Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: BioMarin International Ltd., Shanbally, Ringaskiddy, County Cork, P43 R298, Ireland
Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5) based gene therapy vector causing the expression of the B-domain deleted SQ form of a recombinant human factor VIII (hFVIII-SQ) under the control of a liver-specific promoter. The expressed hFVIII-SQ replaces the missing coagulation factor VIII needed for effective haemostasis. Following valoctocogene roxaparvovec infusion, vector DNA is processed in vivo to form full-length, episomal transgenes that persist as the stable DNA forms that support long-term production of hFVIII-SQ.
The pharmacodynamic effect of valoctocogene roxaparvovec was assessed by circulating factor VIII activity levels (see subsection Clinical efficacy and safety below).
The efficacy of a single intravenous infusion of 6 × 1013 vg/kg valoctocogene roxaparvovec was evaluated in a Phase 3 open-label single-arm study (study 270-301) in adult males (18 years of age and older) with severe haemophilia A (residual factor VIII activity ≤1 IU/dL). Patients had been treated with prophylactic factor VIII replacement therapy for at least 12 months prior to study entry and exposed to factor VIII concentrates.
The study excluded patients with active hepatitis B or C infection, prior liver biopsy showing significant fibrosis (stage 3 or 4 on the Batts-Ludwig scale or equivalent), known hepatic cirrhosis, or history of hepatic malignancy. Except for elevated total bilirubin in 2 patients with Gilbert’s syndrome, ALT, AST, GGT, bilirubin and alkaline phosphatase was normal or below 1.25 × ULN in study 270-301. Detectable antibodies to AAV5 at screening, active infections, and/or history of venous or arterial thrombotic/thromboembolic events (outside of catheter-associated thromboses) or known thrombophilia were exclusion criteria in study 270-301. Patients with an immunocompromised state (including patients on immunosuppressive medication) were excluded. See section 4.4.
In study 270-301, 134 patients (intent-to-treat population; ITT), aged 18 to 70 years (median: 30 years; 1 patient (0.7%) was ≥65 years), received 6 × 1013 vg/kg of ROCTAVIAN with follow-up ranging from 66 to 197 weeks (mean: 122 weeks). The population was 72% White (96 patients), 14% Asian (19 patients), 11% Black (15 patients), and 3% Other or not specified. One hundred thirty-two (132) patients were HIV-negative (modified intent-to-treat population; mITT). One hundred twelve (112) patients previously participated in a non-interventional study (NIS) with at least 6 months of prospectively collected baseline data prior to enrolment in study 270-301. One hundred six of the 134 patients initiated corticosteroid treatment only in response to ALT elevation (generally starting at 60 mg/day and gradual tapering thereafter); see section 4.8.
The primary efficacy endpoint was change in factor VIII activity at week 104 post-ROCTAVIAN infusion from baseline (imputed as 1 IU/dL), as measured by CSA. The secondary efficacy endpoints were change from baseline in ABR requiring exogenous factor VIII and annualised use of exogenous factor VIII in the post-factor VIII prophylaxis period.
Factor VIII activity levels (IU/dL) over time post-ROCTAVIAN infusion are reported in Table 7 by both the CSA and OSA. The following central laboratory tests were used in clinical studies: ellagic acid for OSA (similar results were obtained for silica and kaolin) and bovine factor IX for CSA (similar results were obtained for human factor IX). The time profile of factor VIII activity is generally characterised by a tri-phasic response with rapid increase within approximately the first 6 months, followed by an initial decline, and then a more gradual decline thereafter.
