A phase 1 study compared pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity between SB12, a proposed eculizumab biosimilar, and the European Union and United States reference products (Soliris) in healthy adults.

Eculizumab is a monoclonal antibody that binds to the terminal complement protein C5, inhibiting the complement pathway to reduce the risk of hemolysis and thrombosis in paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder.

The study, published in the International Journal of Clinical Pharmacology and Therapeutics, randomized 240 healthy subjects (95.8% male) to the biosimilar, reference product sourced from the United States, or reference product sourced from the EU. A single 300 mg dose of the study drug was delivered via intravenous infusion, and blood samples were taken multiple times throughout the following 64 days.

Pharmacokinetics and Pharmacodynamics

Overall, pharmacokinetic parameters, including the primary PK endpoint (area under the serum concentration-time curve from time zero to infinity [AUCinf]) and secondary PK endpoints were comparable between the 3 treatment groups. In comparisons between pairs of treatments, pharmacokinetic similarity was demonstrated, as the 90% confidence intervals of the geometric least squares means ratios of the primary and secondary PK endpoints were within the predefined bioequivalence margins of 80-125%.

To evaluate pharmacodynamics, terminal complement activity over time was measured. The authors explained that terminal complement activity was selected as the PD endpoint “based on the correlation with clinical outcome and the understanding of mechanism of action (MOA) in PNH patients.” They reported that the PD profile of the proposed biosimilar “was similar to known eculizumab profiles,” and terminal complement activity over time was similar between the 3 treatment groups.

Safety and Immunogenicity

Most subjects (68.8%) experienced treatment-emergent adverse events (TEAEs), 56 (70.0%) in the SB12 group, 52 (65.0%) in the EU reference product group, and 57 (71.3%) in the US reference product group. The proportions of TEAEs considered to be related to the study drugs were 31.3% in the biosimilar group, 21.3% in the EU reference product group, and 36.3% in the US reference product group.

The most frequent TEAE considered related to the study drug was headache. Infusion-related reactions, an AE of special interest, were reported by 7.5% of subjects in the SB12 group, 5.0% in the EU reference group, and 1.3% in the US reference group. Most adverse events were mild to moderate; 3 participants (one in each treatment group) experienced severe TEAEs, all of which were considered unrelated to the study drug.

The incidence of anti-drug antibodies (ADA) was comparable between groups, according to the authors. Following the infusion, ADAs were detected in 2.5%, 1.3%, and 0% of participants in the biosimilar, EU reference, and US reference groups. No neutralizing antibodies were detected in ADA-positive subjects.

The investigators concluded their results demonstrated pharmacokinetic bioequivalence of SB12 to the EU and US eculizumab reference products based on EMA and FDA requirements. Furthermore, that safety and pharmacodynamic profiles were comparable between the treatment groups. They added that their findings “represent an important contribution to the totality of evidence for supporting the biosimilarity of SB12 to its reference drugs, following the demonstration of analytical and functional similarity in extensive quality and non-clinical results”

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