Analytical Characterization, Pharmacokinetics, Safety, and Preliminary Immunogenicity of GNR-062, an Agalsidase Beta Biosimilar Candidate, in Healthy Male Volunteers

Abstract

Fabry disease is a rare genetic multisystemic lysosomal disease characterized by progressive cellular accumulation of globotriaosylceramide (GL-3) in various organs with specific cutaneous (angiokeratoma), neurological (pain), renal (proteinuria, chronic kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleovestibular and cerebrovascular manifestations (transient ischemic attacks, strokes). The phenotypic expression depends on the age of onset and, in females, on the level of X-inactivation. Enzyme replacement therapy is currently the standard therapy for the disease. JSC GENERIUM recently developed a potential biosimilar of Fabrazyme®, GNR-062, and investigated its physicochemical and biological properties, pharmacokinetics and immunogenicity to assess its bioequivalence to Fabrazyme®. Direct evaluation of the N-glycosylation profile by HPLC revealed differences mainly related to the distribution of complex sialylated glycans. The overall sialylation level was comparable between the two products. The same conclusion follows from the results of direct analysis of the sialic acid content. Despite a small difference of a few percent in biphosphorylated glycan content, the overall measured M6P values were comparable. Thus, the internalization of agalsidase β into the inner space of lysosomes by binding to key receptors appear to be the same for both products. In a single-blind, randomized comparative study of the pharmacokinetics and safety of a single intravenous infusion of GNR-062 (JSC GENERIUM, Russia) and Fabrazyme® (Genzyme Europe B.V., The Netherlands) in a crossover design in healthy volunteers, the ratio of geometric means (90% CI) of AUCinf and Cmax for GNR-062 to agalsidase β was 0.9736 (0.9413–1.0070) and 0.9867 (0.9546–1.0199), respectively. These studies demonstrated pharmacokinetic bioequivalence of GNR-062 to agalsidase β. Immunogenicity findings are preliminary, as the study was not powered for formal immunogenicity equivalence, and the single-dose design in healthy volunteers does not reflect repeated long-term administration in patients with Fabry disease. In conclusion, GNR-062 demonstrated acceptable short-term tolerability in healthy volunteers and warrants further investigation as a potential therapeutic option for patients with Fabry disease.