Efficacy of Infliximab, Abatacept, and Cenicriviroc for the Treatment of Adults Hospitalized with COVID-19 Pneumonia.

A randomized, double-blind, placebo-controlled clinical trial was conducted to investigate the efficacy of infliximab, abatacept, and cenicriviroc in treating patients hospitalized with COVID-19. The patient's clinical status was assessed daily on an 8-point ordinal scale. We evaluated the totality of evidence on the efficacy of the 3 immunomodulators by considering all possible changes in the clinical status of each patient over time. We demonstrated that infliximab accelerated improvement and reduced deterioration of clinical status when added to standard of care. There was also evidence for the benefit of abatacept. There was no evidence for the benefit of cenicriviroc.

Evaluating treatment efficacy in hospitalized COVID-19 patients, with applications to Adaptive COVID-19 Treatment Trials.

BACKGROUND: The current endpoints for therapeutic trials of hospitalized COVID-19 patients capture only part of the clinical course of a patient and have limited statistical power and robustness. METHODS: We specify proportional odds models for repeated measures of clinical status, with a common odds ratio of lower severity over time. We also specify the proportional hazards model for time to each level of improvement or deterioration of clinical status, with a common hazard ratio for overall treatment benefit. We apply these methods to Adaptive COVID-19 Treatment Trials. RESULTS: For remdesivir versus placebo, the common odds ratio was 1.48 (95% confidence interval (CI) = 1.23-1.79; p < 0.001), and the common hazard ratio was 1.27 (95% CI = 1.09-1.47; p = 0.002). For baricitinib plus remdesivir versus remdesivir alone, the common odds ratio was 1.32 (95% CI = 1.10-1.57; p = 0.002), and the common hazard ratio was 1.30 (95% CI = 1.13-1.49; p < 0.001). For interferon beta-1a plus remdesivir versus remdesivir alone, the common odds ratio was 0.95 (95% CI = 0.79-1.14; p = 0.56), and the common hazard ratio was 0.98 (95% CI = 0.85-1.12; p = 0.74). CONCLUSIONS: The proposed methods comprehensively characterize the treatment effects on the entire clinical course of a hospitalized COVID-19 patient.

'Totality of Evidence' Approach in the Development of GP2017, an Approved Adalimumab Biosimilar.

INTRODUCTION: Hyrimoz®, (GP2017 [SDZ-ADL]), is a biosimilar to Humira® (REF-ADL). SDZ-ADL was approved in 2018 by both the United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) for the indications of REF-ADL not protected by orphan exclusivity. In 2023, the US FDA and EMA also approved a citrate-free high-concentration formulation (HCF) of SDZ-ADL. TOTALITY OF EVIDENCE-THE APPROACH: Approval of SDZ-ADL was based on data gathered using the US FDA, EMA and World Health Organization (WHO)-recommended step-wise Totality of Evidence approach. This approach is a robust dataset confirming high confidence in analytical, functional, pharmacokinetic (PK) and clinical biosimilarity between the biosimilar and reference medicine determined through analytical and clinical investigation. EVIDENCE OF BIOSIMILARITY: Evidence supporting the biosimilarity of SDZ-ADL and REF-ADL was reported at each stage of investigation. Comprehensive comparative analytical and functional assessments demonstrated that SDZ-ADL was analytically indistinguishable from REF-ADL in required critical quality attributes, including receptor binding. Phase I clinical data showed PK similarity of SDZ-ADL and REF-ADL in healthy volunteers, with similar safety, tolerability and immunogenicity profiles. Phase III confirmatory efficacy and safety studies, ADACCESS (included in US/EU dossiers) and ADMYRA (separate to US/EU dossiers), both confirmed that SDZ-ADL's efficacy, safety, and immunogenicity matched REF-ADL in all patient groups with no clinically meaningful differences. More recently, this data package was the basis for a citrate-free HCF of SDZ-ADL to be developed, and its PK, safety and immunogenicity were confirmed against the initially approved formulation of SDZ-ADL. CONCLUSION: Overall, the Totality of Evidence provided for biosimilar adalimumab, SDZ-ADL, confirmed the analytical, functional and clinical similarity of SDZ-ADL to REF-ADL, supporting its regulatory approval and providing a data bridge with which to evaluate and support the approval of citrate-free HCF SDZ-ADL for clinical use.

