Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542–50. MB02 was developed by mAbxience Research SL as a biosimilar to the reference bevacizumab following the recommendations of the existing international guidelines [ 11, 12, 13, 14]. A biosimilar is a medicine similar to another biological medicine (the reference product) already marketed, in terms of its physical, chemical and biological properties. Its approval follows the same strict standards of quality, safety and efficacy that apply to any other biological medicine [ 15]. The comparability exercise at the quality and functional level forms the basis of the biosimilarity demonstration and, in this sense, MB02 has demonstrated similarity to reference bevacizumab in a comprehensive program of drug chemistry, manufacturing and controls (CMC), and analytical similarity. A full comparison of the in vitro pharmacodynamic properties of MB02 versus the reference product was conducted as part of the comparability exercise. This exercise demonstrated comparable binding affinities to all VEGF isoforms, similar neutralization potencies and similar mode of action [ 16]. This most important foundation of biosimilarity had been further confirmed by another highly sensitive model, the investigation of clinical equivalence in pharmacokinetics (PK). PK similarity between MB02 and bevacizumab has been demonstrated in three bioequivalence studies comparing the PK profiles of MB02 with reference bevacizumab (US- or EU-approved) following the administration of a single dose (3 mg/kg IV) in 276 healthy male subjects (ClinicalTrials.gov identifiers: NCT04238663; NCT03293654 and NCT04238650). Results from secondary endpoints and sensitivity analyses reflected those of the primary analysis. Similar efficacy between MB02 and EU-bevacizumab was supported by the ad-hoc analyses of BORR at Week 18 based on IRC assessments in the ITT population (RR 0.926; 90% CI 0.818 to 1.049; RD −4.04%; 95% CI −11.86 to 3.78) (Table ​ (Table2 2). 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.

SAP Program associated with transaction MB02For further details and documentation see program SAPMM07MLee SJ, Lee J, Park YS, Lee CH, Lee SM, Yim JJ, et al. Impact of smoking on mortality of patients with non-small cell lung cancer. Thorac Cancer. 2014;5(1):43–9. The study was supported by mAbxience Research SL. Employees of the sponsor had a role in study design, data analysis and manuscript preparation. Employees of the funder had no role in data collection. Competing interests Tobelem G. VEGF: a key therapeutic target for the treatment of cancer-insights into its role and pharmacological inhibition. Target Oncol. 2007;2(3):153–64.

MB02 is a bevacizumab biosimilar developed by mAbxience Research S.L. and recently approved by the EMA in March 2021 and by the FDA in April 2022. 3 Analytical similarity was demonstrated, including non‐clinical in vitro studies evaluating the biological activity of the antibody, followed by an extensive clinical development program as per EMA and FDA guidelines for biosimilar development. 4, 5 Firstly, MB02 has showed to be bioequivalent to reference bevacizumab in three pharmacokinetic (PK) studies conducted in healthy volunteers. 6, 7 The last step in the similarity assessment was a confirmatory clinical study in a highly sensitive population (STELLA clinical trial). 8 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. 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. Niho S, Kunitoh H, Nokihara H, Horai T, Ichinose Y, Hida T, et al. Randomized phase II study of first-line carboplatin and paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer. Lung Cancer. 2012;76(3):362–7.Most TEAEs were considered by the investigator as related to any study treatment (bevacizumab or chemotherapy) and were reported in a similar number of subjects with MB02 (264 [84.9%]) and with EU-bevacizumab (270 [87.1%]), observing a risk difference of <5% between treatment groups. Overall, 189 (30.4%) subjects had Grade 3 or 4 study drug-related TEAEs, with a similar distribution observed in each treatment group ( p = 0.56). No differences were noted for IP-related TEAEs ( p = 0.97). This 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).

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. 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. Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, et al. Bevacizumab (Avastin®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat Rev. 2020;86:102017. A dose of 1mg/kg for MB02‐DM, MB02‐SP, and US‐bevacizumab was chosen based upon the dosages used in previously published studies and to minimize safety issues in volunteers. Linear PK of bevacizumab has been previously described between 0.3 and 10mg/kg. 13 aAn adverse event was related if assessment of causality was possible, probable or very likely/certain

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All subjects who were reported TEAEs detected were followed up until the event was resolved or stabilized in the opinion of the investigator. All patient‐reported AEs were analyzed in the safety population. EMA. Biosimilars in the EU. Information guide for healthcare professionals. Prepared jointly by the European Medicines Agency and the European Commission, 2017. http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf. Accessed 24 Feb 2021.