Table 7. Factor VIII activity levels (IU/dL) over time in patients with severe haemophilia Aa (ITT population; N=134):
| Timepoint | Patients (n) | Factor VIII activity level (IU/dL)b | |
|---|---|---|---|
| CSA | OSA | ||
| Month 6 Mean (SD) Median (Range) | 134 | 52.6 (54.8) 38.1 (0, 367.3) | 80.8 (79.5) 60.5 (1.8, 483.9) |
| Month 12 Mean (SD) Median (Range) | 134 | 42.4 (45.3) 23.9 (0, 231.2) | 63.4 (64.5) 40.2 (0, 311.1) |
| Month 18 Mean (SD) Median (Range) | 134 | 26.1 (30.8) 13.2 (0, 167.9) | 38.6 (44.1) 21.4 (0, 232.2) |
| Month 24 Mean (SD) Median (Range) | 134 | 22.6 (32.9) 11.6 (0, 187.1) | 35.4 (47.2) 21.3 (0, 271.3) |
| Month 36 Mean (SD) Median (Range) | 134 | 18.2 (30.6) 8.2 (0, 217.7) | 29.3 (43.3) 16.0 (0, 291.4) |
a Patients with residual factor VIII ≤1 IU/dL as evidenced by medical history.
b Based on the median factor VIII activity level measures taken during weeks 23 to 26 for month 6, during weeks 49 to 52 for month 12, a 4-week window around week 76 for month 18, a 4-week window around week 104 for month 24, and at week 156 for month 36.
The proportion of patients achieving factor VIII activity level thresholds by year are presented in Table 8 by both the CSA and OSA. The majority (95%) of patients who reach factor VIII activity levels of ≥5 IU/dL do so within 5 months post-infusion.
Table 8. Patients achieving factor VIII activity thresholds by year (ITT population; N=134):
| Factor VIII activity threshold achieved by assaya | Year 1 N=134 n (%) | Year 2 N=134 n (%) | Year 3 N=134 n (%) |
|---|---|---|---|
| CSA | |||
| >150 IU/dL | 7 (5%) | 2 (1%) | 2 (1%) |
| 40 - ≤150 IU/dL | 42 (31%) | 18 (13%) | 12 (9%) |
| 15 - <40 IU/dL | 46 (34%) | 34 (25%) | 26 (19%) |
| 5 - <15 IU/dL | 23 (17%) | 45 (34%) | 48 (36%) |
| 3 - <5 IU/dL | 3 (2%) | 14 (10%) | 13 (10%) |
| <3 IU/dLb | 13 (10%) | 21 (16%) | 33 (25%) |
| OSA | |||
| >150 IU/dL | 13 (10%) | 5 (4%) | 4 (3%) |
| 40 - ≤150 IU/dL | 55 (41%) | 31 (23%) | 22 (16%) |
| 15 - <40 IU/dL | 43 (32%) | 45 (34%) | 45 (34%) |
| 5 - <15 IU/dL | 13 (10%) | 31 (23%) | 36 (27%) |
| 1 - <5 IU/dL | 8 (6%) | 14 (10%) | 15 (11%) |
| <1 IU/dLb | 2 (1%) | 8 (6%) | 12 (9%) |
a Based on the median of factor VIII activity level measures taken during weeks 49 to 52 for year 1, a 4-week window around week 104 for year 2, and a 6-week window around week 156 for year 3.
b 3 IU/dL is the lower limit of quantitation of the CSA used and 1 IU/dL is the lower limit of quantitation of the OSA used.
Table 9 describes the ABR and exogenous factor VIII use results following ROCTAVIAN treatment in study 270-301 for the patients previously enrolled in the non-interventional study.
