The calibration standard and QC sample data indicated that the method performed satisfactorily for all reported runs. IP investigational medicinal product, N number of subjects on intended set, PT preferred term, TEAE treatment-emergent adverse event 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.

All subjects were monitored for safety during the follow‐up. A TEAE was defined as any untoward medical occurrence or clinical investigation in a patient or subject administered a pharmaceutical product. Other safety assessments included clinical laboratory data, vital signs, electrocardiogram, and physical examination.

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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. 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. 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 Long‐term stability was tested at 366days and −50°C. Based on a fixed effects meta-analysis of five historical reference studies selected for their applicability to this study, a sample size of 300 randomized subjects per group (600 total) was chosen to provide adequate power for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. 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.

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). 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. Of the 159 reported TEAEs, 27 (17.0%) were at least possibly related, probably related, or related. The spring is fundamental to that all-important fire, so ensuring you’re giving your pride and joy the best airsoft parts on the market goes without saying. Don’t forget to measure your gun first to ensure your new spring is a seamless fit. And choose carefully from our range of spring gun spring sizes. A possible limitation for the study was that the study protocol definition used for smoking-status classification differed from the new standard definition currently in use in NSCLC clinical study protocols. The current definition regards smokers as subjects who had smoked >100 cigarettes in a lifetime and non-smokers as subjects who had never smoked or had smoked <100 cigarettes in a lifetime [ 27]. In consequence, the proportion of subjects included in smoker/non-smoker categories according to the study protocol definition used in the study protocol (smokers: 309 [49.3%]; non-smokers: 318 [50.7%]) is slightly different to that reported in recent NSCLC publications [ 28]. After the study completion, the proportion of smokers/non-smokers was re-assessed using the current new standard definition (smokers: 390 [62.2%]/non-smokers: 237 [37.8%]), observing that the percentage of smokers in the study is in line with recent publications. Efficacy analysis conducted for the primary endpoint with inclusion of this definition for smoker status was similarly in line with the reported results of the study. Thus, the smoking status definition as defined in the protocol was considered valid, especially considering that subjects were randomized under this stratification factor as per study protocol.As bevacizumab has a long t 1/2 and as the appearance of ADA/nAbs could interfere with PK parameters a parallel group design was chosen. The efficacy of MB02 was tested in STELLA clinical trial. This study provided information of the interference in multiple doses with ADA/nAbs. 7 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). Logistics->Logistics Execution->JIT Inbound->Environment->Inventory Management->Material Document->Change(MB02) After six cycles (i.e., at the start of Cycle 7), subjects received monotherapy treatment with the investigational product (IP; MB02 or EU-bevacizumab) under blinded conditions every 3 weeks until evidence of disease progression, unacceptable toxicity, death, withdrawal of consent or end of study (Week 52). Until the Week 18 assessment, reduction in MB02/EU-bevacizumab dose was not permitted, but was allowed after Week 18, if clinically necessary, to a dose level of 7.5mg/kg. Dose reductions were allowed for paclitaxel/carboplatin according to the indications in the corresponding effective product information. 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.

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 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]. The following TEAEs were commonly seen and known to be associated with bevacizumab: two events of infusion‐related reactions by two subjects (in MB02‐SP arm), five events of epistaxis by five subjects (three in MB02‐DM arm and two in US‐bevacizumab), and one event of deep vein thrombosis by one subject (in MB02‐SP arm). All these TEAEs were resolved by EOS. Except deep vein thrombosis, which was evaluated as grade 2, all of them were grade 1.

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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 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. 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). MB02 SPRO IMG Menu PathLogistics->Production->KANBAN->Environment->Inventory Management->Material Document->Change(MB02)