A biosimilar is a type of medicine that is designed to match the structure and function of a 'reference' biologic medicine. Hyrimoz^® (SDZ-ADL) is a biosimilar of the adalimumab reference medicine, Humira^® ([REF-ADL]). SDZ-ADL was approved in the US and Europe in 2018. For SDZ-ADL to be approved, a collection of evidence needed to be created, called the 'Totality of Evidence.' The purpose of this collection of data is to show there is a high confidence that the new biosimilar medicine matches the reference medicine, from the structure of the medicine to the effect of the medicine on the human body. For SDZ-ADL, this investigation started with comparing the physical structure and other functional properties of SDZ-ADL versus REF-ADL and ended with clinical studies in both healthy volunteers and in patients with diseases treated with adalimumab. This Totality of Evidence gathered for biosimilar adalimumab, SDZ-ADL, confirmed the similarity of SDZ-ADL to REF-ADL and therefore supported the approval of SDZ-ADL. In 2018, a citrate-free high-concentration version (high concentration formulation [HCF]) of REF-ADL was launched that matched REF-ADL. HCF REF-ADL has since become the primary formulation of REF-ADL used in practice. In 2023, a HCF version of SDZ-ADL was also approved in the US and EU based on evidence confirming that HCF SDZ-ADL matched SDZ-ADL. As SDZ-ADL had been previously confirmed to match the reference medicine, this meant that HCF SDZ-ADL could be directly compared against SDZ-ADL to confirm biosimilarity and support its approval.

Streamlining biosimilar development based on 20 years' experience.

INTRODUCTION: Biosimilar clinical programs could be streamlined by prudent application of improved methodologies and knowledge accumulated over the past 20 years. This review focuses on whether complex comparative efficacy trials are routinely needed and how to achieve a more tailored approach to biosimilar development. AREAS COVERED: Key learnings over the past 20 years are summarized. It is noted that a one size fits all approach to biosimilar development is not appropriate: biological medicines fall within a wide spectrum of complexity, with blurring at the interface between biological products and small molecules. The interrelationship between quality, potency, pharmacokinetics, pharmacology, immunogenicity, efficacy, and safety are reviewed. Current regulatory thinking is reviewed with a look into what future challenges lie ahead. EXPERT OPINION: To tailor regulatory requirements for marketing approval of biosimilars, it is proposed that a biosimilarity report be introduced. This report would integrate quality, pharmacology, immunogenicity, efficacy and safety findings and address how the clinical program could be tailored based on the totality of evidence.

The totality of evidence approach in the development of AVT02 (adalimumab), a biosimilar to Humira.

The development of a biosimilar is based on comparative structural, physicochemical, functional and clinical assessments. The sum of these analyses encompasses the 'totality of evidence', which demonstrates no clinically meaningful differences between the biosimilar and the reference product (RP). Once biosimilarity has been established, provided there is suitable scientific justification, clinical data may be extrapolated to other indications of the RP. AVT02 has been developed as a biosimilar to high-concentration, low-volume Humira (adalimumab), an anti-tumour necrosis factor-alpha monoclonal antibody approved for various chronic inflammatory indications. The totality of evidence for AVT02 is described, supporting its approval as an adalimumab biosimilar for all approved indications globally. Analytical similarity assessments using mass spectrometry methods demonstrated identical amino acid sequences for AVT02 and the RP, with high similarity in terms of primary structure, post-translational modifications and higher-order structural attributes. The mechanism of action was assessed by various cell-based potency assays and binding assays, and the results demonstrated that AVT02 is highly similar to the RP. No clinically meaningful differences in terms of purity, potency and safety were observed, and minor differences in a few physiochemical attributes did not impact the in vitro biologic activity and were not considered clinically relevant. Clinical similarity was demonstrated by comparing the pharmacokinetic, efficacy, safety and immunogenicity profiles of AVT02 with those of the RP. Clinical studies supported similar pharmacokinetic and comparable immunogenicity profiles between AVT02 and the RP in healthy participants and participants with moderate-to-severe chronic plaque psoriasis, with no new safety signals detected. The totality of evidence described demonstrates the biosimilarity of AVT02 to the RP, thereby fulfilling the scientific and regulatory requirements for AVT02 as a high-concentration biosimilar for the treatment of chronic plaque psoriasis and all approved indications of the RP.

