5%). Tabulated list of adverse reactions Assessment of adverse reactions was based on exposure in 48 ARG1-D patients (8 adults and 40 children between the ages of 2 and 31 years at enrolment) with treatment duration of up to approximately 5 years across 3 clinical trials.
Adverse reactions are listed by MedDRA system organ class and by frequency in Table 1 below. Frequencies are defined as: 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 available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Due to the small size of the medicinal product safety ARG1-D population database (N=48), the adverse reaction frequency for uncommon, rare and very rare could not be reliably estimated.
Table 1. Adverse reactions System organ class Very common Immune system disorders Hypersensitivity General disorders and administration site conditions Injection site reactions Description of selected adverse reactions Hypersensitivity Hypersensitivity reactions with symptoms including facial swelling, rash, flushing and dyspnoea have been reported.
5%) Loargys-treated patients, experienced signs and symptoms either consistent with, or that may be related to a hypersensitivity reaction. The reactions generally occurred with the first few doses. The reactions were mild or moderate and resolved spontaneously, or rapidly after treatment with standard medical care.
None of the reactions led to discontinuation of treatment. 4). Post-marketing, hypersensitivity reactions were reported, even involving patients treated by subcutaneous administration who were pre-medicated with antihistamines. 6% (6/44) of Loargys-treated patients after subcutaneous administration.
Signs and symptoms included pain, erythema, swelling, irritation and rash at the injection site. The injection site reactions were mild in severity and resolved spontaneously or with standard medical care without dose interruption. Immunogenicity There is potential for immunogenicity to pegylated therapeutic proteins.
The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Across all clinical trials in the pegzilarginase ARG1-D development program, 12 of 48 subjects (25%) tested positive for ADAs against PEG and/or the protein moiety of pegzilarginase, with the majority detected early after the first dose.
There was no assay available for detecting neutralising antibodies during the clinical development programme. The ADAs were transient in nature and resolved during continued treatment. The presence of ADAs was associated with transient changes in the pharmacokinetics (PK) and pharmacodynamics (PD) of Loargys in patients with ARG1-D.
Paediatric population The majority of patients treated with pegzilarginase in the ARG1-D development programme were paediatric patients with 88% (40/48) being children (2-18 years old). The safety profile of pegzilarginase presented in the safety section is therefore considered representative for the paediatric population above 2 years.
Reporting of suspected adverse reactions 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.