SAT0040 Safety, tolerability, pharmacokinetics and pharmacodynamics of bcd-089, novel monoclonal anti-il-6 receptor antibody: results from the first-in-human single dose escalation study in healthy volunteers

Abstract

BackgroundBCD-089 is a fully human monoclonal antibody targeting membrane-bound and soluble forms of IL-6Rα, thereby blocking of IL-6 classic and trans- signalling. IL-6, a proinflammatory cytokine, plays a central role in the pathogenesis of many chronic inflammatory and autoimmune diseases. Thereby inhibition of IL-6 signalling is a promising approach in the treatment of immune-mediated pathology.ObjectivesTo assess safety, immunogenicity, pharmacokinetics and pharmacodynamics of a single administration of BCD-089.MethodsThis was a phase I, open label, single ascending dose clinical study in healthy male volunteers, aged 22–37 years (n=19). In 1 st cohort, one «sentinel» volunteer received 0.006 mg/kg of BCD-089. Volunteers in cohorts 2–7 received single doses of BCD-089 0.3, 0.625, 1.0, 1.6, 2.2 and 2.9 mg/kg, respectively. Every next cohort was included after completed safety evaluation for the previous one. Safety, PK/PD and immunogenicity were assessed during 71 days follow up.ResultsAll enrolled subjects have completed follow up period of 71 days. No withdrawals occurred. Single SC administration of BCD-089 was well tolerated and showed good safety profile at all tested doses: no grade 3/4 AEs, SAEs, DLTs or allergic reactions were reported in any cohort. None of the volunteers developed ADA to BCD-089. The only AEs reported were grade 1 or 2 laboratory abnormalities.Abstract SAT0040 – Table 1Subjects with abnormal test results, n (%). Table shows only cohorts where at least one abnormal test result was reported.Adverse events0.3 mg/kg(n=3)0.625 mg/kg(n=3)1.0 mg/kg (n=3)2.2 mg/kg(n=3)2.9 mg/kg (n=3) Grade 1 WBC decrease--1 (33.3%)2 (66.6%)1 (33.3%)Grade 1 neutropenia--1 (33.3%)1 (33.3%)-Grade 2 neutropenia---1 (33.3%)1 (33.3%)Grade 2 t.bilirubin increase-1 (33.3%)---Grade 1 AST decrease1 (33.3%)----Grade 1 Creatinine decrease-1 (33.3%)---Single SC administration of BCD-089 had a dose-dependent PK: the drug became detectable in the serum within the first 12 hour after injection for all tested doses (2–8 hour for doses>1.0 mg/kg). Serum concentration dose-proportionally increased and reached maximum at day 3 after administration, then gradually decreased. Elimination half-life showed significant inter-personal variability and dose-dependency, reflecting non-linear PK typical for drugs with target-mediated disposition.Abstract SAT0040 – Figure 1BCD-089(A), sIL6R(B), IL6(C) and CRP(D) serum concentration (Median and IQR).The concentration of soluble IL-6 receptor increased after BCD-089 administration in a dose-dependent manner. A raise in the concentration of IL-6 was seen at doses>1.0 mg/kg. Membrane IL-6R saturation of 90%>100% was seen at doses≥0.6 mg/kg. Regardless to the dose, serum CRP decreased below the limit of detection in most volunteers within the first week after injection. All tested PD markers returned to baseline at the end of the follow-up.ConclusionsSingle SC administration of BCD-089 was well tolerated, showed favourable safety profile and low immunogenicity at all tested doses in healthy vo...

Efficacy and safety of levilimab in combination with methotrexate in subjects with rheumatoid arthritis: Results of phase II AURORA study

“…Ранее в ходе клинического исследования I фазы была определена дозозависимая нелинейная фарма кокинетика (ФК) ЛВЛ, типичная для ингибиторов ИЛ-6Р [7]. В данном исследовании показатель сывороточной концентрации ЛВЛ перед следующим введением (C trough ) был дозозависимым и демонстрировал более высокие значения в группе ЛВЛ 1 р./нед., чем в ЛВЛ 1 р./2 нед., во всех исследуемых временных точках (рис.…”

“…3). 3-й степени 4 (11,4) 5 (14,3) 2 (5,7) 4-й степени 0 0 2 (5,7) Повышение уровня АЛТ (всего) 7 (20,0) 8 (22,9) 5 (14,3) 3-й степени 2 (5,7) 3 (8,6) 2 (5,7) Повышение уровня АСТ (всего) 3 (8,6) 3 (8,6) 3 (8,6) 3-й степени 0 1 (2,9) 1 (2,9) Гиперхолестеринемия (всего) 13 (37,1) 11 (31,4) 4 (11,4) 3-й степени 1 (2,9) 2 (5,7) 0 Гипертриглицеридемия (всего) 7 (20,0) 5 (14,3) 5 (14,3) 3-й степени 4 (11,4) 2 (5,7) 0…”

“…Генитальный герпес (2-й степени) 0 0 1 (2,9) Латентный туберкулез (2-й степени) 0 1 (2,9) 0 Досрочное прекращение лечения по причинам, связанным с безопасностью 0 4 (11,4) 2 (5,7) Смерть 0 2 (5,7) 0…”

“…Левилимаб (ЛВЛ) -оригинальное моноклональное антитело, мишенью которого являются связанные с мембраной (мИЛ-6Р) и растворимые (рИЛ-6Р) α-рецепторы ИЛ-6, благодаря чему препарат блокирует как классический, так и транс-сигнальный путь ИЛ-6. В исследовании фазы I ЛВЛ продемонстрировал хорошую переносимость, имел благоприятный профиль безопасности и низкую иммуногенность [7].…”

The efficacy and safety of levilimab in severely ill COVID-19 patients not requiring mechanical ventilation: results of a multicenter randomized double-blind placebo-controlled phase III CORONA clinical study

“…Levilimab (LVL) is an original monoclonal antibody that binds to the alpha subunit of the IL-6 receptor (IL-6R) and blocks the transmission of IL-6 signal into cells. In a phase I clinical study LVL was well tolerated, showed favorable safety profile and low immunogenicity in doses ranged from 0.006 mg/kg to 2.9 mg/kg in healthy volunteers [ 7 ]. A phase II placebo-controlled clinical study showed that LVL 162 mg administered subcutaneously (SC) either once weekly (QW) or once every 2 weeks (Q2W) plus methotrexate (MTX) was superior to MTX alone in patients with active rheumatoid arthritis (RA) and inadequate response to MTX (NCT03455842) [ 8 ].…”