Demonstrating the high similarity between the biosimilar AVT02 (adalimumab) and Humira, supporting AVT02 to be used to treat all conditions currently treated with Humira Biosimilars are drugs that have similar quality, effectiveness, and safety profiles to an already approved biological drug, which is referred to as the 'reference product (RP)'. Although biosimilars have identical amino acids (the building blocks that make up proteins) to the RPs, they are manufactured in living cells which leads to a small amount of natural variability. Therefore, extensive testing is required to confirm that a biosimilar is highly similar to the RP. The 'totality of evidence' is a set of tests to demonstrate that there are no meaningful differences between the biosimilar and the RP, in other words, that there is 'biosimilarity' between the biosimilar and RP. Once biosimilarity has been proven, the biosimilar may be used to treat all the diseases currently treated with the RP, without the need for separate clinical trials in each disease. AVT02 has been developed as a biosimilar to Humira, an antibody approved for various chronic inflammatory diseases such as chronic plaque psoriasis (PsO). A step-by-step approach was used to show biosimilarity of AVT02 to Humira. This included clinical studies (in healthy individuals and participants with moderate to severe chronic PsO) and non-clinical studies (comparisons of the chemistry of the drugs and how they work in the body). Clinical studies in healthy individuals and participants with PsO showed that AVT02 and Humira were taken up and degraded by the body in a similar way, peoples' immune response to the two drugs were similar, and both drugs had similar side effects. No clinically meaningful differences in the purity, effectiveness, and safety of AVT02 compared with Humira were seen. The evidence demonstrates the biosimilarity of AVT02 to Humira and supports the use of AVT02 to treat all conditions which are currently treated with Humira.

SB8, an approved bevacizumab biosimilar based on totality of evidence: scientific justification of extrapolation.

SB8 is a biosimilar of bevacizumab based on its similarity demonstrated by physicochemical, functional, non-clinical and clinical studies. Supported by the concept of extrapolation, SB8 was authorized and is used in a similar manner across all types of tumors as reference bevacizumab. Furthermore, SB8 offers convenience with prolonged stability compared with reference bevacizumab in diluted form. Although a biosimilar must demonstrate biosimilarity to a reference product with the 'totality of evidence' in a stringent regulatory process for marketing authorization, some concerns remain among healthcare practitioners, particularly about extrapolation. This review summarizes the concepts of the totality of evidence and extrapolation in biosimilar development and the role of bevacizumab biosimilars in the management of metastatic colorectal cancer as an extrapolated indication.

Pós-modernidade e decadência ideológica: "O sono da razão desperta monstros" / Post-modernity and ideological decay: "The sleep of reason awakens monsters" / Postmodernidad y decadencia ideológica: "El sueño de la razón despierta monstruos"

RESUMO O presente ensaio objetivou apresentar o dossiê sobre epistemologia da Educação Física, produzido pela RBCE. Como viés de apresentação, optou-se por trazer elementos que permitem entrar no debate dos fundamentos norteadores das críticas à chamada pós-modernidade. Sem pretensão de esgotar esse debate, foi mostrada uma expressão do pensamento pós-moderno com caracterizações que acabam por desconsiderar categorias centrais do pensamento marxiano. Detivemo-nos, em especial, em uma delas: a categoria da totalidade. Esperamos, assim, contribuir para que, diante do combate às manifestações autoritárias e mesmo de corte fascista que visualizamos na atualidade contemporânea do capitalismo, a nossa "batalha das ideias" decorra em ambiente fértil e profícuo.

