Clinical considerations for the development of biosimilars in oncology

Despite availability of biologic therapies, limited patient access to many of the most-effective cancer treatments affects overall health outcomes. To address this issue, many governments have enacted legislation for the approval of biosimilars. The term “biosimilar” refers to a biologic product that is developed to be highly similar, as opposed to identical, to a licensed biologic product (the reference or innovator product), such that, per US Food and Drug administration draft guidelines, “no clinically meaningful differences [exist] between the biological product and the reference product in terms of safety, purity, and potency.” This article presents some considerations about the development of biosimilars in cancer treatment through an overview of biosimilars from a clinical perspective. Topics covered include the development requirements and unique regulatory requirements for biosimilars, labeling considerations, potential limitations to the uptake of biosimilars, and review of some biosimilars in development for oncology indications.     

Biosimilars 2.0: Guiding principles for a global “patients first” standard

In the European Union, biosimilar products have been approved since 2006 under an abbreviated pathway that leverages their similarity to an existing “reference” biological product. The products approved to date are based on recombinant versions of endogenous proteins with well-understood structures and pharmacology, but complicated safety and immunogenicity profiles. The period during the 2000s that included the first reviews, approvals, sale and use of biosimilars is referred to herein as “Biosimilars 1.0.” Over the next several years, a new and advanced tranche of biosimilars will be developed for complex reference products, including medicines used in the treatment of cancer and autoimmune diseases. A global market for biosimilars is developing and this may well foreshadow the beginning of the second era of product development. This Biosimilars 2.0 period will likely be characterized by the development of complex products, global harmonization of standards and the increasing demand for long-term monitoring of pharmaceuticals. The products developed in this period should exhibit high levels of fidelity to the reference products and should be rigorously evaluated in analytical, non-clinical and clinical comparisons. Additionally, Biosimilars 2.0 manufacturers should strive for transparency in their labels and take proactive strides to be accountable to providers and patients for the quality of their products. An important opportunity now exists for the healthcare community, industry and regulators to work in partnership, to outline the appropriate standards for these products and to facilitate increased access while meeting patients'' needs.Key words: biotechnology, biosimilars, generic drugs, monoclonal antibodies, pharmacodynamics, pharmacokinetics     

Worldwide experience with biosimilar development

Limited access for high-quality biologics due to cost of treatment constitutes an unmet medical need in the US and other regions of the world. The term “biosimilar” is used to designate a follow-on biologic that meets extremely high standards for comparability or similarity to the originator biologic drug that is approved for use in the same indications. Use of biosimilar products has already decreased the cost of treatment in many regions of the world and now a regulatory pathway for approval of these products has been established in the US. The Food and Drug Administration (FDA) led the world with the regulatory concept of comparability and the European Medicines Agency (EMA) was the first to apply this to biosimilars. Patents on the more complex biologics, especially monoclonal antibodies, are now beginning to expire and biosimilar versions of these important medicines are in development. The new Biologics Price Competition and Innovation Act (BPCIA) allows the FDA to approve biosimilars and allows the FDA to lead on the formal designation of interchangeability of biosimilars with their reference products. The FDA''s approval of biosimilars is critical to facilitating patient access to high-quality biologic medicines and will allow society to afford the truly innovative molecules currently in the global biopharmaceutical industry''s pipeline.Key words: monoclonal antibodies (mAbs), biosimilars, recombinant biopharmaceuticals     

Inability and Obligation in Moral Judgment

It is often thought that judgments about what we ought to do are limited by judgments about what we can do, or that “ought implies can.” We conducted eight experiments to test the link between a range of moral requirements and abilities in ordinary moral evaluations. Moral obligations were repeatedly attributed in tandem with inability, regardless of the type (Experiments 1–3), temporal duration (Experiment 5), or scope (Experiment 6) of inability. This pattern was consistently observed using a variety of moral vocabulary to probe moral judgments and was insensitive to different levels of seriousness for the consequences of inaction (Experiment 4). Judgments about moral obligation were no different for individuals who can or cannot perform physical actions, and these judgments differed from evaluations of a non-moral obligation (Experiment 7). Together these results demonstrate that commonsense morality rejects the “ought implies can” principle for moral requirements, and that judgments about moral obligation are made independently of considerations about ability. By contrast, judgments of blame were highly sensitive to considerations about ability (Experiment 8), which suggests that commonsense morality might accept a “blame implies can” principle.     

