Efficacy and Safety of Biosimilar Candidate ABP 959 As Compared with Eculizumab Reference Product in Paroxysmal Nocturnal Hemoglobinuria

Introduction: ABP 959 is a biosimilar candidate to eculizumab reference product (RP). Eculizumab is a humanized recombinant immunoglobulin antibody that binds to the human complement component 5 protein to inhibit progression of complement cascades and is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder.

Methods: This multicenter, randomized, double-blind, active-controlled, 2-period crossover study compared the efficacy and safety of ABP 959 and eculizumab RP in adult patients with PNH who were stable on eculizumab 900 mg IV every 14 ± 2 days. The primary objective of this study was to evaluate the efficacy of ABP 959 compared to eculizumab RP based on control of intravascular hemolysis, with a secondary objective to compare their safety, pharmacokinetics (PK), and immunogenicity. Results from Period 1 of the crossover study are presented here. Patients were randomized 1:1 to receive either ABP 959 at 900 mg IV for 52 weeks in Period 1 followed by eculizumab RP 900 mg IV for 26 weeks in Period 2 (ABP 959/RP) or eculizumab RP 900 mg IV for 52 weeks followed by ABP 959 at 900 mg IV for 26 weeks (RP/ABP 959) (Figure). The primary efficacy endpoint for the parallel comparisons was hemolysis, measured by lactate dehydrogenase (LDH) at week 27; clinical similarity between treatments was assessed by comparing the 1-sided 97.5% upper confidence interval (CI) limit for the geometric least squares (LS) mean ratio between ABP 959 and eculizumab RP, with a non-inferiority (NI) margin of 2.873. To assess the robustness of the primary analysis result, a sensitivity analysis was conducted using a subset of randomized patients who did not experience any important protocol deviation affecting their primary efficacy evaluation. Secondary endpoints included total complement (50% total hemolytic complement activity [CH50]), LDH-time profile, number of units of packed red blood cells (pRBCs) transfused, safety, immunogenicity, and PK area under the serum concentration-time curve (PK AUC) of ABP 959 and eculizumab RP.

Results: Forty-two patients (20 in the ABP 959/RP group; 22 in the RP/ABP 959 group) were randomized and treated in Period 1 across 25 centers. Forty-one (97.6%) patients (20 [100%] in ABP 959/RP and 21 [95.5%] in RP/ABP 959) completed Period 1 dosing. Baseline demographic and disease characteristics were comparable between the 2 treatment groups - mean (SD) age: 50.2 (16.6) years; time since original PNH diagnosis: 128.3 (116.1) months; duration of pre-study treatment: 68.4 (39.8) months. Results for week 27 LDH geometric LS means are presented below (Table). The ratio of the geometric LS means of LDH (ABP 959/RP) was 1.0628, with a 1-sided 97.5% upper CI of 1.1576 contained within the prespecified NI margin of 2.873, establishing similarity in clinical efficacy between ABP 959 and eculizumab RP in the parallel comparison; 95% CI was 0.9758 to 1.1576. Results from the sensitivity analysis were identical with results from the primary efficacy analysis. Total complement (CH50), total hemoglobin, serum-free hemoglobin, haptoglobin, bilirubin, and type III erythrocytes values were generally stable over time and results were comparable between the 2 treatment groups. The overall LDH profile and the mean number of units of pRBCs transfused during the study period were also comparable. Total PK AUC from week 13 to week 15 were similar between the 2 treatment groups. A comparable safety profile was observed in Period 1 between treatment groups, with only a single patient (4.5%) in the eculizumab RP group discontinuing the study due to any adverse event (grade 2 non-serious asthenia and grade 2 non-serious fatigue). The nominal difference in serious adverse event incidence was determined to be not clinically meaningful. Additionally, immunogenicity results through Period 1 were similar between ABP 959 and eculizumab RP groups. No patients in either treatment group tested positive for binding antidrug antibodies (ADAs), neutralizing ADAs, or treatment-boosted ADAs.

Conclusions: Similarity in clinical efficacy was established between ABP 959 and eculizumab RP in the primary endpoint of hemolysis, measured by LDH at week 27. Additionally, comparable safety, PK, and immunogenicity results support the conclusion of clinical similarity between ABP 959 and eculizumab RP.

Kulasekararaj:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Samsung: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Achillion: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau. Lanza:Abbvie: Consultancy; Alexion: Consultancy; Amgen: Consultancy; Pfizer: Research Funding. Arvanitakis:Ablynx/Sanofi: Consultancy; Bayer: Research Funding; Shire: Research Funding; Sobi: Consultancy; Chiesi: Consultancy; Amgen: Consultancy; Takeda: Research Funding. Chonat:Forma Therapeutics: Consultancy; Novartis: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Alexion: Consultancy, Research Funding; Agios: Consultancy, Research Funding. Chow:Amgen Inc: Current Employment. Pan:Amgen Inc: Current Employment. Saportas:Amgen Inc: Current Employment. Hanes:Amgen Inc: Ended employment in the past 24 months. Henary:Amgen Inc: Current Employment, Current equity holder in publicly-traded company.