ABSTRACT This essay aimed to present the dossier about epistemology of Physical Education, produced by the RBCE. As a presentation bias, it was decided to bring elements that allow us to enter into the debate on the guiding foundations of criticism of the so-called postmodernity. Without intending to exhaust this debate, an expression of postmodern thought was shown with characterizations that end up disregarding central categories of Marxian thought. We focused, in particular, on one of them: the category of totality. We hope, therefore, to contribute so that, in times of fight against authoritarian and even fascist manifestations that we see in contemporary capitalism, our "battle of ideas" takes place in a fertile and fruitful environment.

RESUMEN Este ensayo tuvo como objetivo presentar el dossier sobre epistemología de la Educación Física", elaborado por la RBCE. Como sesgo de presentación, optamos por traer elementos que nos permitan entrar en el debate sobre los fundamentos rectores de la crítica a la llamada posmodernidad. Sin pretender agotar este debate, se mostró una expresión del pensamiento posmoderno con caracterizaciones que terminan por desconocer categorías centrales del pensamiento marxista. Nos centramos, en particular, en uno de ellos: la categoría de totalidad. Esperamos, por tanto, contribuir para que, frente a la lucha contra las manifestaciones autoritarias e incluso fascistas que vemos en el capitalismo contemporáneo, nuestra "batalla de ideas" se desarrolle en un ambiente fértil y fructífero.

A review of the totality of evidence supporting the development and approval of a pegfilgrastim biosimilar (LA-EP2006).

OBJECTIVE: The totality-of-evidence approach requires that similarity between a proposed biosimilar and a reference biologic is demonstrated across a range of analytical, preclinical, and clinical parameters to establish biosimilarity. We describe the totality of evidence for Sandoz biosimilar pegfilgrastim (LA-EP2006 [marketed as Ziextenzo]) that supported its regulatory approval in Europe and the United States. METHODS: Analytical similarity to the reference biologic [marketed by Amgen as Neulasta] was first investigated with regard to physiochemical quality attributes such as primary structure, pegylation, higher-order structures, variants and impurities, molecular size variants, and formulation (protein content, pH, excipients, etc.). In vitro biological activity studies were performed to examine the primary mechanism of action of pegfilgrastim. Bioequivalence (clinical pharmacokinetics [PK] and pharmacodynamics [PD]) of Sandoz biosimilar pegfilgrastim to the reference biologic was studied in healthy volunteers; efficacy, safety, and immunogenicity were assessed during confirmatory clinical efficacy studies in patients undergoing treatment for breast cancer. RESULTS: No meaningful or relevant differences were identified between Sandoz biosimilar pegfilgrastim and the reference biologic during analytical testing. Similar receptor binding and induction of cellular proliferation in vitro confirmed no functional differences between the biologics. Clinical studies in healthy adult participants demonstrated PK/PD biosimilarity and a similar safety profile between biosimilar and reference pegfilgrastim. Clinical studies in a sensitive patient population also demonstrated similar efficacy, safety, and immunogenicity between Sandoz biosimilar pegfilgrastim and the reference biologic. CONCLUSIONS: The totality of evidence confirms that Sandoz biosimilar pegfilgrastim matches the reference biologic and will therefore provide equivalent efficacy and safety in all eligible indications.

Causal necessitarianism and the monotonicity objection.

Do causes necessitate their effects? Causal necessitarianism (CN) is the view that they do. One major objection-the "monotonicity objection"-runs roughly as follows. For many particular causal relations, we can easily find a possible "blocker"-an additional causal factor that, had it also been there, would have prevented the cause from producing its effect. However-the objection goes on-, if the cause really necessitated its effect in the first place, it would have produced it anyway-despite the blocker. Thus, CN must be false. Though different from Hume's famous attacks against CN, the monotonicity objection is no less important. In one form or another, it has actually been invoked by various opponents to CN, past and present. And indeed, its intuitive appeal is quite powerful. Yet, this paper argues that, once carefully analysed, the objection can be resisted-and should be. First, I show how its success depends on three implicit assumptions concerning, respectively, the notion of cause, the composition of causal factors, and the relation of necessitation. Second, I present general motivations for rejecting at least one of those assumptions: appropriate variants of them threaten views that even opponents to CN would want to preserve-in particular, the popular thesis of grounding necessitarianism. Finally, I argue that the assumption we should reject is the one concerning how causes should be understood: causes, I suggest, include an element of completeness that excludes blockers. In particular, I propose a way of understanding causal completeness that avoids common difficulties.

