BCD-020 is a proposed rituximab biosimilar, which has shown high similarity to rituximab in quality and nonclinical studies in vitro and in vivo.International multicenter clinical trial was conducted to compare efficacy and safety of BCD-020 and reference rituximab in adult (older than 18 years) patients with indolent lymphomas (follicular lymphoma grade 1-2, splenic marginal zone lymphoma, and nodal marginal zone lymphoma). Pharmacokinetics, pharmacodynamics, and immunogenicity were also studied.Patients with no previous biologic treatment for lymphoma were randomly assigned 1:1 to receive BCD-020 or comparator 375 mg/m 2 for 4 weeks.Primary study outcome was day 50 overall response rate defined as complete or partial remission. Equivalence range was −20% to 20% for 95% CI for overall response rates difference. Secondary outcomes included adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity.One hundred seventy-four patients were enrolled, 89 in BCD-020 arm and 85 in comparator arm. The overall response rate was 44.71% in BCD-020 arm and 41.89% in comparator arm. Limits of 95% confidence interval (CI) for difference of overall response rates between arms were (−12.62%-18.24%) showing equivalent efficacy.Sixty-one (68.54%) and 59 (69.41%) patients had at least one adverse event in BCD-020 arm or comparator arm, respectively. No unexpected adverse reactions were reported.Antidrug antibodies with no neutralizing activity were detected in two patients in comparator arm on day 14 further declining below detection threshold.Rituximab concentrations had equivalent pattern after intravenous administration of both drugs. Both drugs caused depletion of B-cells without significant influence on other blood cell lineages.In this study, we showed equivalent efficacy of BCD-020 and reference rituximab when used in patients with CD20-positive indolent lymphomas. We also confirmed pharmacokinetic equivalence of BCD-020 and reference rituximab. Safety profile,
BCD-020 (Acellbia, rituximab biosimilar candidate) was shown to be highly similar to innovator rituximab (MabThera®/Rituxan®) in terms of its quality characteristics, in vitro biological activity, as well as toxicology and PK/PD characteristics in non-human primates. International multicenter comparative randomized open-label clinical study was carried out in a period from 2011 to 2013 and involved over 30 centers in Russia, Ukraine and India. Its methodology and design complies with current EMA guidelines on similar biological products containing monoclonal antibodies (EMA/CHMP/BMWP/403543/2010). 92 patients with follicular non-Hodgkin’s lymphoma, stage I-IV by Ann Arbor, or marginal zone lymphoma, stage I-IV by Ann Arbor, ECOG 0-2, who had at least 1 measurable lesion were enrolled. According to study protocol patients with secondary transformed B-cell lymphomas or with highly aggressive types of tumor, bulky disease, severe concomitant somatic disorders and some other conditions were excluded. If a patient had previous story of chemotherapy or radiation he could be included after at least 3 weeks post-treatment. Participation of patients who were previously treated with any kind of monoclonal antibodies was prohibited. After signing standard informed consent form and completion of 28-days screening period eligible patients underwent stratification in accordance to their prognostic risk (FLIPI or IPI) and previous treatment (naïve or pretreated). Subsequently patients were randomized (1:1) into 2 groups: 46 patients were included in the main group where Acellbia (rituximab biosimilar) was administered at a dose of 375 mg/m2 as a slow IV infusion on day 1, 8, 15 and 22; 46 patients were included in the reference group where MabThera was used at the same regimen. Use of any other medicines for the treatment of lymphoma was strictly prohibited. Efficacy was assessed on the basis of computed tomography and bone marrow evaluation which were performed 1 month after the completion of treatment. Median age of patients in each group was 57.5 years (main group [50.0-64.0], reference group [47.0-65.0]). Manageable comorbidities were reported in 50% of patients in the main group and 34.78% of patients in the reference group, p=0.2053. Comparative analysis of the prognostic risk factors confirmed the equivalence