Current Pharmaceutical Design - Volume 23, Issue 44, 2017

Background: Biological products are subject to constant reappraisal by regulatory agencies and pharmaceutical companies once they have entered the market, since every improvement in their manufacturing process has the potential to alter the basic properties of these molecules. Methods: Narrative review focusing on scientific literature as well as legal documents from regulatory agencies. Results: Evaluating the impact of each manufacturing change of these drugs requires rigorous analyses in proportion to the anticipated risk of inducing more or less molecular micro-heterogenicity. There are currently more than 30 biosimilars of TNF-α blockers at different stages of testing, each with a specific manufacturing process. Although the initial demonstration of biosimilarity is now a well-established exercise, it does not guarantee that successive manufacturing changes will not result in a widening gap between drifted/evolved innovators and drifted/evolved biosimilars, as well as among the different biosimilars of a given original biologic. Conclusion: Given the structural complexity of TNF-α blockers—as well as of other biologic drugs included in the armamentarium of systemic inflammatory diseases—regulatory agencies should make available to the practitioner, in a simple and constantly updated way, all available data regarding quality standards of both original molecules and biosimilars. Furthermore, they should strive to guarantee that, once a compound has received approval, it maintains a level of consistency throughout its commercial life in order to maintain and increase confidence in these valuable drugs.

The expiry of the patent of several leading biological medicinal products has led to a surge in the development of ‘biosimilar’ products. However, in contrast to generic small-molecule medicines, biosimilars are not identical to their reference medicinal products. Full comparability in quality as well as in preclinical and clinical issues is required to register a biosimilar. The potential to induce antidrug antibodies after treatment with biological medicinal products is a safety issue that is an important consideration in the development of biosimilars and a critical aspect of regulatory filings. Regulatory authorities in the European Union require antidrug antibody responses to be evaluated and to be approached from a safety perspective: the higher the potential of immunogenicity to adversely affect a patient's health, the more diligently one should clarify the immunogenicity of the product. So far, however, no specific recommendations were given on a method for risk assessment or on the extent of the requisite antidrug antibody characterization. In this review, we will discuss the current state of knowledge on biosimilar products of infliximab, adalimumab and etanercept and present risk level–based schemes for the investigations of antidrug antibodies in non-clinical, clinical and pharmacovigilance studies.

Background: Biologic drugs have revolutionised the management of many inflammatory conditions. Patent expirations have stimulated development of highly similar but non-identical molecules, the biosimilars. Extrapolation of indications is a key concept in the development of biosimilars. However, this has been met with concerns around mechanisms of action, equivalence in efficacy and immunogenicity, which are reviewed in this article. Methods: Narrative overview composed from literature search and the authors' experience. Literature search included Pubmed, Web of Science, and online document archives of the Food and Drug Administration and European Medicines Agency. Results: The concepts of biosimilarity and extrapolation of indications are revisited. Concerns around extrapolation are exemplified using the biosimilar infliximab, CT-P13, focusing on mechanisms of action, immunogenicity and trial design. The opportunities and cautions for using biologics and biosimilars in unlicensed inflammatory conditions are reviewed. Conclusions: Biosimilars offer many potential opportunities in improving treatment access and increasing treatment options. The high cost associated with marketing approval means that many bio-originators may never become licenced for rarer inflammatory conditions, despite clinical efficacy. Biosimilars, with lower acquisition cost, may improve access for off-label use of biologics in the management of these patients. They may also provide opportunities to explore off-label treatment of conditions where biologic therapy is less established. However, this potential advantage must be balanced with the awareness that off-label prescribing can potentially expose patients to risky and ineffective treatments. Post-marketing surveillance is critical to developing long-term evidence to provide assurances on efficacy as well as safety.

Background: Infliximab biosimilars are the first biosimilars of monoclonal antibodies approved by the main regulatory agencies. Up to the present day, two infliximab biosimilars have been approved: CT-P13 (Celltrion), and SB2 (Biogen), but other companies have been developing candidate infliximab biosimilars that are on clinical trials: PF 06438179 (Pfizer), the ABP710 (bioCentury/Amgen) the BCD055 (JSC Biocad Russica) and BOW015 (Epirus). Methods: We have made a literature search in MedLine database using the key words [Infliximab] and [biosimilars] and [rheumatic diseases] and [rheumatisms]. We have also made a search in the clinicaltrials.org website. Conclusions: Clinical data published so far have provided important evidence on long-term efficacy and safety, immunogenicity and switching, supporting the use of CT-P13 and SB2 for the treatment of rheumatic diseases. In addition, the European experience has proved the economic advantages of the incorporation of infliximab biosimilars in clinical practice. Despite the widespread use of infliximab biosimilars there is still a lack of data regarding interchangeability between reference products and biosimilars.