The Actualization of the Transplantation Complex on the Axis of Psychosomatic Totality-Results of a Qualitative Study.

Although transplantation medicine is not new, there is a clinically justified gap in the existing literature with respect to the psychological processing of lung transplants. The present study aims to examine whether lung transplantation leads to an actualization of psychological, e.g., oral-sadistic fantasies. Following a qualitative approach, 38 lung transplant patients were interviewed three times within the first six months after transplantation. Data analysis focused on identifying unconscious and conscious material. The inter-rater reliability for all codes was calculated using Krippendorff's Alpha (c-α-binary = 0.94). Direct and implicit evidence of a so-called transplantation complex was detected e.g., regarding the "incorporation" of the dead donor and his lungs. These processes occur predominantly at an imaginary level and are related to the body. Our findings emphasize that such psychological aspects should be borne in mind in the psychological treatment of lung-transplant patients in order to improve the processing of lung transplants, and that this might have a positive effect on patient adherence.

Evaluating the Efficacy of Coronavirus Disease 2019 Vaccines.

A large number of studies are being conducted to evaluate the efficacy and safety of candidate vaccines against coronavirus disease 2019 (COVID-19). Most phase 3 trials have adopted virologically confirmed symptomatic COVID-19 as the primary efficacy end point, although laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also of interest. In addition, it is important to evaluate the effect of vaccination on disease severity. To provide a full picture of vaccine efficacy and make efficient use of available data, we propose using SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19 as dual or triple primary end points. We demonstrate the advantages of this strategy through realistic simulation studies. Finally, we show how this approach can provide rigorous interim monitoring of the trials and efficient assessment of the durability of vaccine efficacy.

Evaluating the Efficacy of Therapies in Patients With Coronavirus Disease 2019.

There is a proliferation of clinical trials worldwide to find effective therapies for patients diagnosed with coronavirus disease 2019 (COVID-19). The endpoints that are currently used to evaluate the efficacy of therapeutic agents against COVID-19 are focused on clinical status at a particular day or on time to a specific change of clinical status. To provide a full picture of the clinical course of a patient and make complete use of available data, we consider the trajectory of clinical status over the entire follow-up period. We also show how to combine the evidence of treatment effects on the occurrences of various clinical events. We compare the proposed and existing endpoints through extensive simulation studies. Finally, we provide guidelines on establishing the benefits of treatments.

Non-sterilizing Hysterectomies? A Catholic Critique of the CDF.

In 2019, the Congregation for the Doctrine of the Faith (CDF) issued a statement that a woman could morally undergo a hysterectomy to avoid serial miscarriages if her uterus were incapable of sustaining a child until viability because the procedure would not constitute a direct sterilization. We believe the CDF's conclusion and line of argumentation are both mistaken. Since the proposed hysterectomy seeks to make impossible what is presently possible-conceiving a child-it must therefore constitute a direct sterilization, which the Church has long taught is immoral. Using the Principle of Totality, we offer and defend a more straightforward interpretation of the case, arguing that while the woman's condition is both tragic and chronic, spiritual counseling and training in natural family planning should be recommended, as a hysterectomy is not medically indicated in this case. SUMMARY: The Congregation for the Doctrine of the Faith (CDF)'s recently issued a statement claiming that a woman could morally undergo a hysterectomy to avoid serial miscarriages if her uterus were incapable of sustaining a child until viability on the grounds that the procedure would not constitute a direct sterilization. We argue this is mistaken, and that the procedure would constitute a direct sterilization.

Association between periodontal disease and tooth loss and mortality in an elderly Chinese population.

