Pharmacogenomics: An Update on Biologics and Small-Molecule Drugs in the Treatment of Psoriasis.
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ABSTRACT:
SUBMITTER: Caputo V
PROVIDER: S-EPMC8470543 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although initially described as an anti-tumor mediator, tumor necrosis factor-alpha (TNF) is generally considered as the master pro-inflammatory cytokine. It plays a crucial role in the pathogenesis of inflammatory diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease, ankylosing spondylitis (AS), and psoriasis. Consequently, anti-TNF therapy has become mainstay treatment for autoimmune diseases. Historically, anti-inflammatory agents were developed before the identification of TNF. Salicylates, the active components of Willow spp., were identified in the mid-19th century for the alleviation of pain, fever, and inflammatory responses. Study of this naturally occurring compound led to the discovery of aspirin, which was followed by the development of non-steroidal anti-inflammatory drugs (NSAIDs) due to the chemical advances in the 19th-20th centuries. Initially, the most of NSAIDs were organic acid, but the non-acidic compounds were also identified as NSAIDs. Although effective in the treatment of inflammatory diseases, NSAIDs have some undesirable and adverse effect, such as ulcers, kidney injury, and bleeding in the gastrointestinal tract. In the past two decades, anti-TNF biologics were developed. Drugs belong to this class include soluble TNF receptor 2 fusion protein and anti-TNF antibodies. The introduction of anti-TNF therapeutics has revolutionized the management of autoimmune diseases, such as RA, psoriatic arthritis (PsA), plaque psoriasis (PP), AS, CD and ulcerative colitis (UC). Nevertheless, up to 40% of patients have no response to anti-TNF treatment. Furthermore, this treatment is associated with some adverse effects such as increased risk of infection, and even triggered the de novo development of autoimmune diseases. Such harmful effect of anti-TNF treatment is likely caused by the global inhibition of TNF biological functions. Therefore, specific inhibition of TNF receptor (TNFR1 or TNFR2) may represent a safer and more effective treatment, as proposed by some recent studies. In this review article, the historical development of anti-inflammatory drugs after World War II as briefly described above will be reviewed and analyzed. The future trend in the development of novel TNF receptor-targeting therapeutics will be discussed in the context of latest progress in the research of TNF biology.
| S-EPMC5506195 | biostudies-other
Project description:Psoriasis is a common immune-mediated chronic skin disease. Disease severity is influenced by several factors including the extent and localization of skin lesions, severity of pruritus and comorbidities, such as psoriatic arthritis. Moderate to severe psoriasis is defined when cutaneous involvement is diffuse, covering more than 10% of the body surface areas and/or involving the sensitive areas such as face, genitalia, folds or nails or has high impact on patients' quality of life, and it occurs in approximately 15% of cases. In recent years, a growing understanding of psoriasis pathophysiology allowed the development of an increasing number of effective and safe treatments, including biologicals that are indicated for moderate to severe psoriasis. Different classes of biologicals have been already approved, including TNF-α (etanercept, infliximab, adalimumab and certolizumab pegol), IL-12/23 (ustekinumab), IL-17 (secukinumab, ixekizumab, brodalumab) and IL-23 (guselkumab, risankizumab, tildrakizumab) inhibitors. The objective of this narrative review is to revise efficacy and safety data of the latest biologicals, small oral molecules and biosimilar drugs for the treatment of chronic plaque psoriasis at Phase III of clinical development. The latest IL-17 and IL-23 inhibitors include bimekizumab, netakimab and mirikizumab as well as oral small molecules, such as deucravacitinib, a tyrosine kinase 2 selective inhibitor, and piclidenoson, an agonist of the Gi protein-associated A3 adenosine receptor. Additional molecules are in an early phase of development. Highly promising biologicals and small oral molecules are the leading edge of the systemic treatment of psoriasis.