of study groups. The number of pretreated patients in both groups was equal – 8 individuals per group. Statistical analysis didn’t find any difference in overall response rate in general population of patients (39.52% patients in the main group vs. 36.57% patients in the reference group, p=0.8250), as well as in population of pretreated patients (28.6% vs 37.5% respectively, p=1.00) and in population of naïve patients (42.8% vs 39.4% respectively, p=1.00). The lower limit of the two-tailed 95% CI for difference in proportions of ORR was equal to -0.17 and exceeded the predefined non-inferiority margin -0.2, which confirmed non-inferiority of Acellbia to MabThera in terms of efficacy. Treatment-associated AE of any grade were reported in 21.74% patients in both arms, in the absence of statistically or clinically significant difference (p = 0.8005). There were 2 cases of CTCAE 4.03 grade 3-4 AEs in each group. PK and PD parameters were shown to be equivalent in both study groups. Thus, study results suggest that Acellbia has same efficacy and safety in patients with B-cell non-Hodgkin’s lymphoma. Disclosures Chernyaeva: JCS BIOCAD: Employment. Ivanov:JCS BIOCAD: Employment. Isaev:JCS BIOCAD: Employment.
Netakimab, the original monoclonal antibody against IL-17A, is an innovative drug for the treatment of moderate-to-severe plaque psoriasis in patients who have indications for systemic therapy or phototherapy. Netakimab was approved in Russian Federation, registration certificate number ЛП-005439 from 04.04.2019. This article outlines the first 12-week results of a phase III clinical trial in patients with psoriasis.Materials and methods. The BCD-085-7 study (PLANETA) is a comparative, randomized, double-blind, placebo-controlled phase 3 clinical study of the efficacy and safety of netakimab in patients with moderate-to-severe plaque psoriasis. This review presents the results of the first 12 weeks. The study is ongoing at the moment, the total duration of treatment for each patient is 3 years (154 weeks). Patients were randomized in a ratio of 2:2:1 into one of three arms: group 1 received netakimab subcutaneously at a dose of 120 mg once a week for the first three weeks (induction) and then once every 2 weeks up to week 10, group 2 received netakimab subcutaneously at a dose of 120 mg once a week for the first three weeks (induction) and then once every 4 weeks up to week 10, group 3 received a placebo subcutaneously on day 1 at weeks 0, 1, 2, 4, 6, 8 10. In order to maintain a double-blind design, placebo was administered to patients in group 2 at weeks 4 and 8.Results. Both netakimab groups showed a significant superiority over placebo (p < 0.001) and the absence of statistically significant differences between the two regimens of therapy (p > 0.05) across all endpoints. PASI 75 at week 12 was reached by 77.65 % of patients using netakimab once every 2 weeks and 83.33 % of patients using netakimab once every 4 weeks (ITT population). The rate of clear and almost clear skin (sPGA 0–1) was reached by 81.18 and 79.76 % of patients using netakimab once every 2 weeks and once every 4 weeks, respectively. The safety assessment showed no statistically significant differences between the groups, the incidence rate of adverse events in netakimab arms was not higher than in the placebo arm. There were no cases of early withdrawal due to adverse events and cases of grade 4 toxicity according to CTCAE 4.03. During the 12 weeks of the study, one serious adverse event was registered in group 2 (pneumonia grade 3), which was recovered without any consequences. The immunogenicity assessment showed binding antibodies formation at week 12 in one patient who received BCD-085 every 2 weeks. Neutralizing antibodies were not detected. Conclusion. Netakimab showed high efficacy in the treatment of psoriasis, more than 80 % of patients achieved PASI 75 and sPGA 0–1 (clear and almost clear skin) by the week 12 of treatment. The drug showed a favorable safety profile and low immunogenicity. Based on the study results the regimen once a week during the first 3 weeks (induction), then once every 4 weeks was chosen for medical use in patients with psoriasis.
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...
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