Development of a Biosimilar of Agalsidase Beta for the Treatment of Fabry Disease: Preclinical Evaluation

Overview

Journal Drugs R D

Specialty Pharmacology

Date 2023 Apr 21

PMID 37083901

Authors

Andre B P van Kuilenburg

Carla E M Hollak

Ana Travella

Melisa Jacobs

Lucas D Gentilini

Rene Leen

Karen M M Ghauharali-van der Vlugt

Femke S Beers Stet

Susan M I Goorden

Sanne van der Veen

Marcelo Criscuolo

Mariana Papouchado

Affiliations

Soon will be listed here.

Abstract

Background And Objective: Fabry disease (FD) is a rare lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (aGal A). Since 2001, two different enzyme replacement therapies have been authorized, with agalsidase beta being used in most parts of the Western world. Currently, biosimilars of several expensive enzyme therapies are under development to improve their accessibility for patients. We present the preclinical results of the development of a biosimilar to agalsidase beta.

Methods: Produced in a Chinese hamster ovary (CHO)-cell system, the biosimilar aGal A Biosidus (AGABIO), was compared with agalsidase beta with respect to amino acid sequence, glycosylation, specific α-galactosidase activity, stability in plasma, and effects on cultured human Fabry fibroblasts and Fabry mice.

Results: AGABIO had the same amino acid composition and similar glycosylation, enzymatic activity, and stability as compared with agalsidase beta. After uptake in fibroblasts, α-galactosidase A activity increased in a dose-dependent manner, with maximum uptake observed after 24 h, which remained stable until at least 48 h. Both enzymes were localized to lysosomes. Reduction of accumulated globotriaosylceramide (Gb3) and lysoGb3 in cultured Fabry fibroblasts by AGABIO and agalsidase beta showed comparable dose-response curves. In Fabry knockout mice, after a single injection, both enzymes were rapidly cleared from the plasma and showed equal reductions in tissue and plasma sphingolipids. Repeated dose studies in rats did not raise any safety concerns. Anti-drug antibodies from patients with FD treated with agalsidase beta showed equal neutralization activity toward AGABIO.

Conclusion: These findings support the biosimilarity of AGABIO in comparison with agalsidase beta. The clinical study phase is currently under development.

Citing Articles

Comparative pharmacokinetics and pharmacodynamics of two formulations of agalsidase beta (agalsidase Biosidus) and Fabrazyme® by intravenous infusion in healthy male volunteers.

Berstein V, Pirotzky E, Taconelli H, Gobbi M, Beider L, Salgueiro N Mol Genet Metab Rep. 2024; 41:101149.

PMID: 39435314 PMC: 11492607. DOI: 10.1016/j.ymgmr.2024.101149.

References

Ioannou Y, Zeidner K, Gordon R, Desnick R . Fabry disease: preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice. Am J Hum Genet. 2000; 68(1):14-25. PMC: 1234907. DOI: 10.1086/316953. View

Jeon Y, Jung N, Park J, Park H, Jung S . Epithelial-Mesenchymal Transition in Kidney Tubular Epithelial Cells Induced by Globotriaosylsphingosine and Globotriaosylceramide. PLoS One. 2015; 10(8):e0136442. PMC: 4546309. DOI: 10.1371/journal.pone.0136442. View

Arends M, Biegstraaten M, Wanner C, Sirrs S, Mehta A, Elliott P . Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study. J Med Genet. 2018; 55(5):351-358. PMC: 5931248. DOI: 10.1136/jmedgenet-2017-104863. View

Lee H, Park H, Sohn Y, Ryu J, Park J, Rhee W . α-Galactosidase delivery using 30Kc19-human serum albumin nanoparticles for effective treatment of Fabry disease. Appl Microbiol Biotechnol. 2016; 100(24):10395-10402. DOI: 10.1007/s00253-016-7689-z. View

Zhou Q, Avila L, Konowicz P, Harrahy J, Finn P, Kim J . Glycan structure determinants for cation-independent mannose 6-phosphate receptor binding and cellular uptake of a recombinant protein. Bioconjug Chem. 2013; 24(12):2025-35. DOI: 10.1021/bc400365a. View

