Drugs in Research & Development最新文献

{"title":"Demonstration of Physicochemical and Functional Similarity of Biosimilar Adalimumab-aqvh to Adalimumab.","authors":"Yijia Jiang, Taruna Arora, Scott Klakamp, Janice Davis, Yasmin A Chandrasekher, Glen Young, Yue Du, Bin Yu, Karen J Miller","doi":"10.1007/s40268-023-00437-3","DOIUrl":"10.1007/s40268-023-00437-3","url":null,"abstract":"<p><strong>Background: </strong>Adalimumab-aqvh/CHS-1420 (YUSIMRY^TM) (hereafter referred to as adalimumab-aqvh) was recently approved by the US Food and Drug Administration as a biosimilar for adalimumab.</p><p><strong>Objective: </strong>The current study was conducted to investigate the analytical similarity of adalimumab-aqvh and the reference product, adalimumab.</p><p><strong>Methods: </strong>The structural, functional, and stability attributes of adalimumab-aqvh and adalimumab were compared using state-of-the-art assays. The primary structure, disulfide structure, glycan profile, secondary and tertiary structures, molar mass, size variants, free thiol, charge variants, hydrophobic variants, post-translational modifications, subvisible particles, host cell proteins, and protein concentration were investigated. The functional similarity between adalimumab-aqvh and adalimumab was demonstrated by comparing fragment antigen-binding (Fab)-associated and fragment crystallizable (Fc)-associated biological activities. The stability of adalimumab-aqvh and of adalimumab was compared through forced degradation.</p><p><strong>Results: </strong>The structural attributes of adalimumab-aqvh were identical to those of adalimumab or met the similarity criteria, with a few exceptions. Adalimumab-aqvh and adalimumab exhibited comparable stability profiles and functional activities. Any observed differences in the physiochemical attributes did not impact the conclusion of similarity because they did not influence any functional activities related to the adalimumab mechanism of action.</p><p><strong>Conclusion: </strong>The structural, functional, and stability data provide convincing evidence of biosimilarity between adalimumab-aqvh and the reference product, adalimumab.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"377-395"},"PeriodicalIF":3.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10065428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Looking into the Kinetics of NT-proBNP and sST2 Changes in Patients with Heart Failure Treated with Sacubitril/Valsartan: A Hint to Different Therapeutic Pathways.","authors":"Massimo Mapelli, Irene Mattavelli, Elisabetta Salvioni, Alice Bonomi, Nicolò Capra, Pietro Palermo, Cristina Banfi, Stefania Paolillo, Maria Luisa Biondi, Piergiuseppe Agostoni","doi":"10.1007/s40268-023-00438-2","DOIUrl":"10.1007/s40268-023-00438-2","url":null,"abstract":"<p><strong>Background and objective: </strong>N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. Both are potential targets of HFrEF treatment, but the first is associated with the patient's hemodynamic status, while the second is more indicative of the inflammatory status and of myocardial fibrosis. The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF.</p><p><strong>Methods: </strong>We analyzed blood samples of patients with HFrEF at baseline (before sacubitril/valsartan treatment), after 1, 2, and 3 months (respectively, after a month taking the 24/26 - 49/51 - 97/103 mg twice daily, or b.i.d., doses), and 6 months after the maximum-tolerated dose was reached (end study).</p><p><strong>Results: </strong>We obtained samples from 72 patients with HFrEF (age 64.0 ± 10.5 years, 83% males). NT-proBNP and sST2 values progressively and significantly reduced to 37% and 16%, respectively, with a greater reduction for NT-proBNP (p < 0.001). Specifically, NT-proBNP reduced from 1144 [593-2586] pg/mL to 743 [358-1524] pg/mL and sST2 from 27.3 [20.5-35.0] ng/mL to 23.1 [15.9-30.7] ng/mL, p for trend < 0.001 in both cases. The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT-proBNP. No significant changes in renal function and potassium levels were recorded.</p><p><strong>Conclusion: </strong>These findings suggest that, in patients with HF, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic anti-fibrotic, delayed one. