Non-clinical evaluation of JR-051 as a biosimilar to agalsidase beta for the treatment of Fabry disease

Abstract

Fabry disease (FD) is an X-linked lysosomal storage disease. It is caused by deficiency of the enzyme α-galactosidase A (α-Gal A), which leads to excessive deposition of neutral glycosphingolipids, especially globotriaosylceramide (GL-3), in cells throughout the body. Progressive accumulation of GL-3 causes life-threatening complications in several tissues and organs, including the vasculature, heart, and kidney. Currently available enzyme replacement therapy for FD employs recombinant α-Gal A in two formulations, namely agalsidase alfa and agalsidase beta. Here, we evaluated JR-051 as a biosimilar to agalsidase beta in a non-clinical study. JR-051 was shown to have identical primary and similar higher-order structures to agalsidase beta. Mannose-6-phosphate content was higher in JR-051 than in agalsidase beta, which probably accounts for a slightly better uptake into fibroblasts in vitro. In spite of these differences in in vitro biological features, pharmacokinetic profiles of the two compounds in mice, rats, and monkeys were similar. The ability to reduce GL-3 accumulation in the kidney, heart, skin, liver, spleen, and plasma of Gla-knockout mice, a model of FD, was not different between JR-051 and agalsidase beta. Furthermore, we identified no safety concerns regarding JR-051 in a 13-week evaluation using cynomolgus monkeys. These findings indicate that JR-051 is similar to agalsidase beta in terms of physicochemical and biological properties.

Optimizing human α-galactosidase for treatment of Fabry disease

“…As previously reported 31 , GLA activity in plasma decreased rapidly after administration and was undetectable after 1 h in mouse and after 2 h in NHP. In contrast, GLAv05 and GLAv09 exhibited much greater perdurance with measurable activity remaining 6 h after administration in mouse (Fig.…”

Treatment of Fabry Nephropathy: A Literature Review

“…JR-051 is also produced in CHO cells and has a primary structure that is identical to that of the original agalsidase β, a similar charge isoform profile, and similar glycosylation profiles as well as enzyme activity [ 17 ]. In a Gla-knockout Fabry murine model, JR-051 reduced the accumulation of Gb3 in the kidney, heart, skin, liver, spleen and plasma, and there were no safety concerns regarding JR-051 in a 13-week evaluation using cynomolgus monkeys [ 18 ]. JR-051 was developed in Japan by JCR Pharmaceuticals and is available in Japan.…”

Physicochemical and biological evaluation of JR-131 as a biosimilar to a long-acting erythropoiesis-stimulating agent darbepoetin alfa

“…CD spectra were obtained with a JASCO J-802 spectropolarimeter (JASCO, Tokyo, Japan), as described previously [14]. Briefly, each sample was diluted to 0.2 mg/mL (far-UV) or 0.5 mg/ mL (near-UV) with the JR-131 formulation buffer.…”

“…Biosimilars are biological drugs demonstrating highly similar safety, efficacy, and quality to already approved biotechnology-applied products, which may be less expensive than their reference medical product (RMP), and thus could save healthcare costs. Sponsors of biosimilar medicines are required to demonstrate that the product has comparable safety and efficacy to the RMP through comprehensive physicochemical and biological analyses, in addition to nonclinical and clinical data [12][13][14].…”