The Safety of Agalsidase Alfa Enzyme Replacement Therapy in Canadian Patients with Fabry Disease Following Implementation of a Bioreactor Process

Abstract

Background and objective: Fabry disease, an X-linked lysosomal storage disorder characterized by absent or reduced alpha-galactosidase activity, is a lifelong disease that impairs patients' quality of life. Patients with Fabry disease have a considerably shortened lifespan, with mortality being mainly due to renal failure, cardiovascular disease, or cerebrovascular disease. Enzyme replacement therapy with agalsidase alfa has been shown to attenuate the renal, cardiovascular, and neuropathic disease progression associated with Fabry disease. The objective of this study was to investigate the safety of a new animal component-free version of agalsidase alfa.

Methods: A phase III/IV, open-label, single-arm, multicenter safety study was conducted in Canadian patients with Fabry disease between August 2011 and September 2017 as a regulatory requirement to assess the safety of agalsidase alfa produced using an animal component-free bioreactor process. Eligible patients had a documented diagnosis of Fabry disease and satisfied current Canadian guidelines for receiving enzyme replacement therapy for Fabry disease. Following treatment with animal component-free bioreactor-processed agalsidase alfa, treatment-emergent adverse events were monitored, and post hoc analyses of infusion-related reactions by antidrug antibody and neutralizing antibody statuses were conducted. The data were analyzed using descriptive statistics.

Results: A total of 167 patients (mean [standard deviation] age, 48.9 [14.8] years), including six pediatric patients (< 18 years of age), received at least one full or partial infusion of agalsidase alfa animal component-free. Fewer than 5% of treatment-emergent adverse events (212/4446) observed in 40 patients were reported as infusion-related reactions. Antidrug antibody and neutralizing antibody status did not affect the proportion of patients with infusion-related reactions. No clinically significant changes in vital signs were observed in patients over the course of the study.

Conclusions: Long-term treatment with bioreactor-produced agalsidase alfa animal component-free did not reveal new safety signals in this population of Canadian patients with Fabry disease. The treatment-emergent adverse event profile was consistent with the clinical manifestations of the disease and the known safety profile of roller bottle-produced agalsidase alfa.

Clinical trial registration: ClinicalTrials.gov identifier NCT01298141.

Fig. 1

Study design. AF animal component-free, EOW every other week

Fig. 2

Most common [i.e., reported in more than two patients] (A) severe treatment-emergent adverse events (TEAEs), (B) serious TEAEs, (C) possibly related TEAEs, and (D) infusion-related reaction (IRRs) for the study population (n = 167). Medical Dictionary for Regulatory Activities Preferred Terms

Fig. 3

Proportion of patients with positive or negative antidrug antibody (ADA) status (A) and neutralizing antibody (Nab) status (B) over time. Baseline was defined as the time at which data were collected prior to the first administration of the study drug

Fig. 4

Persisting antidrug antibody [ADAs] (n = 29) and neutralizing antibodies [Nabs] (n = 16) by previous enzyme replacement therapy status. For patients with more than one positive or negative result for ADA/NAb, patients with persisting ADAs/NAbs were defined as those with a positive antibody titer at the time of testing and at the previous sampling. Other treatment included agalsidase alfa (roller bottle [RB] or animal component-free) and agalsidase beta, those who had received agalsidase alfa RB and agalsidase alfa animal component-free, and those whose enzyme replacement therapy status was unknown

Fig. 5

Infusion-related reactions (IRRs) occurring in two or more patients who were antidrug antibody positive (A), antidrug antibody negative (B), neutralizing antibody positive (C), or neutralizing antibody negative (D) in the study population (n = 167). Medical Dictionary for Regulatory Activities Preferred Terms