Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: BioMarin International Ltd., Shanbally, Ringaskiddy, County Cork, P43 R298, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active infections, either acute or uncontrolled chronic; or patients with known significant hepatic fibrosis, or cirrhosis (see section 4.4).
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Experience in patients with pre-existing antibodies to the AAV5 vector capsid is limited. Studies 270-201 and 270-301 excluded patients with detectable anti-AAV5 antibodies at screening (see section 5.1).
Anti-AAV5 antibody formation can take place after natural exposure. As it is not yet known whether or under what conditions valoctocogene roxaparvovec can be safely and effectively administered in the presence of anti-AAV5 antibodies, this medicinal product is not indicated for use in patients with detectable anti-AAV5 antibodies. Before administration, the absence of antibodies to AAV5 must be demonstrated using an appropriately validated assay (see sections 4.1 and 4.2)
There is limited experience in patients with hepatic disorders or receiving potentially hepatotoxic medicinal products (see section 5.1). Safety and efficacy of ROCTAVIAN in these circumstances have not been established. The efficacy of valoctocogene roxaparvovec relies on hepatocellular expression of hFVIII-SQ. It is not known to what extent a reduced number of transducible liver cells (e.g., due to cirrhosis) or loss of transduced liver cells over time (e.g., due to active hepatitis or exposure to hepatotoxic agents) may affect the therapeutic effect of valoctocogene roxaparvovec.
Valoctocogene roxaparvovec is contraindicated in patients with acute or uncontrolled chronic hepatic infections, or in patients with known significant hepatic fibrosis, or cirrhosis (see section 4.3). This medicinal product is not recommended in patients with other hepatic disorders, hepatic laboratory abnormalities (ALT, AST, GGT, or total bilirubin above 1.25 times ULN based on at least 2 measurements, or INR of 1.4 or above) or in patients with a history of hepatic malignancy (see Hepatic function and factor VIII monitoring). Patients should be screened for hepatic malignancy prior to prescribing valoctocogene roxaparvovec.
Before using this medicinal product in patients with any hepatic disorder or receiving potentially hepatotoxic medications, physicians should consider the potential for reduced therapeutic effect and more serious hepatic reactions and the potential need to change concomitant medicinal products, allowing time for a washout period as needed (see sections 4.5 and 4.8).
The effect of alcohol consumption on the magnitude and duration of the therapeutic effect is not known. In clinical studies, some ALT elevations have been attributed to alcohol consumption. It is recommended that patients abstain from consuming alcohol for at least one year after administration of this medicinal product and, thereafter limit alcohol use.
Following administration of valoctocogene roxaparvovec, the majority of patients (80%) experienced hepatic reactions indicated by an increase in ALT (see section 4.8); some of these reactions were temporally associated with decreased expression of the factor VIII transgene protein. The mechanism of these reactions has not yet been established.
ALT and factor VIII activity levels should be monitored after valoctocogene roxaparvovec administration (see Hepatic function and factor VIII monitoring), and corticosteroid treatment should be instituted in response to ALT elevations as needed, to control hepatic reactions and prevent or mitigate a potential reduction in transgene expression.
When establishing indication and timing of valoctocogene roxaparvovec administration for an individual patient, physicians should ensure the availability of the patient for close monitoring of hepatic laboratory parameters and factor VIII activity after administration and verify that the risks associated with the corticosteroid regimen are acceptable for the individual patient. Experience with regimens using other immunosuppressive agents is limited (see section 4.8).
Factor VIII activity produced by ROCTAVIAN in human plasma is higher if measured with one-stage clotting assays (OSA) compared to chromogenic substrate assays (CSA). In clinical studies, there was a high correlation between OSA and CSA factor VIII activity levels across the entire range of each assay’s results. For routine clinical monitoring of factor VIII activity levels, either assay may be used. The conversion factor between the assays can be approximated based on clinical study results to be: OSA = 1.5 × CSA. For example, a factor VIII activity level of 50 IU/dL using CSA calculates to a level of 75 IU/dL using 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).
