Rituximab biosimilars for lymphoma in Europe

ABSTRACT

Introduction: The approval of rituximab, a monoclonal antibody targeting CD20, revolutionized the treatment of B-cell non-Hodgkin lymphomas and became an undisputed standard of care. However, as with all biologic medicines, the complex development and manufacturing process for rituximab have meant that the medicine attracts high treatment costs. Approved rituximab biosimilars have been comprehensively demonstrated to match the reference medicine. With the potential to increase access to biologic therapy, they have a key role in helping to improve patient outcomes in lymphoma care.

Areas covered: In this review, we discuss the role of rituximab in the treatment of lymphoma. We explore development and regulatory requirements for biosimilar development and the potential impact of these medicines on access and sustainability. Focusing on biosimilars of rituximab, we examine in detail the evidence for biosimilarity for the two rituximab biosimilars that are approved in Europe and provide an overview of rituximab biosimilars currently in development.

Expert opinion: We foresee a wider uptake of biosimilar medicines for lymphoma treatment over the next 5 years. The associated cost savings should be invested in broadening patient access to biological therapies, enabling wider use of more expensive treatment strategies and driving innovation in cancer care.     

Biosimilars: Review of current applications,obstacles, and their future in medicine

Biosimilars are a growing drug class designed to be used interchangeably with biologics. Biologics are created in living cells and are typically large, complex proteins that may have a variety of uses. Within the field of gastroenterology alone, biologics are used to treat inflammatory bowel diseases, cancers, and endocrine disorders. While biologics have proven to be effective in treating or managing many diseases, patient access is often limited by high costs. The development of biosimilars is an attempt to reduce treatment costs. Biosimilars must be nearly identical to their reference biologics in terms of efficacy, side effect risk profile, and immunogenicity. Although the manufacturing process still involves production within living cells, biosimilars undergo fewer clinical trials than do their reference biologics. This ultimately reduces the cost of production and the cost of the biosimilar drug compared to its reference biologic. Currently, seven biosimilars have been approved by the United States Food and Drug Administration (FDA) for use in Crohn’s disease, ulcerative colitis, and colorectal cancer. There are other biologics involved in treating gastroenterologic diseases for which there are no FDA approved biosimilars. Although biosimilars have the potential to reduce healthcare costs in chronic disease management, they face challenges in establishing a significant market share. Physician comfort in prescribing reference biologics instead of biosimilars and patient reluctance to switch from a biologic to a biosimilar are two common contributing factors to biosimilars’ slow increase in use. More time will be needed for biosimilars to establish a larger and more consistent market share compared to their reference biologics. Additional data confirming the safety and efficacy of biosimilars, increased number of available biosimilars, and further cost reduction of biosimilars will all be necessary to improve physician confidence in biosimilars and patient comfort with biosimilars.     

Epoetin Biosimilars in Europe: Five Years On

Biosimilars have been developed for several biologic therapeutic agents, including erythropoiesis-stimulating agents (ESAs). However, biosimilars cannot be assumed to be completely identical to the reference product, nor can two different biosimilars of the same reference product be considered equivalent. Accordingly, standards for approving biosimilars are distinct from those for generic versions of conventional pharmaceuticals. By late 2007, two biosimilar epoetins (HX575 and SB309) had been approved by the European Medicines Agency (EMA), following a series of pharmacokinetic and pharmacodynamic equivalence studies, as well as phase 3 clinical comparability evaluations. Additionally, the results of a limited number of postauthorization interventional or observational studies and quality comparisons were published subsequently on both products. The reported differences in glycosylation profiles between these epoetin biosimilars and their reference product, as well as the lack of long-term safety and efficacy evaluation, could indicate a need to develop a more comprehensive analysis of the available data, and to evaluate the post-authorization real-life data, in order to gain a better understanding of any potential implications of molecular structural or formulation differences on longterm safety and effectiveness. Switching between an original reference ESA and a biosimilar (and possibly also switching between biosimilar versions of the same product) should be regarded as a change in clinical management. Clinicians need to be fully involved in such decisions. Prescribing by brand name will prevent unintentional substitution by pharmacists and allow for effective pharmacovigilance, in accordance with recent EU directives. In this review, the authors have analyzed most of the published information on the two epoetin biosimilars, HX575 and SB309, to highlight the points that healthcare providers may need to consider when assessing an epoetin biosimilar.     

