For each subject, a total of five blood samples (for both, anti‐drug antibodies [ADA], and neutralizing antibodies [NAb]) detection were collected by venipuncture or cannulation at Days −1, 14, 28, 56, and 78. It was assessed anti‐MB02‐SP, anti‐MB02‐DM, and anti‐US‐bevacizumab. 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 The majority (144; 90.6%) of the reported TEAEs were mild in severity, with 15 (9.4%) as grade 2 (moderate) in severity. There were no severe TEAEs, no SAEs, no deaths during the study. No subjects were discontinued from the study due to TEAEs. MB02 or EU-bevacizumab (15mg/kg) were administered as an IV infusion in combination with chemotherapy (paclitaxel 200mg/m 2 and carboplatin AUC6) on Day 1 of every 3-week cycle for six cycles (Week 18) unless there was evidence of disease progression or unacceptable toxicity to study treatment. The first MB02 or EU-bevacizumab treatment was administered as a 90-minute infusion. If the study drug was well tolerated, the next infusion was given over a 60-minute period. Thereafter, the drug was given as a 30-minute IV infusion. Bevacizumab is a recombinant humanized monoclonal antibody which binds the vascular endothelial growth factor ( VEGF), neutralizing endothelial receptors. This mechanism of action inhibits microvascular growth and causes inhibition of tumor growth and progression. 1 In addition, it sensitizes tumor vasculature to chemotherapy‐induced damage. Since initial approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2004 and 2005, respectively, bevacizumab (Avastin®) has been authorized for a wide range of oncology indications. 2 Bevacizumab was the first angiogenesis inhibitor to obtain marketing authorization, and it is part of the standard of care in the treatment of some advanced cancers. For this reason, bevacizumab's vast evidence of use allows a very well‐established efficacy and safety profile. The high cost related to biologics manufacturing is currently limiting access to these treatment alternatives in many locations.

Non-small cell lung cancer (NSCLC), the most common type of lung cancer, is among the leading causes of death worldwide and contributes significantly to growing health care costs [ 1, 2]. Avastin ®, the reference bevacizumab, has been approved for use in many cancer indications and settings, including first-line treatment of advanced NSCLC in combination with other chemotherapeutic agents [3, 4]. Several international guidelines recommend the use of bevacizumab in association with chemotherapy in first-line and maintenance settings in advanced NSCLC [ 5, 6]. In addition, recent evidence points to novel combinations of bevacizumab with new molecular therapies or immuno-oncology drugs, as well as for maintenance beyond disease progression [ 7, 9]. Upgrade your airsoft spring gun or spring sniper rifle to stay ahead of the game on the battlefield. Our spring gun springs - say that five times fast - allow you to modify your airsoft gun, or simply replace a worn-out part. 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. dThe ORR estimate was adjusted for the actual randomization strata sex (male/female), smoking status (smoker/non-smoker), disease diagnosis (newly diagnosed/recurrent disease), and disease stage (Stage IIIB/Stage IV) using the Cochran–Mantel–Haenszel estimate of the risk ratio and corresponding 2-sided 90% CI The ORR estimate was stratified using the Cochran–Mantel–Haenszel estimate of the RR and RD, and the corresponding two-sided 90% and 95% CIs based on the Mantel–Haenszel method (RR) or Wald asymptotic method (RD) were presented. BOR and BORR per IRC review were also analyzed, utilizing the same procedures as described above. Additional sensitivity analyses were conducted on ORR and BORR, implementing a multiple imputation (MI) process for imputation of missing data, analyzed using the same Cochran–Mantel–Haenszel procedure as above, with results for each imputation combined using Rubin’s rule, applied using SAS Proc Mianalyze [ 18].MB02 SPRO IMG Menu PathLogistics->Production->KANBAN->Environment->Inventory Management->Material Document->Change(MB02) SAP GUI Support for tcode MB02When a tcode is created you can select which SAP GUI it has support for from HTML, Java and the main Windows GUI you are probably most familiar with. 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– 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.

The inter‐assay precision in the determination of the QC samples was 9.6% at the LQC, 9.4% at the MQC, and 11.1% at the HQC. The mean accuracy values at these levels were 1.5%, 1.2%, and 0.1% bias, respectively. 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. Based on a fixed effects meta-analysis of five historical reference studies selected for their applicability to this study, a sample size of 300 randomized subjects per group (600 total) was chosen to provide adequate power for the proposed analyses. 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 STELLA clinical equivalence study compared both drugs in the first-line treatment of advanced non-squamous non-small cell lung cancer (NSCLC) patients as the last step in biosimilarity assessment. Results from this study provide reassurance that clinical activity, and hence efficacy, clinical safety and immunogenicity of MB02 and reference bevacizumab are comparable.The primary objective of the study was to investigate and compare the PK profiles of MB02‐SP, MB02‐DM, and US‐bevacizumab to establish bioequivalence between them. PK primary endpoints were area under the serum concentration–time curve from time zero to infinity (AUC0–∞) and maximum observed serum concentration ( C max).