When switching from haemostatic products (e.g., emicizumab) prior to valoctocogene roxaparvovec therapy, physicians should refer to the relevant product information to avoid the potential for factor VIII activity assay interference during the transition period.
In the first year after ROCTAVIAN administration, the purpose of hepatic and factor VIII monitoring is to detect increases in ALT, which may be accompanied by decreased factor VIII activity and may indicate the need to initiate corticosteroid treatment (see sections 4.2 and 4.8). Following the first year of administration, hepatic and factor VIII monitoring is intended to routinely assess liver health and bleeding risk, respectively.
A baseline assessment of liver health (including liver function tests within 3 months and recent fibrosis assessment using either imaging modalities, such as ultrasound elastography, or laboratory assessments, within 6 months) should be obtained before administration of ROCTAVIAN. Consider obtaining at least two ALT measurements prior to administration, or use an average of prior ALT measurements (for example within 4 months) to establish patient’s baseline ALT. It is recommended that the hepatic function is evaluated through a multidisciplinary approach with involvement of a hepatologist to best adjust the monitoring to the patient’s individual condition.
It is recommended (where possible) to use the same laboratory for hepatic testing at baseline and monitoring over time, particularly during the timeframe for corticosteroid treatment decision making, to minimise the impact of inter-laboratory variability.
After administration, the patient’s ALT and factor VIII activity levels should be monitored according to Table 2. To assist in the interpretation of ALT results, monitoring of ALT should be accompanied by monitoring of aspartate aminotransferase (AST) and creatine phosphokinase (CPK) to help rule out alternative causes for ALT elevations (including potentially hepatotoxic medicinal products or agents, alcohol consumption, or strenuous exercise). Based on patient’s ALT elevations, corticosteroid treatment may be indicated (see Corticosteroid treatment). Weekly monitoring is recommended, and as clinically indicated, during corticosteroid tapering.
It should be ensured the availability of the patient for frequent monitoring of hepatic laboratory parameters and factor VIII activity after administration.
Table 2. Hepatic function and factor VIII activity monitoring:
| Measurements | Timeframe | Monitoring frequencya | |
|---|---|---|---|
| Before administration | Liver function tests | Within 3 months prior to infusion | Baseline measurement |
| Recent fibrosis assessment | Within 6 months prior to infusion | ||
| After administration | ALT and factor VIII activityb | First 26 weeks | Weekly |
| Weeks 26 to 52 (Year 1) | Every 2 to 4 weeks | ||
| Year 1 to end of Year 2 | • Every 3 months for patients with factor VIII activity levels >5 IU/dL • Consider more frequent monitoring in patients with factor VIII activity levels ≤ 5 IU/dL and consider the stability of factor VIII levels and evidence of bleeding. | ||
| After Year 2 | • Every 6 months for patients with factor VIII activity >5 IU/dL • Consider more frequent monitoring in patients with factor VIII activity levels ≤5 IU/dL and consider the stability of factor VIII levels and evidence of bleeding. |
a Weekly monitoring is recommended, or as clinically indicated, during corticosteroid tapering. Adjustment of the monitoring frequency may also be indicated depending on the individual situation.
b Monitoring of ALT should be accompanied by monitoring of AST and CPK, to rule out alternative causes for ALT elevations (including potentially hepatotoxic medications or agents, alcohol consumption, or strenuous exercise).
If a patient returns to prophylactic use of factor VIII concentrates/haemostatic agents for haemostatic control, consider following monitoring and management consistent with instructions for those agents. An annual health check-up should include liver function tests.