Is there a reason for concern or is it just hype? – A systematic literature review of the clinical consequences of switching from originator biologics to biosimilars

Introduction: While prescribing biosimilars to patients naive to a biologic treatment is a well-accepted practice, switching clinically stable patients from an originator to a biosimilar is an issue for clinicians. Well-designed clinical trials and real-world data which study the consequences of switching from an originator biologic treatment to its biosimilar alternative are limited, especially for monoclonal antibodies.

Areas covered: A systematic literature review was conducted on PubMed to identify evidence of the consequences of switching from original biologics to biosimilars. References of included papers were also scrutinized. After a title-, abstract- and full text screening, out of the 153 original hits and 77 additional ones from screening the references, 58 papers (12 empirical papers, 5 systematic reviews and 41 non-empirical papers) were included.

Expert opinion: Preventing patients on biologic medicines from switching to biosimilars due to anticipated risks seems to be disproportional compared to the expected cost savings and/or improved patient access. Indeed, it is the opinion of the authors that the concern of switching to biosimilars is overhyped.     

Pharmacovigilance and biosimilars: considerations,needs and challenges

Introduction: Biosimilars are biologic medicines that are highly similar to approved biologics, notwithstanding minor differences in clinically inactive components. Since 2007, biosimilars have been approved for use in patients in the European Union (EU) and other regions. European experience provides several lessons as the United States (US) healthcare system prepares for biosimilar approvals. These lessons emphasize the need for adequate efficacy and safety studies, post-marketing surveys and a robust pharmacovigilance system that can accurately track and trace biologics, including biosimilars and their reference products, from the patient to the manufacturer.

Areas covered: We review the EU experience with biosimilar pharmacovigilance and discuss the implications for biosimilar pharmacovigilance in the USA. Furthermore, we review several aspects of biosimilar pharmacovigilance, including cohort event monitoring, traceability, biosimilar interchangeability, pharmacovigilance system development, nomenclature and counterfeit tracking.

Expert opinion: The availability of biosimilars as lower-cost biologics must carefully consider issues of safety, efficacy and traceability. Stringent pharmacovigilance procedures are required to detect potential differences in safety signals between biosimilars and their reference products. Pharmacovigilance of biologics should include processes that are easily used by prescribing practitioners to ensure that data are consistent and new safety signals are properly reported and assigned to the correct product.     

To See or NOsee: The Debate on the Nocebo Effect and Optimizing the Use of Biosimilars

Abstract

In addition to the general clinical benefit offered, biosimilars may not only generate savings for healthcare budgets but also improve patient access to biologic products. Since the first biosimilar was approved in Europe in 2006, a further 36 different biosimilar drugs have been approved for several indications. Despite the wealth of experience gained and the reported data supporting the use of biosimilars, both in naïve and biologic-experienced patients, some healthcare professionals continue to express doubt regarding the rigorous approval process for biosimilars and uncertainty with how to incorporate them into daily clinical practice. These opinions can be transferred to patients through poor or lack of communication, meaning that patients may lack confidence in treatment quality and, as a result, be susceptible to the nocebo effect. At the 2017 American College of Rheumatology/Association of Rheumatology Health Professionals annual meeting, during a debate the question was asked as to whether the nocebo effect was in fact being used to describe “any result you don’t agree with”. Here, we detail that the nocebo effect has been demonstrated in a number of clinical trials, and that this effect may negatively affect acceptance in patients switching from an originator product to a biosimilar. Awareness of the potential for the nocebo effect and adoption of enhanced communication techniques may be useful in mitigating the nocebo effect. Effective healthcare professional–patient dialogue is key in transferring confidence to the patient, and has been shown to reduce nocebo effects in patients when switching from an originator to a biosimilar.