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"397-402"},"PeriodicalIF":3.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10215930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin Preferentially Targets FLT3/ITD Acute Myeloid Leukemia by Inhibiting MEK/ERK and p38-MAPK Signaling Pathways.","authors":"Genhong Li, Jingwei Yao, Zhen Lu, Lian Yu, Qinwei Chen, Lihong Ding, Zhihong Fang, Yin Li, Bing Xu","doi":"10.1007/s40268-023-00442-6","DOIUrl":"10.1007/s40268-023-00442-6","url":null,"abstract":"<p><strong>Background: </strong>The FLT3/ITD mutation exists in many acute myeloid leukemia (AML) patients and is related to the poor prognosis of patients. In this study, we attempted to evaluate the antitumor activity of simvastatin, a member of the statin class of drugs, in vitro and in vivo models of FLT3/ITD AML and to identify the potential mechanisms.</p><p><strong>Methods: </strong>Cell Counting Kit-8 (CCK-8) and Annexin V/propidium iodide (PI) staining kits were used to detect cell viability and apoptosis, respectively. Subsequently, Western blot and rescue experiment were applied to explore the potential molecular mechanism. In vivo anti-leukemia activity of simvastatin was evaluated in xenograft mouse models.</p><p><strong>Results: </strong>In vitro experiments revealed that simvastatin inhibited AML progression in a dose- and time-dependent manner, while in vivo experiments showed that simvastatin significantly reduced tumor burden in FLT3/ITD xenograft mouse models. After simvastatin treatment of FLT3/ITD AML cells, intracellular Rap1 was downregulated and the phosphorylation levels of its downstream targets MEK, ERK and p38 were significantly inhibited. The rescue experiment showed that mevalonate, an intermediate product of the metabolic pathway of mevalonate, and its downstream geranylgeranyl pyrophosphate (GGPP) played a key role in this process. Finally, we demonstrate that simvastatin can induce apoptosis of primary AML cells, while having no effect on peripheral blood mononuclear cells from normal donors.</p><p><strong>Conclusions: </strong>Simvastatin can selectively and effectively eradicate FLT3/ITD AML cells in vitro and in vivo, and its mechanism may be related to the disruption of the HMG-CoA reductase pathway and the downregulation of the MEK/ERK and p38-MAPK signaling pathways.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"439-451"},"PeriodicalIF":3.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Tucatinib on Cardiac Repolarization in Healthy Volunteers.","authors":"Ariel R Topletz-Erickson, JoAl G Mayor, Hsu-Tai Liu, Layth I Abdulrasool, Christopher J Endres","doi":"10.1007/s40268-023-00440-8","DOIUrl":"10.1007/s40268-023-00440-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Tucatinib is a selective tyrosine kinase inhibitor of the human epidermal growth factor receptor 2 (HER2) approved to treat metastatic HER2-positive breast and colorectal cancers. The International Council for Harmonisation of Technical Requirements for Human Use (ICH) E14 guideline mandates that new drugs are assessed for potential effects on cardiac repolarization through electrocardiogram (ECG) evaluation in a QT/corrected QT (TQT) study.</p><p><strong>Methods: </strong>We evaluated the effect of tucatinib on cardiac repolarization in healthy volunteers in a phase I, randomized, partially double-blind, placebo-and positive-controlled three-period crossover study. The primary endpoint was the placebo-corrected change from baseline in QT interval values, corrected for heart rate using Fridericia's method (ΔΔQTcF).</p><p><strong>Results: </strong>After achieving steady-state tucatinib exposures with 300 mg twice daily, the observed ΔΔQTcF ranged from -2.9 msec at 2 hours post-dose to 0 msec at 4 hours post-dose. The upper bound of the 90% confidence interval (CI) was below 5 ms at all post-dose timepoints. Assay sensitivity was confirmed as the lower bound of the 90% CI and was >5 ms following moxifloxacin dosing. As the mean ΔΔQTcF of tucatinib was predicted to be -  1.80 ms (90% CI -  3.90, 0.30) at clinically relevant tucatinib concentrations (511 ng/mL), an effect of tucatinib on QTcF exceeding 10 ms was excluded within observed ranges of tucatinib (up to ~1000 ng/mL). Tucatinib had no clinically relevant effect on heart rate or cardiac conduction. The safety profile of tucatinib was manageable after multiple doses.