Tolerogenic nanoparticles mitigate the formation of anti-drug antibodies against pegylated uricase in patients with hyperuricemia

Biologic drugs have transformed the standard of care for many diseases. However, many biologics induce the formation of anti-drug antibodies (ADAs), which can compromise their safety and efficacy. Preclinical studies demonstrate that biodegradable nanoparticles-encapsulating rapamycin (ImmTOR), but not free rapamycin, mitigate the immunogenicity of co-administered biologic drugs. Here we report the outcomes from two clinical trials for ImmTOR. In the first ascending dose, open-label study (NCT02464605), pegadricase, an immunogenic, pegylated uricase enzyme derived from Candida utilis, is assessed for safety and tolerability (primary endpoint) as well as activity and immunogenicity (secondary endpoint); in the second single ascending dose Phase 1b trial (NCT02648269) composed of both a double-blind and open-label parts, we evaluate the safety of ImmTOR (primary endpoint) and its ability to prevent the formation of anti-drug antibodies against pegadricase and enhance its pharmacodynamic activity (secondary endpoint) in patients with hyperuricemia. The combination of ImmTOR and pegadricase is well tolerated. ImmTOR inhibits the development of uricase-specific ADAs in a dose-dependent manner, thus enabling sustained enzyme activity and reduction in serum uric acid levels. ImmTOR may thus represent a feasible approach for preventing the formation of ADAs to a broad range of immunogenic biologic therapies.

Methotrexate in the therapeutic pathway of patients with psoriasis. Analysis of clinical practice data and comparison with guidelines

Introduction Psoriasis is an inflammatory skin disease with a chronic-relapsing course. It is estimated that the prevalence in Italy is 3%. An adequate model of taking care of the patient with psoriasis allows the patient to benefit from the most suitable treatment option for his health needs. In this position statement the observations, criticalities and proposals for improvement of the Pso-Path Working Group, composed by health economists, clinicians and patients, on the diagnostic-therapeutic pathway of the patient with psoriasis have been collected. In particular, the deviation of clinical practice from the current Guidelines for the management of patients with psoriasis, which recommend the use of biologic drugs in case of non-response, intolerance or contraindication to Methotrexate or Cyclosporine, was evaluated. Method A Working Group was convened whose participants were asked to express their thoughts on the diagnostic and therapeutic pathway of the patient with psoriasis, bringing out critical elements and proposals for improvement, based on their experiences. Conclusion This position statement summarizes the experiences and consensus between clinicians and patients on actions to optimize the management of patients with psoriasis undergoing biological treatment. Compared to the epidemiological data currently available, it is believed that only a small percentage of patients with psoriasis are treated with systemic drugs. The perception of clinicians, according to their experience, confirms the data emerging from the National Report "National Observatory on the Use of Medicines" (Osmed) compiled by AIFA in 2015, according to which more than 77% of patients with psoriasis are started to treatment with biological drugs without a previous use of Methotrexate or Cyclosporine for at least 3 months. The Pso-Path Working Group came to the conclusion that it would be desirable to incentivize, through the formalization of regional guidelines, the creation of a network system that promotes not only a greater awareness, at the territorial level, of the importance and impact of the disease and the possible paths, but also the collaboration and connection between all the actors involved in the overall care of the patient.

The Role of Molecular Modeling and Bioinformatics in Treating a Pandemic Disease: The Case of COVID-19

The COVID-19 pandemic first appeared in Wuhan, China, in December 2019 in a cluster of pneumonia patients. The causative agent was found to be SARS-CoV-2. Here, we are summarizing current treatment strategies and highlighting the role of bioinformatics, molecular modeling, and structural biology during the COVID-19 pandemic. There are different pharmacological treatments, mostly repurposed drugs, employed for the treatment of COVID-19, including antiviral drugs, corticosteroids, biologic drugs, antibiotics, antifungal agents, and anticoagulants. Some immune-based therapies are also under evaluation, including convalescent plasma, IL-1, IL-6 inhibitors, and interferons. Different bioinformatics networks are established to provide information about the structure, transcriptome, and pathogenicity of the virus. The genotyping analysis for SARS-CoV-2 is also useful in identifying different mutations, SNPs, and conservative domains along the viral genome. Cryo-EM and X-ray diffraction had a crucial role in determining the structure of viral proteins such as spike (S) protein, main protease, and RdRp. NMR had a minor role and determining the structure of nucleocapsid (N) protein only. Several docking studies were performed to predict the interaction of certain FDA-approved drugs with known efficacy and toxicity, while others used natural products. Among different study types, in silico drug prediction and repurposing have the lowest risk with less off-target results. Therefore, bioinformatics and in silico studies have an important role during pandemics in providing information about viral structure and function and predicting potential treatments.