Inter-patient factor VIII activity level variability was observed after administration with no identified potential factors of variability. In study 270-301, inter-patient variability could not be explained by patient baseline characteristics, demographics, or other predictive factors. Some patients might have low factor VIII activity levels following ROCTAVIAN treatment, but could still derive a clinical benefit in terms of a reduction of exogenous factor VIII requirement and annualised bleeding rates. A trend of lower factor VIII activity levels was observed in Black patients within the study population. Given the small sample size, the limited number of sites enroling Black patients relative to the total population, the existence of potential confounding factors, and multiple post-hoc analyses, this trend was insufficient to allow meaningful conclusions about the differences in response rates based on race or other factors therein influencing factor VIII expression following valoctocogene roxaparvovec infusion. Despite differences in factor VIII activity levels, ABR and annualised factor VIII usage was similar across races.
In study 270-301, corticosteroids were initiated upon observed ALT elevations to dampen potential inflammatory responses and associated possible reductions in factor VIII expression. The recommended corticosteroid regimen based on current clinical experience is provided. Reference to the corticosteroid product information for risks and required precautions is recommended.
If a patient’s ALT rises above 1.5 × baseline (see definition of baseline above in Hepatic function and factor VIII monitoring) or above ULN, it is recommended to evaluate alternative causes of the ALT elevation (including potentially hepatotoxic medicinal products or agents, alcohol consumption, or strenuous exercise). Repeating ALT laboratory testing within 24 to 48 hours and, if clinically indicated and performing additional tests to exclude alternative etiologies should be considered, (see section 4.5). In the absence of an alternative cause for the ALT elevation, a corticosteroid regimen should be promptly initiated at a daily dose of 60 mg prednisone (or equivalent dose of another corticosteroid) for 2 weeks. The daily corticosteroid dose can be gradually tapered in a stepwise manner according to Table 3. Patients with baseline ALT levels between > ULN to 1.25 × ULN should initiate the corticosteroid regimen described in Table 3 if their ALT increases above 1.5 × baseline.
In patients who have not reached factor VIII activity levels of at least 5 IU/dL by 5 months, administration of corticosteroids did not improve factor VIII expression. There is limited benefit of initiating or extending a corticosteroid course beyond 5 months in this population, unless it is to manage significant ALT elevations or concerns about liver health.
There is limited information with regards to the benefit of starting a new corticosteroid course after the first year of ROCTAVIAN administration.
Table 3. Recommended corticosteroid regimen in response to ALT elevations:
| Regimen (prednisone or equivalent dose of another corticosteroid) | |
|---|---|
| Starting dosea | 60 mg daily for 2 weeks |
| Taperingb | 40 mg daily for 3 weeks 30 mg daily for 1 week 20 mg daily for 1 week 10 mg daily for 1 week |
a If ALT continues to rise or has not improved after 2 weeks, increase the corticosteroid dose up to a maximum of 1.2 mg/kg, after ruling out alternative causes for ALT elevation.
b Tapering of corticosteroids can start after 2 weeks if ALT levels remain stable and/or earlier when ALT levels start to decline. The taper may be individualised based on the course of hepatic function, taking into account the patient’s medical condition, corticosteroid tolerance, and potential for withdrawal symptoms.
If corticosteroids are contraindicated, other immunosuppressive therapy could be considered. It is recommended to set a multidisciplinary consultation involving a hepatologist, to best adjust the alternative to corticosteroids and the monitoring to the patient’s individual condition. Physicians should also consider discontinuing corticosteroids in cases where corticosteroids are ineffective or not tolerated. There is limited experience on the use of alternative immunosuppressants (see section 4.8). If ALT has not improved despite 4 weeks on the maximum corticosteroid dose and is above 3 × ULN, alternative immunosuppressants may be considered and in addition, consider further workup for alternative causes of ALT elevation.
Investigations are ongoing to determine the optimal corticosteroid regimen.
The patient’s ability to receive corticosteroids that could be required for an extended time period should be evaluated. It should be ensured that the risks associated with the described regimen are likely to be acceptable for the individual patient.
Infusion-related reactions to valoctocogene roxaparvovec can have multiple manifestations (such as skin, mucosal, respiratory, gastrointestinal and cardiovascular manifestations, and pyrexia) and may require reduction in infusion rate, interruption of infusion, pharmacologic intervention, and prolonged observation (see sections 4.2 and 4.8).
