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Similarity of MB02 to EU-bevacizumab was demonstrated in the relevant characteristics assessed by and founded on a comprehensive CMC and bioanalytical similarity program, and was further confirmed by the investigation of clinical equivalence in PK. The next step in the program of biosimilar clinical development was to confirm comparable clinical performance of MB02 and the reference bevacizumab, rather than demonstrate patient benefit per se, which has already been demonstrated for the reference bevacizumab in numerous clinical trials and published studies [ 8]. Due to the absence of pharmacodynamic markers for bevacizumab that can be related to patient outcome, a comparative study designed to demonstrate similar clinical efficacy between MB02 and EU-bevacizumab was required to confirm efficacy. The choice of non-squamous NSCLC patients as the study population was made in accordance with the relevant regulatory guidelines and endorsed by the main international regulatory competent authorities, as a sensitive model with known effect sizes to test for potential differences in efficacy between MB02 and EU-bevacizumab [ 11, 12, 13, 14, 15]. Likewise, the primary efficacy endpoint, ORR at study Week 18, was considered the most sensitive endpoint for the detection of differences in clinical efficacy between MB02 and EU-bevacizumab, as it primarily measures activity and, unlike other endpoints such as PFS and OS, is not likely to be influenced as much by factors not attributable to product differences such as underlying tumor burden, performance status, previous treatments and underlying clinical conditions. In the current study, the primary analysis in the ITT population met the predefined criteria for demonstrating equivalence, and results from sensitivity analyses support similarity of MB02 to EU-bevacizumab with respect to the primary efficacy endpoint ORR, with comparable safety and immunogenicity profiles. aAn adverse event was related if assessment of causality was possible, probable or very likely/certain Ultra‐high QC sample were prepared in MB02‐DM and serially diluted to a minimum of five times within curve range three dilutions above ULOQ and one dilution below LLOQ. Lipemic and hemolyzed interferences were tested. Long‐term stability was tested at 366days and −50°C.
MB02, a bevacizumab biosimilar, has demonstrated analytical similarity to reference bevacizumab on a comprehensive chemistry, manufacturing, and control (CMC) and bioanalytical similarity program. PK similarity has been further confirmed in three bioequivalence studies comparing the pharmacokinetic profiles of MB02 and reference bevacizumab following the administration of a single dose (3mg/kg IV) in more than 276 healthy male subjects. PK parameters that were not covered by the primary endpoints were assessed as secondary endpoints: time to maximum observed serum concentration, area under the serum concentration–time curve from time zero to the time of the last observable concentration (AUC[0– t]), total body clearance, apparent serum terminal elimination half‐life ( t 1/2), constant of the terminal phase; volume of distribution during the terminal phase after IV administration; and volume of distribution at steady‐state after IV administration. Samples were performed in three tiers: first, all samples were screened, then any positive samples were subjected to a confirmation assay, and finally the semi‐quantification assay was performed. Long‐term stability was tested at 366days and −50°C.Secondary efficacy endpoints (PFS, OS, duration of OR and time to OR) and ad-hoc endpoints (BORR) were also comparable between treatment groups and were consistent with the observed results of the primary endpoint. In particular, BORR was assessed to confirm primary endpoint ORR results. BORR reduces potentially confounding factors of diverse cycles and delayed administration due to toxicity, and is commonly used in an oncological clinical setting. When comparing the analysis based on BORR up to Week 18 to that of primary ORR analysis, there was almost no difference, which is considered reassuring. Sacristán D, Beydon ME, Ruppen I, Almeida AM, Miriyala SK. Analytical Similarity Assessment of Bevacizumab Biosimilar MB02 Using Multiple State-of-the-art Assays., DIA Europe, 2021.
