Firalis SAS

Huningue, France

Firalis SAS

Huningue, France
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Gyongyosi M.,Medical University of Vienna | Winkler J.,Medical University of Vienna | Ramos I.,Innovative Technologies in Biological Systems SL INNOPROT | Do Q.-T.,Greenpharma SAS | And 9 more authors.
European Journal of Heart Failure | Year: 2017

Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network that occur in response to cardiac ischaemic insults, systemic diseases, drugs, or any other harmful stimulus affecting the circulatory system or the heart itself. Myocardial fibrosis alters the architecture of the myocardium, facilitating the development of cardiac dysfunction, also inducing arrhythmias, influencing the clinical course and outcome of heart failure patients. Focusing on myocardial fibrosis may potentially improve patient care through the targeted diagnosis and treatment of emerging fibrotic pathways. The European Commission funded the FIBROTARGETS consortium as a multinational academic and industrial consortium with the primary aim of performing a systematic and collaborative search of targets of myocardial fibrosis, and then translating these mechanisms into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. This review focuses on those methodological and technological aspects considered and developed by the consortium to facilitate the transfer of the new mechanistic knowledge on myocardial fibrosis into potential biomedical applications. © 2017 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.


PubMed | Hospital Nord, Trophos, Copenhagen University, University of Oslo and 12 more.
Type: Clinical Trial, Phase II | Journal: European heart journal | Year: 2015

The MITOCARE study evaluated the efficacy and safety of TRO40303 for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI).Patients presenting with STEMI within 6 h of the onset of pain randomly received TRO40303 (n = 83) or placebo (n = 80) via i.v. bolus injection prior to balloon inflation during primary percutaneous coronary intervention in a double-blind manner. The primary endpoint was infarct size expressed as area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI) over 3 days. Secondary endpoints included measures of infarct size using cardiac magnetic resonance (CMR) and safety outcomes.The median pain-to-balloon time was 180 min for both groups, and the median (mean) door-to-balloon time was 60 (38) min for all sites. Infarct size, as measured by CK and TnI AUCs at 3 days, was not significantly different between treatment groups. There were no significant differences in the CMR-assessed myocardial salvage index (1-infarct size/myocardium at risk) (mean 52 vs. 58% with placebo, P = 0.1000), mean CMR-assessed infarct size (21.9 g vs. 20.0 g, or 17 vs. 15% of LV-mass) or left ventricular ejection fraction (LVEF) (46 vs. 48%), or in the mean 30-day echocardiographic LVEF (51.5 vs. 52.2%) between TRO40303 and placebo. A greater number of adjudicated safety events occurred in the TRO40303 group for unexplained reasons.This study in STEMI patients treated with contemporary mechanical revascularization principles did not show any effect of TRO40303 in limiting reperfusion injury of the ischaemic myocardium.


PubMed | Novartis, Pfizer, Firalis SAS, Integrated Cancer Prevention Center and 7 more.
Type: Journal Article | Journal: Toxicologic pathology | Year: 2015

Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public-private partnership funded within the European Commissions Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes.


PubMed | Pfizer, Firalis SAS and Hospital Of La Santa Creu I Sant Pau
Type: Journal Article | Journal: Toxicologic pathology | Year: 2015

Drug-induced vascular injury (DIVI) is commonly associated with phosphodiesterase (PDE) inhibitors. Despite histological characterization, qualified biomarkers for DIVI detection are lacking. We investigated whether a single administration of roflumilast (PDE-IV inhibitor) induces vascular damage and identified novel surrogate biomarkers of acute vascular injury. Pigs received postoperative 250, 375, or 500 g of roflumilast or placebo/control. After 1.5 hr, coronary reactivity was determined by catheter-based administration of acetylcholine and sodium nitroprusside (SNP) in the coronary sinus. Immunohistochemical analysis of vessel integrity (von Willebrand factor [vWF]) and fibrin(ogen) deposition was performed in the coronary artery and aorta. Peripheral blood was collected for differential proteomics and microparticles analysis. Circulating interleukin (IL)-6 was analyzed. Roflumilast-treated animals displayed higher vasodilation to acetylcholine and SNP versus controls (p < .05). Roflumilast-treated animals showed a dose-dependent (p < .05) decrease in vessel integrity and dose-dependent increase in fibrin deposition forming a continuous layer at roflumilast-500 g. Peripheral blood of roflumilast-500-g-treated animals showed increased levels of total and endothelial-derived microparticles and exhibited a coordinated change in proteins kininogen-1, endothelin-1, gelsolin, apolipoprotein A-I, and apolipoprotein-J associated with vascular injury (p < .05 vs. controls). IL-6 remained unaltered. Roflumilast-induced vascular injury can be detected by novel markers in peripheral blood. Validation of these surrogate markers in human samples seems required.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-2011-IAPP | Award Amount: 1.60M | Year: 2012