Funding

Biogen International GmbH.

     

Biosimilars for breast cancer

ABSTRACT

Introduction: Cancer treatment has evolved significantly with the introduction of biologic agents, especially in the breast cancer (BC) area. The use of trastuzumab for HER2 amplified BCsignificantly improves survival in both metastatic and early stage disease. Although the efficacy of biologics is undeniable, their high costs increased the expenses of cancer care, becoming a problem to health-care systems, mainly in low and middle-income, but also for high-income countries. In an attempt to lower the costs and allow a greater access of biologics to cancer patients, biosimilars are rapidly being developed as an alternative to the reference biologics.

Areas covered: A literature review based on the MEDLINE/PubMed search about biosimilars allied with the FDA and EMA’s latest statements of this topic were conducted to summarize the development and the use of currently available biosimilars for BC, with a focus on trastuzumab.

Expert opinion: Biosimilars are drugs that have similar efficacy and safety profile to those of the original biological product with equivalent immunogenicity and, as these agents hold the potential to improve patient´s access to monoclonal antibodies because their production costs are estimated to be 20–30% lower compared to the reference product, they are progressively being incorporated into clinical practice.     

Management of the patient receiving parenteral biologic therapy.

Biologic therapies are becoming the preferred treatment option for many complex medical conditions, especially in the areas of oncology and immunology. Cytokines, monoclonal antibodies, and immunomodulators all have their own specific roles, clinical applications, mechanisms of action, and side effects. As newer biologic agents are approved and used for treatment, the nurse involved in the care of the patient receiving parenteral biologic therapy or in the administration of parenteral biologic therapies must know and understand the technology and mechanisms of action associated with these agents as well as guidelines for their safe administration to ensure positive patient outcomes. This article discusses biologic therapies, focusing on monoclonal antibodies used in oncology and immunology. The indications, use, and administration of parenteral biologic therapies, as well as the nursing management of the patients receiving the therapies, are presented.     

Biosimilar recombinant human erythropoietins ("epoetins") and future erythropoiesis-stimulating treatments

INTRODUCTION: Recombinant human erythropoietin (rhEPO, epoetin) has prospered in the treatment of renal and chemotherapy-associated anemias. Since the patents of the original epoetins expired, biosimilars have been launched. Because these are not fully identical to the original products, non-clinical and clinical studies are necessary to show similarity with respect to quality, safety, and efficacy. AREAS COVERED: The article summarizes experiences with EU-approved biosimilar epoetins. In particular, the issue of immunogenicity is considered. Neutralizing anti-EPO antibodies can cause pure red cell aplasia (PRCA). Further, a first view is offered on future erythropoiesis-stimulating therapies. EXPERT OPINION: The term "biosimilar" should only be used for follow-on biopharmaceuticals approved under a defined regulatory pathway. The primary rationale for the therapy with biosimilars is cost saving. Two biosimilar epoetins are available in the EU that are used at the same dose(s) and dosing regimen(s) for indications of the reference product. Their advent has stimulated innovator companies to develop second-generation products with improved pharmacokinetic properties. EPO-mimicking peptides are a new therapeutic option. Other strategies focus on orally active chemical drugs that induce endogenous EPO production ("HIF stabilizers"). Epo gene transfer is also possible, but needs to be further explored with respect to efficacy and safety.     

