Summary of the safety profile The most common adverse reactions to ROCTAVIAN were increases in ALT (83%), AST (70%), LDH (57%), and CPK (48%), nausea (37%), and headache (35%). 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).
14 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.
15 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.
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 5 describes hepatic laboratory abnormalities following administration of ROCTAVIAN. 4). 0 × ULN ALT increases Forty-four percent of ALT increases above ULN occurred within the first 26 weeks; 29% of ALT increases occurred within week 27 to 52, and 27% of ALT increases occurred beyond 52 weeks after administration.
The median duration of ALT increases above ULN was 3 weeks. Ninety-seven of the 141 patients (69%) had two or more episodes of ALT increases above ULN. 16 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 […]