FDA Thinking on Biosimilar Immunogenicity Issues - A Case Study Based on the Enoxaparin ANDA Approval

Following extensive marketing of Lovenox® (enoxaparin sodium), a low-molecular weight heparin, a number of biosimilar versions of enoxaparin and one ANDA-approved formulation (enoxaparin sodium, approved Nov. 2011) have been developed and accepted for marketing. Enoxaparin, a low molecular weight heparin, is a large carbohydrate used to prevent coagulation (or clotting) of the blood. Low molecular weight heparins are quite heterogeneous products, comprising a wide range of chain lengths. They have a diversity of the disaccharide building blocks, and heterogeneity in the distribution of sulfated and acetylated sugars. Not surprisingly, the scientific rationale for approval of generic and/or biosimilar versions was long contentious. Now that both biosimilar and generic low molecular weight heparin products have been approved, it has become clear that “close-enough” is a sufficient criterion for approvability, although to this point such decisions have been made on a case-by-case basis.

Generic enoxaparin sodium must have the ‘same’ active ingredient as Lovenox, with the caveat that sameness determinations must take into account the inherent complexity of enoxaparin. Demonstration of sameness requires extensive data relating to the physical and chemical characteristics of innovator and biosimilar enoxaparin drug substances, certain aspects of the manufacture of the drug substance, and various characterizations of the products’ bioactivity that can predict in vivo qualities. A key clinical aspect for consideration of a biosimilar enoxaparin is that of its risk for immunogenicity. The recently published Draft Guidance for Industry: Immunogenicity-Related Considerations for the Approval of Low Molecular Weight Heparin for NDAs and ANDA focuses on this clinical risk.

Immunogenicity, or the ability of a drug to provoke an immune response, is a complex issue, taking into account the risk that a patient’s immune response to the biosimilar might affect its efficacy, safety profile, or both. An immune response could interfere with heparin’s ability to bind to antithrombin III, which is necessary for the drug to work, thus potentially resulting in heparin resistance. Currently, there is not enough information to determine if this is a valid concern or how heparin potency might be affected. While possible efficacy implications are still theoretical, safety concerns such as heparin-induced thrombocytopenia are known to have potentially fatal consequences. Heparin-induced thrombocytopenia is a relatively uncommon result of antibodies directed against a heparin molecule complexed with a specific platelet protein, chemokine platelet factor 4, resulting in platelet aggregation and depletion, and vascular thrombosis. The draft guidance mentioned above provides some technical recommendations for producing the required evidence for product characterization and manufacture that would support a conclusion of equivalent risks for production of heparin-induced thrombocytopenia, all in the absence of actual clinical investigation.

How common is heparin-induced thrombocytopenia, and do biosimilar versions of enoxaparin vary in their risk for such adverse safety outcomes? In a presentation of data obtained by investigators at the Cardiovascular Institute, Loyola University Medical Center, the prevalence of anti-heparin/platelet factor 4 antibodies in patients receiving heparin and several biosimilar versions of low molecular weight heparin was variable (cited as 12-18%). Consequences of anti-heparin/PF4 production, such as platelet activation and aggregation, also were variable between products. The implication of their data is that such products may have intrinsic differences in their immunogenicity, and the investigators recommended clinical investigations to explore them further.

Only time will tell whether FDA’s guidance approach, in the absence of patient exposure data, will suffice to ensure that low molecular weight heparins have equivalent safety profiles once in clinical use. However, a case report of a fatal hemorrhage in a woman who had switched from Lovenox to generic enoxaparin suggests that these formulations may have differed in some important manner. It is not clear that the process involved in the hemorrhagic complications represented heparin-induced thrombocytopenia, yet the report does raise questions about the predictive value of the pre-market investigations that are only surrogates for the generic’s safety and efficacy.

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