Agalsidase beta (Fabrazyme), the first Fabry disease-specific therapy to be approved by the FDA, effectively reduces globotriaosylceramide deposits. However, the drug comes with a high price tag of approximately $300,000 per patient per year, and has been subject to shortages due to manufacturing issues.
Fabry disease (FD) is a rare lysosomal storage disorder caused by absent or deficient activity of the lysosomal enzyme alpha-galactosidase A (a-Gal A) (encoded by the GLA gene), and causes buildup of globotriaosylceramide in cells, which can result in irreversible organ damage.
Agalsidase beta (Fabrazyme), the first FD-specific therapy to be approved by the FDA, effectively reduces globotriaosylceramide deposits. However, the drug comes with a high price tag of approximately $300,000 per patient per year, and has been subject to shortages due to manufacturing issues.
A proposed biosimilar agalsidase beta, JR-051, developed by JCR Pharmaceuticals, is currently under Japanese regulatory review, and, if approved, could provide patients with a lower-cost option and help to prevent future supply issues for patients who rely on the therapy to treat FD. A newly published paper in Molecular Genetics and Metabolism explains that nonclinical evaluation of the proposed biosimilar reveals JR-051 to be highly similar to the reference drug.
The researchers tested 4 lots of the reference versus the biosimilar, and determined that the amino acid sequence of the 2 products was identical, and assessment of higher-order structures revealed the products to have similar structural properties. Enzyme activity was comparable between the 2 products.
JR-051 had a similar glycosylation profile to the reference, though it had a higher mannose 6-phosphate (M6P) content, which can affect binding and pharmacokinetics (PK), though no difference in PK was found in a test in animals. In a test of binding, JR-051 had a higher affinity to M6P. The cellular uptake of enzymes was slightly better for JR-051 than the reference, which the investigators attributed to the higher M6P content of the biosimilar.
In mice, both products markedly reduced the concentration of globotriaosylceramide in the kidney, liver, heart, spleen, skin, and plasma, and there was no difference in the degree of clearance. In monkeys, no differences in safety were observed between the 2 products.
“A high degree of similarity was observed in terms of all physicochemical and biological properties tested,” concluded the authors. “A notable exception to this was the higher M6P content in JR-051 than in agalsidase beta, which resulted in a slightly better uptake into fibroblasts in vitro. However, these differences did not result in substantial differences in pharmacokinetics or efficacy.”
Morimoto H, Ito Y, Yoden E, et al. Non-clinical evaluation of JR-051 as a biosimilar to agalsidase beta for the treatment of Fabry disease. [Published online July 23, 2018.] Mol Genet Metab. doi: 10.1016/j.ymgme.2018.07.009.