Groener J, Poorthuis B, Kuiper S, Helmond M, Hollak C, Aerts J . HPLC for simultaneous quantification of total ceramide, glucosylceramide, and ceramide trihexoside concentrations in plasma. Clin Chem. 2007; 53(4):742-7. DOI: 10.1373/clinchem.2006.079012. View

Morimoto H, Ito Y, Yoden E, Horie M, Tanaka N, Komurasaki Y . Non-clinical evaluation of JR-051 as a biosimilar to agalsidase beta for the treatment of Fabry disease. Mol Genet Metab. 2018; 125(1-2):153-160. DOI: 10.1016/j.ymgme.2018.07.009. View

van der Veen S, van Kuilenburg A, Hollak C, Kaijen P, Voorberg J, Langeveld M . Antibodies against recombinant alpha-galactosidase A in Fabry disease: Subclass analysis and impact on response to treatment. Mol Genet Metab. 2018; 126(2):162-168. DOI: 10.1016/j.ymgme.2018.11.008. View

Aerts J, Groener J, Kuiper S, Donker-Koopman W, Strijland A, Ottenhoff R . Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A. 2008; 105(8):2812-7. PMC: 2268542. DOI: 10.1073/pnas.0712309105. View

10.

Yamaguchi T, Amin M, Toonstra C, Wang L . Chemoenzymatic Synthesis and Receptor Binding of Mannose-6-Phosphate (M6P)-Containing Glycoprotein Ligands Reveal Unusual Structural Requirements for M6P Receptor Recognition. J Am Chem Soc. 2016; 138(38):12472-85. PMC: 5705180. DOI: 10.1021/jacs.6b05762. View

11.

Eng C, Guffon N, Wilcox W, Germain D, Lee P, Waldek S . Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease. N Engl J Med. 2001; 345(1):9-16. DOI: 10.1056/NEJM200107053450102. View

12.

BLIGH E, Dyer W . A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959; 37(8):911-7. DOI: 10.1139/o59-099. View

13.

Schiffmann R, Goker-Alpan O, Holida M, Giraldo P, Barisoni L, Colvin R . Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial. J Inherit Metab Dis. 2019; 42(3):534-544. DOI: 10.1002/jimd.12080. View

14.

Thurberg B, Rennke H, Colvin R, Dikman S, Gordon R, Collins A . Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int. 2002; 62(6):1933-46. DOI: 10.1046/j.1523-1755.2002.00675.x. View

15.

Arends M, Biegstraaten M, Hughes D, Mehta A, Elliott P, Oder D . Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors. PLoS One. 2017; 12(8):e0182379. PMC: 5538714. DOI: 10.1371/journal.pone.0182379. View

16.

Togawa T, Takada M, Aizawa Y, Tsukimura T, Chiba Y, Sakuraba H . Comparative study on mannose 6-phosphate residue contents of recombinant lysosomal enzymes. Mol Genet Metab. 2014; 111(3):369-373. DOI: 10.1016/j.ymgme.2013.12.296. View

17.

Teare J, Kates D, Shah A, Garger S . Increased branching and sialylation of N-linked glycans correlate with an improved pharmacokinetic profile for BAY 81-8973 compared with other full-length rFVIII products. Drug Des Devel Ther. 2019; 13:941-948. PMC: 6435118. DOI: 10.2147/DDDT.S188171. View

18.

Gold H, Mirzaian M, Dekker N, Ferraz M, Lugtenburg J, Codee J . Quantification of globotriaosylsphingosine in plasma and urine of fabry patients by stable isotope ultraperformance liquid chromatography-tandem mass spectrometry. Clin Chem. 2012; 59(3):547-56. DOI: 10.1373/clinchem.2012.192138. View

19.

Mayes J, Scheerer J, Sifers R, Donaldson M . Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry's disease. Clin Chim Acta. 1981; 112(2):247-51. DOI: 10.1016/0009-8981(81)90384-3. View

20.

Lee K, Jin X, Zhang K, Copertino L, Andrews L, Baker-Malcolm J . A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology. 2003; 13(4):305-13. DOI: 10.1093/glycob/cwg034. View