Comparison of biosimilar Tigerase and Pulmozyme in long-term symptomatic therapy of patients with cystic fibrosis and severe pulmonary impairment (subgroup analysis of a Phase III randomized open-label clinical trial (NCT04468100)).

BACKGROUND: Patients with cystic fibrosis (CF) need costly medical care and adequate therapy with expensive medicinal products. Tigerase® is the first biosimilar of dornase alfa, developed by the lead Russian biotechnology company GENERIUM. The aim of the manuscript to present post hoc sub-analysis of patients' data with cystic fibrosis and severe pulmonary impairment of a larger comparative study (phase III open label, prospective, multi-centre, randomized study (NCT04468100)) of a generic version of recombinant human DNase Tigerase® to the only comparable drug, Pulmozyme®. METHODS: In the analyses included subgroup of 46 severe pulmonary impairment patients with baseline FEV1 level 40-60% of predicted (23 patients in each treatment group) out of 100 patients registered in the study phase III open label, prospective, multi-center, randomized study (NCT04468100), and compared efficacy endpoints (FEV1, FVC, number and time of exacerbations, body weight, St.George's Respiratory Questionnaire) as well as safety parameters (AEs, SAEs, anti-drug antibody) within 24 treatment weeks. RESULTS: All outcomes were comparable among the studied groups. In the efficacy dataset, the similar mean FEV1 and mean FVC changes for 24 weeks of both treatment groups were observed. The groups were also comparable in safety, all the secondary efficacy parameters and immunogenicity. CONCLUSIONS: The findings from this study support the clinical Tigerase® biosimilarity to Pulmozyme® administered in CF patients with severe impairment of pulmonary function.

Shifting Paradigms Revisited: Biotechnology and the Pharmaceutical Sciences.

In 2003, Crommelin et al. published an article titled: "Shifting paradigms: biopharmaceuticals versus low molecular weight drugs" (https://doi.org/10.1016/S0378-5173(03)00376-4). In the present commentary, 16 years later, we discuss pharmaceutically relevant aspects of the evolution of biologics since then. First, we discuss the increasing repertoire of biologics, in particular, the rapidly growing monoclonal antibody family and the advent of advanced therapy medicinal products. Next, we discuss trends in formulation and characterization as well as summarize our current insights into immunogenicity of biologics. We spend a separate section on new product(ion) paradigms for biologics, such as cell-free production systems, production of advanced therapy medicinal products, and downscaled production approaches. Furthermore, we share our views on issues related to reaching the patient, including routes and techniques of administration, alternative development models for affordable biologics, biosimilars, and handling of biologics. In the concluding section, we outline outstanding issues and make some suggestions for resolving those.

Use of biosimilars in inflammatory bowel disease: a position update of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD).

The first infliximab biosimilar for the treatment of inflammatory bowel disease (IBD) was introduced in 2013, and today eight anti-TNF alpha biosimilars (three for infliximab and five for adalimumab) have been approved and licensed by the European Medicines Agency. Biosimilars present great potential in terms of cost saving and possible consequential reinvestment in the health care system. The increasing knowledge about the process of biosimilar development and use in IBD and the publication of many prospective clinical studies and real-life clinical experiences have progressively changed the point of view of IBD physicians. In the present position paper, the Italian Group for the Study of Inflammatory Bowel Disease present and discuss their updated statements and positions on this topic, with emphasis on the concepts of biosimilarity and extrapolation across indications, safety and immunogenicity, interchangeability and switching, automatic substitution, and, finally, patient education about biosimilars.

[Developability assessment]. / Développabilité.

The therapeutic antibodies and their by-products (antibody fragments, conjugated, etc.) establish one of the most dynamic biopharmaceutical market segments today. Due to their intrinsic properties of specificity towards their target, towards their flexible affinity and due to their stability, antibodies became therapeutic agents of the very first choice. One of the challenges of this sector is to create antibodies of very good quality, more and more quickly, while having less and less consequent development costs in fine.

TITLE: Développabilité. ABSTRACT: Les anticorps thérapeutiques et leurs dérivés (fragments d'anticorps, conjugués, etc.) constituent aujourd'hui l'un des segments du marché biopharmaceutique les plus dynamiques. De par leurs propriétés intrinsèques de spécificité vis-à-vis de leur cible, de leur affinité modulable et de par leur stabilité, les anticorps sont devenus des agents thérapeutiques de tout premier choix. Un des challenges de ce secteur est de créer des anticorps de très bonne qualité, de plus en plus rapidement, tout en ayant des coûts de développement de moins en moins conséquents in fine.

Formulary Considerations for Insulins Approved Through the 505(b)(2) "Follow-on" Pathway.

