Background/Purpose:  M923 (BAX923), which is jointly being developed by Momenta and Baxalta, is a proposed biosimilar of reference adalimumab. Reference adalimumab is recognized to elicit antidrug antibodies (ADAs; seroconversion) in a significant proportion of patients, with a potential negative impact on efficacy. Host factors, including nature of the disease and background immunosuppressive therapy, are associated with the frequency of seroconversion. Normal healthy volunteers provide a relatively homogeneous and sensitive population in which to assess the relative immunogenicity of M923 and reference adalimumab with a focus on factors that are inherent to the products.

Methods:  324 healthy volunteers were randomized 1:1:1 to receive a single 40 mg dose of M923, US-sourced reference adalimumab, or EU-sourced reference adalimumab by subcutaneous injection then followed for 10 weeks, during which serum concentration of adalimumab and ADAs were recorded. Samples were screened for antibodies to M923, then confirmed for binding, sequentially, to EU reference adalimumab, US reference adalimumab, and M923. Samples positive on any confirmation assay were assessed for titer, neutralizing capacity (nADAs), and the presence of ADAs of IgE isotype. Bioequivalence of primary PK endpoints (C_max, AUC_0-inf , and AUC_0-336) was assessed in the primary analysis set (all evaluable subjects), and explored in subsets characterized by ADA and nADA status.

Results:  The incidence, titer, time to emergence of ADAs, and proportion with nADAs were similar across groups (proportion of subjects with confirmed ADAs/nADAs positive titers: M923 = 78.0%/16.5%; US reference adalimumab = 80.6%/27.8%; EU reference adalimumab = 78.5%/20.6%). Presence of high titer nADAs was also associated with presence of IgE ADAs and with a reduction in exposure. PK bioequivalence, defined as 90% confidence intervals (CIs) for the geometric least squares mean ratios for all comparisons were within the confidence bounds of 80.00 to 125.00%, was achieved for all primary PK endpoints. Specifically, for the comparison of M923 with US reference adalimumab, the geometric LS mean ratios (90% CI) were C_max = 102.58 (97.31-108.14); AUC_0-inf = 104.20 (96.47-112.54); and AUC_0-336 = 102.94 (97.88-108.27); similar results were observed for comparisons of M923 with EU reference adalimumab, and between US and EU reference adalimumab.

Conclusion:  M923, demonstrated equivalent PK and comparable immunogenicity relative to both US- and EU-sourced reference adalimumab following administration of a single dose in normal healthy volunteers. Seroconversion and nADA formation were sufficiently frequent to support a robust comparison of immunogenicity and assessment of impact of ADA formation on PK.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/assessment-of-comparative-immunogenicity-in-biosimilar-development-immunogenicity-and-pharmacokinetics-following-a-single-dose-of-m923-a-proposed-biosimilar-for-reference-adalimumab-humira/