX vector DNA was not detected in the female reproductive tissues nor offspring, indicating no paternal germline transmission.
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