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Project description:Inflammatory bowel disease (IBD) is a spectrum of immune-mediated inflammatory disorders with a complex multifactorial pathogenesis, where different pathways may predominate in different individuals. This complexity will most likely require a panoply of drugs targeting different pathways if one wants to treat to steroid-free sustained remission and mucosal healing. Presently, the mainstay of medical management of IBD is based on 5-aminosalicylates, corticosteroids, thiopurines, methotrexate, antitumor necrosis factor, anti-alpha4 beta7 (α4β7) integrin and anti-interleukin (IL)-12/IL-23 therapies. The discovery of new pathways involved in the pathogenesis of IBD resulted in new drugs targeting Janus kinase/signal transducers and activators of transcription, IL-6, spingosine-1-phosphate, and phosphodiesterase 4, among others. These new therapies might result in more advantageous safety profiles. Several of these new drugs have already been successfully tested in other inflammatory disorders, such as psoriasis or rheumatoid arthritis. In this review, evidence from phase II and phase III randomized controlled clinical trials in patients with IBD involving new biologicals and small molecules are summarized.
| S-EPMC6537282 | biostudies-literature
Project description:Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.
| S-EPMC6025289 | biostudies-literature
Project description:Electron cryo-microscopy (cryo-EM) is a powerful technique for the structural characterization of biological macromolecules, enabling high-resolution analysis of targets once inaccessible to structural interrogation. In recent years, pharmaceutical companies have begun to utilize cryo-EM for structure-based drug design. Structural analysis of integral membrane proteins, which comprise a large proportion of druggable targets and pose particular challenges for X-ray crystallography, by cryo-EM has enabled insights into important drug target families such as G protein-coupled receptors (GPCRs), ion channels, and solute carrier (SLCs) proteins. Structural characterization of biologics, such as vaccines, viral vectors, and gene therapy agents, has also become significantly more tractable. As a result, cryo-EM has begun to make major impacts in bringing critical therapeutics to market. In this review, we discuss recent instructive examples of impacts from cryo-EM in therapeutics design, focusing largely on its implementation at Pfizer. We also discuss the opportunities afforded by emerging technological advances in cryo-EM, and the prospects for future development of the technique.
| S-EPMC8786282 | biostudies-literature
Project description:Background: The response time-course information of biologics and small targeted molecules for the treatment of moderate to severe plaque psoriasis which helps clinicians to understand the onset of action and maintenance of effect are unclear. Quantitative information about the efficacy comparation of different systemic agents are needed. Methods: Model-based meta-analysis was conducted and longitudinal models were developed by applying two clinical end points commonly reported in the clinical trials of psoriasis: the proportion of patients achieving ≥75% reduction from baseline Psoriasis Area and Severity Index score (PASI75) and the proportion of patients achieving ≥90% reduction from baseline Psoriasis Area and Severity Index score (PASI90). Results: A total of 80 trials of thirteen biological agents and four small targeted molecules covering 235 treatment arms and 40323 patients with moderate to severe plaque psoriasis were included in this analysis. The drugs were divided into five classes of biologics and three classes of small molecules. Two longitudinal models of PASI75 and PASI90 were used to describe the time-varying drug effect and dose-effect relationship. The typical response-time courses for PASI75 and PASI90 increased over time and finally reached to the platform. For PASI75 end point at week 12, of all the therapeutic drugs, risankizumab administered as 150 mg at week 0, week 4, and q12w showed the most efficacious with PASI75 was 85.95% (95%CI, 75.71-92.60%), followed by ixekizumab administered as 160 mg at week 0, and q4w with PASI75 was 85.9% (95%CI, 76.12-92.79%). As for PASI90 end point at week 12, ixekizumab 160 mg at week 0, and q4w showed the greatest percentage of person achieved PASI90 (67.2%; 95%CI, 49.91-77.2%), followed by risankizumab 150 mg at week 0, week 4, and q12w (65.5%; 95%CI, 47.8-75.7%). What's more, the risankizumab provided the highest response of PASI90 at week 16 and week 24. Conclusions: This study provided a quantitative efficacy comparation of 17 systemic agents for psoriasis in term of efficacy only and that safety was not considered. Risankizumab and ixekizumab showed superiority for both the two end points.