BACKGROUND: Poor oral health is a risk indicator of poor quality of life and mortality. However, whether these associations remain potent in elderly subjects after adequately considering the confounding factors is not yet clearly elucidated. The present study aimed to investigate the associations between periodontal disease and tooth loss and total mortality and cardiovascular disease (CVD) outcomes in the elderly > 75 years old. METHODS: A total of 1385 individuals, receiving periodontal treatment in Shanghai, participated in this retrospective study. Data on oral status were obtained from radiographs to calculate the proportion of residual bone. The information about mortality was collected from the Shanghai Municipal Center for Disease Control and Prevention (SCDC). Univariate Cox proportional hazards model, multivariable-adjusted model, and competing risk hazard model were used to analyze the association between periodontal disease or tooth loss and mortality. RESULTS: Those with severe periodontitis were associated with higher risk of total mortality than healthy individuals [hazard ratio (HR) = 1.48, 95% confidence interval (95% CI) 1.11-1.98]. Further, missing teeth increased the risk of total mortality (HR = 1.02, 95% CI 1.01-1.03). However, no significant difference was detected in the association between periodontitis or tooth loss and CVD mortality. In competing risk hazard model, an increased risk was observed for other-cause mortality, not CVD mortality, in those with severe periodontitis and missing teeth. CONCLUSION: Periodontal diseases and tooth loss were the potential predictors of total mortality even after adjustment for confounding factors. However, these were not independent indicators for CVD mortality.

As principais diferenças entre a Psicologia Analítica e a Psicologia Simbólica Junguiana / The main differences between Analytical Psychology and Jungian Symbolic Psychology / Las principales diferencias entre la Psicología Analítica y la Psicología Simbólica Junguiana

Este texto apresenta 27 pontos em que a Psicologia Simbólica Junguiana difere da Psicologia Analítica. Esta descrição tem um caráter didático e objetiva facilitar a compreensão das modificações introduzidas pela Psicologia Simbólica Junguiana na Psicologia Analítica. O autor ressalta que considera suas formulações um desenvolvimento da Psicologia Analítica e que estão em consonância com a criatividade e o espírito científico de Jung.

This article presents twenty seven aspects in which Jungian Symbolic Psychology differs from Analytical Psychology. This description has a didactic character and aims to facilitate the understanding of the modifications introduced in Analytical Psychology by Jungian Symbolic Psychology. The author stresses considering his formulations a development of Analytical Psychology, harmonic with Jung's creativity and scientific spirit.

Este texto presenta veintisiete puntos en los que la Psicología Simbólica Junguiana difiere de la Psicología Analítica. Esta descripción tiene un carácter didáctico y objetivo para facilitar la comprensión de las modificaciones introducidas por la Psicología Simbólica Junguiana en Psicología Analítica. El autor señala que considera que sus formulaciones son un desarrollo de la Psicología Analítica y que están en línea con la creatividad y el espíritu científico de Jung.

Scientific rationale underpinning the development of biosimilar rituximab in hematological cancers and inflammatory diseases.

Sandoz rituximab (SDZ-RTX; Rixathon®; GP2013), a rituximab biosimilar, was approved in June 2017 in Europe in all indications of reference rituximab. The stepwise SDZ-RTX development program generated extensive physicochemical, structural, functional, and biological data demonstrating a match with reference rituximab on all clinically relevant attributes. A focused clinical development program followed, in two indications selected for sensitivity to detect potential differences versus reference rituximab: rheumatoid arthritis (pivotal pharmacokinetics and efficacy evaluation) and follicular lymphoma (pivotal efficacy/safety evaluation). These trials demonstrated highly similar pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity profiles. The totality of evidence for biosimilarity for SDZ-RTX, combined with knowledge that B-cell depletion is common to each approved indication, allowed SDZ-RTX approval for use in all indications of reference rituximab.

Totality of evidence in the development of ABP 215, an approved bevacizumab biosimilar.

ABP 215 (MVASI™) is the first approved biosimilar to Avastin® (bevacizumab). It is approved in the USA and the European Union (EU) for all bevacizumab indications in these jurisdictions except for ovarian cancer in the USA due to orphan drug exclusivity. ABP 215 was shown to be structurally, functionally and clinically (pharmacokinetic, efficacy and safety) similar to the bevacizumab reference product; the pharmacokinetic study was conducted in healthy adult men (n = 202); safety and efficacy were evaluated in patients with advanced nonsquamous non-small-cell lung cancer (n = 642). Together, these results comprise the totality of evidence that provides scientific justification for extrapolation to all approved indications of the reference product and supports the clinical value of ABP 215 as an additional treatment option.

