Research carried out by Sandoz describes how a novel incorrect disulfide bridge structure present at low levels in commercial etanercept inhibits etanercept potency by reducing its ability to neutralize soluble tumour necrosis factor alpha (TNF-α) [1].
Although previous reports have speculated that product impurities present in etanercept may impact its potency, this research represents the first description of a clear structure – function relationship between incorrect disulfide bridging and TNF-α neutralization in vitro.
The study describes novel methodology for the characterization and quantitation of the incorrect disulfide impurity and demonstrates that increased levels of incorrect disulfide bridging in commercial Enbrel (etanercept) batches explain a recent decrease in its potency. Notably, this finding was of regulatory importance for the US Food and Drug Administration (FDA) approval of the etanercept biosimilar Erelzi [2, 3].
Specifically, Erelzi was developed in line with biosimilar guidance to contain consistent low levels of the incorrect disulfide bridge impurity and consistent high potency within the range of the reference medicine. Nonetheless, the variability of this impurity in the reference medicine, Enbrel, resulted in a shift in its mean potency over time and precluded demonstration of comparable mean values using the predefined FDA acceptance criteria of equivalence testing. This regulatory hurdle was resolved by additional studies described in the research article, demonstrating that incorrect disulfide bridging is corrected under in vivo-like redox conditions, normalizing mean Enbrel potency and allowing fulfilment of equivalence testing.
Conflict of interest
The authors of the research paper [1] are all employees of Sandoz or Novartis. For full details of the authors’ conflict of interest, see the research paper [1].
Abstracted by Dr William Christopher Lamanna, PhD, Global Scientific Affairs Manager, Sandoz Biopharmaceuticals, Sandoz GmbH, Kundl, Austria.
Editor’s comment
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Importance of manufacturing consistency of the glycosylated monoclonal antibody adalimumab (Humira®) and potential impact on the clinical use of biosimilars
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References
1. Lamanna WC, Mayer RE, Rupprechter A, Fuchs M, Higel F, Fritsch C, et al. The structure-function relationship of disulfide bonds in etanercept. Sci Rep. 2017;7(1):3951.
2. GaBI Online - Generics and Biosimilars Initiative. FDA approves biosimilar etanercept Erelzi [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Feb 9]. Available from: www.gabionline.net/Biosimilars/News/FDA-approves-biosimilar-etanercept-Erelzi
3. U.S. Food & Drug Administration. Briefing information for the July 13, 2016 meeting of the Arthritis Advisory Committee (AAC) [homepage on the Internet]. [cited 2018 Feb 9]. Available from: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ucm510492.htm
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