| S-EPMC8281289 | biostudies-literature
Project description:BackgroundPsoriasis is an immune-mediated inflammatory disease for which treatment has evolved over the past few years due to the introduction of immunobiologic and small molecule inhibitor medications. A better understanding of the comparative efficacies of drugs may help doctors to choose the most appropriate treatment for patients.ObjectiveThe aim of this study was to conduct a systematic review and meta-analysis to assess the efficacy of immunobiologic and small molecule inhibitor drugs for patients with moderate to severe psoriasis.Data sourcesThe EMBASE, PUBMED, LILACS, Web of Science and ClinicalTrials.org databases were searched for trials published to 21 July 2016.Study selectionOnly randomized, double-blind, placebo-controlled clinical trials that evaluated the efficacy of immunobiologics or small molecule inhibitors for moderate to severe plaque-type psoriasis were selected by two independent authors. No restrictions were used.Data extraction and synthesisTwo authors independently extracted the data and a random-effects model meta-analysis was performed.Main outcomes and measuresThe Psoriasis Area and Severity Index (PASI) 75 was considered the primary outcome, measured at the primary endpoint of each study.ResultsThirty-eight studies were included in our analysis. The overall pooled effect favored biologics and small molecule inhibitors over placebo (risk difference [RD] 0.59, 95% confidence interval [CI] 0.58-0.60). Ixekizumab at a dose of 160 mg on week 0 and then every 2 weeks (RD 0.84, 95% CI 0.81-0.88), brodalumab 210 mg (RD 0.79, 95% CI 0.76-0.82), infliximab 5 mg/kg (RD 0.76, 95% CI 0.73-0.79), and secukinumab 300 mg (RD 0.76, 95% CI 0.71-0.81) showed a greater chance of response (PASI 75) when compared with placebo.LimitationsThe methodology of a traditional meta-analysis does not allow for drugs to be ranked. Included studies used short-term endpoints (10-16 weeks) to evaluate the primary outcome, therefore long-term efficacy could not be determined.Conclusions and relevanceThe anti-IL-17 drugs brodalumab, ixekizumab and secukinumab showed an equal or greater chance of helping patients achieve a 75% improvement on PASI compared with other reviewed drugs.
| S-EPMC5318320 | biostudies-literature
Project description:BackgroundThe Dermatology Life Quality Index (DLQI) is commonly used to assess the quality of life of patients with skin diseases. Clinical trials confirm the positive effect of the use of biologics and new molecules on the quality of life of patients with plaque psoriasis.Main objectivesInvestigation of the effect of infliximab, adalimumab, ixekizumab, secukinumab and tofacitinib on Health-Related Quality of Life (HRQOL) measured by the DLQI in adult plaque psoriatic patients with respect to the patients' race, type of used agent/placebo, agent's dosage and treatment duration as well as the DLQI score prior to and after commencement of treatment.Material and methodsSystematic literature searching for referential papers written in English using four databases: PubMed, EMBASE, Scopus, ClinicalTrials.gov as well as and manual searching (Google) Cochran's (Q) and I2 tests were used for evaluation of heterogeneity or the degree of variation in the true effect size estimates between the analysed studies. The standardized mean difference (the SMD; Hedge's g score) was applied to measure the differences between the two means (i.e. two groups: treated vs non-treated or treated vs placebo). The data coding and Hedge's g values were calculated according to the guidance of MetaXL software version 5.3.Main results43 studies, in total 25,898 individuals, were evaluated by the DLQI and weighted mean scores were derived for the analysis. The mean DLQI scores ranged from 6.83 to 17.8 with the overall DLQI score of 12.12 (95%CI: 11.24 to 13.06). A random-effects model demonstrated significant considerable heterogeneity of the study results (I2 = 98%; p<0.001).ConclusionInfliximab, adalimumab, ixekizumab, secukinumab and tofacitinib in adult plaque psoriatic patients improved HRQOL measured by the DLQI. The patients with lower quality of life before treatment obtained better results.