Patients should be monitored during and after the infusion for possible acute infusion reactions (see section 4.8). Instructions should be provided when discharging the patient to seek medical attention in case of a new or recurrent reaction.
An increase in factor VIII activity may contribute to a patient’s individual, multifactorial risk for venous and arterial thrombotic events. There is no experience in patients with a relevant history of venous or arterial thrombotic/thromboembolic events or known history of thrombophilia.
Some patients have experienced elevations of factor VIII activity to levels greater than the ULN (see section 4.8).
Patients should be evaluated before and after administration of valoctocogene roxaparvovec for risk factors for thrombosis and general cardiovascular risk factors. Based on factor VIII activity levels achieved, patients should be advised according to their individual condition. Patients should seek immediate medical attention if they observe signs or symptoms that may indicate a thrombotic event.
Male patients should be informed on the need for contraceptive measures for them and their female partners of child bearing potential (see section 4.6).
There is a lack of experience with donation of blood or organs, tissues and cells for transplantation following AAV vector-based gene therapy. Therefore, patients treated with this medicinal product must not donate blood or organs, tissues or cells for transplantation. This information is provided in the Patient Card which should be given to the patient after treatment.
No immunocompromised patients, including patients undergoing immunosuppressive treatment within 30 days before valoctocogene roxaparvovec infusion, were enrolled in the pre-registration clinical studies. Safety and efficacy of this medicinal product in these patients have not been established. Use in immunocompromised patients is based on prescriber judgment, taking into account the patient’s general health and potential for corticosteroid use post-valoctocogene roxaparvovec treatment.
Only a few HIV infected patients have been treated with valoctocogene roxaparvovec as part of the clinical studies. Among them, one patient experienced elevation in hepatic enzymes suggestive of an interaction with efavirenz in the patient’s HIV treatment regimen. Given the risk of hepatotoxicity and/or effect on factor VIII expression, the HIV patient’s existing antiretroviral therapy regimen should be carefully evaluated prior to initiating treatment and following treatment with valoctocogene roxaparvovec. The physician treating the HIV infection should be consulted to consider whether a less hepatotoxic antiretroviral therapy regimen could be available and suitable for the patient, and if indicated, switch the patient to the new antiretroviral therapy regimen whenever feasible (see sections 4.5).
There is no experience with administration of ROCTAVIAN in patients with acute infections (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic infections (such as chronic active hepatitis B). It is possible that such infections affect the response to valoctocogene roxaparvovec and reduce its efficacy and/or cause adverse reactions. Therefore, this medicinal product is contraindicated in patients with such infections (see section 4.3). If there are signs or symptoms of acute or uncontrolled chronic active infections, treatment must be postponed until the infection has resolved or is controlled.
Patients who have or had inhibitors (neutralising antibodies) to factor VIII were excluded from participation in the clinical studies. It is not known whether or to what extent such inhibitors affect the safety or efficacy of valoctocogene roxaparvovec.
All patients remained negative for factor VIII inhibitors at all time points evaluated post-infusion.
ROCTAVIAN is not indicated for use in patients with a history of factor VIII inhibitors.
After administration of valoctocogene roxaparvovec, patients should be monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests.
Following administration of valoctocogene roxaparvovec:
It is not yet known whether or under what conditions valoctocogene roxaparvovec therapy may be repeated, and to what extent cross-reacting antibodies could interact with the capsids of AAV vectors used by other gene therapies, potentially impacting their efficacy.
Integration site analysis was performed on liver samples from 5 patients treated with ROCTAVIAN in clinical studies. Samples were collected approximately 0.5-4.1 years post-dose. Vector integration into human genomic DNA was observed in all samples.
