7196 research outputs found
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Sustainability as a trigger for innovation !
No full textThere is now not a single day without alarming news of climate change, or the unsustainable pace at which the world is growing. It is our responsibility, of each of us scientists especially, and collectively within our respective organizations, to change the culture, to offer disruptive options to dramatically revert the unsustainable practices, and to encourage these courageous changes. Around the end of 2010, We, at Novartis, actively started to tackle the environmental issues rightly raised by the legislation. Of paramount importance to us was the improper usage of toxic substances, and more specifically of the highly common polar aprotic solvents flagged to be reprotoxic. The REACH legislation and its Substance of Very High Concern arm especially prompted us to act in a strategic way.[1] About a dozen of projects of various levels of ambition and scope were started, either internally, or externally with chemical suppliers and vendors, along with academic collaborators. We investigated the potential of supercritical media ,[2] evaluated various amphoteric solvents in an unbiased manner (collaboration Fribourg), promoted the development of more desirable alternatives ,[3] and more generally as will be explained in the following manuscript on developing a toolbox of chemistry in bulk water. For this latter approach, we were obviously strengthening our arsenal of biocatalytic tools, and complemented this aspect with a de novo toolbox of surfactant-mediated chemistry
Tim-3 finds its place in the cancer immunotherapy landscape
No full textThe blockade of immune checkpoint receptors has made great strides in the treatment of major cancers, including melanoma, Hodgkin's lymphoma, renal, and lung cancer. However, the success rate of immune checkpoint blockade is still low and some cancers, such as microsatellite-stable colorectal cancer, remain refractory to these treatments. This has prompted investigation into additional checkpoint receptors. T-cell immunoglobulin and mucin domain 3 (Tim-3) is a checkpoint receptor expressed by a wide variety of immune cells as well as leukemic stem cells. Coblockade of Tim-3 and PD-1 can result in reduced tumor progression in preclinical models and can improve antitumor T-cell responses in cancer patients. In this review, we will discuss the basic biology of Tim-3, its role in the tumor microenvironment, and the emerging clinical trial data that point to its future application in the field of immune-oncology
Data driven CRO benchmarking for biomarker analysis
No full textOutsourcing is a common strategy across the Pharmaceutical industry and clinical research. Clinical Research Organizations (CRO) offer many choices for selecting outsourcing partners for bioanalytical and biomarker support. We aimed this paper to provide critical insights into CRO benchmarking and selection using a bioanalytical challenge approach performing fit-for-purpose ligand binding assay.
Bioanalytical challenge (method validation and sample analysis) offer sponsors a great opportunity to stress test CRO technical and scientific competency, quality systems and operational capabilities. In addition, CROs demonstrated their real-life performance in communication, time management, and cost – key contributors to a successful sponsor-CRO partnership. Benchmarking CROs based on objective assay data and real-life experiences will help support sponsors to make better-informed decisions in vendor selection
An Artificial Intelligence Approach to Proactively Inspire Drug Discovery with Recommendations.
No full textArtificial intelligence (AI) is becoming established in drug discovery. For example, many in the industry are applying machine learning approaches to target discovery or to optimize compound synthesis. While our organization is certainly applying these sorts of approaches, we propose an additional approach: using AI to augment human intelligence. We have been working on a series of recommendation systems that take advantage of our existing laboratory processes, both wet and computational, in order to provide inspiration to our chemists, suggest next steps in their work, and automate existing workflows. We will describe five such systems in various stages of deployment within the Novartis Institutes for BioMedical Research. While each of these systems addresses different stages of the discovery pipeline, all of them share three common features: a trigger that initiates the recommendation, an analysis that leverages our existing systems with AI, and the delivery of a recommendation. The goal of all of these systems is to inspire and accelerate the drug discovery process
A study of the effect of cyclosporine on fevipiprant pharmacokinetics and its absolute bioavailability using an intravenous microdose approach
No full textThis drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/ mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios [90% confidence interval (CI)] for oral fevipiprant with or without cyclosporine were 3.02 (2.38, 3.82) for Cmax, 2.50 (2.17, 2.88) for AUClast, and 2.35 (1.99, 2.77) for AUCinf. The geometric mean ratios (90% CI) for fevipiprant intravenous microdose with or without cyclosporine were 1.04 (0.86, 1.25) for Cmax, 2.04 (1.83, 2.28) for AUClast, and 1.95 (1.76, 2.16) for AUCinf. The absolute bioavailability for fevipiprant was approximately 0.3 to 0.4 in the absence and 0.5 in the presence of cyclosporine. The intravenous microdose allowed differentiation between systemic and presystemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately twofold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant, whereas P-gp does not have a relevant effect on oral absorption
Lack of evidence for expression and function of IL-39 in human immune cells