BRAINVECTORS aims devising new gene therapy(GT)-based treatments for Parkinsons and other neurodegenerative diseases, in substitution of current systemic treatments, by delivering neurotrophic factors (GDNF) into the CNS with new vectors derived from adeno-associated (AAV), canine adenoviruses (CAV) and lentiviruses (LV) with inducible gene expression. Although AAV, CAV and LVV are considered acceptable in terms of bio-safety, their immune response must be well characterized in order to further develop these vectors for clinical trials. Furthermore, the possibility to switch-off the expression of neurotrophic factors in case of adverse effects represents a significant pharmacological progress of the gene therapy approach for Parkinsons disease. BRAINVECTORS will: - devise new inducible gene expression cassettes with increased sensitivity of transactivators and inducers reducing thus the dose of drugs necessary to obtain GDNF expression in brain; - characterise the immune responses induced by the components of GDNF-AAV, -CAV and -LVV in rodent models for Parkinsons disease by using biomarker-based immunological screening. The project is based upon a network of 12 participants of public academic institutions and private non-profit organisations and SMEs in France, Germany, Italy, Netherland, Portugal, Spain, Sweden and Switzerland. Some of them are traditionally linked together in developing vectors backbones, vector production technologies and Parkinsons animal models. Others have strong immunological background, pioneering the biomarkers-based immuno-technologies for GT vectors, and have R&D expertise/facilities on/for animal cell technologies cGMP for biopharmaceuticals. 142 p-m will be involved during 48 months in R&D and TOK activities with 72 p-m of recruited postdocs and 70 p-m of seconded staff.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.2-1 | Award Amount: 8.18M | Year: 2013

The Fibro-Targets project is a multi-disciplinary 4 years program involving 10 partners ambitioning the identification, characterisation and validation of in vitro and in vivo models of novel therapeutically relevant targets for myocardial interstitial fibrosis (MIF) in heart failure. The project is based on the hypothesis that the intervention on novel fibrosis-related targets involved in the processes of fibroblast differentiation to myofibroblasts, the predominance of collagen synthesis over degradation and/or collagen maturation may allow for interstitial repair, thus providing a new strategy for the prevention and treatment of adverse cardiac remodeling involved in the transition to and the progression of heart failure. From a large body of existing multi-omics, literature data and previous hypothesis-driven research conducted by members of the consortium, a number of specific extracellular and intracellular targets have been identified whose involvement in MIF is beginning to be understood and that may be targeted by specific therapies. The specific aims of the Fibro-Targets are: (i) To provide further evidence on the mechanisms of action of the above targets (ii) To validate experimentally that new anti-fibrotic strategies can be developed based on the above targets (iii) To approach the potential clinical scenario of the above targets for HF therapy To reach these aims the following studies will be performed: (i) Observational and interventional experimental studies in already existing and/or de novo generated appropriate in vitro and in vivo models. (ii) Clinical studies, stratifying large scale populations of patients available to the consortium, at risk to develop HF and likely to be responsive to specific novel and/or exiting anti-fibrotic therapies. The stratification will be based on specific fibrogenetic phenotypic profiles using multi-panel imaging and circulating markers descriptive of mechanisms involving the proposed novel targets.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.1.2-1 | Award Amount: 7.41M | Year: 2011

The aim is to develop tools for imaging and characterising protein/protein and protein/RNA interactions in cancer using Designed Ankyrin Repeat Proteins (DARPins). DARPins are small, ultrahighly stable, antibody-like proteins that bind specific targets with high affinity in monovalent form and are readily engineered for site-specific chemical modification. The exemplar protein family will be EGFR, with focus on HER2-mediated processes in cancer. 1. EGFR-reactive DARPins will be used to characterise HER2 homo- and hetero-dimers using 4 novel technologies: Single Molecule Fluorescence, Proximity Ligation, super-resolution microscopy and FRET/FLIM. The collected data will be analysed with information on clinical outcome to determine which HER2 interactions are associated with resistance to HER2 targeted treatments. 2. Protein/RNA complexes will be isolated and characterised. These complexes may be new biomarkers for breast cancer and their characterisation is aimed at elucidating mechanisms of transcriptional regulation in response to anti-HER2 treatment. 3. Protein networks associated with EGFR signalling by imaging clusters of at 50-100 different proteins in a single cell or tissue section. This will be achieved with a robot, using large dye-conjugated tag libraries, and automatically bleaching a dye after imaging and re-labelling with another. 4. Whole body imaging (Phase I/II) clinical trial will use radiolabelled anti-HER2 DARPins to improve specificity and sensitivity of quantitative PET/SPECT/CT. The trial aims to image HER2 positive metastatic cancer and provide circulating tumour cells (CTCs) and biopsies for more detailed analysis. 5. Multivariate data obtained by the new technologies will be analysed with a range of bioinformatic tools, including artificial neural network methods, to determine novel biomarkers that aim to classify breast cancer patients at an individualised level. The outcome is to increase the tool panel of clinicians.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.2-2 | Award Amount: 8.19M | Year: 2011

