BioDrugs最新文献

The uptake of biosimilar medicines in Europe and the USA remains highly variable and at times slow, despite the significant potential for cost savings for both patients and healthcare systems. One of the most recommended measures to address this issue is the use of prescribing incentives. On the basis of a well-defined concept of individual prescribing incentives, we conducted a scoping literature review aimed at exploring their role in promoting the uptake of biosimilars in six countries with advanced healthcare systems (the USA, Denmark, England, Italy, France and Germany), with a particular focus on gain-sharing initiatives. Online databases and other sources were used to identify papers published between 2010 and 2023, resulting in the selection of 47 publications. The results suggest that there are few real-world programmes that use provider incentives offered by health systems to encourage prescribing of biosimilars. However, we found gain-sharing schemes of particular interest in England, Italy, France and Germany, where savings are reinvested to improve the quality of care, incentivizing physicians and raising satisfaction, but without financial rewards. In contrast, we found unplanned disincentives hindering the uptake of biosimilars in the USA, as well as very successful top-down strategies that do not rely on individual incentives, including centralized procurement in Denmark, although it remains to be seen whether the success is idiosyncratic to its specific circumstances. In addition, the hypothesis that gain-sharing initiatives with the aforementioned characteristics are more adaptable to different cultural, organizational and political settings to promote biosimilar prescribing merits further research.

Background and objective: Tocilizumab is a recombinant, humanised monoclonal antibody of the immunoglobulin G1 (IgG1) subclass, which specifically targets the interleukin-6 receptor (IL-6R). The RGB-19 product was developed as a biosimilar to the reference medicinal product RoActemra^® (authorised for use in the European Union [EU]). The current study focuses on the demonstration of structural, physico-chemical and functional similarity between RGB-19 (intravenous [IV] and subcutaneous [SC] presentations) and EU-sourced RoActemra^® (IV and SC presentations).

Methods: The RGB-19 biosimilar tocilizumab product was comprehensively tested using an extensive state-of-the-art analytical and functional panel of 44 methods to demonstrate similarity to the EU-sourced RoActemra^®. Biosimilarity was rigorously evaluated through an extensive array of orthogonal physico-chemical and functional assays, supplemented by a detailed comparative characterisation of the primary and higher order structures of the therapeutic proteins.

Results: Extensive structural analyses confirmed that the primary and higher order structures of tocilizumab proteins in RGB-19 IV and SC drug products are identical or exhibit a high degree of similarity to those of the RoActemra^® reference products. The impurity profiles of RGB-19 and RoActemra^® products were found to be highly comparable, as demonstrated by a series of physico-chemical techniques. A high level of similarity was shown for the most critical (soluble IL-6R binding and cell-based anti-proliferation assay) and for all other bioassay attributes. Based on the statistical evaluation, negligible differences could be detected for sialylation, glycation, fragments and charge variants, which do not affect the functional properties.

Conclusion: Based on the similarity study, RGB-19 and RoActemra^® can be considered highly similar drug products. The minor differences found for some physico-chemical attributes do not affect the biological potency, binding and other critical attributes, and are therefore not considered clinically meaningful.

Background and objectives: Biopharmaceuticals add value in the treatment of many diseases but different health systems in Europe face clinical and economic challenges with introducing them. Joint efforts across Europe are therefore essential to ensure their sustainable and equitable use. However, to date few cross-national comparative studies have assessed their introduction. This study aimed to assess the availability of health authority data and variation in the early diffusion of biopharmaceuticals across Europe.

Methods: A cross-sectional study was undertaken to analyze the diffusion of 17 biopharmaceuticals, approved between 2015 and 2019, among European countries between 2015 and 2022. The study assessed data availability, diffusion rates measured as accumulated defined daily doses per 1000 inhabitants, as well as relative rankings between countries during the first 4 years following market authorization.

Results: Twenty countries and two regions out of 31 European countries provided data on biopharmaceutical utilization for out-of-hospital care, 15 provided wholesaler data, and 14 provided hospital data. Certain countries and regions contributed data in multiple categories, while six did not provide any data. Diffusion rates were assessed for 17 countries and two regions, which showed appreciable variation, with secukinumab and erenumab being introduced in most countries and follitropin delta and tildrakizumab in the least number of countries. Germany, Austria, and Norway demonstrated the highest early diffusion rates, while Lithuania, Romania, and Latvia had the lowest.

