Abstract
The bioengineered tissue plasminogen activator tenecteplase is an important treatment modality of acute myocardial infarction recommended by international guidelines. Following introduction of originator tenecteplase (brand names Metalyse® and TNKase®), a “biosimilar” tenecteplase became available for commercial use in India under the brand name Elaxim® in the absence of Indian biosimilar guidelines which came into force from September 15th, 2012. Based on a report of biochemical and fibrinolytical differences between Metalyse and Elaxim, we have systematically compared them in a range of routine quality testing assays. As compared to Metalyse, Elaxim exhibited less clot lysis activity and contained less of the two-chain form of tenecteplase. Even upon full in vitro conversion to the two-chain form Elaxim exhibited less clot lysis activity. This was linked to differences in sialic acid content and glycosylation pattern with Elaxim exhibiting less bi- and more tetra-antennary glycosylation, leading to a different charge heterogeneity profile. Regarding purity, Elaxim contained more tenecteplase aggregates and, in contrast to Metalyse, considerable amounts of Chinese hamster ovary cell protein. Taken together these data demonstrate that Metalyse and Elaxim differ considerably in clot lysis activity and biochemical properties. These data question whether Elaxim indeed can be considered a “biosimilar” of Metalyse, i.e., whether and to which extent the clinical efficacy and safety properties of Metalyse can be extrapolated to Elaxim in the absence of comparative clinical data.
Highlights
Acute myocardial infarction is a leading cause of heart failure and premature death (Kunadian and Gibson, 2012)
A lower biological activity of the two lots of Elaxim (72–78%) was confirmed in two other assays, i.e., the activity assay performed using an alternative quality control assay and the clot lysis activity method described in the European Pharmacopoeia monograph on alteplase, where Metalyse exhibited activities of 99–100%
After in vitro enzymatic conversion of tenecteplase yielding 95–97% two-chain form for both tested batches, clot lysis activity was determined and found to be lower for the two Elaxim batches as compared to Metalyse (Figure 2)
Summary
Acute myocardial infarction is a leading cause of heart failure and premature death (Kunadian and Gibson, 2012). In those who survive the acute phase, it may pose a financial catastrophe due to high out-of-pocket expenditures for acute cardiovascular care in countries lacking a comprehensive health insurance system, e.g., India (Mohanan et al, 2013). The serine protease tissue plasminogen activator (t-PA) is a physiologically occurring 527 amino acid glycoprotein and the main endogenous mediator of clot lysis. In contrast to classic zymogens, the intact onechain form of t-PA is already active in in vitro clot lysis assays, but full activity is obtained by cleavage between amino acids 275 and 276 to the two-chain form
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