Pegunigalsidase alfa

There are no or limited amount of data from the use of pegunigalsidase alfa in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of pegunigalsidase alfa during pregnancy unless clearly necessary.

It is unknown whether pegunigalsidase alfa/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of pegunigalsidase alfa in milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from pegunigalsidase alfa therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no studies assessing the potential effect of pegunigalsidase alfa on fertility in humans. Animal studies show no evidence of impaired fertility.

Dizziness or vertigo were observed in some patients following pegunigalsidase alfa administration. These patients should refrain from driving or the use of machines until symptoms have subsided.

Summary of the safety profile

The most common adverse reactions were infusion-related reactions reported in 6.3% of patients, followed by hypersensitivity and asthenia reported each by 5.6% of patients.

In clinical studies, 5 patients (3.5%) experienced a serious reaction that was considered related to pegunigalsidase alfa. Four of these reactions were confirmed IgE-mediated hypersensitivity (bronchospasm, hypersensitivity) that occurred at the first infusion of pegunigalsidase alfa and resolved within the day after occurrence.

Tabulated summary of adverse reactions

The data described below reflects data from 141 patients with Fabry disease who received pegunigalsidase alfa in 8 clinical studies, following the posology of 1 mg/kg every two weeks or 2 mg/kg every four weeks for a minimum of 1 infusion up to 6 years.

Adverse reactions are listed in the table below. Information is presented by system organ class. 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); frequency not known (cannot be estimated from available data).

Adverse reactions reported during treatment with pegunigalsidase alfa:

The following preferred terms have been grouped in the table:

• hypersensitivity includes: drug hypersensitivity
• agitation includes: nervousness
• abdominal pain includes: abdominal discomfort
• rash includes: rash maculo-papular and rash pruritic
• musculoskeletal stiffness recorded as musculoskeletal pain includes: myalgia
• asthenia includes: malaise and fatigue
• chest pain includes: chest discomfort and non-cardiac chest pain
• pain includes: pain in extremity
• oedema peripheral recorded as oedema

^* Preferred terms considered as IRR as described in the section below.

Description of selected adverse reactions

Infusion related reactions (adverse reactions within 2 hours of infusion)

IRRs were reported in a total of 32 patients (22%): 26 patients (23%) treated with 1 mg/kg every two weeks and 6 patients (20%) treated with 2 mg/kg every four weeks. The most commonly reported symptoms associated with IRRs reported for 1 mg/kg dosage were: hypersensitivity, chills, dizziness, rash and itching. For the 2 mg/kg dose the most commonly reported symptom was pain. IRRs were mostly mild or moderate in intensity and resolved with continuous treatment; however, 5 patients (all male, 1 mg/kg dose) experienced 5 severe IRRs. These 5 IRRs were also serious. Four of these events were confirmed type I hypersensitivity reactions and 3 led to the discontinuation from the study. Another patient was later withdrawn from the study, after the occurrence of another moderate IRR. All 5 patients however recovered within the day after of occurrence with appropriate treatment. IRRs predominantly occurred within the first year of treatment with pegunigalsidase alfa and no serious IRR was observed during the second year and beyond.

Immunogenicity

In clinical studies, 17 out of 111 of patients (16%) treated with 1 mg/kg pegunigalsidase alfa every two weeks and 0 out of 30 patients treated with 2 mg/kg pegunigalsidase alfa every four weeks developed treatment-induced antidrug antibodies (ADAs).

Glomerulonephritis membranoproliferative

During the clinical development of pegunigalsidase alfa, one patient out of 136 reported a severe event of glomerulonephritis membranoproliferative after receiving treatment for more than 2 years. The patient was ADA positive at the start of the infusions. The event led to a transitory reduction in the eGFR and an increase on the level of proteinuria, with no additional signs or symptoms. A biopsy revealed the immune-complex mediated nature of this event. Upon discontinuation of the treatment, the eGFR values stabilised and the glomerulonephritis was reported as resolving.