ROCTAVIAN can also insert into DNA of other human body cells (as observed in parotid gland DNA samples from one patient treated with ROCTAVIAN in a clinical study). The clinical relevance of individual integration events is not known to date, but it is acknowledged that individual integration events could potentially contribute to a risk of malignancy (see section 5.3).
So far, no cases of malignancies associated with ROCTAVIAN treatment have been reported. In the event that a malignancy occurs, the marketing authorisation holder should be contacted to obtain instructions on collecting patient samples for integration site analysis.
Patients are expected to be enrolled in a registry to follow haemophilia patients for 15 years, to substantiate the long-term efficacy and safety of this gene therapy.
This medicinal product contains 29 mg sodium per vial, equivalent to 1.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Prior to valoctocogene roxaparvovec administration, the patient’s existing medicinal products should be reviewed to determine if they should be modified to prevent anticipated interactions described in this section.
Patients' concomitant medications should be monitored after valoctocogene roxaparvovec administration, particularly during the first year, and the need to change concomitant medicinal products based on patient’s hepatic status and risk should be evaluated. When a new medication is started, close monitoring of ALT and factor VIII activity levels (e.g., weekly to every 2 weeks for the first month) is recommended to assess potential effects on both levels.
No in vivo interaction studies have been performed.
Caution of use with hepatotoxic medications or hepatotoxic substances should be applied due to limited experience. The safety and efficacy of valoctocogene roxaparvovec in these circumstances have not been established (see section 4.4).
Before administering valoctocogene roxaparvovec to patients receiving potentially hepatotoxic medicinal products or using other hepatotoxic agents (including alcohol, potentially hepatotoxic herbal products and nutritional supplements) and when deciding on the acceptability of such agents after treatment with valoctocogene roxaparvovec, physicians should consider that they may reduce the efficacy of valoctocogene roxaparvovec and increase the risk for more serious hepatic reactions, particularly during the first year following valoctocogene roxaparvovec administration (see section 4.4).
In one patient, decreased factor VIII activity without ALT elevation was detected after starting treatment with systemic isotretinoin following valoctocogene roxaparvovec infusion; factor VIII activity was 75 IU/dL at week 60 and transiently decreased to <3 IU/dL at week 64, after initiating isotretinoin. After discontinuing isotretinoin at week 72, factor VIII activity recovered to 46 IU/dL at week 122. An in vitro study in human primary hepatocytes indicated that isotretinoin suppressed factor VIII expression independent of hepatotoxicity. Isotretinoin is not recommended in patients who are benefiting from valoctocogene roxaparvovec.
One HIV positive patient treated with an antiretroviral therapy regimen consisting of efavirenz, lamivudine, and tenofovir experienced asymptomatic Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 elevations of ALT, AST, and GGT (> 5.0 × ULN) and a Grade 1 elevation of serum bilirubin (> ULN and up to 1.5 × ULN) at week 4, suggestive of an interaction with efavirenz (see section 4.4). The reaction did not respond to corticosteroid treatment but responded to withdrawal of efavirenz and resolved after his antiretroviral therapy regimen was changed to a regimen without efavirenz. The patient later reverted to prophylactic use of factor VIII concentrates/haemostatic agents. An in vitro study in human primary hepatocytes indicated that efavirenz suppressed factor VIII expression independent of hepatotoxicity. Efavirenz is not recommended in patients who are benefiting from valoctocogene roxaparvovec. The use of non-efavirenz treatments should be considered.
Agents that may reduce or increase the plasma concentration of corticosteroids (e.g., agents that induce or inhibit cytochrome P450 3A4) can decrease the efficacy of the corticosteroid regimen or increase their side effects (see section 4.4).
Prior to valoctocogene roxaparvovec infusion, ensure that the patient’s vaccinations are up to date. The patient’s vaccination schedule may need to be adjusted to accommodate concomitant immunomodulatory therapy (see section 4.4). Live vaccines should not be administered to patients while on immunomodulatory therapy.
