Background/Purpose:

Biosimilars are copy versions of existing biologic medicines that have lost patent exclusivity and are approved via stringent regulatory pathways. Biosimilars are designed to be similar to their reference medicinal product (originator) and can contribute to savings for health care systems that can be used to treat more patients or fund novel therapies. Development of a biosimilar involves extensive characterization of the originator product and a target-directed iterative development process to ensure a product is highly similar to the reference medicinal product. During this process, product specific post-translational properties were engineered into GP2015, a proposed biosimilar etanercept (p75TNF-R IgG1 Fc-fusion protein), to ensure similarity in functional/structural relationships with the approved reference medicinal product etanercept. At in vitro level, we show comparable binding affinities of both products to TNFα and FcR, as well as functional inhibition of TNFα and LTα.  Data from pre-clinical models confirm in vivo comparability for the proposed biosimilar etanercept GP2015, in terms of PK and efficacy.

Methods:

By employing surface plasmon resonance, the binding of GP2015 to TNFα and to a panel of Fc-receptors that may impact on pharmacokinetics and effector functions, was determined and compared. Bioactivity of GP2015 was measured as functional neutralization of TNFα or TNFβ in an NFκB-dependent luciferase reporter gene assay. In vivo efficacy was assessed in a human TNF transgenic mouse model of polyarthritis. Comparative pharmacokinetics (PK) was assessed in a single dose study in rabbits (8 mg/kg) and a multiple dose (10 s.c. administrations of 15 mg/kg over 4 weeks) study in cynomolgus monkeys.

Results:

Comparative in vitro binding data of GP2015 and the reference medicinal product showed comparable high-affinity binding to TNFα, and similar binding affinities to the tested panel of Fc receptors within the pre-established values for the reference product. Biological neutralization of TNFα- and LTα-mediated cellular responses also displayed an overlapping pharmacological potency over a wide dose-response range. Preclinical evaluation in the polyarthritis TNFα transgenic mouse model showed similar clinical and histological response to treatment with either product when tested at a therapeutic sensitive dose. Single and multiple dose pre-clinical studies further demonstrated comparable systemic C_max, T_max and AUC of the two compounds.

Conclusion:

This non-clinical similarity exercise confirms that GP2015 and the reference medicinal product are pharmacologically highly-similar with regard to target binding, anti-TNFα biological activity and PK exposure. Future clinical trial(s) are needed to provide evidence of similar efficacy and safety of GP2015 to that of the originator product.

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« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/target-directed-development-of-a-proposed-biosimilar-etanercept-gp2015-comparability-of-in-vitro-target-binding-and-pre-clinical-efficacy-and-pharmacokinetics/