Cancer-linked targets modulated by curcumin

In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting.     

Unusual Non-Occupational Exposure to Metals

Exposure to metals at workplaces is well known and in many cases occupational studies led to an adoption of limit values. For airborne concentrations of substances as metals refer to the “Maximaleo Arbeitsplatz-Konzentration” (MAK) in Germany or the “Threshold Limit Value” (TLV) in USA. Biological monitoring consists of an assessment of overall exposure to chemicals at the workplace and in the environment. The “Biologischer Arbeitsstoff Toleranzwert” (BAT) in Germany and the “Biological Exposure Index” in the USA serve as reference values. Besides these occupational limit values, reference values exist in Germany for the background exposure of the non occupationally exposed general population. In some cases the reference values are exceeded without any occupational exposure. Several cases of unusual environmental exposure to cobalt, mercury and manganese are reported. In such cases, it is often difficult to evaluate the measured concentration. In Germany, therefore, the “Human-Biomonitoring-Werte” (HBMValues) have been adopted in order to evaluate such high background exposures. The HBM-concept is presented. Environmental exposure to metals is usual within some limits. Reference values are helpful for an assessment. Unusual exposure occurs and the physician should be alert to symptoms of poisoning.     

Molecular Diagnostics of Fine Needle Aspiration for the Presurgical Screening of Thyroid Nodules

“The incidence of thyroid cancer, the most common endocrine malignancy, is rising. The two most common types of thyroid cancer are papillary and follicular” thyroid carcinomas. “Fine-needle aspiration (FNA) of thyroid nodules” can permit to detect many genetic mutations and other molecular alterations, including RAS and BRAF point mutations, PAX8/peroxisome proliferator-activated receptor (PPAR)γ and “RET/PTC rearrangements, occurring in thyroid papillary and follicular carcinomas” (more than 70% of cases), which can be used successfully to improve the diagnosis “and the management of patients with thyroid nodules”. The most extensive experience has been accumulated with “the diagnostic use of BRAF mutation”, which is highly specific for malignancy. “Testing FNA samples for a panel of mutations” that typically includes RAS, BRAF, PAX8/PPARγ and RET/PTC could permit to achieve the biggest diagnostic impact. “The accuracy of cancer diagnosis in thyroid nodules could be improved significantly using these and other emerging molecular markers”.     

Biosimilars: Key regulatory considerations and similarity assessment tools

A biosimilar drug is defined in the US Food and Drug Administration (FDA) guidance document as a biopharmaceutical that is highly similar to an already licensed biologic product (referred to as the reference product) notwithstanding minor differences in clinically inactive components and for which there are no clinically meaningful differences in purity, potency, and safety between the two products. The development of biosimilars is a challenging, multistep process. Typically, the assessment of similarity involves comprehensive structural and functional characterization throughout the development of the biosimilar in an iterative manner and, if required by the local regulatory authority, an in vivo nonclinical evaluation, all conducted with direct comparison to the reference product. In addition, comparative clinical pharmacology studies are conducted with the reference product. The approval of biosimilars is highly regulated although varied across the globe in terms of nomenclature and the precise criteria for demonstrating similarity. Despite varied regulatory requirements, differences between the proposed biosimilar and the reference product must be supported by strong scientific evidence that these differences are not clinically meaningful. This review discusses the challenges faced by pharmaceutical companies in the development of biosimilars.     