| S-EPMC7714099 | biostudies-literature
Project description:Some Network Meta-analysis (NMA) has been published regarding atopic dermatitis (AD). These studies have considered drugs under investigation both in monotheraphy or in combination with topical corticosteroids, as well as systemic immunosuppressant therapies. The objective of this study is to evaluate the efficacy and safety of biological agents and small molecules in AD. A systematic review and NMA of biologics agents and small molecules in AD was performed. A literature search was performed using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for clinical trials and systematic reviews between January 2000 and 19 December 2020. Only randomized clinical trials (RCTs) were included. It was limited to English language and adult human subjects. Two networks were evaluated: monotherapy and combination with TCS. The two primary outcomes were Eczema Area and Severity Index (EASI) 75 and EASI 90 change from baseline to week 12-16, depending on source study cut-off. The Cochrane's Risk of Bias tool 2011 update was used to analyze the risk of bias, focused on the primary objectives. 30 RCTs (included in 26 publications) were included in the systematic review. Finally, 23 RCTs were included in the quantitative analysis (14 RCTs including 3582 patients in monotherapy; and 9 RCTs including 3686 patients with TCS). In monotherapy, a higher percentage of patients achieving EASI-75 was obtained with Upadacitinib 30 mg [OR: 18.90 (13.94; 25.62)] followed by Abrocitinib 200 mg [OR = 11.26 (7.02; 18.05)] and Upadacitinib 15 mg [OR: 10.89 (8.13; 14.59)]. These results were also observed in studies where the use of topical corticosteroid (TCS) was allowed (OR Upadacitinib 30 mg = 9.43; OR Abrocitinib 200 mg = 6.12; OR Upadacitinib 15 mg = 5.20). Regarding IGA, the percentage of patients achieving IGA0/1 was higher with both doses of Upadacitinib 30 mg [OR: 19.13 (13.14; 27.85)] and 15 mg [OR = 10.95 (7.52; 15.94). In studies where the use of TCS were allowed, however, the dose of Abrocitinib 200 mg [OR = 6.10 (3.94; 9.44)] showed higher efficacy than Upadacitinib 15 mg [OR = 5.47 (3.57; 8.41)]. Regarding safety, the drugs with the highest probability of presenting adverse effects were the Janus kinases (JAK) inhibitors, Upadacitinib and Abrocitinib in monotherapy and Baricitinib in combination with TCS. Some risks of bias have been found, which must be taken into account when interpreting the results. The funnel plot shows a possible publication bias that may underestimate the efficacy of drugs. Upadacitinib and Abrocitinib are the drugs with the highest efficacy, both in monotherapy and in association with TCS. However, they were also those associated with the highest risk of adverse effects, showing monoclonal antibodies better safety profile. We have included molecules still in the development phase as well studies completed and presented at conferences and with data available in Trialsgov® but not published yet. Several molecules' development had included a small number of patients from 12 to 17 years of age, without being able to differentiate the results from the adult population. Other: Founding: None. PROSPERO database registration number CRD42021225793.
| S-EPMC8470048 | biostudies-literature
Project description:PoSSuM (http://possum.cbrc.jp/PoSSuM/) is a database for detecting similar small-molecule binding sites on proteins. Since its initial release in 2011, PoSSuM has grown to provide information related to 49 million pairs of similar binding sites discovered among 5.5 million known and putative binding sites. This enlargement of the database is expected to enhance opportunities for biological and pharmaceutical applications, such as predictions of new functions and drug discovery. In this release, we have provided a new service named PoSSuM drug search (PoSSuMds) at http://possum.cbrc.jp/PoSSuM/drug_search/, in which we selected 194 approved drug compounds retrieved from ChEMBL, and detected their known binding pockets and pockets that are similar to them. Users can access and download all of the search results via a new web interface, which is useful for finding ligand analogs as well as potential target proteins. Furthermore, PoSSuMds enables users to explore the binding pocket universe within PoSSuM. Additionally, we have improved the web interface with new functions, including sortable tables and a viewer for visualizing and downloading superimposed pockets.
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