7196 research outputs found
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Systematic risk identification and assessment using a new risk map in pharmaceutical R&D
No full textDelivering transformative therapies to patients while maintaining growth in the pharmaceutical industry requires an efficient use of research and development (R&D) resources and technologies to develop high-impact new molecular entities (NMEs). However, increasing global R&D competition in the pharmaceutical industry, growing impact of generics and biosimilars, more stringent regulatory requirements, as well as cost-constrained reimbursement frameworks challenge current business models of leading pharmaceutical companies. Big data-based analytics and artificial intelligence (AI) approaches have disrupted various industries and are having an increasing impact in the biopharmaceutical industry, with the promise to improve and accelerate biopharmaceutical R&D processes. Here, we systematically analyze, identify, assess, and categorize key risks across the drug discovery and development value chain using a new risk map approach, providing a comprehensive risk–reward analysis for pharmaceutical R&D
Screening a Library of FDA-Approved and Bioactive Compounds for Antiviral Activity against SARS-CoV-2
No full textSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has emerged as a major global health threat. The COVID-19 pandemic has resulted in over 168 million cases and 3.4 million deaths to date, while the number of cases continues to rise. With limited therapeutic options, the identification of safe and effective therapeutics is urgently needed. The repurposing of known clinical compounds holds the potential for rapid identification of drugs effective against SARS-CoV-2. Here, we utilized a library of FDA-approved and well-studied preclinical and clinical compounds to screen for antivirals against SARS-CoV-2 in human pulmonary epithelial cells. We identified 13 compounds that exhibit potent antiviral activity across multiple orthogonal assays. Hits include known antivirals, compounds with anti-inflammatory activity, and compounds targeting host pathways such as kinases and proteases critical for SARS-CoV-2 replication. We identified seven compounds not previously reported to have activity against SARS-CoV-2, including B02, a human RAD51 inhibitor. We further demonstrated that B02 exhibits synergy with remdesivir, the only antiviral approved by the FDA to treat COVID-19, highlighting the potential for combination therapy. Taken together, our comparative compound screening strategy highlights the potential of drug repurposing screens to identify novel starting points for development of effective antiviral mono- or combination therapies to treat COVID-19
Animal models for in vivo lactation studies: anatomy, physiology and milk compositions in the most used non-clinical species, a contribution from the ConcePTION project
No full textThe present review aims to summarize the main features of mammary gland anatomy, and the physiology of lactation and colostrum/milk in the most commonly used animal species for regulatory toxicity. The final goal is the selection of a preferred animal species to be enrolled in studies investigating the potential transfer of drugs and exogenous molecules through milk, within the Innovative Medicines Initiative (IMI) funded project ConcePTION. Reference data regarding humans were also collected and analyzed in order to highlight critical similarities and differences with the studied species. Additional practical considerations were also taken into account, such as
ethical consideration regarding the chosen species which affects the group size, financial implications and technical feasibility of lactation trials (e.g., ease of sampling, volume of sampling, husbandry requirements and scientific recognition). In conclusion, the present analysis of the literature confirms the complexity of the decisional process behind the choice of an animal model for in vivo trials. For some of the evaluated species, data were either poor or missing, highlighting the necessity to generate more physiological background studies for species that are routinely used in laboratory settings. Overall, when taking into consideration ethical factors, feasible group size, milk volume and ease of milk collection, and physiological similarities with humans, minipigs seem to represent the most appropriate choice
Opportunities and challenges in developing a Cryptosporidium controlled human infection model for testing novel anti-parasitic agents
No full textCryptosporidiosis is a leading cause of moderate-to-severe diarrhea in the developing countries, responsible for high mortality in children younger than two years of age, and also strongly associated with childhood malnutrition and growth stunting. There is no vaccine for cryptosporidiosis and no effective chemotherapeutic options are available to prevent morbidity and mortality in young children. Recently, novel therapeutic agents have been discovered through high-throughput through phenotypic and target-based screening strategies, repurposing malaria hits etc. and these agents have a promising preclinical in vitro and in vivo anti-Cryptosporidium efficacy. A challenge to bringing safe and effective new therapies to young vulnerable children in the clinic is the ethical obligation to establish some prospect of benefit before initiating pediatric studies, especially in low- and middle-income populations. A Cryptosporidium controlled human infection model (CHIM) in healthy adult volunteers can be a robust clinical proof of concept model for evaluating novel therapeutics. CHIM could potentially accelerate the development path to pediatric studies by establishing the safety of a proposed pediatric dosing regimen and documenting preliminary efficacy in adults. We present here some perspectives on the opportunities and perceived challenges with Cryptosporidium CHIM
The Price is Right: Predicting Reagent Prices
No full textWe present a model for estimating the price of a reagent from its chemical structure. It is intended to be useful when doing reagent selection for library design. The model is a Random Forest regressor which is trained on the MolPort catalog of 302K reagents and the log of their price. For descriptors we use topological fingerprints from RDKit: chiral Morgan fingerprints, its medicinal chemis-try descriptors, and counts of undetermined chiral centers. The model has an out-of-bag performance of 34% variance explained in log Price. When predicting on known reagents, the model explains 91% of the variance in log Price. We analyzed the model to understand the errors that the model makes. We show that the compounds with the highest errors have only a subtly different structure from similar molecules, but very different in price
Pharmacokinetics of asciminib in individuals with hepatic or renal impairment