No full textMembers of the IL-6/IL-12 cytokine family are critical regulators of innate and adaptive immunity and have emerged as key players controlling inflammatory and autoimmune disorders. This cytokine family is comprised of IL-12, IL-23, IL-27, and IL-35 and the members consists of distinct α- and β-cytokine subunits and form heterodimers. A new member belonging to this family, IL-39, was identified in the murine system and was shown to consist of the IL-23p19 and Epstein-Barr Virus-induced 3 (EBI3) subunits. Subsequently, it was shown that IL-39 was implicated in the immunopathogenesis of murine experimental lupus erythematosus. The existence of IL-39 in the human system has yet to be confirmed. Based on the clinical success of IL-23p19 neutralizing approaches in moderate-to-severe psoriasis, anti-IL-23p19 antibodies in the clinic may not only neutralize IL-23, but additionally IL-39, implying that IL-39 might also contribute to the pathogenesis of psoriasis. It is therefore pivotal to demonstrate IL-39 expression and to characterize its function in the human system. In this study, we provided evidence for the existence of secreted heterodimeric p19 and EBI3 assemblies from supernatants originating from p19 and EBI3 transfected HEK293FT cells. We attempted to detect IL-39 expression from stimulated B-cells, human keratinocytes and in vitro polarized macrophages. Whereas, the expression of p19 and EBI3 were elevated, we failed to detect the heterodimeric p19 and EBI3 protein complex. Functional assays were conducted with conditioned media containing IL-39 or with a chimeric human recombinant IL-39 Fc protein. Reported immune cells targeted by IL-39, such as neutrophils and PBMCs, did not respond to IL-39 stimulation and IL-39 failed to activate STAT3 in a reporter cell line. These results suggest that immune cell derived human IL-39 cytokine is too low to be detectable or that it does not exist and has no functional role in the human system
Discovery of roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4
No full textFGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly-conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarised which made use of both rationale and unbiased screening approaches. The optimisation of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimisation are improving the FGFR4 potency, metabolic stability and solubility leading ultimately to the highly-selective first-in-class clinical candidate roblitinib
General considerations of model-based meta-analysis
No full textWith the increasing cost of drug development and clinical trials, it is of great value to make full use of all kinds of data to improve the efficiency of drug development and to provide valid information for medication guidelines. Model-based meta-analysis (MBMA) combines mathematical models with meta-analysis to integrate information from multiple sources (preclinical and clinical data, etc.) and multiple dimensions (targets/mechanisms, pharmacokinetics/pharmacodynamics, diseases/indications, populations, regimens, biomarkers/efficacy/safety, etc.), which not only provides decision-making for all key points of drug development, but also provides effective information for rational drug use and cost-effectiveness analysis. The classical meta-analysis requires high homogeneity of the data, while MBMA can combine and analyze the heterogeneous data of different doses, different time courses, and different populations through modeling, so as to quantify the dose-effect relationship, time-effect relationship, and the relevant impact factors, and thus the efficacy or safety features at the level of dose, time and covariable that have not been involved in previous studies. Although the modeling and simulation methods of MBMA are similar to population pharmacokinetics/pharmacodynamics (Pop PK/PD), compared with Pop PK/PD, the advantage of MBMA is that it can make full use of literature data, which not only improves the strength of evidence, but also can answer the questions that have not been proved or can not be answered by a single study. At present, MBMA has become one of the important methods in the strategy of model-informed drug development (MIDD). This paper will focus on the application value, data analysis plan, data acquisition and processing, data analysis and reporting of MBMA, in order to provide reference for the application of MBMA in drug development and clinical practice
From Candidate to Clinic: Strategies to Accelerate you Molecule's Development Path
No full textThe development of orally administered small molecules is becoming more challenging as an increasing number of molecules in pipelines have poor aqueous solubility and bioavailability. This article will introduce an efficient development process that can help deliver the right clinical candidate, optimal formulation strategy and the most appropriate dosage form to clinic. It will also review some established data-driven approaches to formulation development, focus on the value proposition for discovery
biopharmaceutics and discuss a preformulation toolkit for drug discovery
PISCES: a package for rapid quantitation and quality control of large scale mRNA-seq datasets
No full textPISCES eases processing of large mRNA-seq experiments by encouraging capture of metadata using sim- ple textual file formats, processing samples on either a single machine or in parallel on a high performance computing cluster (HPC), validating sample identity using genetic fingerprinting, and summarizing all outputs in analysis-ready data matrices. PISCES consists of two modules: 1) compute cluster-aware analy- sis of individual mRNA-seq libraries including species detection, SNP genotyping, library geometry detec- tion, and quantitation using salmon, and 2) gene-level transcript aggregation, transcriptional and read- based QC, TMM normalization and differential expression analysis of multiple libraries to produce data ready for visualization and further analysis.
PISCES is implemented as a python3 package and is bundled with all necessary dependencies to enable reproducible analysis and easy deployment. JSON configuration files are used to build and identify tran- scriptome indices, and CSV files are used to supply sample metadata and to define comparison groups for differential expression analysis using DEseq2. PISCES builds on many existing open-source tools, and re- leases of PISCES are available on GitHub or the python package index (PyPI)