Table 9. ABR and annualised factor VIII usage at baseline and post-factor VIII prophylaxis:
| Study 270-301 Patients from non-interventional study (NIS) N=112 | |||
|---|---|---|---|
| Baseline | Post-factor VIII prophylaxis period | ||
| Duration of data collection (week) | Mean (SD) Median (Range) | 36.5 (9.4) 32.9 (26, 68) | 159.7 (13.8) 157.6 (91, 194) |
| ABR (bleeds/year) for bleeds treated with exogenous factor VIII replacement | |||
| Overalla | Mean (SD) Median (Range) | 4.8 (6.5) 2.8 (0, 33.1) | 0.8 (2.3) 0 (0, 15.4) |
| Change from baseline Mean (SD) 95% CI | 4.0 (6.6) -5.2, -2.8 | ||
| Patients with 0 bleeds | 32% | 61% | |
| Joint bleeds | Mean (SD) Median (Range) | 2.8 (4.3) 1.4 (0, 23.1) | 0.5 (1.4) 0 (0, 8.3) |
| Patients with 0 bleeds | 44% | 74% | |
| Target joint bleedsb | Mean (SD) Median (Range) | 0.5 (1.6) 0 (0, 9.2) | 0.1 (0.6) 0 (0, 6.2) |
| Patients with 0 bleeds | 88% | 94% | |
| Spontaneous bleeds | Mean (SD) Median (Range) | 2.0 (3.5) 0 (0, 21.3) | 0.4 (1.2) 0 (0, 8.6) |
| Patients with 0 bleeds | 55% | 75% | |
| Annualised factor VIII usage | |||
| Infusion rate (infusions/year) | Mean (SD) Median (Range) | 135.9 (52.0) 128.6 (39.5, 363.8) | 4.5 (12.8) 0.3 (0, 92.0) |
| Change from baseline Mean (SD) 95% CI | -131.4 (52.0) -141.1, -121.6 | ||
| Utilisation rate (IU/kg/year) | Mean (SD) Median (Range) | 3961 (1751) 3754 (1296, 11251) | 125 (316) 11 (0, 2045) |
| Change from baseline Mean (SD) 95% CI | -3836 (1777) -4169, -3504 | ||
| Patients with zero factor VIII infusions | 0% | 41% | |
a Bleeds due to surgery/procedures not included.
b Baseline target joints, as assessed by the Investigator, were identified at screening visit.
In study 270-301 for the patients previously enrolled in the non-interventional study, 82% (92/112), 84% (94/112), and 75% (82/110) of patients had zero treated bleeds during years 1, 2 and 3, respectively. Seventy-six percent (76%; 85/112), 73% (82/112), and 58% (64/110) of patients had zero factor VIII infusions during years 1, 2 and 3, respectively.
In study 270-301 patients (ITT population), ABR for bleeds treated with exogenous factor VIII replacement [median (range): 0 (0, 15.4) bleeds per year] and annualised factor VIII usage [median (range): 0.6 (0, 92.0) infusions per year)] were similar to patients who previously enrolled in the NIS described in Table 9 for the post-factor VIII prophylaxis period following ROCTAVIAN treatment. The median (range) time to discontinuation of prophylactic use of factor VIII concentrates was 4 (0.1, 16.7) weeks, with 130 out of 134 patients discontinuing within 8 weeks.
One-hundred twenty-four of the 134 patients (93%) remained off prophylaxis post-ROCTAVIAN by end of year 3; ten patients returned to continuous prophylactic use of factor VIII concentrates/other haemostatic agents during this time period. Through the full duration of follow-up, 17 patients at some point returned to continuous prophylactic use of factor VIII concentrates/other haemostatic agents as defined in the study protocol (range: 58, 232 weeks).
Data on the durability of the treatment are still limited at this stage. At least 2 years of durability data are available in study 270-301. Additionally, 5 years of follow-up data are available from 7 patients receiving the recommended dose of 6 × 1013 vg/kg in study 270-201, and patients continued to show a clinically meaningful response to treatment.
The European Medicines Agency has deferred the obligation to submit the results of studies with ROCTAVIAN in one or more subsets of the paediatric population in the treatment of haemophilia A (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.
Valoctocogene roxaparvovec transgene DNA levels (total amount of vector DNA) in various tissues (evaluated in nonclinical studies), blood, and shedding matrices were determined using a quantitative polymerase chain reaction (qPCR) assay. 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. Plasma and semen matrices were further evaluated by measuring encapsidated (potentially infectious) vector DNA using an immunoprecipitation quantitative PCR assay in studies 270-201 and 270-301.
