Relationship between Pharmacokinetics and Antidrug Antibody Status of ABP 959, a Biosimilar Candidate to Eculizumab: Results from a Pharmacokinetic Similarity Study

Background: ABP 959 is being developed as a biosimilar to eculizumab, a recombinant humanized IgG2/4 chimeric monoclonal antibody that binds to the human C5 complement protein (C5), thereby inhibiting the complement cascade. Eculizumab is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis (gMG), atypical hemolytic uremic syndrome (aHUS), and neuromyelitis optica spectrum disorder (NMOSD). ABP 959 has demonstrated pharmacokinetic (PK) and pharmacodynamic (PD) similarity to eculizumab reference product (RP) in healthy male subjects (Chow et al., EHA 2019). Treatment with eculizumab can result in the development of anti-drug antibodies (ADAs), which may lead to loss of clinical efficacy; therefore, evaluating the incidence of ADAs and assessing their relationship to PK parameters is important.

Objectives: To assess the relationship between PK parameters and ADAs for ABP 959 and eculizumab RP.

Methods: This was a randomized, double-blind, single-dose, 3-arm, parallel-group study in healthy adult male subjects, between 18 to 45 years of age, with a body mass index of 18 to 30.0 kg/m², who were randomized to receive a 300 mg IV infusion of ABP 959, FDA-licensed eculizumab (eculizumab US), or EU-authorized eculizumab (eculizumab EU). Serum samples for PK evaluations were collected over 57 days. A primary objective of the study was to demonstrate PK equivalence of ABP 959 versus eculizumab RP, as assessed by area under the total serum concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC_inf). Secondary PK endpoints included AUC from time 0 to the time of the last observed quantifiable concentration (AUC_last) and maximum observed concentration (C_max). The pre-specified equivalence criterion for the primary PK parameters was a 90% confidence interval (CI) for the geometric means ratio (GMR) within 0.80 to 1.25, for ABP 959 versus eculizumab US and ABP 959 versus eculizumab EU comparisons. Immunogenicity assessment was a secondary endpoint of the study. Sensitivity analysis of the PK primary endpoint was performed for the binding ADA-negative and neutralizing ADA-negative subjects, with the point estimates and 90% CIs for test-to-reference GMR calculated for PK parameters (AUC_inf, AUC_last, and C_max) for total eculizumab and total ABP 959. Samples for ADA assessments were collected predose on Day 1, Day 11, Day 29, and at the end of study (EOS) Visit (Day 57) or upon early study discontinuation.

Results: A total of 219 subjects were enrolled (ABP 959, n=71; eculizumab US, n=74; eculizumab EU, n=74); overall, 19 (8.8%) subjects had positive binding ADAs over the course of the study. At any time during the study, the incidence of binding ADAs across treatments was: ABP 959, n=7 (9.9%); eculizumab US, n=5 (6.9%); and eculizumab EU, n=7 (9.5%). At EOS, 4 (1.9%) subjects had positive binding ADAs (ABP 959, n=1 [1.4%]; eculizumab US, n=2 [2.9%]; and eculizumab EU, n=1 [1.4%]). In these subjects, their PK or exposure was within the same range as ADA-negative subjects. In binding ADA-negative subjects, the 90% CIs for the adjusted least square GMRs for all comparisons were within the bioequivalence range of 0.80 to 1.25. No subjects developed neutralizing antibodies throughout the study.

Conclusions: The incidence of ADAs was similar between ABP 959 and eculizumab RP and did not impact the overall PK similarity assessment.