Introducing the Biosimilar Paradigm to Neurology: The Totality of Evidence for the First Biosimilar Natalizumab

Abstract

A biosimilar medicine is a successor to a reference ('originator'/'original-brand') biologic medicine brought to market once the patent and exclusive marketing rights for the reference have expired. Biosimilar natalizumab (PB006 [biosim-NTZ]; developed by Polpharma Biologics S.A. and marketed globally as Tyruko^®; Sandoz) has been developed as a successor to reference natalizumab (Tysabri^® [ref-NTZ]; Biogen) and is the first US Food and Drug Administration (FDA)-approved and European Medicines Agency (EMA)-approved biosimilar in neurology. As per the FDA and EMA indications for ref-NTZ, biosim-NTZ is approved to treat relapsing forms of multiple sclerosis (USA, EU) and Crohn's disease (USA only). Approval of biosim-NTZ was based on the 'totality of evidence', a comprehensive body of data collected during the development process, demonstrating similarity to its reference medicine. The foundational step of demonstrating structural and functional similarity between biosim-NTZ and ref-NTZ confirmed identical primary and indistinguishable higher order structures, as well as matching binding affinity to α4β1/α4β7 integrins. Following the confirmation of matching structure and function, pharmacokinetic/pharmacodynamic similarity of biosim-NTZ to ref-NTZ in healthy subjects was demonstrated, with no clinically meaningful differences identified in safety and immunogenicity. A comparative, double-blind, randomized study (Antelope) was also conducted in patients with relapsing-remitting multiple sclerosis and demonstrated matching efficacy, safety, and immunogenicity with no clinically meaningful differences between biosim-NTZ and ref-NTZ. This review presents the totality of evidence that confirmed the biosimilarity of biosimilar natalizumab to its reference medicine, which supported its approval by the FDA and the EMA. [Graphical plain language summary available].

Fig. 1

The totality of evidence data package for the development and approval of biosimilar medicines compared to reference medicines. In vivo preclinical studies are not a requirement from the European Medicines Agency and US Food and Drug Administration for the approval of biosimilar medicines when extensive analytical and functional characterization has already demonstrated the proposed biosimilar and reference medicines to be highly similar [9, 22, 38]. PD pharmacodynamics, PK pharmacokinetics

Fig. 2

Potency of natalizumab samples by competitive enzyme-linked immunosorbent assay (ELISA). A Inhibition of interaction between vascular cell adhesion molecule 1 (VCAM-1) and α4β1; B Inhibition of interaction between mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) and α4β7 integrin. Biosim-NTZ biosimilar natalizumab, ref-NTZ reference natalizumab. The boxes indicate quartiles and the horizontal line in each box represents the median value; the whiskers show the data distribution; the circles represent the individual batches of US-ref-NTZ, EU-ref-NTZ, and biosim-NTZ

Fig. 3

Semi-logarithmic plot of mean total serum concentration over time for biosimilar natalizumab (biosim-NTZ) versus USA (US)-licensed and European Union (EU)-approved reference natalizumab (ref-NTZ) [pharmacokinetic set]. IV intravenous. Wessels et al. [49]. Reprinted by permission of Informa UK Limited, trading as Taylor & Francis Group, https://www.tandfonline.com

Fig. 4

Primary pharmacodynamic endpoints (engagement set). A Change from baseline in mean (SD) CD19+ cell counts over time for biosimilar natalizumab (biosim-NTZ) versus USA (US)-reference natalizumab (ref-NTZ) and European Union (EU)-ref-NTZ. B Change from baseline in mean (SD) α4-integrin percentage receptor saturation (RS) over time for biosim-NTZ versus US-ref-NTZ and EU-ref-NTZ. IV intravenous, PD pharmacodynamic. Wessels et al. [49]. Reprinted by permission of Informa UK Limited, trading as Taylor & Francis Group, https://www.tandfonline.com

Fig. 5

Cumulative number of new active lesions over 48 weeks for biosimilar natalizumab (biosim-NTZ) versus reference natalizumab (ref-NTZ) groups by primary randomization in the Antelope study. Hemmer et al. [50]. Reprinted by permission of JAMA Network

Fig. 6

Sequential demonstration of biosimilar natalizumab (biosim-NTZ) biosimilarity to reference natalizumab (ref-NTZ) via analytical/functional and clinical data. ARR annualized relapse rate, AUC_0-inf area under the curve from time of dosing to infinity, CUAL cumulative number of active lesions, EDSS Expanded Disability Status Scale, MAdCAM-1 mucosal vascular addressin cell adhesion molecule 1, PD pharmacodynamic, PK pharmacokinetic, VCAM-1 vascular cell adhesion molecule 1