OBJECTIVE: To summarize formulary-relevant issues for follow-on insulins approved through the Food and Drug Administration (FDA) 505(b)(2) approval pathway (Basaglar and Admelog). DATA SOURCES: A search of the MEDLINE database was performed for articles pertaining to clinical and formulary considerations for follow-on insulin products through July 2018. STUDY SELECTION AND DATA EXTRACTION: All clinical trials used in the 505(b)(2) approval process for follow-on insulin glargine and insulin lispro products were included and summarized. DATA SYNTHESIS: Follow-on insulin glargine and insulin lispro products have been recently approved as the first lower-cost alternatives to innovator insulin products. The follow-on insulins were approved via the 505(b)(2) pathway, making them neither generics nor biosimilars. Current data do not suggest any clinically relevant differences between the follow-on insulins and their respective innovator products. Clinicians should be aware that follow-on insulins will be reclassified as biologic products in the year 2020. Relevance to Patient Care and Clinical Practice: This article provides information about currently available follow-on insulin products that were approved through the 505(b)(2) pathway, including product characteristics and efficacy and safety data. These products will likely be considered for both clinical use and formulary placement because of their potentially lower cost compared with innovator products. CONCLUSIONS: Follow-on insulin products approved through the 505(b)(2) pathway are supported by robust efficacy and safety data. As new follow-on insulins are approved and the regulatory change that will occur with these products in 2020 approaches, formulary decisions and clinical policies (eg, substitution) will continue to be revisited.

Comparative functional and pharmacological characterization of Sandoz proposed biosimilar adalimumab (GP2017): rationale for extrapolation across indications.

BACKGROUND: Biosimilars are approved biologics that match reference medicine in quality, safety, and efficacy. The development of Sandoz proposed biosimilar adalimumab (SPBA; GP2017) involved a target-directed, iterative state-of-the-art quality-by-design development program. Here, we describe the functional and pharmacological characterization of SPBA and its proposed mechanism of action in immune-mediated inflammatory diseases. METHODS: Sensitive in vitro binding and functional characterization studies, and nonclinical evaluations (pharmacokinetics, pharmacodynamics, and safety/toxicology) were performed as part of a stepwise approach to confirm the biosimilarity of SPBA with reference adalimumab. RESULTS: Matching values were reported for SPBA and reference adalimumab in binding assays involving tumor necrosis factor (TNF)-α, complement 1q and human immune effector cell Fcγ receptor subtypes in cell-based bioassays for Fc receptor function (complement- and antibody-dependent cytotoxicity), and in apoptosis inhibition. Furthermore, SPBA and reference adalimumab were equivalent in terms of membrane TNF binding and induction of reverse signaling. Pharmacokinetics of SPBA and reference adalimumab were comparable in rabbits, and the two biologics were equally effective in a human TNF transgenic mouse model of polyarthritis. CONCLUSION: SPBA matches reference adalimumab with regards to target binding, functional, pharmacokinetic, and pharmacodynamic properties at the nonclinical level supporting its approval in all indications of the reference adalimumab.

Development of Glatopa® (Glatiramer Acetate): The First FDA-Approved Generic Disease-Modifying Therapy for Relapsing Forms of Multiple Sclerosis.

The multiple sclerosis (MS) treatment landscape in the United States has changed dramatically over the past decade. While many disease-modifying therapies (DMTs) have been approved by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS, DMT costs continue to rise. The availability of generics and biosimilars in the MS-treatment landscape is unlikely to have a major impact on clinical benefit. However, their availability will provide alternative treatment options and potentially lower costs through competition, thus increasing the affordability of and access to these drugs. In April 2015, the first generic version of the complex drug glatiramer acetate (Glatopa® 20 mg/mL) injection was approved in the United States as a fully substitutable generic for all approved indications of the 20 mg/mL branded glatiramer acetate (Copaxone®) dosage form. Despite glatiramer acetate's complex nature-being a chemically synthesized (ie, nonbiologic) mixture of peptides-the approval occurred without conducting any clinical trials. Rather, extensive structural and functional characterization was performed to demonstrate therapeutic equivalence to the innovator drug. The approval of Glatopa signifies an important milestone in the US MS-treatment landscape, with the hope that the introduction of generic DMTs and eventually biosimilar DMTs will lead to future improvements in the affordability and access of these much-needed treatments for MS.

Follow-on products for treatment of multiple sclerosis in Latin America: An update.

Both proprietary and non-proprietary medicines are expected to undergo rigorous pre-approval testing and both should meet stringent health authority regulatory requirements related to quality to obtain approval. Non-proprietary (also known as copy or generic) medicines, which base their authorization and use on the proprietary documentation and label, are often viewed as a means to help lower cost and thus increase patient access. If these medicines fail to meet quality standards, such as good manufacturing practice and bioequivalence (in humans), they are then defined as substandard copies and can pose serious risks to patients in terms of safety and efficacy. Availability of this type of compounds is more prevalent in regions where health authorities do not enforce registration regulations as stringent as those of the Food and Drug Administration, European Medicines Agency, or World Health Organization, including preestablished quality standard requirements. This article focuses on non-proprietary medicines for multiple sclerosis, that are not identical to proprietary versions and could thus fail to meet efficacy or have different impact on the safety of patients with multiple sclerosis.

