PF347 PHARMACOKINETIC AND PHARMACODYNAMIC SIMILARITY OF ABP 959 WITH ECULIZUMAB: RESULTS FROM A RANDOMIZED, DOUBLE-BLIND, SINGLE-DOSE, PARALLEL-GROUP STUDY IN HEALTHY SUBJECTS

Abstract

Background: ABP 959 is being developed as a biosimilar candidate to eculizumab. Eculizumab is a recombinant humanized IgG2/4 chimeric monoclonal antibody that binds to the human C5 complement protein (C5), thereby inhibiting the complement cascade. It is indicated for the treatment of patients with generalized myasthenia gravis (gMG), paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis, and atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. ABP 959 has been evaluated to be analytically similar to eculizumab. Aims: To demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity of ABP 959 relative to the reference product (RP) eculizumab. 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, or FDA-licensed eculizumab (eculizumab US), or EU-authorized eculizumab (eculizumab EU). Serum samples for PK and PD evaluations were collected over 56 days. Primary objectives were to demonstrate PK and PD equivalence of ABP 959 versus eculizumab US and ABP 959 versus eculizumab EU, as assessed by area under the total serum concentration—time curve (AUC) from time 0 extrapolated to infinity (AUCinf) and an area between the effect curve (ABEC) of 50% total hemolytic complement activity (CH50). Secondary PK endpoints included AUC from time 0 to the time of the last observed quantifiable concentration (AUClast) and maximum observed concentration (Cmax). Pre-specified equivalence criterion for the primary PK and PD parameters was 90% confidence interval (CI) for geometric mean (GM) ratios within 0.80 to 1.25. Other secondary endpoints included the safety, tolerability, and immunogenicity of the investigational products (IPs). Results: A total of 219 subjects were enrolled (ABP 959, n = 71; eculizumab US, n = 74; eculizumab EU, n = 74). The GM of PK and PD parameters following a single IV infusion of IP, were similar between ABP 959 vs. eculizumab US and ABP 959 vs. eculizumab EU. The GM of AUCinf (h.μg/mL) was: 18996.3 for ABP 959; 19777.5 for eculizumab US and 18921.1 for eculizumab EU. The GM of ABEC of CH50 (%∗h) was 17724.5 for ABP 959; 16549.4 for eculizumab US and 16361.1 for eculizumab EU. For both PK and PD comparisons of ABP 959 with eculizumab US and ABP 959 with eculizumab EU, the 90% CIs of the GM ratios were fully contained within the bioequivalence criteria of 0.80 to 1.25 for all PK (AUCinf, Cmax, AUClast) and PD (ABEC of CH50) evaluations, confirming the PK and PD bioequivalence between ABP 959 and eculizumab US and ABP 959 and eculizumab EU. Additionally, eculizumab US and eculizumab EU were similar in PK and PD assessments. There were no deaths or treatment-emergent adverse events (TEAEs) leading to study discontinuation. Five subjects experienced 8 SAEs; only the SAE of headache was considered probably related to study drug. The incidence of overall TEAEs or any single category of TEAE was similar across treatment groups. A total of 19 (8.8%) subjects had positive binding ADAs over the course of the study; the incidence of binding ADAs was similar across treatments. No subjects developed neutralizing antibodies. Summary/Conclusion: This phase 1 study demonstrated PK and PD bioequivalence of ABP 959 to eculizumab RP. Safety and immunogenicity profiles were similar between ABP 959 and eculizumab RP.