Biosimilars: An Opportunity to Update the Product Information of Biological Drugs Regarding their Immunogenicity

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.

Extrapolation in Practice: Lessons from 10 Years with Biosimilar Filgrastim Abstract Biosimilar filgrastim (Sandoz) was approved in Europe in 2009 and, in 2015, was the first biosimilar approved in the USA. These authorizations were based on the “totality of evidence” concept, an approach that considers data from structural and functional characterization and comparability analysis and non-clinical and clinical studies. For biosimilar filgrastim, phase III confirmatory clinical studies were performed in the most sensitive population, patients with breast cancer undergoing myelosuppressive chemotherapy. In Europe and the USA, approval was granted for all indications of the reference biologic. Hence, stem cell mobilization and severe chronic neutropenia indications were approved on the basis of extrapolation, with no clinical data available at the time of market authorization in the EU. Although extrapolation is well-accepted in biologic development and regulatory contexts, it remains a misunderstood part of the biosimilarity concept in the medical community. Since approval, more than a decade of obtained clinical experience supports the totality of evidence and reassures clinicians regarding the efficacy and safety of biosimilar filgrastim. This includes real-world data from MONITOR-GCSF, a multicenter, prospective, observational study describing treatment patterns and clinical outcomes of patients with cancer (n = 1447) receiving biosimilar filgrastim for the prophylaxis of chemotherapy-induced neutropenia in solid tumors and hematological malignancies. Evidence is also available from unrelated healthy donors and those with severe chronic neutropenia. Together, the experience from a decade of use of biosimilar filgrastim includes over 24 million patient-days of exposure, which can help reassure oncologists that extrapolation is based on strong scientific evidence and works in practice.

Steady-State Plasma Concentrations of Polyethylene Glycol (PEG) are Reached in Children and Adults During Once-Weekly Prophylactic Treatment with Nonacog Beta Pegol (N9-GP) Abstract Background Nonacog beta pegol (N9-GP, Refixia®, Rebinyn®) is a human recombinant coagulation factor IX (rFIX) conjugated to a 40-kDa polyethylene glycol (PEG) moiety. PEGylation significantly prolongs the circulation half-life compared with conventional FIX replacement treatments, resulting in higher FIX levels. Although there is extensive clinical experience with PEGylated molecules, the potential for abnormal and/or indefinite PEG accumulation during long-term treatment and the hypothetical impact on long-term safety is still under discussion. Aim The aim of this study was to examine plasma PEG concentrations in children, adolescents and adults undergoing once-weekly intravenous prophylactic treatment with N9-GP for up to 6.5 years. Methods Plasma samples were collected as part of the PARADIGM clinical development programme (PARADIGM 2/4 [NCT01333111 and NCT01395810] and PARADIGM 5 [NCT01467427]). Proton nuclear magnetic resonance (1H-NMR) was used to measure plasma PEG concentrations. Results Steady-state plasma PEG concentrations were reached approximately 6 months after initiation of weekly prophylactic treatment with 40 IU/kg N9-GP. Mean steady-state plasma PEG concentrations were 5.6 μg/mL in children ≤ 12 years old at enrolment (PARADIGM 5) and 5.3 μg/mL in adolescents/adults > 12 years old (PARADIGM 2/4). Plasma PEG concentrations tended to be lower in younger children < 7 years old (mean 4.6 μg/mL). There was a correlation between plasma PEG and FIX activity levels in all age groups. Conclusion PEG steady-state plasma levels were maintained for up to 6.5 years during continuous prophylactic treatment and PEG levels correlated with FIX activity. Apart from the initial increase to steady state, no further systemic PEG accumulation was observed.

An Efficient Development Paradigm for Biosimilars Abstract The current development paradigm for biosimilars required by regulators in highly regulated jurisdictions is derived from the development of novel drugs and is unnecessarily burdensome and inefficient. It requires the accumulation of data from analytical, nonclinical (including in vivo studies in some jurisdictions), and clinical studies (including powered efficacy studies in most cases); this paradigm is known as ‘totality of evidence’ (ToE) and does not admit a conclusion of biosimilarity from analytical data alone. The record of biosimilar approvals in these jurisdictions shows that no biosimilar candidate that has been found highly similar to its reference in analytical and pharmacokinetic studies has failed to be approved. We propose a new paradigm (‘confirmation of sufficient likeness’, CSL) that emphasizes the demonstration of analytical resemblance between the biosimilar candidate and its reference, and permits the conclusion of biosimilarity upon this basis. CSL does not entail bridging studies between reference products, in vivo nonclinical studies, or powered efficacy studies and is, therefore, substantially more efficient than ToE while maintaining equivalent scientific rigor. Such efficiency will contribute to the attractiveness as well as the sustainability of biosimilars as a therapeutic modality.

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.