Background: biosimilars are similar versions of existing innovator biologic agents but with distinct manufacturing processes. They were approved in inflammatory bowel disease (IBD) by extrapolation of indication from rheumatic diseases. As regulatory requirements for biosimilar approval focus on pre-clinical evidence of similarity rather than clinical data on efficacy, safety and immunogenicity, it is critical to review clinical evidence supporting their use in IBD in order to overcome reluctance from patients and clinicians alike. Objective: to review clinical studies using infliximab (IFX) biosimilars in IBD. Method: we reviewed PubMed for original articles published up to July 1st 2017, reporting data on efficacy and/or safety of IFX biosimilars in IBD. Results: 23 observational studies were found, 12 of them assessing switch from IFX originator to biosimilar and 17 assessing induction therapy with IFX biosimilar. Efficacy, safety and immunogenicity were compared, generally yielding similar results for originator and biosimilar IFX. So far only one randomized controlled trial assessed switching from originator to biosimilar IFX and it was not powered to show similarity in IBD. Ongoing trials are comparing IFX biosimilar and originator head to head in patients in remission, as well as switch versus reverse-switch. Current IBD clinical guidelines are discussed as well as future perspectives for biosimilars in IBD. Conclusion: observational studies seem to confirm biosimilarity in a real-world clinical setting. Current trials are expected to elucidate the remaining doubts about clinical biosimilarity.

Background: Biological drugs represent highly effective but costly treatments for chronic immunemediated inflammatory diseases posing substantial burden on health care budgets. Introduction of biosimilars since 2013 has brought forward the potential of market competition, and as a societal benefit, the hope of increased access at a lower cost. Objective: We aim to provide a descriptive review on economic aspects and market changes related to the introduction of biosimilar drugs. Method: Our focus is on chronic immune-mediated inflammatory conditions in rheumatology, gastroenterology and dermatology. Based on available literature data, we discuss the determinants of access to biological treatment, summarize the available health economic evidences with special focus on cost-utility and budget impact analyses. Market penetration of biosimilars and their overall impact on biological markets are analyzed. Results: Biosimilar markets are country specific due to differences in the regulatory and reimbursement systems. Cost-utility analyses suggest, that given the lower price of biosimilars, formerly established biological treatment sequence practices and the eligibility criteria for biological treatment deserve reconsideration. Budget impact analyses forecasted significant budget savings in various diagnoses and countries, providing opportunity for the treatment of more patients. Conclusion: Biosimilars may contribute to better patient-access and provide savings to governments. To increase their acceptability, further clinical evidences and real world experiences are needed, as well as education of physicians and patients. The high biosimilar penetration rates in Norway, Denmark and Poland suggest that policies which support interchanging from the reference product may be important drivers of biosimilar uptake.

Background: Biosimilars have the potential to create competition, lower costs, and increase patient access to biological medications. However, biological medications are sensitive to their manufacturing processes and difficult to precisely characterize, leading to questions about substitution and interchangeability among products. Methods: This article reviews the role of biosimilars in patient access to therapeutic antibodies. Results: Although pathways for the approval of biosimilars have been developed, important issues remain unresolved. Interchangeability, or the designation of one medicine as clinically similar to and/or substitutable for another, is specified in some countries but restricted or awaiting policy resolution in others. Non-medical switching, or the switching among biological medications to select a less expensive product, for reasons unrelated to patient health and safety, is controversial because of the potential for complications related to repeated switching (e.g., immunogenicity and loss of therapeutic effect), and transfer of prescribing responsibility for patient medications from the physician to the insurance company. Although biosimilars have different names in different countries, the World Health Organization (WHO) calls for nomenclature that incorporates the international nonproprietary name of the original biological medication followed by a distinguishing suffix qualifier. Naming consistency across countries seems sensible, and adoption of the WHO recommended suffix would greatly simplify pharmacovigilance. Conclusions: Support for the WHO proposal is advised by numerous stakeholders, and resolution of the remaining outstanding issues is urged so that patients and physicians can safely access biosimilars.

A review of applications of the Immobilized Artificial Membrane (IAM) chromatography in drug discovery is given. IAM chromatography is presented as a tool to predict the interactions of solutes with biomembranes, blood-brain barrier permeability, volume of distribution, oral and skin absorption of drugs and compared to other in vitro techniques used to study drug bioavailability (caco-2 cells, liposome partition). Unbound phosphatidylcholine based stationary phases are also discussed. Some new trends and ideas in the IAM chromatography are presented.