The Histological Components of the Phoniatrical Body-Cover Model in Minipigs of Different Ages

Pigs are models in human phoniatry. However, features of maturation and ageing have not been considered with regard to the so-called body-cover model in this species. Therefore, the glottis of “young” (2–3 months; n = 6) and “old” (4–7 years; n = 6) minipigs was investigated. Their cranial (CraF) and caudal (CauF) vocal folds were histomorphometrically and stratigraphically analysed with emphasis on their amounts of collagen structures and elastic fibres. A dense subepithelial layer (SEL) was a distinct feature of CraF and CauF of both age groups; it was spread upon the underlying loose, flexible “cover” like a fibro-elastic membrane. The “cover” was characterised by the so-called superficial layer (SL), which was distinctly loose in the “young” minipigs, but had a much denser texture in the “old” minipigs. Here, the SL was dominated by elastic fibres in the CraF, but was of mixed qualities (collagenous and elastic) in the CauF. The structural requirements for the SL’s function as a loose “cover” were thus met only in the “young” animals. A clearly demarcated intermediate layer (IL)—characterised by high amounts of elastic fibres (as in humans)—was only found in the CraF of the “young” animals. In the “old” animals, it had lost its demarcation. In the depth of the CraF of the “old” animals, many thick collagen fibre bundles were detected in a location equivalent to that of the vocal muscle in the CauF. The development of their large diameters was interpreted as part of the maturation process, thereby supporting the hypothesis of their functional importance as a component of the “body.” In the CauF, the amounts of collagen structures increased throughout the entire lamina propria, resulting in a loss of demarcated stratigraphical subdivisions in the “old” minipigs. This situation resembled that described in the vocal fold of geriatric humans.     

Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism,the field effect and genomic instability in cancer cells

Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a “lethal tumor microenvironment.” Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a “metabolic” and “mutagenic” motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, we show that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress and aerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria are removed from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress. As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulate mitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the “Reverse Warburg effect”). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to induce genomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressive behavior. Finally, we directly demonstrate that nitric oxide (NO) over-production, secondary to Cav-1 loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of this notion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or NO inhibitors (L-NAME) was sufficient to reverse many of the cancer-associated fibroblast phenotypes that we describe. Thus, cancer cells use “oxidative stress” in adjacent fibroblasts (1) as an “engine” to fuel their own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability. We also present evidence that the “field effect” in cancer biology could also be related to the stromal production of ROS and NO species. eNOS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunction in adjacent fibroblasts that do not express eNOS. As such, the effects of stromal oxidative stress can be laterally propagated, amplified and are effectively “contagious”—spread from cell-to-cell like a virus—creating an “oncogenic/mutagenic” field promoting widespread DNA damage.Key words: caveolin-1, cancer associated fibroblasts, oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, autophagy, nitric oxide (NO), DNA damage, aneuploidy, genomic instability, anti-oxidant cancer therapy, the “field effect” in cancer biology     

2nd Charles Richet et Jules Héricourt Workshop: Therapeutic antibodies and anaphylaxis; May 31–June 1, 2011; Tours,France