The 90% CIs for the comparability ratios of the exposure parameters were within the prespecified acceptance range of 80.00%–125.00% for the comparison of the three products and are consistent with other bevacizumab biosimilar clinical trials. bIn case of missing evaluation, i.e., in case the subject was withdrawn from study before Week 18, the subject was classified as a non-responder Logistics->Logistics Execution->JIT Inbound->Environment->Inventory Management->Material Document->Change(MB02) As part of MB02 global development, an optimized drug substance manufacturing process using completely chemically defined growth and feed media was implemented. The new process leads to the manufacture of a MB02 protein with an increased purity and reduced levels of heavy–heavy–light fragment, comparable to the reference product. The previous product/process was named MB02‐SP (Standard Process) and the new one MB02‐DM (Defined Media). An exhaustive comparability assessment was carried out using 9MB02‐SP lots and 6MB02‐DM lots. It demonstrated that MB02‐DM is highly comparable to MB02‐SP.Subjects were required to refrain from extreme sports, blood donation, and conception. All subjects provided written informed consent before any screening procedures were done according to local ethical committee regulations. The screening period was up to 30days. On Day −1, subjects were admitted at Clinical Research Unit for 3days, and ambulant follow‐up visits were scheduled to collect blood samples on 4, 5, 6, 7, 8, 10, 14, 21, 28, 42, 56, 78, and 100days. During confinement subjects received a standardized diet at scheduled time in the day. Safety was evaluated during whole duration os clinical trial.

MB02 was developed by mAbxience Research SL as a biosimilar to the reference bevacizumab following the recommendations of the existing international guidelines [ 11– 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 (3mg/kg IV) in 276 healthy male subjects (ClinicalTrials.gov identifiers: {"type":"clinical-trial","attrs":{"text":"NCT04238663","term_id":"NCT04238663"}}NCT04238663; {"type":"clinical-trial","attrs":{"text":"NCT03293654","term_id":"NCT03293654"}}NCT03293654 and {"type":"clinical-trial","attrs":{"text":"NCT04238650","term_id":"NCT04238650"}}NCT04238650). 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). 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). 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. PK similarity was defined if the 90% confidence interval (CIs) for the biosimilar‐to‐reference ratios of PK endpoints (AUC[0–∞] and C max) fell within the predefined 0.80–1.25 acceptance similarity criteria for all three pairwise comparisons. For these parameters, geometric least square means (GLSM) and mean differences were calculated for MB02‐SP versus MB02‐DM, and MB02‐SP versus US‐bevacizumab and MB02‐DM versus US‐bevacizumab. For each comparison only the two treatments involved in the comparison were included in the model. The PK population were used for the analysis defined as all subjects who received the full dose of any treatment, did not have any major protocol deviations, and had evaluable PK data for at least one timepoint. PK values were assessed by noncompartmental analysis using Phoenix WinNonlin®, version 8.1 (Certara).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. Descriptive statistics (sample size, mean, median, standard deviation, minimum, and maximum) were calculated for continuous variables. Frequency counts and percentages were tabulated for categorical variables. To contribute to the totality of evidence and support the similarity of MB02 already demonstrated in preclinical and PK clinical development, a properly conducted confirmatory clinical trial demonstrating comparable efficacy was performed as the last step of the similarity exercise according to guidelines issued by the international authorities worldwide [ 11– 15]. The safety profile of MB02 was comparable to that of EU-bevacizumab and results were those expected for the reference product in an equivalent study population and with the same concomitant therapies. Overall, the number, type, and severity of TEAEs, including those of special interest (such as gastrointestinal perforations, hypertension, thromboembolism or hemorrhage) were consistent with the safety profile reported for NSCLC patients in the reference bevacizumab product information [ 3, 4]. No new safety signals or observable trends were identified in either treatment group in the study. No impact on the safety in general, and no immune-related safety risks in particular, appear to be correlated with treatment-related antibodies. Similarly, from the analyses performed, the effect of treatment-related antibodies does not appear to account for any differences in efficacy between the products.