No dedicated animal fertility/embryofoetal studies have been conducted to substantiate whether the use in women of childbearing potential and during pregnancy could be harmful for the new-born child (theoretical risk of viral vector integration in foetal cells through vertical transmission). Moreover, no data are available to recommend a specific duration of contraceptive measures in women of childbearing potential. Therefore, ROCTAVIAN is not recommended in women of childbearing potential.
In clinical studies, after administration of ROCTAVIAN, transgene DNA was temporarily detectable in semen (see sections 4.4 and 5.2).
For 6 months after administration of ROCTAVIAN
Experience regarding the use of this medicinal product during pregnancy is not available. Animal reproduction studies have not been conducted with ROCTAVIAN. It is not known whether this medicinal product can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. ROCTAVIAN should not be used during pregnancy.
It is unknown whether valoctocogene roxaparvovec is excreted in human milk. A risk to the new-borns/infants cannot be excluded. ROCTAVIAN should not be used during breast-feeding.
No non-clinical or clinical studies were performed to evaluate the effect of valoctocogene roxaparvovec on fertility (see Contraception after administration to males).
Infusion of valoctocogene roxaparvovec may have a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as temporary presyncope, dizziness, fatigue, and headache that have occurred shortly after valoctocogene roxaparvovec administration, patients should be advised to use caution when driving and operating machinery until they are certain that this medicinal product does not adversely affect them (see section 4.8).
The most common adverse reactions to ROCTAVIAN were increases in ALT (82%), AST (69%), LDH (57%), and CPK (44%), nausea (37%), and headache (35%).
The following adverse reactions described are based on a total of 141 patients from Studies 270-201 and 270-301, all dosed at 6 × 1013 vg/kg (see section 5.1).
Adverse reactions are listed by MedDRA body system organ class and by frequency. Frequencies are categorised as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Table 4. Tabulated list of adverse reactions to valoctocogene roxaparvovec:
| MedDRA system organ class | Adverse reaction | Frequency |
|---|---|---|
| Infections and infestations | Flu-like symptoms | Common |
| Blood and lymphatic system disorders | Factor VIII activity levels above ULNa | Very common |
| Immune system disorders | Hypersensitivity reactionb | Common |
| Nervous system disorders | Headache | Very common |
| Dizzinessb | Common | |
| Presyncopeb | Uncommon | |
| Cardiac disorders | Increased blood pressureb | Common |
| Respiratory, thoracic and mediastinal disorders | Dyspnoeab | Uncommon |
| Gastrointestinal disorders | Nausea, vomiting, abdominal pain, diarrhoea | Very common |
| Dyspepsia | Common | |
| Hepatobiliary disordersc | ALT increased, AST increased, GGT increased, bilirubin increased, and LDH increased | Very common |
| Skin and subcutaneous tissue disorders | Rashd, pruritusb | Common |
| Musculoskeletal and connective tissue disorders | CPK increased | Very common |
| Myalgia | Common | |
| General disorders and administration site conditions | Fatiguee | Very common |
| Infusion-related reactionf | Common |
a One or more instances of factor VIII activity levels >170 IU/dL (ULN of the CSA used) or >150 IU/dL (ULN of the OSA used). See Description of selected adverse reactions.
b Considered an adverse reaction only during first 48 hours after infusion.
c Reflects laboratory abnormalities above the ULN.
d Rash includes maculopapular rash and urticaria.
e Fatigue includes lethargy and malaise.
f Infusion-related reactions includes manifestations such as skin, mucosal, and respiratory tract (including urticaria, pruritus, maculopapular rash, sneezing, coughing, dyspnoea, rhinorrhoea, watery eyes, and tingling throat), gastrointestinal (including nausea and diarrhoea), cardiovascular (including increased blood pressure, hypotension, tachycardia, and presyncope) and musculoskeletal (including myalgia and lower back pain), as well as pyrexia, rigours, and chills.