Conclusions: This study revealed a substantial variation between European countries and regions in the early diffusion of biopharmaceuticals and the availability of data to monitor their use. The reasons behind these patterns require further investigation to support European countries in optimizing the use of biopharmaceuticals to reach an equitable and cost-effective use of medicines across Europe.

Objective: To evaluate the impact of demand- and supply-side policies on the biosimilar market penetration and identify effective strategies for promoting biosimilar uptake in eight high-income countries.

Methods: We analyzed biosimilar market penetration for infliximab, rituximab, and trastuzumab in six European countries-France, Germany, Italy, Spain, Sweden, and the UK-and two Asian countries-Japan and South Korea. Biosimilar market penetration was measured using two indicators: biosimilar market share and the time required for biosimilars to reach the majority point (> 50% market share). Policies were categorized into demand- and supply-side measures, and weights were applied to reflect the extent and timing of policy implementation. Spearman correlation examined the relationship between policy implementation and biosimilar market penetration.

Results: Sweden, Italy, and the UK showed the highest biosimilar market shares, adopting various demand-side policies, while Japan and South Korea exhibited slower biosimilar adoption with fewer or no demand-side policies. Biosimilars in most European countries reached the majority point within 5-6 quarters, while projections for Japan and South Korea exceeded 30 quarters. Correlation analysis revealed that adoption of demand-side policies was significantly associated with higher market share (r_s = 0.69, p < 0.001) and shorter time to reach the majority point (r_s = - 0.62, p < 0.01). In contrast, supply-side policies showed a weaker and less consistent association.

Conclusions: Demand-side policies, such as financial incentives and prescribing guidelines, are significantly associated with rapid and widespread biosimilar adoption, while supply-side policies had limited impact. Policymakers should prioritize demand-side measures to improve biosimilar uptake and reduce healthcare expenditures effectively.

Fabry disease is a rare but life-threatening, X-linked, inherited lysosomal storage disorder in which globotriaosylceramide is insufficiently metabolized because of reduced α-galactosidase A activity. Cellular globotriaosylceramide accumulation causes a multisystemic disease, which, if left untreated, reduces life expectancy in female and male individuals by around 10 and 20 years, respectively, leading to progressive renal failure, hypertrophic cardiomyopathy, cardiac arrhythmia, and premature cerebral infarction. The method of choice for confirming the diagnosis is the determination of reduced α-galactosidase A activity in leukocytes in male individuals and the molecular genetic detection of a disease-causing mutation in female individuals. Current approved treatment includes enzyme replacement therapy (agalsidase alfa [0.2 mg/kg body weight], agalsidase beta or pegunigalsidase alfa [both 1.0 mg/kg body weight]) every other week intravenously or, if a responding ('amenable') α-galactosidase A mutation is present, oral pharmacological chaperone therapy (migalastat 123 mg, every other day). Future therapeutic options may include substrate reduction therapy, gene therapy, messenger RNA therapy, and/or vesicle-packaged enzyme replacement therapy. This review presents current and future treatment options with advantages and disadvantages of the different treatment options.

Background: Recombinant immunoglobulin G2 (IgG2) antibodies are effective neutralization agents or antagonists with high medical value because of their high specificity, long half-life, and absent effector functions. During biopharmaceutical process development, charge heterogeneity and bioactivity alternation related to charge variation should be investigated to understand the structure-activity relationship (SAR) in therapeutic antibodies. Isoelectric focusing can provide fine resolution for the charge heterogeneity profiling of IgG2, while ion exchange chromatography cannot achieve effective separation of IgG2 charge variants. In-depth investigation of charge heterogeneity requires a fractionation tool to enrich and isolate acidic and basic variants.

Objectives: This study aims to investigate the structural origins and functional implications of charge heterogeneity in two therapeutic IgG2 antibodies, including an anti-receptor activator of nuclear factor κ-B ligand (RANKL) biosimilar of denosumab and an innovative anti-CD73 IgG2 (H-mab), using free-flow isoelectric focusing (FF-IEF).

Methods: Charge variants of denosumab and H-mab were fractionated using FF-IEF, followed by characterization of isolated IgG2 charge variants to establish the SAR between charge-related antibody modifications and bioactivities. The investigation incorporated in silico 3D modeling of the FcRn-IgG2 Fc complex and the CD73-Fab complex to facilitate the SAR interrogation of these two IgG2s.