The Role of the Laboratory and Transfusion Service in the Management of Ebola Virus Disease

The Ebola outbreak that began in 2013 infected and killed record numbers of individuals and created unprecedented challenges, including containment and treatment of the virus in resource-strained West Africa as well as the repatriation and treatment for patients in the United States and Europe. Valuable lessons were learned, especially the important role that the laboratory and transfusion service plays in the treatment for patients with Ebola virus disease (EVD) by providing data for supportive care and fluid resuscitation as well as the generation of investigational therapies such as convalescent plasma (CP). To provide treatment support, laboratories had to evaluate and update procedures to ensure the safety of laboratory personnel. Because there is no licensed EVD-specific treatment, CP was used in more than 99 patients with only 1 possible severe adverse event reported. However, given the biologic variability inherent in CP as well as the small number of patient treated in a nonrandomized fashion, the efficacy of CP in the treatment of EVD remains unknown.     

Biosimilars of adalimumab: the upcoming challenge in IBD

ABSTRACT

Introduction: Biosimilars represent great potential in cost saving and re-investment opportunities in healthcare and allow patients greater access to effective mAbs. Infliximab biosimilars are successfully used in all indications for whom the reference product (RP) was approved.

Areas covered: In late 2018, adalimumab biosimilars will also be available in patients with inflammatory bowel disease (IBD).

ABP501, BI 695501, GP2017, and SB5 have been approved by the EMA for the same indications of the reference product (RP, Humira®). Preclinical data show high similarity between all biosimilars and the RP. Clinical data in patients with rheumatoid arthritis and psoriasis also show no differences in terms of efficacy, safety, and immunogenicity. Data in IBD patients are still lacking.

Expert opinion: Biosimilars of adalimumab appear to be clinically equivalent to the RP. Decisions based on choosing the ideal patient to receive or to be switched to a biosimilar of adalimumab, or choosing one biosimilar vs. another, or cross-switching among biosimilars remain the next challenge in the field of IBD.     

ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer

Introduction: Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies.

Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016–2017 ASCO and ESMO conference proceedings for ‘ABP 980’ or ‘trastuzumab biosimilar’. ‘ABP 980 and breast cancer’ or ‘trastuzumab biosimilar and breast cancer’ were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included.

Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.     

Immunological risk factors for infection after immunosuppressive and biologic therapies

Immunosuppressive and biologic therapies are costly and can involve a considerable risk of infection. Noninvasive diagnostic tools for early prediction of infection before and after administration of these therapies are of major interest. Serial longitudinal immune monitoring would provide data on immunocompetence and complement clinical follow-up protocols. Biomarkers of immune response may be useful to identify patients at risk of developing infection and who could be candidates for immunosuppressant dose reduction. This article focuses on the potential use of biomarkers of immune response to predict development of infection after immunosuppressive and biologic therapies in selected settings of autoimmune disease (rituximab for treatment of rheumatoid arthritis) and solid organ transplantation.     

风湿免疫病生物制剂治疗进展

生物制剂是一种选择性针对参与免疫反应或炎症过程的分子或以受体为靶目标的单克隆抗体或天然抑 制分子的重组产物。生物制剂种类繁多,主要针对细胞因子,B细胞和共刺激信号分子,包括:肿瘤坏死因子抑制剂、 抗白细胞介素6(IL-6)受体单克隆抗体和抗CD20单克隆抗体利妥昔单抗等多种药物,主要用于治疗强直性脊柱炎、 类风湿关节炎和系统性红斑狼疮等自身免疫性疾病。生物制剂的使用应关注其安全性,用药前进行结核筛查,除外活 动性感染和肿瘤。生物制剂的减停药问题有待探讨。     

Therapeutic vaccines in metastatic castration-resistant prostate cancer: principles in clinical trial design