A Review of the Totality of Evidence Supporting the Development of the First Adalimumab Biosimilar ABP 501.

ABP 501 [United States: AMJEVITA™ (adalimumab-atto); European Union: AMGEVITA® (adalimumab)] is the first approved biosimilar to adalimumab [reference product (RP)], a monoclonal antibody (mAb) targeting tumor necrosis factor-alfa (TNF-α). ABP 501 has received approval for use in indications that adalimumab RP is approved for, except those protected by regulatory exclusivity. A systematic step-wise totality of evidence (TOE) approach formed the basis of approval of ABP 501; this involved methodical accumulation of scientifically robust comparative data supporting similarity in analytical, preclinical, and clinical [pharmacokinetics (PK)], efficacy, safety and immunogenicity) evaluations. As a foundational first step, comprehensive analytical assessments demonstrated that ABP 501 is structurally and functionally similar to adalimumab RP in critical quality attributes. Preclinical assessments confirmed similar activity in assessing mechanisms of action and toxicology. Clinical evaluation included a phase 1 PK equivalence study in healthy subjects and two comparative phase 3 studies that evaluated ABP 501 and adalimumab RP in two sensitive patient populations, plaque psoriasis (PsO) and rheumatoid arthritis (RA). The PK profiles of ABP 501 and adalimumab RP were similar in healthy subjects as well as patients with PsO and RA. The pivotal phase 3 study in patients with PsO demonstrated that ABP 501 was clinically similar to adalimumab RP in terms of efficacy, safety and immunogenicity in both the primary and transition phases. The pivotal phase 3 study in patients with RA also established clinical similarity between ABP 501 and adalimumab RP; an open-label extension of this study demonstrated sustained efficacy over an additional 72 weeks, with no new safety or immunogenicity concerns with ABP 501 treatment. Overall, the TOE supported the conclusion that ABP 501 is highly similar to adalimumab RP and provided scientific justification for extrapolation to all the approved indications of adalimumab RP not protected by exclusivities.Funding: Amgen Inc.

The 'totality-of-the-evidence' approach in the development of PF-06438179/GP1111, an infliximab biosimilar, and in support of its use in all indications of the reference product.

The 'totality-of-the-evidence' biosimilarity concept requires that sufficient structural, functional, nonclinical, and clinical data are acquired in a stepwise manner, to demonstrate that no clinically meaningful differences in quality, safety, or efficacy are observed compared with the reference product. We describe the totality of the evidence for PF-06438179/GP1111 (PF-SZ-IFX; IXIFI™ [infliximab-qbtx]/Zessly®) that supported its approval as an infliximab (IFX) biosimilar for all eligible indications of reference IFX (ref-IFX; Remicade®) in Europe and in the US. Analytical similarity involving in vitro assays capable of distinguishing structural or functional differences between PF-SZ-IFX and ref-IFX formed a foundation for the biosimilarity exercise. Differences identified in N-glycosylation and charge heterogeneity were found not to impact the results in in vitro biological assays reflective of the pharmacology underlying the mechanisms of action (tumor necrosis factor binding, reverse signaling, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) of IFX across disease indications. Similarity was assessed in a comparative clinical pharmacokinetic study and in a clinical efficacy and safety study in patients with rheumatoid arthritis, where therapeutic equivalence between PF-SZ-IFX and ref-IFX provided confirmatory evidence of biosimilarity, and, when coupled with the analytical similarity already established, supported extrapolation to all eligible disease indications of ref-IFX.

Talking to patients about biosimilars.

Biologic therapies target aberrant pathways in diseases including diabetes, cancer and autoimmune disorders. Despite recent scientific advances, patient access to these agents can be limited. Biosimilars are designed to be highly similar to the originator biologic, targeting the same biological pathways, with comparable efficacy and safety. Biosimilars have the advantage of lower treatment costs, offering the potential for increased clinical use and patient access. Several biosimilars are approved for clinical use in the USA and Europe; however, there is a lack of awareness about biosimilars among healthcare providers and patients. This overview of the scientific basis of biosimilars and current indications aim to enhance discussions with patients and increase understanding of the role of biosimilars in individual treatment plans.