Results: The acidic charge variants of denosumab were driven primarily by N-glycan sialylation and deamidation in the Fc region, showing negligible effects on biological functions except for a reproducible reduction in FcRn binding affinity. In contrast, the basic charge variants of H-mab were associated with D₉₉-succinimide formation in the heavy chain complementarity-determining region 3 (CDR3), significantly impairing binding and enzymatic inhibition activities.

Conclusions: This study underscores the irreplaceable role of FF-IEF in both biosimilar and innovative therapeutic pipelines, highlighting the importance of monitoring charge heterogeneity and understanding SAR in therapeutic IgG2 antibodies.

Background: Promoting the use of biosimilars is a global issue from the perspective of reducing medical costs. In Japan, the replacement of original biopharmaceuticals with biosimilars has not progressed as expected. To promote the use of biosimilar monoclonal antibodies, it is necessary to increase the public's understanding of biosimilars by evaluating and confirming the quality of biosimilar products. However, there are limited data to compare among multiple biosimilars and/or the reference, and among their product lots.

Objective: In this study, we evaluated quality attributes of multiple lots of reference products and their biosimilars to determine the extent of distribution in quality attributes between products as well as the quality consistencies from lot to lot.

Methods: As the quality attributes, the glycosylation profile, charge heterogeneity, binding affinity for the antigen and Fcγ receptors, and high-molecular-weight species and subvisible particles were measured.

Results: The degree of similarity in quality attributes with a reference product was different for each biosimilar product. We confirmed the differences between reference and biosimilar product reported in previous articles or review reports, and that some quality attributes of biosimilars were out of the quality ranges of reference products. Although lot-to-lot variations and trends at some degrees were observed for some products, no clear drifts among lots were observed.

Conclusion: Analyzing several lots of these products enabled us to capture a profile of quality characteristics for each product. Overall, the extent of variability of each quality attribute among reference products and biosimilars was revealed by this study for the first time.

Osteoarthritis is a prevalent condition among middle-aged and elderly populations characterized primarily by the progressive degeneration of articular cartilage. Despite advances in medical technology, the complexity of osteoarthritis pathogenesis presents significant challenges in halting or reversing cartilage degradation. Recently, mesenchymal stem cells and their secretome have emerged as promising regenerative therapies for osteoarthritis. Mesenchymal stem cells not only differentiate into chondrocytes to repair cartilage defects but also maintain chondrocyte homeostasis by interacting with existing chondrocytes and modulating synovial inflammation. Additionally, the proteins and bioactive molecules contained within the mesenchymal stem cell secretome offer multifaceted therapeutic benefits. However, challenges such as the limited survival and integration of transplanted mesenchymal stem cells, potential for unwanted differentiation, and variable efficacy of the secretome persist. Hydrogels, which mimic the chemical and mechanical properties of the extracellular matrix, are frequently utilized as carriers for mesenchymal stem cells and their secretome in osteoarthritis treatments. This review explores the current applications of mesenchymal stem cells and their secretome in osteoarthritis therapy, proposing innovative strategies to overcome these existing treatment limitations.

Ten adalimumab biosimilars have been introduced in the United States (USA) since 2023, while adalimumab biosimilars have been available for several years in other countries. These experiences of biosimilar uptake outside the USA can inform US-based healthcare professionals on switching in real-life practice settings. Considerations include how healthcare professionals might meaningfully address patient concerns about outcomes to improve patient satisfaction. A search of the MEDLINE database was used to identify publications on switching to and among adalimumab biosimilars in an ex-US setting, with no restriction on publication language and using a time frame of 1 January 2017 through 12 December 2023, coinciding with the European Union approval of the first adalimumab biosimilar, adalimumab-atto, in March 2017. This narrative review aims to provide insights into the efficacy and safety of transitioning to and among adalimumab biosimilars in adult patients from clinical studies but also, more importantly, using real-world evidence (RWE) from outside the USA. Overall, RWE suggested that efficacy and outcomes were consistent in patients who underwent switching from the reference product (RP) across various immune-mediated inflammatory diseases when compared to patients who did not switch from the RP. The ex-US RWE of RP and biosimilar adalimumab switches generally reflected the experiences observed in clinical trials; however, RWE findings elucidated several challenges to biosimilar uptake, including patient education, provider training, and supportive policies.