Eleven patients (8%; 11/141) experienced infusion-related reactions with symptoms during or within 6 hours after the end of infusion that included one or more of the following: skin, mucosal, and respiratory tract manifestations (including urticaria, pruritus, maculopapular rash, sneezing, coughing, dyspnoea, rhinorrhoea, watery eyes, and tingling throat), gastrointestinal manifestations (including nausea and diarrhoea), cardiovascular manifestations (including increased blood pressure, hypotension, tachycardia, and presyncope) and musculoskeletal manifestations (including myalgia and lower back pain), as well as pyrexia, rigours, and chills. The median time to onset was 1 hour (range: 0.25, 5.87) from the start of the infusion, and median duration was 1 hour. Four patients had reactions during the infusion. Three of these patients experienced CTCAE Grade 3 hypersensitivity reaction, and temporary interruption of the infusion was required, followed by re-initiation at a slower rate. All patients who experienced infusion-related reactions completed their infusions. Seven of the 11 patients received one or more of the following medications: systemic antihistamines, corticosteroids, and/or antiemetics. In addition, 1 patient received intravenous fluids and epinephrine. All events of infusion-related reactions resolved without sequelae.
Table 5 describes hepatic laboratory abnormalities following administration of ROCTAVIAN. ALT increases are further characterised, as they may be accompanied by decreased factor VIII activity and may indicate the need to initiate corticosteroid treatment (see section 4.4).
Table 5. Hepatic laboratory abnormalities in patients administered 6 × 1013 vg/kg ROCTAVIAN in studies 270-201 and 270-301:
| Number of patients (%) N=141 | |
|---|---|
| ALT increases > ULN | 116 (82%) |
| CTCAE Grade 2a | 29 (21%) |
| CTCAE Grade 3b | 12 (9%) |
| AST increases > ULNc | 97 (69%) |
| CTCAE Grade 2a | 16 (11%) |
| CTCAE Grade 3b | 9 (6%) |
| GGT increases > ULNc | 24 (17%) |
| CTCAE Grade 2a | 2 (1%) |
| CTCAE Grade 3b | 1 (1%) |
| Bilirubin increases > ULNc,d | 18 (13%) |
| CTCAE Grade 2e | 5 (4%) |
| LDH increases > ULN | 80 (57%) |
a CTCAE Grade 2: >3.0 and up to 5.0 × ULN
b CTCAE Grade 3: >5.0 × ULN
c Post baseline values are based on the highest CTCAE Grade
d No patients had CTCAE Grade 3 elevations
e CTCAE Grade 2: >1.5 and up to 3.0 × ULN
Forty-six percent of ALT increases above ULN occurred within the first 26 weeks; 31% of ALT increases occurred within week 27 to 52, and 23% of ALT increases occurred beyond 52 weeks after administration. The median duration of ALT increases above ULN was 3 weeks. Ninety-five of the 141 patients (67%) had two or more episodes of ALT increases above ULN.
Twelve (9%) patients experienced Grade 3 ALT elevations (15 episodes total). The range of Grade 3 ALT elevations were 216 IU/dL to 623 IU/dL. The majority of Grade 3 ALT elevations (73%) occurred within the first 26 weeks, 3 (20%) occurred within week 27 to 52, and 1 (7%) occurred beyond 52 weeks after administration. All Grade 3 ALT elevations resolved with corticosteroids, including 2 patients that received IV methylprednisolone.
In the patients who had ALT increases above ULN, the median (range) time to initial reduction in ALT (defined as first drop of at least 10 U/L or ALT ≤ ULN) following a new corticosteroid course or increase in corticosteroid dose was 8 (2, 71) days.