Current interventional treatment of acute myocardial infarction (AMI) focused on re-establishing cardiac reperfusion has significantly improved clinical outcome by reducing infarct size and mortality due to cardiac ischemia.It is now recognized that events triggered at reperfusion also result in cell death and may account for as much as 50% of the infarct volume, this being termed ischemia-reperfusion injury (IRI). Mitochondrial permeability transition pore (mPTP) opening appears to be a responsible for IRI and a recent small clinical trial with cyclosporine A shows that it is a feasible target for the development of new therapies to treat it. Since total infarct size is a major determinant of a patients risk to develop heart failure, treating IRI is expected to further reduce morbidity, mortality and the need for regenerative medicine following cardiac ischemia. By harnessing a multi-disciplinary consortium of clinical and basic scientists along with four SMEs, MitoCare brings state-of-the art expertise together to 1) better understand IRI pathophysiology and factors directly or indirectly influencing patients recovery or response to treatment; 2) investigate the translational usefulness of preclinical models; and 3) compare selected treatments. These objectives will be reached through the following work plan: A) a medium-scale phase II clinical study will evaluate the efficacy of a novel complementary therapy to PCI, the new mPTP modulator TRO40303, while at the same time 1) perform extensive sampling from subjects in the study for analysis of standard and emerging biomarkers; 2) identify confounding factors influencing patients outcomes. B) Parallel investigations in preclinical in vitro and in vivo AMI models. C) Statistical analysis of data from clinical and preclinical studies, to identify better diagnostic and prognostic endpoints in man and assess predictive utility of preclinical models.


Cardiovascular tissue mRNA expression profiles in monkeys treated with coxibs was analyzed. Genomic data indicated that the animals showing vasculitis exhibit a specific mRNA expression pattern. The pattern includes gene expression changes involved in blood and endothelial cell (EC) activation, interaction of blood cells with EC, activation of INF pathway, and release of pro-inflammatory cytokines and chemo-attractants. These results provide direct evidence of minimal vasculitis together with corresponding genomic signature and peripheral biomarkers for minimal vasculatis. These results also suggest that treatment might triggers/aggravate a clinically latent cardiovascular disorder in the context of an endothelium tropic viral infection and/or an autoimmune vascular disorder. The histopathological examination revealed marginal vascular changes consistent with the genomic findings. Measurement of soluble proteins present in serum and plasma using a multiplex assay were in line with the genomic results, showing the increased level of INF inducible proteins. Increased expression of CXCL10 chemokine was confirmed by an ELISA both in serum and plasma. Use of these peripheral biomarkers allows a safe usage of cox-2 inhibitory compounds in clinics and selection of cox-2 inhibitory follow-up compounds with no cardiovascular toxicity. These data together with biochemical and histopathological findings suggest that the specific cox2 inhibitor may exaggerate host immune response during some specific viral infections with endothelial tropism, or subjacent vascular autoimmune disorders.


Cardiovascular tissue mRNA expression profiles in monkeys treated with coxibs was analyzed. Genomic data indicated that the animals showing vasculitis exhibit a specific mRNA expression pattern. The pattern includes gene expression changes involved in blood and endothelial cell (EC) activation, interaction of blood cells with EC, activation of INF pathway, and release of pro-inflammatory cytokines and chemo-attractants. These results provide direct evidence of minimal vasculitis together with corresponding genomic signature and peripheral biomarkers for minimal vasculatis. These results also suggest that treatment might triggers/aggravate a clinically latent cardiovascular disorder in the context of an endothelium tropic viral infection and/or an autoimmune vascular disorder. The histopathological examination revealed marginal vascular changes consistent with the genomic findings. Measurement of soluble proteins present in serum and plasma using a multiplex assay were in line with the genomic results, showing the increased level of INF inducible proteins. Increased expression of CXCL10 chemokine was confirmed by an ELISA both in serum and plasma. Use of these peripheral biomarkers allows a safe usage of cox-2 inhibitory compounds in clinics and selection of cox-2 inhibitory follow-up compounds with no cardiovascular toxicity. These data together with biochemical and histopathological findings suggest that the specific cox2 inhibitor may exaggerate host immune response during some specific viral infections with endothelial tropism, or subjacent vascular autoimmune disorders.

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