Administration of ROCTAVIAN resulted in detectable vector DNA in blood and all shedding matrices evaluated, with peak concentrations observed between 1 and 9 days post-administration. The peak vector DNA concentrations were observed in blood, followed by saliva, semen, stool, and urine. The peak concentration observed to date in blood across studies 270-201 and 270-301 was 2 × 1011 vg/mL. The maximum concentration in any shedding matrix was 1 × 1010 vg/mL. After reaching the maximum in a matrix, the transgene DNA concentration declines steadily.
In the 141 evaluable patients from studies 270-201 and 270-301, encapsidated (potentially infectious) vector DNA was detectable in plasma up to 10 weeks after ROCTAVIAN administration.
In the 140 evaluable patients from studies 270-201 and 270-301, all patients achieved clearance of vector DNA in semen with a maximum time to clearance of 36 weeks. In the 138 evaluable patients from studies 270-201 and 270-301, the maximum time to clearance of encapsidated (potentially infectious) vector DNA in semen was 12 weeks.
In both studies, all patients cleared in urine and saliva, and 126 (89%) patients cleared in stool by the time of the data cut. The maximum time to clearance was 8 weeks for urine, 69 weeks for saliva, and 131 weeks for stool.
Magnitude and duration of shedding appear to be independent of the patient’s attained factor VIII activity.
No pharmacokinetic studies using valoctocogene roxaparvovec have been conducted in special populations.
A single intravenous administration of up to 2 × 1014 vg/kg of valoctocogene roxaparvovec in immunocompetent male mice with intact coagulation (CD1 mice), followed by an observation period of up to 26 weeks, showed dose-dependence of plasma levels of the expressed hFVIII-SQ protein and overall factor VIII activity in plasma. Transgene DNA was detected predominantly in spleen and liver, with lower DNA levels still detected at the end of the study (day 182) in lung, mesenteric lymph node, kidney, heart, testis and brain. Vector RNA transcripts were also detected predominantly in the liver with remaining low RNA levels in lung, heart, brain, kidney, lymph nodes, spleen and testis on study end (day 182).
There were no toxicities associated with valoctocogene roxaparvovec in CD1 mice observed for 26 weeks following single doses up to 2 × 1014 vg/kg, except a pattern of haemorrhages, necrosis and fibrosis, occurring primarily in the heart, lungs, epididymis and thymus that was consistent with a coagulopathy likely caused by the formation of antibodies directed against the expressed hFVIII-SQ, which also cross-reacted with the murine factor VIII protein.
In non-GLP studies conducted in NHP dosed up to 6 × 1013 vg/kg, an immune response specific for the AAV5 capsid, and an immune response specific to the heterologous hFVIII-SQ protein were observed, associated with transient APTT prolongation in a subset of non-human primates.
Vector integration was found following evaluation of liver samples in 12 non-human primates, collected up to 26 weeks following doses up to 6 × 1013 vg/kg of valoctocogene roxaparvovec (which is the corresponding dose level in humans) (see section 4.4 Risk of malignancy as a result of vector integration).
No carcinogenicity study was performed with valoctocogene roxaparvovec.
No dedicated reproductive and developmental toxicity studies, including embryo-foetal and fertility assessments, were performed with ROCTAVIAN, as males comprise the majority of the patient population to be treated with ROCTAVIAN. Since hFVIII-SQ DNA has been estimated to persist around/until 67 weeks in testes of CD1 mice after IV injection of a 6 × 1013 vg/kg dose, the potential for vertical transmission to offspring was studied in Rag2-/- mice. There were no instances of germline transmission to pups sired by male mice dosed with valoctocogene roxaparvovec, when assessing liver of F1 pups for hFVIII-SQ DNA by qPCR.
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