In study 270-301, 106 of the 134 patients (79%) received corticosteroid (prednisone or prednisolone) treatment in response to ALT elevations starting at a median of 8 weeks after ROCTAVIAN administration. The majority of these patients (93%; 99 out of 106) started corticosteroid treatment within the first 26 weeks, 6 patients (6%) started corticosteroid treatment between weeks 26 and 52, and 1 patient started corticosteroid treatment after 52 weeks. The range in the timing for initiating corticosteroids was driven by the variability in time of first ALT elevation among patients and differences in the defined ALT threshold criteria for initiating corticosteroids that changed over the course of the study. The median (range) total duration of corticosteroid use (including repeat treatment) was 33 (3, 120) weeks. A prolonged corticosteroid regimen was also observed in patients not achieving factor VIII activity level >5 IU/dL (low responders). Extending the duration of corticosteroid treatment did not result in significant benefit to factor VIII levels (see section 4.4).
In study 270-301, patients received alternative immunosuppressants (AIS) other than prednisone or prednisolone, due to inability to tolerate corticosteroids or ineffectiveness of corticosteroids. Nineteen (14%) patients had their ALT levels above ULN prior to receiving AIS. These medications included one or more of the following: tacrolimus, mycophenolate, and budesonide. IV methylprednisolone was administered in 2 patients for Grade 3 ALT elevations.
In studies 270-201 and 270-301, there were patients with one or more instances of factor VIII activity levels above ULN (see Table 6 and section 4.4). Two patients had transient factor VIII activity levels above the assays limit of quantitation (>463 IU/dL for CSA and >500 IU/dL for OSA). One patient received enoxaparin for venous thromboembolism prophylaxis based on that patient’s individual risk factors. Six of 39 (15%) patients in study 270-301 and none of the patients in study 270-201 had their factor VIII activity levels remain above ULN at the time of the data cut.
Table 6. Factor VIII activity levels above ULNa:
| Study 270-301 ITT Population (N=134) | Study 270-201 6 × 1013 vg/kg Cohort (N=7) | |||
|---|---|---|---|---|
| OSA | CSA | OSA | CSA | |
| Proportion of patients | ||||
| n (%) | 38 (28%) | 16 (12%) | 4 (57%) | 2 (29%) |
| Time to first factor VIII measure > ULN (weeks) | ||||
| Mean (SD) Median (Range) | 18.9 (24.1) 13.6 (6.1, 158.0) | 18.1 (6.0) 18.1 (8.3, 29.1) | 22.4 (8.5) 20.1 (15.3, 34.1) | 24.7 (4.9) 24.7 (21.3, 28.1) |
| Duration of factor VIII measures > ULN (weeks) | ||||
| Mean (SD) Median (Range) | 31.5 (39.8) 11.7 (0.1, 143.7) | 25.8 (34.2) 13.5 (0.7, 111.9) | 34.8 (33.0) 31.2 (2.3, 74.6) | 2.4 (0.5) 2.4 (2.0, 2.7) |
a ULN of >150 IU/dL for OSA and ULN of >170 IU/dL for CSA.
In studies 270-201 and 270-301, all patients receiving treatment were required to screen negative for anti-AAV5 antibodies and negative (<0.6 BU) for factor VIII inhibitors in a Nijmegen modified Bethesda assay following a lifetime minimum of 150 exposure days to factor VIII replacement therapy (see sections 4.1 and 4.4).
Following infusion of ROCTAVIAN, all patients remained negative for factor VIII inhibitors at all time points evaluated post-infusion by the time of the data cut.
All patients seroconverted to anti-AAV5 antibody positive within 8 weeks of administration. Mean anti-AAV5 total antibody titres peaked by 36 weeks after administration and remained stable until the last time point tested.
ROCTAVIAN-treated patients were tested for cellular immune responses against the AAV5 capsid and the factor VIII transgene product using an IFN-γ ELISpot assay. AAV5 capsid-specific cellular immune responses were detected beginning at week 2 following dose administration and often declined or reverted to negative over the first 52 weeks in the majority of patients with available data. AAV5 capsid-specific cellular immune responses were associated with higher mean ALT values at matched timepoints.
Factor VIII-specific responses were detected in fewer subjects, often sporadically at a single time point and reverting to negative in most patients. No association between factor VIII cellular immune response and ALT or factor VIII activity measures could be detected.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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