Production, Characterization, and Biological Evaluation of Well-Defined IgG1 Fc Glycoforms as a Model System for Biosimilarity Analysis.

Four different well-defined IgG1 Fc glycoforms are proposed as a model system to examine important biological and physicochemical features for protein drug biosimilar analyses. The IgG1 Fc glycoforms were produced by yeast expression combined with in vitro enzymatic synthesis as a series of sequentially truncated high-mannose IgG1 Fc glycoforms with an anticipated range of biological activity and structural stability. Initial characterization with mass spectrometry, SDS-PAGE, size exclusion HPLC, and capillary isoelectric focusing confirmed that the glycoproteins are overall highly similar with the only major difference being glycosylation state. Binding to the activating Fc receptor, FcγRIIIa was used to evaluate the potential biological activity of the IgG1 Fc glycoproteins. Two complementary methods using biolayer interferometry, 1 with protein G-immobilized IgG1 Fc and the other with streptavidin-immobilized FcγRIIIa, were developed to assess FcγRIIIa affinity in kinetic binding studies. The high-mannose IgG1 Fc and Man5-IgG1 Fc glycoforms were highly similar to one another with high affinity for FcγRIIIa, whereas GlcNAc-Fc had weak affinity, and the nonglycosylated N297Q-Fc had no measurable affinity for FcγRIIIa. These 4 IgG1 Fc glycoforms were also evaluated in terms of physical and chemical stability profiles and then used as a model system to mathematically assess overall biosimilarity, as described in a series of companion articles.

The Diversity of Biosimilar Design and Development: Implications for Policies and Stakeholders.

Biosimilars are required to be similar or highly similar in structure to their biologic reference product but are neither expected nor required to contain identical active substances. For example, glycosylated biosimilars approved to date demonstrate quantitative and qualitative structural differences from their reference product and exemplify the latitude of variations permitted for biosimilars. Although differences between a candidate biosimilar and its reference product will be evaluated for differential clinical effects during biosimilarity assessment, it is unlikely that potential differences between any two indirectly related biosimilars will be formally evaluated. Furthermore, biosimilar pathways permit variations in pharmaceutical attributes, clinical development approaches, and regulatory outcomes, resulting in further diversity of attributes among approved biosimilars. Because biosimilars may vary across the ranges of structural and functional acceptance criteria, they should not be treated like multisource, generic drugs.

IBD: Indication extrapolation for anti-TNF biosimilars.

Biosimilar monoclonal antibodies (mAbs) to TNF are being developed that are highly similar, but not identical to the innovator molecules. CT-P13, a biosimilar of infliximab, is the first anti-TNF mAb to get approval in South Korea, Europe and Canada. However, uncertainties remain about indication extrapolation and interchangeability.

Biosimilars in inflammatory bowel diseases: an important moment for Brazilian gastroenterologists.

Biosimilars are not generic drugs. These are more complex medications than small molecules, with identical chemical structures of monoclonal antibodies that lost their patency over time. Besides identical to the original product at the end, the process of achieving its final forms differs from the one used in the reference products. These differences in the formulation process can alter final outcomes such as safety and efficacy of the drugs. Recently, a biosimilar of Infliximab was approved in some countries, even to the management of inflammatory bowel diseases. However, this decision was based on studies performed in rheumatologic conditions such as rheumatoid arthritis and ankylosing spondylitis. Extrapolation of the indications from rheumatologic conditions was done for Crohn's disease and ulcerative colitis based on these studies. In this article, the authors explain possible different mechanisms in the pathogenesis between rheumatologic conditions and inflammatory bowel diseases, that can lead to different actions of the medications in different diseases. The authors also alert the gastroenterological community for the problem of extrapolation of indications, and explain in full details the reasons for being care with the use of biosimilars in inflammatory bowel diseases without specific data from trials performed in this scenario.

Biosimilars: the science of extrapolation.

Despite the establishment of a specific approval pathway, the issuance of detailed scientific guidelines for the development of similar biological medicinal products (so-called "biosimilars") and the approval of several biosimilars in the European Union, acceptance of biosimilars in the medical community continues to be low. This is especially true in therapeutic indications for which no specific clinical trials with the biosimilar have been performed and that have been licensed based on extrapolation of efficacy and safety data from other indications. This article addresses the concerns frequently raised in the medical community about the use of biosimilars in such extrapolated indications and explains the underlying scientific and regulatory decision making including some real-life examples from recently licensed biosimilars.

The advent of biosimilars: challenges and risks.