Hypertension can be referred to as modern scourge in 2017 and although, it seems that an improvement has been done during the passage of time, the full treatment still remains an unmet achievement for clinicians. Hypertension incidence in Mediterranean countries, especially Greece and Turkey, seems to be increasing irrespective of the expected protective effect of Mediterranean diet. The changed lifestyle and dietary habits of both populations led to advanced cardiovascular events and arteriosclerosis both of which are linked with high blood pressure. From statistic aspect, as in this work reviewed, it has been found out that gender, age, sociodemographic characteristics and geographical location could promote the hypertension prevalence. Given the above, as well as the fact that the current pharmaceutical formulations do not present the optimal results on hypertension management, summing up the ongoing research on hypertension field is in high demand. Consequently, the development of novel solutions for high blood pressure management either with new synthesized drugs or fascinated drug delivery systems is required. Moreover, adopting healthy lifestyle and diet also plays a crucial role against hypertension. This review is aimed at assisting researchers working on hypertension management by summarizing update guidelines, various case reports describing hypertension related with other diseases, current medications and newly synthesized drug delivery systems recently found in literature.

Background: Platelet endothelial aggregation receptor 1 (PEAR1) may affect platelet-platelet contact and aggregation. The aim of this study was to assess the association between PEAR1 polymorphisms and risks of platelet aggregation. Methods: We searched the PubMed, EmBase, and Cochrane Library electronic databases for articles published through November 30th. 2016. Meta-analysis was performed to examine the relationship between PEAR1 and platelet aggregation and sensitivity analysis by removing individual study from meta-analysis. We collected and analyzed the results of 5 trials involving 5466 patients. Results: Our results demonstrated that the G allele of rs12041331 was associated with a greater platelet aggregation by multiple agonists, both in the presence and absence of antiplatelet drugs, in several separate cohorts of different ethnicities along with an apparent allelic dose–response effect. However, the results of studies on rs2768759 locus were inconsistent and further studies are required. In the presence or absence of antiplatelet drugs treatment, the lowest platelet aggregation was observed in rs2768759 wild-type (AA) patients, followed by heterozygous (AC) and homozygous mutant (CC). Conclusion: PEAR1 rs12041331 is associated with platelet function and antiplatelet drug pharmacodynamics. Future studies on relationship between single nucleotide polymorphisms of PEAR1 and incidence of cardiovascular diseases are required.

Epigenetic modifications regulate chromatin folding and function. Epigenetic mechanisms regulate transcription mediating effects of various stimuli on gene expression. These mechanisms are involved in transcriptional control in various physiological and pathological conditions including neuropsychiatric disorders and behavioral abnormalities such as depression. In rodents, exposure to chronic social stress was shown to induce behavioral impairments and memory/learning deficits that resemble depressive-like phenotype in humans. The rodent models of chronic stress were widely used to study molecular mechanisms of depression. In these models, early exposure to chronic stress such as prenatal or postnatal stress induces long-term hyperactive stress responses, behavioral abnormalities, and functional impairments in brain function that persist in adulthood. Furthermore, these alterations can be transmitted to offspring of chronically stressed animals across several generations. Molecular studies in animal models showed that chronic stress induces stable epigenetic changes in specific brain regions, primarily in the limbic system. These changes lead to long-lasting abnormalities in behavior that persist in adulthood and can be transmitted to offspring. Treatment with epigenetically active antidepressants disrupts the abnormal stress-induced epigenetic programming and provides epigenetic patterns that resemble epigenetic background of stress resilient individuals.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications in inflammatory illnesses. However, the gastrointestinal bleeding and toxicity associated with NSAIDs long term use prompted the quest towards investigations for new anti-inflammatory agents. Natural and natural-derived molecules proved its anti-inflammatory efficacy in vitro as well as in vivo. Given this background, the scope of this research involves structural changes of the natural polyphenol (tyrosol) generating two new salicylate derivatives and testing their biological properties, focusing on anti-inflammatory effects assessed in vitro and in vivo assays. The first molecular modification was the introduction of a carboxylic acid group adjacent to the phenol group present in this compound, which creates a new salicylate-like tyrosol. In addition, the acetylation of phenol group in this molecule produced an acetylsalicylate derivative, which may be regarded as aspirin-like natural polyphenol. Interestingly, tyrosol and its novel derivatives attenuated the edema in acute inflammatory response on carrageenan- induced local inflammation in mice. In addition, our results demonstrated that tyrosol and its novel derivatives were able to reduce the chemotaxis of neutrophil assessed in vitro model by chemo attractant (fMLP). Furthermore, only derivative 2 was able to reduce this effect in the acute inflammatory model. In (DPPH)- scavenging activity, tyrosol derivatives demonstrated a minor antioxidant activity, which may suggest that radical scavenging is not a major pathway involved in the anti-inflammatory effects of these derivatives. Salicylate-like tyrosol derivatives are of particular interest for future studies.