A pharmacokinetic study demonstrated bioequivalence between SB12 and the eculizumab reference products, along with comparable pharmacodynamics, safety, and immunogenicity.
A double-blind, 3-arm, parallel-group, single-dose phase 1 study was conducted in healthy subjects to demonstrate pharmacokinetic (PK) equivalence between the eculizumab reference product and its candidate biosimilar SB12, and to evaluate the pharmacodynamics (PD), safety, tolerability, and immunogenicity profiles. Eculizumab inhibits terminal complement-mediated intravascular hemolysis and is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, refractory generalized myasthenia gravis, and neuromyelitis optica spectrum disorder. The results of the phase 1 study were presented at the 2021 American Society of Hematology Annual Meeting.
The study enrolled healthy subjects, aged 18 to 55 years, who were randomized (1:1:1) to receive a single dose (300 mg, intravenous infusion for 35 minutes) of SB12, eculizumab reference product sourced from the European Union (EU; eculizumab-EU), or eculizumab reference product sourced from the United States (US; eculizumab-US). Blood samples for PK and PD analysis were collected over 64 days. The primary PK end point was area under the concentration-time curve from time zero to infinity (AUCinf). Secondary PK end points included area under the concentration-time curve from time zero to the last quantifiable concentration and maximum observed concentration. Equivalence for AUCinf was deemed to be established if 90% confidence intervals (CIs) for the ratio of geometric least squared means of SB12 to eculizumab-EU or eculizumab-US, and eculizumab-EU to eculizumab-US, were within the equivalence margin of 80% to 125%.
A total of 240 subjects were enrolled in the study, with 80 patients enrolled in each of the 3 treatment groups. The geometric least squared mean ratio for AUCinf was 99.1 % (90% CI, 95.41-102.85) for the comparison of SB12 with eculizumab-EU, 95.1% (90% CI, 91.40-99.04) for the comparison of SB12 with eculizumab-US, and 96.0% (90% CI, 92.16-100.10) for the comparison of eculizumab-EU with eculizumab-US. Because the corresponding 90% CIs for each of the comparisons were within the predefined equivalence margin of 80% to 125%, bioequivalence was established for each comparison.
PD analysis determined comparable profiles of mean terminal complement activity and mean change from baseline of complement activity following administration of SB12, eculizumab-EU, and eculizumab-US, showing a rapid decrease at the end of infusion and then a slow restoration.
A similar proportion of subjects experienced treatment-emergent adverse events (AEs) in the SB12 (70.0%), eculizumab-EU (65.0%), and eculizumab-US (71.3%) treatment groups. No deaths or treatment discontinuations due to treatment-emergent AEs were reported. Two serious AEs that were deemed not related to the investigational products were reported in 2 subjects: renal colic in the SB12 treatment group and back pain in the eculizumab-US treatment group.
Overall, the incidence of eculizumab antidrug antibodies was comparable in the 3 groups: 2.5% in the SB12 group, 1.3% in the eculizumab-EU group, and 0 (0.0%) in the eculizumab-US group. No subjects with eculizumab antidrug antibodies developed neutralizing antibodies.
Based on the results of the phase 1 study, PK bioequivalence between SB12 and the eculizumab reference products was concluded, and comparable PD, safety, and immunogenicity were demonstrated.
Source: Lee HA, Jang H, Kim Y, et al. A randomized, double-blind, single-dose phase 1 comparative pharmacokinetic study comparing SB12 (eculizumab biosimilar) with reference eculizumab in healthy volunteers. Blood. 2021;138(suppl_1):929.