</p><p><strong>Conclusion: </strong>Tucatinib had no clinically relevant effects on studied ECG parameters. This study constitutes a clearly negative TQT study per ICH E14 guidance.</p><p><strong>Clinical trial registration: </strong>This trial (NCT03777761) was registered on 17 December 2018.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"411-419"},"PeriodicalIF":3.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41153166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acknowledgement to Referees.","authors":"","doi":"10.1007/s40268-023-00447-1","DOIUrl":"https://doi.org/10.1007/s40268-023-00447-1","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71487990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and Safety of Apatinib in Patients with Recurrent Glioblastoma.","authors":"Hao Lin,&nbsp;Xinli Zhou,&nbsp;Xiaofang Sheng,&nbsp;Xiaohua Liang","doi":"10.1007/s40268-023-00429-3","DOIUrl":"https://doi.org/10.1007/s40268-023-00429-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Glioblastoma is a cranial malignant tumor with a high recurrence rate after surgery and a poor response to chemoradiotherapy. Bevacizumab has demonstrated efficacy in the treatment of glioblastoma by inhibiting vascular endothelial growth factor, but the efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors varies in treating glioblastoma. This single-arm prospective study aimed to explore the efficacy and safety of the vascular endothelial growth factor receptor tyrosine kinase inhibitor apatinib in treating recurrent glioblastoma after chemoradiotherapy.</p><p><strong>Methods: </strong>A total of 15 patients with recurrent glioblastoma (2016 World Health Organization grade IV) after chemoradiotherapy were enrolled in this study from September 2017 to September 2019 and treated with apatinib 500 mg once daily. Responses were evaluated according to the Response Assessment in Neuro-Oncology criteria, and adverse events were recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.</p><p><strong>Results: </strong>The overall response rate was 33.3%, and the disease control rate was 66.6%. The median progression-free survival was 2 months, and the median overall survival was 6.5 months. The apatinib dose was adjusted in seven patients because of adverse events (46.6%). The most common adverse events were thrombocytopenia (53.3%), asthenia (40%), and hand-foot syndrome (33.3%).</p><p><strong>Conclusions: </strong>Apatinib might be effective in treating recurrent glioblastoma after chemoradiotherapy in terms of the overall response rate, but the efficacy is not durable and the clinical benefit is limited. The adverse effects of apatinib were acceptable.</p><p><strong>Clinical trial registration: </strong>ChiCTR-ONC-17013098, date of registration: 24 October, 2017.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"239-244"},"PeriodicalIF":3.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/35/74/40268_2023_Article_429.PMC10439071.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10035581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.","authors":"Jan Hilpert, Esther Groettrup-Wolfers, Hristiyan Kosturski, Laura Bennett, Catriona L K Barnes, Kerstin Gude, Isabella Gashaw, Stefanie Reif, Thomas Steger-Hartmann, Christian Scheerans, Alexander Solms, Antje Rottmann, Guangping Mao, Charles Chapron","doi":"10.1007/s40268-023-00427-5","DOIUrl":"10.1007/s40268-023-00427-5","url":null,"abstract":"<p><strong>Introduction: </strong>BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa.</p><p><strong>Objective: </strong>This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period.</p><p><strong>Methods: </strong>Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated.</p><p><strong>Results: </strong>Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed.</p><p><strong>Conclusions: </strong>The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required.</p><p><strong>Clinical trial registration: </strong>NCT03373422 (date registered: November 23, 2017).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"221-237"},"PeriodicalIF":3.