An observational, prospective, multicenter study on the utilization and effectiveness of elbasvir-grazoprevir treatment association for chronic hepatitis C in France (ZEPHYR study).

Background and Aim: The efficacy and safety profiles of elbasvir-grazoprevir (EBR/GZR) has been established in more than 10 clinical trials. However, the characteristics of patients treated in routine clinical practice may differ. The present study was therefore designed to assess the real-life effectiveness of EBR/GZR therapy in the general population and among subgroups with a high hepatitis C virus (HCV) prevalence in France. Methods: The Zephyr study was designed as a French, multicentre, prospective, observational study on EBR/GZR use and effectiveness in current practice in chronic hepatitis C patients. These results are based on data regarding the adult patients who received at least one dose of EBR/GZR between December 2017 and June 2019 in 67 French hospitals and clinics. Results: Overall, 478 patients were included. The Full Analysis Set corresponded to the 467 patients who met all the inclusion criteria and none of the exclusion criteria. Gender was balanced and the mean age was 55.7 ± 13.3 years. The patients were mainly treatment-naive (89.5%) and infected with Genotype 1b (70.4%). Among the 75 patients with HCV Gt1a genotype, 56% had HCV RNA ≥ 800,000 IU/ml. F3-F4 fibrosis stage involved 24.2% of our population. Our subgroups were distributed among 110 migrants (23.6%), 58 (15.3%) using opioid agonist treatment, including people who inject drugs, 30 (6.8%) with chronic kidney disease Stages 3-5, 9 (1.9%) with an inherited blood disorder, and 4 (0.9%) coinfected with HIV. The remaining 269 (58.7%) were included in the general population subgroup. Overall, sustained virologic response 12 weeks after the end of treatment reached 98.0% and remained consistent among genotype, HCV RNA values, fibrosis stage, and the subgroup of interest. The rate of Alcohol Use Disorders Identification Test-Consumption​​​ and Life Habit questionnaire completion was high at each visit, with data suggesting alcohol consumption decrease and an improvement in quality of life. Conclusions: Using real-world evidence data on a French population representative of HCV patients, we confirmed the results obtained during EBR/GZR development program.

Use of iron sucrose and red blood cell transfusions in anaemic cancer patients in France (OncoFer study).

PURPOSE: This report describes the results of an observational, retrospective cohort study, evaluating the use of iron sucrose (IS) and red blood cell (RBC) transfusions in patients with cancer in routine clinical practice in France. A parallel investigated cohort treated with ferric carboxymaltose (FCM) has been reported earlier. METHODS: Data of patients with a solid tumour or haematological malignancy who have received IS or an RBC transfusion during 2010 from 3 months prior (M-3) to 3 months post first treatment (M+3) were analysed. RESULTS: Data from 46 patients who had received IS (400 mg median total iron dose) and 357 patients who had received RBC transfusions as first treatment (baseline) were included. Median haemoglobin levels improved from 9.9 g/dL (interquartile range 9.2; 11.0 g/dL) at baseline to 12.4 g/dL (11.4; 13.1 g/dL) at M+3 in IS-treated patients and from 8.2 g/dL (7.8; 8.8 g/dL) at baseline to 10.1 g/dL (8.8; 11.1 g/dL) in transfused patients. An erythropoiesis-stimulating agent was given to 54.3 and 28.9% of patients in the IS and the RBC transfusion groups, respectively, resulting in slightly better mean haemoglobin increase in both groups (2.4 vs 1.5 g/dL and 2.0 vs 1.6 g/dL, respectively). No severe nor serious adverse reaction and no hypersensitivity reactions were reported. CONCLUSION: Both IS and RBC transfusions effectively increased Hb levels in patients with cancer. IS was safe and well tolerated in this population. Considering prior reported results with FCM, using FCM may reduce ESA dose requirements and the required number of infusions.

Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket properties for ligand binding.

Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery.

Detection, comparison and analyses of binding pockets are pivotal to structure-based drug design endeavors, from hit identification, screening of exosites and de-orphanization of protein functions to the anticipation of specific and non-specific binding to off- and anti-targets. Here, we analyze protein-ligand complexes and discuss methods that assist binding site identification, prediction of druggability and binding site comparison. The full potential of pockets is yet to be harnessed, and we envision that better understanding of the pocket space will have far-reaching implications in the field of drug discovery, such as the design of pocket-specific compound libraries and scoring functions.