Although docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer in 2004, additional therapies are still required. Prostate cancer is often slow-growing and expresses many tumor-associated antigens, making it a feasible target for immunotherapy. Several therapeutic cancer vaccines have been developed for prostate cancer, including antigen-presenting-cell-based, vector-based, and whole tumor cell vaccines. Initial trials demonstrated that vaccine approaches have limited toxicity. Clinical trials of targeted biologic therapies have demonstrated that patient selection is vital, and there is preliminary evidence that clinical parameters can be used to encompass metastatic prostate cancer patients who will more probably respond to vaccine treatment. In addition to appropriate patient selection, a successful clinical trial must have an appropriate primary endpoint as well. Three randomized, ‘placebo’-controlled studies in metastatic castration-resistant prostate cancer have suggested a clinically significant survival advantage in spite of a lack of improvement in time to progression, implying that overall survival is the ideal endpoint for such trials. Careful examination of data from completed immunotherapy clinical trials in prostate cancer has identified appropriate patient populations and endpoints. Those principles need to be applied to future trial design to properly evaluate prostate cancer vaccines.     

The state of the art in the development of biosimilars

The development of biologic therapeutics using advanced technology to copy and improve on nature's design of complex peptides, proteins, and glycoproteins has enabled the treatment of diseases in entirely new ways and brought unique and lifesaving treatments to many people. However, at least in part because of cost pressures, access to these truly amazing products has not been uniformly available; many patients do not qualify for these treatments, or the treatment is postponed until disabilities accumulate. The development of biosimilars--essentially copies of the original biologic drugs after patent expiration--allows for wider and, as important, earlier access to these agents because of their lower cost and consequently greater affordability. The development and commercialization of biosimilars can help address unmet medical needs by improving access to well-established therapeutic interventions while improving health-care affordability.     

Biosimilars: from Technical to Pharmacoeconomic Considerations

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.     

Biosimilar granulocyte–colony‐stimulating factor for healthy donor stem cell mobilization: need we be afraid?

Biosimilars are approved biologics with comparable quality, safety, and efficacy to a reference product. Unlike generics, which are chemically manufactured copies of small‐molecule drugs with relatively simple chemical structures, the biosimilar designation is applied to drugs that are produced by living organisms, implying much more difficult to control manufacturing and purification procedures. To account for these complexities, the European Medicines Agency (EMA), the US Food and Drug Administration, the Australian Therapeutic Goods Administration, and other regulatory authorities have devised and implemented specific, markedly more demanding pathways for the evaluation and approval of biosimilars. To date, several biosimilars have been approved, including versions of somatropin, erythropoietin, and granulocyte–colony‐stimulating factor (G‐CSF), and several biosimilar monoclonal antibodies are currently in development. The reference G‐CSF product (Neupogen, Amgen) has been used for many years for prevention and treatment of neutropenia and also for mobilization of peripheral blood stem cells (PBSCs). However, concerns have been raised about the safety and efficacy of biosimilar G‐CSF during PBSC mobilization procedures, especially in healthy donors. This article reviews the available evidence on the use of biosimilar G‐CSF in this setting. Aggregate clinical evidence supports the assessment by the EMA of biosimilar and originator G‐CSF as highly biologically similar, with respect to desired and undesired effects.     

Autologous cell therapy for cardiac repair

Importance of the field: Ever since the formation of the first biotechnology company almost three decades ago, more than 150 biopharmaceutical products have been marketed across the globe. The oldest of these biotechnology-derived products are now at the end of their patent lives, as a result of which, the development of ‘biosimilars’ is increasing.

Areas covered in the review: The review highlights aspects in which biosimilars differ from generic drugs.

What the reader will gain: The active substance of a biosimilar medicine is similar to the one of the biological reference medicine; however, biosimilars differ from generics of pharmacological drugs in aspects like size and complexity of the active substance, and the nature of the manufacturing process. The manufacture of a biopharmaceutical product is complex and involves several isolation and purification steps. These procedures are proprietary to the manufacturer of the originator product and hence even minor changes in production can have serious implications in terms of safety and efficacy of the product.

Take home message: Biosimilars should not be brought to market using the same procedure applied to generics, and existing and future regulation should prevent inappropriate and automatic substitution of a biosimilar for a reference biopharmaceutical product.