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/58/73/40268_2023_Article_427.PMC10439066.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10035545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioavailability of Melatonin after Administration of an Oral Prolonged-Release Tablet and an Immediate-Release Sublingual Spray in Healthy Male Volunteers.","authors":"Samira Ait Abdellah,&nbsp;Véronique Raverot,&nbsp;Caroline Gal,&nbsp;Isabelle Guinobert,&nbsp;Valérie Bardot,&nbsp;Claude Blondeau,&nbsp;Bruno Claustrat","doi":"10.1007/s40268-023-00431-9","DOIUrl":"https://doi.org/10.1007/s40268-023-00431-9","url":null,"abstract":"<p><strong>Background: </strong>The benefit of exogenous melatonin is based on its bioavailability, which depends on the galenic form, the route of administration, the dosage, and the individual absorption and rate of hepatic metabolism.</p><p><strong>Objective: </strong>The objective of this study is to investigate the bioavailability of melatonin after administration of an oral prolonged-release tablet (PR form) and an immediate-release sublingual spray (IR form). The main metabolite of melatonin, 6-sulfatoxymelatonin (6-SMT), was also measured, which has not been done in previous studies. Its determination is important as an index of the hepatic transformation of melatonin.</p><p><strong>Methods: </strong>In this single-center, open-label, randomized, crossover study, 14 healthy male volunteers received one tablet of the PR form (1.9 mg melatonin) or two sprays of the IR form (1 mg melatonin) during two visits separated by a washout period. Blood samples were collected over 7 and 9 h for the IR and PR form, respectively, to determine the main pharmacokinetic parameters.</p><p><strong>Results: </strong>The observed kinetics were consistent with those expected for immediate and prolonged-release forms. Pulverization of the spray resulted in an early, high plasma melatonin peak (C_max: 2332 ± 950 pg/mL; T_max: 23.3 ± 6.5 min), whereas tablet intake produced a lower peak (C_max: 1151 ± 565 pg/mL; T_max: 64.2 ± 44.2 min; p < 0.001 for comparison of C_max and T_max) followed by a plasma melatonin plateau and a more prolonged decay over time. Plasma melatonin/6-SMT AUC_0-540/420 ratio was 0.09 for the PR form and 0.16 for the IR form. Both galenic forms were well tolerated.</p><p><strong>Conclusions: </strong>The results suggest that the galenic forms containing melatonin assessed in this study are suitable for the treatment of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form.</p><p><strong>Trial registry: </strong>Registration number: NCT04574141.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"257-265"},"PeriodicalIF":3.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ad/83/40268_2023_Article_431.PMC10439092.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10044508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biochemical Characterization of a New 10% IVIG Preparation [IgG Next Generation (BT595)/Yimmugo^®] Obtained from a Manufacturing Process Preserving IgA/IgM Potential of Human Plasma.","authors":"Christian Duellberg,&nbsp;Achim Hannappel,&nbsp;Steffen Kistner,&nbsp;Oliver Maneg","doi":"10.1007/s40268-023-00430-w","DOIUrl":"https://doi.org/10.1007/s40268-023-00430-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Human plasma is used for the generation of several life-saving drugs and contains valuable antibodies from the immunoglobulin classes IgG, IgM and IgA. Purified intravenous IgG solutions (IVIGs) form the majority of plasma-derived medicine to treat patients with various forms of immunodeficiencies. In conventional IVIG manufacturing processes, immunoglobulin classes IgM and IgA are often discarded as contaminants, but these antibody classes have been proven to be effective for the treatment of acute bacterial infections. Considering the increase in demand for human plasma-derived products and the ethical value of the raw material, a more resource-saving usage of human plasma is needed. Intensive research over the last decades showed that adverse reactions to IVIGs depend on the presence of thrombogenic factors, partially unfolded proteins, non-specific activation of the complement system, and blood group specific antibodies. Therefore, new IVIG preparations with reduced risks of adverse reactions are desirable.