EMA. Guideline on similar biological medicinal products containing monoclonal antibodies—non-clinical and clinical issues. European Medicines Agency (EMA/CHMP/BMWP/403543/2010), 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf. Accessed 24 Feb 2021. The PK population included all subjects who received the full dose of any treatment, did not had any major protocol deviations, and had evaluable PK data for at least one timepoint. Kaplan-Meier estimates of OS and PFS were presented stratified by treatment group and were compared using the log-rank test. For PFS, clinical progression (i.e., treatment discontinuation due to progression of disease) was also included as an event. Hazard ratio was estimated using the Cox proportional hazards model, including treatment group, with sex, smoking status, disease diagnosis and disease stage as covariates. Analyses of duration of OR and time to OR followed the same statistical approaches as for PFS and OS. This multinational, double-blind, randomized, parallel group, phase III clinical comparability study (STELLA) was conducted in 93 centers in the following 16 countries: Brazil, Bulgaria, Chile, Georgia, Greece, Hungary, India, Lebanon, Malaysia, Mexico, Philippines, Russia, Serbia, Thailand, Turkey, and Ukraine. This study is registered with EudraCT (No. 2017-001769-26) and ClinicalTrials.gov ( {"type":"clinical-trial","attrs":{"text":"NCT03296163","term_id":"NCT03296163"}}NCT03296163). Plovid Department of Medical Oncology, Multiprofile Hospital for Active Treatment Central Onco Hospital OOD, Plovdiv, BulgariaEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1·1). Eur J Cancer. 2009;45(2):228–47. The primary efficacy endpoint was the objective response rate (ORR), defined as the rate of either CR or PR according to RECIST v1.1 at Week 18 as assessed by an IRC. Best objective response rate (BORR) was also assessed by the IRC, considering the best overall response (BOR) of either CR or PR achieved at any post-baseline time point up to, and including, Week 18. Any subjects who discontinue study treatment before Week 18 were classed as non-responders in the final analysis of the primary efficacy endpoint.
Serious TEAEs were reported in similar frequency with no statistically significant difference between the treatment groups ( p=0.69) (Table (Table4). 4). Serious TEAEs were considered related to MB02 in 21 subjects (6.8%) and to EU-bevacizumab in 18 subjects (5.8%). The most common grade 3 or 4 IP-related serious TEAE in the MB02 group was pulmonary embolism, and in the EU-bevacizumab group the most common were pulmonary embolism, fatigue and pneumonia. No clear treatment-group-related trends were observed for IP-related serious TEAEs. MB02 (bevacizumab biosimilar) showed similar structural, functional, and pharmacokinetic properties to reference bevacizumab (Avastin ®; EU-bevacizumab). Objectives EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. European Medicines Agency (EMEA/CHMP/BMWP/42832/2005 Rev1); 2014. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active_en-2.pdf. Accessed 24 Feb 2021. EMA. Avastin (bevacizumab). Summary of product characteristics 2021. https://www.ema.europa.eu/en/documents/product-information/avastin-epar-product-information_en.pdf. Accessed 24 Feb 2021. Fundacao Universidade de Caxias do Sul, Instituto de Pesquisas Clinicas para Estudos Multicentricos, IPCEM, Caxias do Sul, BrazilThis was a phase 1, double‐blind, triple masking (participant, care provider, and investigator), randomized, parallel‐group, three‐arm, single‐dose study. It was performed in two centers located in New Zealand between December 2020 and September 2021 ( {"type":"clinical-trial","attrs":{"text":"NCT04408989","term_id":"NCT04408989"}}NCT04408989). Eligible subjects were randomly assigned to each treatment arm and stratified into two groups based on weight (≥50.0 to <72.5kg and ≥72.5 to ≤95.0kg, respectively). Randomization was assured by a computer‐generated randomization schedule prior to the start of the study. The schedule was generated through the Statistical Analysis System (SAS) software, version 9.4 (SAS Institute Inc). Exclusion criteria were defined as evidence of clinically significant disease, hypersensitivity to any drug compound, vaccination in the last 3months, use of specific products known to alter drug absorption, metabolism, or elimination processes and previous treatment with other antibody or protein targeting VEGF or VEGF receptor.
The loose ring is a simple stainless steel "O" shape where both the bridle and mouthpiece have no fixed point of attachment but slide freely around the ring. The loose ring allows a lot of play as the mouthpiece slides freely around the ring. The calibration standard and QC sample data indicated that the method performed satisfactorily for all reported runs. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905.TEAEs were coded using the Medical Dictionary for Regulatory Activities (version 22.0). The severity of any TEAE was recorded following the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The causal relationship was defined as not related, unlikely related, possibly related, probably related or related by the principal investigator or a medical sub‐investigator. All patients signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form before any study-specific procedures were performed. Consent for publication In this confirmatory phase III clinical study, the efficacy, safety, and immunogenicity of MB02 and EU-bevacizumab, both in combination with chemotherapy, were compared in patients with advanced non-squamous NSCLC. The primary objective of efficacy, RD of the ORRs (MB02 minus EU-bevacizumab) and RR of the ORRs ( MB02 / EU-bevacizumab) as assessed by an IRC at Week 18 in the ITT population, met the criteria applied for similarity as discussed with the main international regulatory authorities, demonstrating equivalence of clinical efficacy between MB02 and EU-bevacizumab.
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