My Babiie MB02 Samantha Faiers Safari Lightweight Stroller, Lightweight Frame, Comfort, Manoeuvrability, Easy Travel, Umbrella Fold, from Birth to 22kg, with Cup Holder and Raincover (Safari)

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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 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). 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.

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. Fundacao Universidade de Caxias do Sul, Instituto de Pesquisas Clinicas para Estudos Multicentricos, IPCEM, Caxias do Sul, Brazil Eligible study population were male volunteers aged between 18 and 55years, weighted between 50 and 95kg with a body mass index (BMI) between 18.5 and 29.9kg/m 2 and any ethnic origin. Health status was evaluated through medical history, physical examination, 12‐lead electrocardiogram, vital sign measurement, and clinical laboratory evaluation (hematology, coagulation, urinalysis, and chemistry). A total of 627 subjects were randomized 1:1 to MB02 ( n = 315) or EU-bevacizumab ( n = 312). ORR, assessed by the IRC at Week 18, was comparable in MB02 (40.3%) and EU-bevacizumab (44.6%) groups. ORR risk ratio of 0.910 (90% CI 0.780 to 1.060; 95% CI 0.758 to 1.092) and ORR risk difference of −4.02 (90% CI −10.51 to 2.47; 95% CI −11.76 to 3.71) were within the similarity predefined margins. There were no significant differences between MB02 and EU-bevacizumab groups in median PFS (36.0 vs 37.3 weeks, respectively; HR 1.187; 95% CI 0.98 to 1.44) and median OS (not achieved; HR 1.108; 95% CI: 0.83 to 1.49) at the end of study. The safety profile of MB02 and EU-bevacizumab regarding nature, frequency and severity of the adverse events (AE) was comparable. The most frequent grade ≥3 investigational-product-related AEs were hypertension and anemia, with a difference between treatment groups of <5%. Anti-drug antibodies (ADA) and neutralizing ADA (NAb) incidence were similar in both treatment groups. Conclusion

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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. 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).

Immunogenicity data (overall ADA incidence and titers, non‐neutralizing ADA results, and neutralizing ADA results) were listed and evaluated by treatment arm.The present phase 1 clinical trial was designed to evaluate PK similarity among MB02‐SP, MB02‐DM, and US‐bevacizumab. To ensure the homogeneity of the population and to detect PK differences between groups healthy male subjects were selected, as in other biosimilar clinical trials. 11, 12, 13, 14 The use of healthy male volunteers avoids factors that can confound the interpretation of PK, safety result, and the influence of sex‐related factors upon bevacizumab clearance. Female PK data were obtained in STELLA phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02069704","term_id":"NCT02069704"}}NCT02069704). 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. 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 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. Subjects were followed up for survival until death or end of study. After study completion, all subjects were offered the opportunity to continue receiving biosimilar MB02 monotherapy until disease progression, unacceptable toxicity, initiation of any new treatment or death. 2.4 Outcomes

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.aAn adverse event was related if assessment of causality was possible, probable or very likely/certain Hospital Universitario “Dr. Jose Eleuterio Gonzalez” (Centro Universitario contra el Cancer), Monterrey, Nuevo Leon, Mexico Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–301. Day Patient Facility of Dispensary and Policlinic Department, Odessa Regional Oncological Dispensary, Odessa, Ukraine