The Charles Richet and Jules Héricourt workshops honor the memory of Jules Héricourt (1850–1938) and Charles Richet (1850–1935) who described the principle of serotherapy in 1888 and made the very first attempts to fight cancer with serotherapy in 1895. In 1902, Charles Richet and Paul Portier described “anaphylaxis,” a discovery awarded the Nobel Prize in 1913. The first workshop, “Towards the clinical use of monoclonal antibodies with higher cytolytic efficacy in cancer” was held in Tours, France on November 20–21, 2008. The second Charles Richet and Jules Héricourt workshop, held May 31–June 1, 2011 at the University of Tours, France, was also organized by the Cancéropôle Grand Ouest. The topic of the workshop was therapeutic antibodies and anaphylaxis, a subject rarely addressed in congresses focused on mAbs. To have discussions about mAb side effects with complete objectivity, the congress was organized independently of any sponsorship from pharmaceutical companies. This academic event was motivated by the high incidence of shocks to cetuximab and the need to compile and evaluate scattered information. This growing public health concern was thus analyzed from different scientific and medical angles. The first session was devoted to acute infusion reactions, with an emphasis on deconvolution of the terms “cytokine-release syndrome,” “cytokine storms,” “anaphylaxis” and their epidemiology. This session concluded with the Charles Richet lecture on cetuximab anaphylaxis and anti-αGal IgE by Thomas Platts-Mills, its discoverer. In the next session, the involvement of anti-glycan antibodies in both anaphylaxis and delayed hypersensitivity reactions to therapeutic antibodies was discussed. A gala dinner was held in the gardens of the beautiful château of Villandry, which was acquired and restored by Joachim Carvalho, a pupil of Charles Richet''s and great-grandfather of the present owner. The final session focused on strategies to prevent cetuximab anaphylaxis in clinical practice included a variety of topics, e.g., premedication, biobetters and biosimilars, skin testing and predictive assays. All speakers and attendees enjoyed this very stimulating and rewarding meeting, which gathered many people with divergent scientific backgrounds and medical specialties.Key words: cetuximab, anaphylaxis, α-Gal epitope, anti-αGal IgE, anti-cetuximab IgE, allergy, monoclonal antibodies, glycosylation     

A review of family-based tests for linkage disequilibrium between a quantitative trait and a genetic marker

Quantitative trait transmission/disequilibrium tests (quantitative TDTs) are commonly used in family-based genetic association studies of quantitative traits. Despite the availability of various quantitative TDTs, some users are not aware of the properties of these tests and the relationships between them. This review aims at outlining the broad features of the various quantitative TDT procedures carried out in the frequently used QTDT and FBAT packages. Specifically, we discuss the “Rabinowitz” and the “Monks-Kaplan” procedures, as well as the various “Abecasis” and “Allison” regression-based procedures. We focus on the models assumed in these tests and the relationships between them. Moreover, we discuss what hypotheses are tested by the various quantitative TDTs, what testing procedures are best suited to various forms of data, and whether the regression-based tests overcome population stratification problems. Finally, we comment on power considerations in the choice of the test to be used. We hope this brief review will shed light on the similarities and differences of the various quantitative TDTs.     

THE MANAGEMENT OF CANCER OF THE BREAST

Radical mastectomy is excellent only for cases of operable breast cancer in which the tumor is limited to the breast or to the nodes in the axilla. That there is metastasis to the internal mammary lymph nodes in a high proportion of cases has been “overlooked” for many years. Also it is probable that metastasis occurs to the supraclavicular lymph nodes more often than is suspected. Hence the extended radical mastectomy operation leaves much to be desired. There has been no significant improvement in recent years in the mortality rate of mammary cancer.Simple mastectomy and thorough adequate postoperative radiation therapy have much to offer.Treatment of “operable” breast cancer should be a cooperative effort of surgeon, radiation therapist and pathologist.     

Studies on Bacterial Pyrogenicity: III. Specificity of the United States Pharmacopeia Rabbit Pyrogen Test

The specificity of the first or “presumptive” portion of the USP rabbit pyrogen test was investigated by use of a new absolute standard of reference. The reference standard was a 0.9% sodium chloride solution prepared to be pyrogen-free. Details of the preparation were described. The hypothesis was explored that the temperature response of rabbits after intravenous injection of the standard solution was independent of exogenous pyrogen. Reactions observed among the rabbits in our colony allowed a classification of these animals ranging from “consistently reliable” to “consistently unreliable.” Details of the experimental results and implications for pyrogen testing are discussed. The recommendation was made that all rabbit test animals be “screened” in sham and actual tests before being used for pyrogen testing.     

