Delivering on the Promise of Biosimilars Abstract Fifteen years of experience with biosimilar evaluation in Europe and advancement in the science behind biological medicines, provides a timely moment to open up debate as to whether the requirements for biosimilar approval could be further tailored. Further optimizing of data requirements to truly decisional information will allow to continuously deliver on the promise of biosimilars, providing benefits for patients and society.

Analysis of Immunogenicity Data in the Product Information of Biological Drugs: A Need to Report Immunogenicity Data Systematically Abstract Objective The aim of this analysis was to evaluate whether the current unsystematic assessment leads to sufficient reporting of immunogenicity-related information in the Summary of Product Characteristics (SmPCs) of biological products approved in the European market. Methods Immunogenicity-related information was identified and extracted from a group of 72 biological drugs that complied with drug-selection criteria. Afterwards, 12 dichotomous questions were proposed to evaluate whether any issues are being commonly neglected. Results Most SmPCs (92%) do not have any recommendations on how to report immunogenicity-related adverse drug reactions by patients or healthcare professionals. Furthermore, 80% of SmPCs do not identify the assay used to assess the reported immunogenicity rates, while 81% do not address the possible impact of immunogenicity on their drug’s pharmacokinetics. It was also identified that a group factor (i.e. older drugs’ SmPCs) could be influencing how/which issues were being addressed by newer drugs’ SmPCs. To transform SmPCs into useful tools when an immunogenic response occurs, a proposal on how to report immunogenicity-related information in the SmPCs of biological products is advanced. This decision tree should contribute towards increasing the quality and transparency of the immunogenicity-related information being reported in the SmPCs, thus leading to better informed medical decisions. Conclusions Based on these results, an unsystematic assessment does not yield enough reporting across products and thus immunogenicity-related information should be reported in a systematic way. Further guidance about reporting immunogenicity-related information is required, otherwise SmPCs will not be the basis of information for healthcare professionals on how to use a biological product safely and effectively.

In Search of Predictors of Switching Between Erythropoiesis-Stimulating Agents in Clinical Practice: A Multi-Regional Cohort Study Abstract Background and objectives Switching between different erythropoiesis-stimulating agents (ESAs) during the first year of therapy is frequent (15–20%), much more so toward reference products than biosimilars. The objectives of this study were to investigate the frequency and identify the potential predictors of switching between biosimilar and originator ESAs during the first year of treatment in patients with chronic kidney disease (CKD), or chemotherapy-related anemia from six large Italian geographic areas in the years 2009–2015. Methods A retrospective cohort study was conducted using six Italian regional claims databases (≥ 13 million inhabitants) during 2009–2015. Among incident epoetin users, the frequency of single, multiple, and backward switch during the first year of treatment was evaluated. Using frailty Cox models, potential predictors of first switch were identified. All analyses were stratified by the main indications for use. Results Among 102,240 incident epoetin users, 15,853 (15.5%) switched to another epoetin during the first year of therapy; only 18% of these switched to biosimilars. Single switch was more common (62.2% of the switchers) than multiple (23.5%) or backward switch (14.3%). In cancer, the cumulative number of transfusions and iron preparations dispensed, as well as hyperparathyroidism, were predictors of switching. In CKD, the cumulative number of transfusions, number of vitamin A/D preparations dispensed, and CKD severity increased the probability of switching. Conclusions Switching between ESAs was frequent in both CKD and cancer patients. The number of cumulative transfusions and severity of disease seemed to affect the switch.

Comparative Physicochemical and Biological Characterisation of the Similar Biological Medicinal Product Teriparatide and Its Reference Medicinal Product Abstract Background In January 2017, the European Commission approved Terrosa® (company code RGB-10) as one of the first biosimilar medicinal products of teriparatide for the same indications as for the reference medicinal product Forsteo® (Lilly France S.A.S.), which has been on the market in the European Union since 2003. The active pharmaceutical ingredient of the reference medicinal product is the biologically active 1-34 fragment of the endogenous human parathyroid hormone [PTH(1-34)]. It is one of the three bone anabolic agents used in the treatment of osteoporosis promoting bone formation and preventing fragility fractures. Objective The objective of this paper is to summarise the results of the comparative analysis of representative batches of both the RGB-10 drug product and the reference medicinal product performed by physicochemical and in vitro biological methods. Methods A series of state-of-the-art analytical methods were applied in a comparative head-to-head manner for testing the similarity in respect to purity, content, structure and potency. Results Based on the results of the comprehensive physicochemical and biological characterisation, RGB-10 proved to be highly similar to the reference medicinal product with respect to the critical quality attributes investigated. Conclusion The results of the quality comparability study demonstrated similarity of RGB-10 to the reference medicinal product, providing the scientific basis for conducting a specifically designed clinical programme, and supported registration of the Marketing Authorisation Application of RGB-10 in the EU.

Correction to: Efficacy and Safety of Supportive Care Biosimilars Among Cancer Patients: A Systematic Review and Meta‑Analysis The authors unintentionally included in the meta-analysis both the initial abstract and the final paper of the study by Puertolas et al. [45, 48]. In order to remove this duplication, the following corrections are required.

Comment on: “Efficacy and Safety of Supportive Care Biosimilars Among Cancer Patients: A Systematic Review and Meta-Analysis”

Author’s Reply to Puértolas-Tena and Pérez-Surio: “Efficacy and Safety of Supportive Care Biosimilars Among Cancer Patients: A Systematic Review and Meta-Analysis”

Comment on “Analysis of Pharmacokinetic and Pharmacodynamic Parameters in EU-Versus US-Licensed Reference Biological Products: Are In Vivo Bridging Studies Justified for Biosimilar Development?”

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer Abstract MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the ‘undruggable’ may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

Factors Influencing Drug Disposition of Monoclonal Antibodies in Inflammatory Bowel Disease: Implications for Personalized Medicine Abstract Monoclonal antibody (mAb) therapies have revolutionized the treatment of several chronic inflammatory diseases, including the inflammatory bowel diseases (IBD), Crohn’s disease, and ulcerative colitis. While efficacious, responses to these therapies vary considerably from patient to patient, due in part to inter- and intra-individual variability in pharmacokinetics (PK) and drug exposure. The concept of personalized medicine to monitor drug exposure and to adjust dosing in individual patients is consequently gaining acceptance as a powerful tool to optimize mAb therapy for improved outcomes in IBD. This review provides a brief overview of the different mAbs currently approved or in development for the treatment of IBD, including their presumed mechanisms of action and PK properties. Specifically described are (1) the factors known to affect mAb PK and drug exposure in patients with IBD, (2) the value of population PK/pharmacodynamic (PD) modeling to identify and understand the influence of these factors on drug exposure and effect, and (3) the clinical evidence for the potential of therapeutic drug monitoring (TDM) to improve IBD outcomes in response to mAb-based therapy. Incorporation of PK/PD parameters into clinical decision support tools has the potential to guide therapeutic decision making and aid implementation of personalized medicine strategies in patients with IBD.