A social-economic burden of rhinosinusitis with nasal polyps with comorbid asthma and influence of dupilumab

Rhinosinusitis with nasal polyps (RwNP) is a one of most common comorbidities in asthma and contrariwise and can lead to exacerbation of severe asthma (SA). Dupilumab is a perspective medicine for treatment of both, because it decreases exacerbations and prevents of a necessity of surgeon. Economics aspects of dupilumab treatment in RwNP + SA are not examined yet. Thus aim of this study was evaluation of social-economic burden of RwNP + SA in the Russian Federation and dupilumab influence on it. Materials and methods. Direct medical (cost of medicines, treatment in outpatients department and in hospital, including surgery and rate of exacerbations per year) and non-medical (payment for temporary and stable disability) and indirect costs (GDP loses) in RwNP + SA patients have been evaluated. Medical cure of a patient with RwNP + SA was created according to survey of experts from different regions of Russia. Modelling of expenditures was prepared on all calculated cohort of potential patients with RwNP + SA from “State” position and growing approach. Results. Expenditures for cure of one patient with RwNP were as 234 217,71 RUR/year. Weighted average costs for one patient with RwNP + SA were 1 881 883,39 RUR, and mostly were associated with indirect costs. Dupilumab can decrease expenditures for one patient with RwNP + SA till 1 593 162,87 RUR (on 15,3 %) annually. Potential cohort with RwNP + SA has been estimated above 39 thousand patients. Total economic burden of RwNP + SA in Russia were estimated as 1,7 bln RUR. Dupilumab usage in patients with RwNP + SA fixed in Register can help decrease economic burden on 259 mln RUR annually. Hidden economic burden of comorbidity can reach 73,4 bln RUR (for all calculated / modelled cohort of patients with RwNP + SA), dupilumab saves 11,3 bln RUR annually in this scenario. Conclusion. Comorbid pathology — RwNP+SA has a sufficient social-economic burden in Russia, that could be decreased by modern biologic drugs, in particular, with dupilumab.

Sex-associated and gender-associated differences in the diagnosis and management of axial spondyloarthritis: addressing the unmet needs of female patients

Emerging evidence suggests that axial spondyloarthritis (axSpA) should not be seen as a predominantly male disease, as the non-radiographic form occurs with roughly equal frequency in women and men. However, men and women experience this disease differently. The purpose of this review is to highlight sex-associated and gender-associated differences in the patient’s journey through the diagnosis and management of axSpA, in order to increase the awareness about the unmet needs of female axSpA patients.Female patients experience a longer diagnostic delay compared with men, possibly due to the different pattern of clinical presentations across genders. Therefore, it is crucial to sensitise physicians to pay attention and identify the red flags of axSpA in women and promote early referral to a rheumatologist. Women with a diagnosis of axSpA experience greater limitations in physical function, although they have less structural spinal damage compared with men. Women tend to have less adherence and a lower response to treatment, so more gender-oriented data are needed about drugs used for axSpA, especially biological disease-modifying antirheumatic drugs.Lifestyle factors have a strong impact on the disease course. Interventions regarding physical activity, smoking cessation and diet should be communicated to the patients, with particular attention to the gender-related cultural background.Patients of childbearing age living with axSpA should be engaged in a discussion about reproductive health, in terms of preservation of fertility, management of pregnancy and delivery and use of biologic drugs during pregnancy and breastfeeding.

Genetically Engineered Biologic Drugs in Management of Children with Bronchial Asthma

Current article represents the modern clinical guidelines on management of severe bronchial asthma (BA) in children and practical use of genetically engineered biologic drugs. Clinical efficacy and safety of omalizumab has its special role. Efficacy analysis was carried out in real-life' clinical setting (considering high economical expenses of biological treatment) to estimate effective response predictors and principles of patients selection for such therapy. Two years of anti-IgE treatment experience in inpatient pediatric department settings demonstrates that omalizumab inclusion to treatment of children with severe asthma resistant to standard therapy allows to solve asthma symptoms, to forgo high doses inhaled glucocorticosteroids, to improve lung function parameters, and to increase significantly quality of life in 95% of our patients.

Biosimilar approval and checkpoints

Biologic drugs and subsequently developed biosimilars treat chronic inflammatory autoimmune conditions such as rheumatoid or psoriatic arthritis, ankylosingspondylitis, crohn's disease, ulcerative colitis, and psoriasis. Biologics can target the cancer in a specific way and may work synergistically with chemotherapy to improve outcome. It is expected that in the next five years, 50% of biological products will originate from biotechnology. Biological products, including those manufactured by biotechnology, tend to be heat sensitive and susceptible to microbial contamination. There are no expected clinically meaningful differences in efficacy and safety between a biosimilar and the biologic drugs which are authorized for sale. The global market for Biosimilars is dominated by oncology (nearly 39% share) whereas the total biosimilar market size is expected to reach nearly 70 billion by 2025. Biosimilars are generally marketed at prices 25 to 40 percent below original branded productsie Biologics. The number of biosimilars approved by US FDA are nearly 30. There are about 25 top global manufacturers of biosimilars. Many Domestic companies in India are making strong presence even in regulated markets. (BPCIA) guidelines in the United States (US), mention that a biosimilar can be designated as “interchangeable”, whereby it may be substituted for the reference product (original biological drug).

Genetically Engineered Biologic Drugs in Management of Children with Bronchial Asthma

Current article represents the modern clinical guidelines on management of severe bronchial asthma (BA) in children and practical use of genetically engineered biologic drugs. Clinical efficacy and safety of omalizumab has its special role. Efficacy analysis was carried out in real-life' clinical setting (considering high economical expenses of biological treatment) to estimate effective response predictors and principles of patients selection for such therapy. Two years of anti-IgE treatment experience in inpatient pediatric department settings demonstrates that omalizumab inclusion to treatment of children with severe asthma resistant to standard therapy allows to solve asthma symptoms, to forgo high doses inhaled glucocorticosteroids, to improve lung function parameters, and to increase significantly quality of life in 95% of our patients.