Background/Purpose:  Biosimilars are created to be essentially the same as their reference marketed biopharmaceuticals which have lost exclusivity, and they aim to offer more affordable treatment. Development of the proposed adalimumab biosimilar GP2017 involved extensive characterization of the originator adalimumab followed by a step-wise target-directed and re-iterative technical development program involving state-of-the-art physicochemical and functional characterization methods. The nonclinical pharmacological characterization was designed to demonstrate similarity to the originator adalimumab at multiple stages. These included assessment of target molecular interactions, functional assays reflecting the mechanisms of action of adalimumab, pharmacokinetics (PK) and assessment of efficacy in an established human TNFα transgenic murine model of polyarthritis.

Methods:  In vitro functional characterization of GP2017 to confirm similarity with the originator consisted of comparative assays addressing binding to TNFα, complement component C1q, FcγR and FcRn and cell-based TNFα neutralization, antibody dependent cell mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) potency assays. In vivo, GP2017 was evaluated in comparative rabbit PK studies and in the Tg197 human TNFα transgenic mouse model of polyarthritis. Shortly after the onset of disease, mice were treated twice weekly from 6 weeks until the age of 10 weeks, with either placebo, or 3 mg/kg GP2017 vs. originator adalimumab which is a most sensitive sub-therapeutic dose or saturating dose (30 mg/kg) of originator adalimumab. All the animals were sacrificed 3 days after the last treatment. Histological analysis of the joints and circulating TNFα and IL-6 levels were analyzed as pharmacodynamics (PD) endpoints. Swelling of ankles, hind limb distortion, impaired movement and body weight were also assessed.

Results:  High degree of similarity was observed in target binding affinity and functional activity for TNFα, Fc-receptors and C1q binding for both GP2017 and the originator adalimumab. Also, bioassays for TNFα neutralization and for Fc dependent effector functions (ADCC and CDC) showed that GP2017 is similar to the originator adalimumab. Similar in vivo PK, efficacy and PD effects were shown for GP2017 and the originator adalimumab. In the murine model of polyarthritis, at 3 mg/kg dose level, a superimposable time-course profile could be demonstrated. GP2017 showed similar increase in body weight, same effect on in life arthritic symptoms and histopathological examination of the underlying lesions in the arthritic joints compared to the originator. Total TNFα and IL-6 levels were similar between the treatment groups at 3 mg/kg dose level. Consistent correlations were observed between total TNFα, IL-6, clinical and histopathology scores.

Conclusion:  Similarity of GP2017 and the originator adalimumab was demonstrated based on in vitro pharmacology, in vivo PK, efficacy and safety in human TNFα transgenic murine models of polyarthritis at nonclinical level.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/comparison-of-nonclinical-pharmacology-pharmacodynamics-and-efficacy-response-of-the-proposed-adalimumab-biosimilar-gp2017-to-originator-adalimumab/