The study, carried out by researchers from the UK’s National Institute for Biological Standards and Control, investigated and quantified the impact of an amino-terminal methionine on the activity of blood clot dissolving drug streptokinase.

The researchers cloned mature native streptokinase (rSK) and constructed a novel variant to include an amino-terminal methionine (rSK-Met) that is not susceptible to processing during expression. The potencies of rSK and rSK-Met were then determined relative to the current WHO 3rd International Standard for Streptokinase (00/464) using a chromogenic solution (European Pharmacopoeia) assay and fibrin-clot overlay and lysis assays.

In the chromogenic solution assay there was no measurable difference between rSK and rSK-Met activities. However, when using the fibrin-based assay methods, the authors found that potency estimates for rSK-Met were greatly reduced compared with rSK. In addition, fibrinolytic activity for rSK-Met was also shown to increase over time with methionine aminopeptidase treatment.

The consequence of this, according to the authors, would be that different potencies would be assigned to therapeutic recombinant streptokinase products depending on the degree of amino-terminal methionine processing, and on the pharmacopoeial assay method used, thus affecting the dosage patients receive.

The authors recommended that potencies of recombinant streptokinase should not be labelled in international units (IU) when there is likely to be a significant proportion of molecules with an amino-terminal methionine present. The administration of a too low dose is associated with decreased rates of reperfusion (restored blood flow) in the infarct-related artery and higher doses are associated with increased intracranial haemorrhage.

The authors concluded that ‘this highlights the truth in the adage ‘the process is the product’. They added that ‘this has serious health implications and provides an example of the danger in the unregulated clinical use of biosimilars’.

Conflict of interest
The authors of the research paper [1] declared no conflicts of interest.

Editor’s comment
Although the authors use the term ‘biosimilar’, no biosimilars of streptokinase are approved in Europe. At least two ‘similar biologics’ of streptokinase have been approved in India (Myokinase – Biocon and Shankinase – Shantha Biotechnics) [2]. Streptokinase is the most widely used thrombolytic agent in the developing world.

It should be noted that ‘similar biologics’ approved in India might not have been authorized following as strict a regulatory process as is required for approval of biosimilars in the European Union. The EMA (European Medicines Agency) regulatory requirements ensure the same high standards of quality, safety and efficacy for biosimilars as for originator biologicals, and also include a rigorous comparability exercise with the reference product.

Readers interested to learn more about safety and toxicity regulation for biosimilars in Europe and the US are invited to visit www.gabi-journal.net to view the following manuscript published in GaBI Journal:

Safety and toxicity of biosimilars—EU versus US regulation

Readers interested in contributing a research or perspective paper to GaBI Journal – an independent, peer reviewed academic journal platform – please send us your submission here.

Related article
Variation in biosimilar recombinant streptokinase

References
1.   Thelwell C, Longstaff C. Biosimilars: the process is the product. The example of recombinant streptokinase. J Thromb Haemost. 2014;12(8):1229-33.
2.   GaBI Online - Generics and Biosimilars Initiative. ‘Similar biologics’ approved and marketed in India [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 June 2]. Available from: www.gabionline.net/Biosimilars/General/Similar-biologics-approved-and-marketed-in-India 

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