No full textAsciminib is an investigational, first-in-class, Specifically Targeting the ABL Myristoyl Pocket (STAMP), inhibitor of BCR-ABL1 with a new mechanism of action compared with approved ATP-competitive tyrosine kinase inhibitors. This report describes findings from two Phase 1 studies assessing the pharmacokinetics (PK) profile of a single dose of asciminib (40 mg) in individuals with impaired renal function (based on absolute glomerular filtration rate; NCT03605277) or impaired hepatic function (based on Child-Pugh classification; NCT02857868). Individuals with severe renal impairment exhibited 49─56% higher exposure (area under the curve [AUC]), with similar maximum plasma concentration (Cmax), than matched healthy controls. Based on these findings, as per protocol, the PK of asciminib in individuals with mild or moderate renal impairment was not assessed. In individuals with mild and severe hepatic impairment, asciminib AUC was 21─22% and 55─66% higher, respectively, and Cmax, was 26% and 29% higher, respectively, compared with individuals with normal hepatic function. Individuals with moderate hepatic impairment had similar asciminib AUC and Cmax than matched healthy controls. The increase in asciminib AUC and Cmax in the mild hepatic impairment cohort was mainly driven by one participant with particularly high exposure. Asciminib was generally well tolerated and the safety data were consistent with its known safety profile. In summary, these findings indicate that renal or hepatic impairment have no clinically meaningful effect on the exposure or safety profile of asciminib, and support its use in patients with varying degrees of renal or hepatic dysfunction
Chemistry in bulk water. Challenges and opportunities ahead of us
No full textIn conclusion, while we have started witnessing more and more sustainable advantages of chemistry using water as the bulk medium, there is still very limited physical and mechanistic understanding, which prevents us to unleashing the full power of such an approach. The ultimate goal being to rapidly switch towards better and more sustainable practices, moving away from fossil feedstock is an undeniable asset to exploit optimally and collectively in order to have a chance to respond to the needs of the Society. A collaborative and cross-functional effort will be required to have a chance to go through such a profound change of how to conduct chemistry. We do hope such accounts will entice the best minds to delve into this fascinating world that can radically impact our overall footprint
Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia
No full textVarious subunits of mammalian SWI/SNF chromatin remodeling complexes display loss-of- function mutations characteristic of tumor suppressors in different cancers, but an additional role for SWI/SNF supporting cell survival in distinct cancer contexts is emerging. In particular, dependence on the catalytic subunit BRG1/SMARCA4 has been observed in acute myeloid leukemia (AML), yet the feasibility of direct therapeutic targeting of SWI/SNF catalytic activity in leukemia remains unknown. Here, we evaluated the activity of BRG1/BRM ATPase inhibitors across a genetically diverse panel of cancer cell lines and observed that hematopoietic cancer cell lines were among the most sensitive compared to other lineages. This result was striking in comparison to data from pooled short hairpin RNA screens, which showed that only a subset of leukemia cell lines display sensitivity to BRG1 knockdown. We demonstrate that combined genetic knockdown of BRG1 and BRM is required to recapitulate the effects of dual inhibitors, suggesting that SWI/SNF dependency in human leukemia extends beyond a predominantly BRG1-driven mechanism. Through gene expression and chromatin accessibility studies, we show that the dual inhibitors act at genomic loci associated with oncogenic transcription factors, and observe a downregulation of leukemic pathway genes including MYC, a well-established target of BRG1 activity in AML. Overall, small molecule inhibition of BRG1/BRM induced common transcriptional responses across leukemia models resulting in a spectrum of cellular phenotypes. Our studies reveal the breadth of SWI/SNF dependency and support targeting SWI/SNF catalytic function as a potential therapeutic strategy in AML
Secukinumab for the treatment of psoriasis, psoriatic arthritis, and axial spondyloarthritis: Physical and pharmacological properties underlie the observed clinical efficacy and safety
No full textPsoriasis, psoriatic arthritis, and axial spondyloarthritis are systemic inflammatory diseases, each commonly manifesting as a spectrum of symptoms, complications, and comorbidities that arise differently in individual patients. Drugs targeting inflammatory cytokines common to the pathogenesis of each of these conditions have been developed, although their specific actions in the different tissues involved are variable. For a drug to be effective, it must be efficiently delivered to and locally bioactive in disease-relevant tissues. Detailed clinical data shed light on the therapeutic effects of individual biologics on specific domains or clinical manifestations of disease and assist in guiding treatment decisions. Pharmacologic, molecular, and functional properties of drugs strongly impact their observed safety and efficacy, and an understanding of these properties provides complementary insight. Secukinumab, a fully human monoclonal IgG1/κ antibody selectively targeting interleukin (IL)-17A, has been in clinical use for >6 years in the treatment of moderate to severe psoriasis, psoriatic arthritis, and both radiographic (also known as ankylosing spondylitis) and nonradiographic axial spondyloarthritis. In this review, we discuss pharmacokinetic and pharmacodynamic data for secukinumab to introduce clinicians to the pharmacological properties of this widely used drug. Understanding how these properties affect the observed clinical efficacy, safety, and tolerability of this drug in the treatment of IL-17A–mediated systemic inflammatory diseases is important for all physicians treating these conditions
Coronary artery disease polygenic risk score identifies patients at higher risk for recurrent cardiovascular events in the CANTOS Trial
No full textNo formal abstract in format we plan to submit to journal (a short report). Informally, the work presented here adds to a body of evidence that shows how polygenic risk scores (PRS) for coronary artery disease (CAD) can be used to inform on patient's disease severity, disease progression, and potential for treatment response stratification. Key results include, patients in highest tertile PRS have a higher CAD disease burden at baseline (measured by number of myocardial infractions at trail start), progress faster in CAD (measured by time to first major adverse cardiovascular event, MACE), and may respond better to Canakinumab therapy at the highest dose of 300mg