Assessment of the Molecular Mechanism of Action of SB3, a Trastuzumab Biosimilar Abstract Background SB3, a biosimilar of Herceptin® (trastuzumab, hereinafter referred to as reference product) is currently approved in the EU, Korea, Australia, the USA, and Brazil for the treatment of human epidermal growth factor receptor (HER) 2-positive early and metastatic breast cancer and HER2-positive metastatic gastric cancer. Previously, the biological similarity of SB3 to EU- or US-sourced reference product was assessed using various cell-based and binding assays. Objective In this paper, as a part of its similarity assessment, SB3 was evaluated for additional characteristics related to its molecular mechanism of action (MoA). Methods For extracellular effects of SB3, HER2-overexpressing cancer cell lines were used to assess expression of surface HER2, shedding of the extracellular domain of HER2, and antibody-dependent cell-mediated phagocytosis (ADCP) activity. For intracellular effects, Akt phosphorylation and vascular endothelial growth factor (VEGF) release were assessed. Additionally, in vitro docetaxel or pertuzumab combination experiments were performed for further characterization; anti-proliferation, HER2/HER3 dimerization inhibition, apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC) assays were used. Results It was confirmed that SB3 is highly similar to the reference products on quality attributes related to extracellular/intracellular efficacy. This similarity was also confirmed during combination studies with docetaxel and pertuzumab. Conclusion Overall, the equivalence of SB3 with reference product in MoA-related qualities in in vitro mono- and combination therapy experiments may support clinical bioequivalence of the two substances.

Evolution of the EU Biosimilar Framework: Past and Future Abstract The approval of biosimilars in the EU follows a comprehensive scientific assessment based on stringent regulatory standards. While the initial approach to biosimilars was understandably cautious and conservative in that uncharted territory to protect patients’ safety, the analytical and scientific progress and accumulated experience with biosimilars continues to reshape regulatory requirements, generally leading to a reduced burden of clinical trials. This trend is expected to continue, for example, by increasingly employing pharmacodynamic endpoints and biomarkers, but much work remains to make this happen, especially for complex molecules with several or unknown mechanisms of action. We reviewed the available guidance and European Public Assessment Reports (EPARs) of biosimilars approved in the EU via the centralised procedure. This review focuses on the nature and extent of clinical confirmation of biosimilarity considered necessary in addition to analytical and functional data. Cases with conflicting results from different parts of the comparability exercise are discussed, with the aim of identifying whether certain elements of the comparability exercise are more important than others in determining biosimilarity. Taken together, analytical and functional comparison is the foundation of any biosimilar development. In addition, pharmacokinetic similarity is an indispensable prerequisite for any biosimilar approval, so careful planning on behalf of the applicant is mandated to avoid potential failure of such studies, for example, because of large interindividual variability, underpowered trial designs or other methodological causes. Comparative pharmacokinetic studies are a basic requirement for biosimilar development and are usually more sensitive than clinical efficacy trials when detecting potential product-related differences. This may explain why a demonstration of equivalent efficacy could not overrule a finding of dissimilar pharmacokinetic profiles in two cases of biosimilar pegfilgrastim. However, the outcome of efficacy trials depends not only on drug exposure but also on proper pharmacological action of the biological substance in vivo. Therefore, the objectives of both types of studies differ. Efficacy trials should usually be designed as equivalence trials to ensure that the efficacy of the biosimilar is neither decreased nor increased compared with the reference product. However, some remaining uncertainty regarding potentially increased efficacy of the biosimilar may be acceptable in exceptional cases, provided that the data from other parts of the comparability exercise clearly support a conclusion of biosimilarity and safety is assured. In contrast, uncertainties regarding potentially inferior efficacy of the biosimilar may not be acceptable at all. We conclude that the EU biosimilar regulatory framework is robust and able to adapt to advancing knowledge and experience and to strike a balance between regulatory standards, patient safety and feasibility of biosimilar development.

CAR-T Engineering: Optimizing Signal Transduction and Effector Mechanisms Abstract The adoptive transfer of genetically engineered T cells expressing a chimeric antigen receptor (CAR) has shown remarkable results against B cell malignancies. This immunotherapeutic approach has advanced and expanded rapidly from preclinical models to the recent approval of CAR-T cells to treat lymphomas and leukemia by the Food and Drug Administration (FDA). Ongoing research efforts are focused on employing CAR-T cells as a therapy for other cancers, and enhancing their efficacy and safety by optimizing their design. Here we summarize modifications in the intracellular domain of the CAR that gave rise to first-, second-, third- and next-generation CAR-T cells, together with the impact that these different designs have on CAR-T cell biology and function. Further, we describe how the structure of the antigen-sensing ectodomain can be enhanced, leading to superior CAR-T cell signaling and/or function. Finally we discuss how tissue-specific factors may impact the clinical efficacy of CAR-T cells for bone and the central nervous system, as examples of specific indications that may require further CAR signaling optimization to perform in such inhospitable microenvironments.