</p><p><strong>Method: </strong>A new manufacturing process that yields two biologics was established and quality attributes of the new IVIG solution (Yimmugo^®) obtained from this process are presented.</p><p><strong>Results: </strong>Here, we provide a biochemical characterization of Yimmugo^®, a new 10% IVIG preparation. It is derived from human blood plasma by a combined manufacturing process, where IgM and IgA are retained for the production of a new biologic (trimodulin, currently under investigation in phase III clinical trials). Several improvements have been implemented in the manufacturing of Yimmugo^® to reduce the risk of adverse reactions. Gentle and efficient mixing by vibration (called \"vibromixing\") during a process step where proteins are at risk to aggregate was implemented to potentially minimize protein damage. In addition, a dedicated process step for the removal of the complement system activator properdin was implemented, which resulted in very low anticomplementary activity levels. The absence of measurable thrombogenic activity in combination with a very high degree of functional monomeric antibodies predict excellent efficacy and tolerability.</p><p><strong>Conclusion: </strong>Yimmugo^® constitutes a new high quality IVIG preparation derived from a novel manufacturing process that takes advantage of the full therapeutic immunoglobulin potential of human plasma.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"245-255"},"PeriodicalIF":3.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/59/c7/40268_2023_Article_430.PMC10439088.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10042548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physicochemical and Functional Similarity Assessment Between Proposed Bevacizumab Biosimilar BAT1706 and Reference Bevacizumab.","authors":"Di Cao,&nbsp;Chunping Deng,&nbsp;Guangying Wang,&nbsp;Xiong Mei,&nbsp;Jianhua Xie,&nbsp;Yuanmei Liu,&nbsp;Yujie Liu,&nbsp;Yili Yang,&nbsp;Shengfeng Li,&nbsp;Cuihua Liu","doi":"10.1007/s40268-023-00432-8","DOIUrl":"https://doi.org/10.1007/s40268-023-00432-8","url":null,"abstract":"<p><strong>Background: </strong>BAT1706 is a proposed biosimilar of bevacizumab, a vascular endothelial growth factor A (VEGF-A)-targeting biologic used to treat several different cancers, including metastatic colorectal cancer. A comprehensive physicochemical and functional similarity assessment is a key component of demonstrating biosimilarity between a reference biologic and a proposed biosimilar. Here we report the physicochemical and functional similarity of BAT1706 and reference bevacizumab sourced from both the United States (US-bevacizumab) and the European Union (EU-bevacizumab).</p><p><strong>Method: </strong>A large range of product attributes, including primary and higher order structure, post-translational modifications, purity, stability, and potency, were characterized for BAT1706 and EU/US-bevacizumab using sensitive state-of-the-art analytical techniques. Up to 18 lots of US- and 29 lots of EU-bevacizumab, and 10 unique drug substance lots of BAT1706, were assessed.</p><p><strong>Result: </strong>BAT1706 was shown to have an identical amino acid sequence and an indistinguishable higher-order structure compared with EU/US-bevacizumab. BAT1706 and EU/US-bevacizumab also exhibited similar post-translational modifications, glycan profiles, and charge variants. Potency, assessed using a wide range of bioassays, was also shown to be comparable between BAT1706 and EU/US-bevacizumab, with statistical equivalence demonstrated for VEGF-A binding and neutralizing activity.</p><p><strong>Conclusion: </strong>Overall, this extensive comparability exercise demonstrated BAT1706 to match EU/US-bevacizumab in terms of all physicochemical and functional attributes assessed.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"267-288"},"PeriodicalIF":3.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d5/eb/40268_2023_Article_432.PMC10439073.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10419756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}