Valoctocogene roxaparvovec

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. Live vaccines should not be administered to patients while on immunomodulatory therapy.

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. 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.

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.

There is limited experience in patients with hepatic disorders or receiving potentially hepatotoxic medicinal products. Safety and efficacy of valoctocogene roxaparvovec 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. 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. 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.

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.

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.

Experience regarding the use of valoctocogene roxaparvovec during pregnancy is not available. Animal reproduction studies have not been conducted with valoctocogene roxaparvovec. It is not known whether valoctocogene roxaparvovec can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Valoctocogene roxaparvovec 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. Valoctocogene roxaparvovec should not be used during breast-feeding.

Women of childbearing potential

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, valoctocogene roxaparvovec is not recommended in women of childbearing potential.

Fertility

No non-clinical or clinical studies were performed to evaluate the effect of valoctocogene roxaparvovec on fertility.

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.

Summary of the safety profile

The most common adverse reactions to valoctocogene roxaparvovec were increases in ALT (82%), AST (69%), LDH (57%), and CPK (44%), nausea (37%), and headache (35%).

Tabulated list of adverse reactions

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.

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 1. Tabulated list of adverse reactions to valoctocogene roxaparvovec:

^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.

Description of selected adverse reactions

Infusion-related reactions

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.

Hepatic laboratory abnormalities

Table 2 describes hepatic laboratory abnormalities following administration of valoctocogene roxaparvovec. ALT increases are further characterised, as they may be accompanied by decreased factor VIII activity and may indicate the need to initiate corticosteroid treatment.

Table 2. Hepatic laboratory abnormalities in patients administered 6 × 10¹³ vg/kg valoctocogene roxaparvovec in studies 270-201 and 270-301:

^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

ALT increases

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.

Immunosuppressant use to prevent or mitigate ALT elevations

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 valoctocogene roxaparvovec 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.

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.

Factor VIII activity levels above ULN

In studies 270-201 and 270-301, there were patients with one or more instances of factor VIII activity levels above ULN. 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 3. Factor VIII activity levels above ULN^a:

^a ULN of >150 IU/dL for OSA and ULN of >170 IU/dL for CSA.

Immunogenicity

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.

Following infusion of valoctocogene roxaparvovec, 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.

Valoctocogene roxaparvovec-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.