Biosimilars represent a new class of medicinal products that will have significant impact on clinical use. They are identical on an amino acid sequence level to existing reference biopharmaceutical products (originals). However, they may exhibit differences on a protein level. This paper provides a brief overview of biosimilar development and describes the risk and challenges that should be considered during the admission of biosimilars into the clinic.

Regulatory and cost barriers are likely to limit biosimilar development and expected savings in the near future.

In March 2010 Congress established an abbreviated Food and Drug Administration approval pathway for biosimilars-drugs that are very similar but not identical to a reference biological product and cost less. Because bringing biosimilars to the market currently requires large investments of money, fewer biosimilars are expected to enter the biologics market than has been the case with generic drugs entering the small-molecule drug market. Additionally, given the high regulatory hurdles to obtaining interchangeability-which would allow pharmacists to substitute a biosimilar for its reference product, subject to evolving state substitution laws-most biosimilars will likely compete as therapeutic alternatives instead of as therapeutic equivalents. In other words, biosimilars will need to compete with their reference product on the basis of quality; price; and manufacturer's reputation with physicians, insurers, and patient groups. Biosimilars also will face dynamic competition from new biologics in the same therapeutic class-including "biobetters," which offer incremental improvements on reference products, such as extended duration of action. The prospects for significant cost savings from the use of biosimilars appear to be limited for the next several years, but their use should increase over time because of both demand- and supply-side factors.

Biosimilars in the therapy of inflammatory bowel diseases.

A biosimilar is a copy of an approved biological medicine whose patent protections have expired. Biosimilars of antibodies to tumour necrosis factor α (TNFα) are becoming important in the treatment of inflammatory bowel diseases (IBD). The first one introduced commercially is an infliximab biosimilar. The aim of this study was to provide an overview of anti-TNFα biosimilars. The literature on biosimilars of monoclonal anti-TNFα antibodies was reviewed, including their manufacture and approval pathways, concerns about efficacy, safety, immunogenicity, extrapolation, switching and labelling. Previous experience with biosimilars of epoetin and other growth factors was also reviewed. The infliximab biosimilar CT-P13 was the first biosimilar monoclonal antibody registered for the treatment of IBD. The major advantage of biosimilars is the reduced cost of therapy. Concerns have arisen, however, about the efficacy and safety of CT-P13 in IBD, the extrapolation of results from rheumatologic trials to IBD and the free interchangeability of CT-P13 with infliximab. Experience with simple peptide biosimilars, such as epoetins and growth factors, has generally been positive, with these biosimilars having similar efficacy and safety as the original products, although immunogenicity remains a major concern. Upcoming postregistration studies will address concerns on biosimilars in IBD, including their efficacy, safety, immunogenicity, switching and interchangeability. Biosimilars active against the same epitopes, but with improved pharmacokinetic properties that enhance their efficacy and/or safety, may be the next stage in the development of biosimilars. Anti-TNFα biosimilars represent promising new treatment options for patients with IBD. However, data on their efficacy and safety in IBD are needed.

Developing oncology biosimilars: an essential approach for the future.

The treatment of many diseases, particularly cancer, has been profoundly impacted by the introduction of biologic therapies (biologics), which are incorporated into the treatment algorithms of most oncology clinical practice guidelines. Biologics are large molecular weight, structurally complex proteins that are produced via complex manufacturing processes. With the patents of key biologics, including many widely used in oncology, set to expire in the near future, a number of pharmaceutical companies have focused on developing biosimilars. While the goal of development is to demonstrate that the biosimilar product is highly similar to the reference biologic product, biosimilars should not be viewed as "generic" biologics. Generic drugs are small chemical moieties that are identical to the patent-expired "reference" small-molecule drugs. It is not possible to produce an identical copy of a biologic, so the term "biosimilar" was chosen to define an appropriately similar biologic product. Improving patient access to cancer therapies such as biologics and reducing healthcare costs are key initiatives of the US Government; the integration of approved biosimilars into clinical practice will be instrumental in accomplishing these goals.

Conference report: reviving pharmaceutical R&D with translational science, regulatory efficiency and innovative models.

The 4th Annual Shanghai Symposium on Clinical & Pharmaceutical Solutions through Analysis (CPSA Shanghai 2013) was held on 24-27 April 2013 in Shanghai, China. The meeting provided an educational forum for scientists from pharmaceutical industry, academia, CROs and instrument vendors to share experience and ideas, and discuss current challenges, issues and innovative solutions associated with pharmaceutical R&D. The meeting featured highly interactive events, including diversified symposia, roundtable discussions, workshops, poster sessions and conference awards. Education and specialized training are the foundation of CPSA events. The CPSA Shanghai 2013 meeting also featured an inaugural satellite workshop event in Beijing, as well as joint sessions traditionally held with local bioanalytical and drug metabolism discussion groups.