An Integrated Approach to Uncover Driver Genes in Breast Cancer Methylation Genomes

Background

Cancer cells typically exhibit large-scale aberrant methylation of gene promoters. Some of the genes with promoter methylation alterations play “driver” roles in tumorigenesis, whereas others are only “passengers”.

Results

Based on the assumption that promoter methylation alteration of a driver gene may lead to expression alternation of a set of genes associated with cancer pathways, we developed a computational framework for integrating promoter methylation and gene expression data to identify driver methylation aberrations of cancer. Applying this approach to breast cancer data, we identified many novel cancer driver genes and found that some of the identified driver genes were subtype-specific for basal-like, luminal-A and HER2+ subtypes of breast cancer.

Conclusion

The proposed framework proved effective in identifying cancer driver genes from genome-wide gene methylation and expression data of cancer. These results may provide new molecular targets for potential targeted and selective epigenetic therapy.     

Modeling spatial–temporal operations with context-dependent associative memories

We organize our behavior and store structured information with many procedures that require the coding of spatial and temporal order in specific neural modules. In the simplest cases, spatial and temporal relations are condensed in prepositions like “below” and “above”, “behind” and “in front of”, or “before” and “after”, etc. Neural operators lie beneath these words, sharing some similarities with logical gates that compute spatial and temporal asymmetric relations. We show how these operators can be modeled by means of neural matrix memories acting on Kronecker tensor products of vectors. The complexity of these memories is further enhanced by their ability to store episodes unfolding in space and time. How does the brain scale up from the raw plasticity of contingent episodic memories to the apparent stable connectivity of large neural networks? We clarify this transition by analyzing a model that flexibly codes episodic spatial and temporal structures into contextual markers capable of linking different memory modules.     

CYTOLOGIC DETECTION OF CERVICAL CANCER—Four Years' Experience with Routine Smear Examination in Private Practice

Simplified Papanicolaou smear techniques appear to be adaptable to private clinical practice when experienced cytodetection laboratory facilities are available. A private physician''s office seems potentially an efficient, economical and practical place for detection of cervical cancer by use of the smear technique as a routine part of examination of patients.In a series here reported upon, examination of 11,207 cervical smears taken at the first examination of patients of all ages led to diagnosis of unsuspected malignant disease in 80 cases—in all instances at a stage when it should be easily curable. Cancer was not detected in examination of 6,060 smears taken later from women who had had a “negative” smear at the time of first examination, which seems to indicate that the first screening was reasonably accurate.In a few cases, early cancer was detected when smears were reported as “atypical” or “suspicious.” Such reports demand as careful follow-up as do “positive” reports.There are dangers and limitations in wide-spread clinical application of screening by this method. Care must be observed in the development of programs for its use lest the potential benefits in early detection be outweighed by the dangers from misuse.     

Mutation to Overproduction of Bacteriophage T4 Gene Products

R9 was isolated as one of several mutations that enhanced the growth of a leaky amber (am) mutant of bacteriophage T4 gene 62 (product required for phage DNA synthesis) under conditions of partial suppression by ribosomal ambiguity. R9 also enhanced the growth of leaky am mutants of some, but not all, other T4 “early” gene functions. R9 mapped between mutations in genes 43 and 62. By using assays involving polyacrylamide slab gel electrophoresis in the presence of sodium dodecyl sulfate, we observed the following. (i) R9 resulted in an overproduction of many T4 “early” proteins in infected cells. The most pronounced effects of R9 were observed when phage DNA synthesis and/or the functions of maturation genes 55 and 33 were not expressed. (ii) In rifampintreated infected cells, the capacity to synthesize T4 “early” proteins decayed more slowly in the presence of the R9 mutation than in the presence of the wild-type counterpart of R9. R9 appeared to have no effect on the rates of RNA synthesis either during early or late times after infection. The results suggest that the R9 mutation leads to increased functional stability of T4 “early” messengers.