Establishing the Safe Space via Physiologically Based Biopharmaceutics Modeling. Case Study: Fevipiprant/QAW039.

Physiologically based pharmacokinetic and absorption modeling has increasingly been implemented for biopharmaceutics applications to define the safe space for drug product quality attributes such as dissolution. For fevipiprant/QAW039, simulations were performed to assess the impact of in vitro dissolution on the in vivo performance of immediate-release film-coated tablets during development and scaling up to commercial scale. A fevipiprant dissolution safe space was established using observed clinical intravenous and oral PK data from bioequivalent and non-bioequivalent formulations.

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Hypnozoites.

Radical cure of malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against and hypnozoites.

CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon restoration of RB function in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options, and novel effective therapeutic strategies are desperately needed. We observe anti-proliferative efficacy of genetic depletion or pharmacological inhibition using the clinically available SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy.

A proteogenomic view of Parkinson's disease causality and heterogeneity.

The pathogenesis and clinical heterogeneity of Parkinson's disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed.

The most common linkers in bioactive molecules and their bioisosteric replacement network.

Structures of the large majority of bioactive molecules are composed of several rings that are decorated by substituents and connected by linkers. While numerous cheminformatics studies focusing on rings and substituents are available, practically nothing has been published about the third important structural constituent of bioactive molecules - the linkers. The current study attempts to fill this gap.

Secukinumab long-term efficacy and safety in psoriasis through to year 5 of treatment: results of a randomized extension of the phase III ERASURE and FIXTURE trials.

Background: In the long-term extension study of the ERASURE and FIXTURE trials, the efficacy of secukinumab (a fully human anti-interleukin-17A monoclonal antibody) was demonstrated to have been maintained through to year 3 of treatment in moderate-to-severe plaque psoriasis.

Objectives: To assess the efficacy and safety of secukinumab through to year 5 of treatment in moderate-to-severe plaque psoriasis.

Methods: Responders with ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) from two core trials - ERASURE and FIXTURE - were randomized 2 : 1 at year 1 (end of core trials) to either the same dose (300 or 150 mg, continuous treatment) or placebo (treatment withdrawal) every 4 weeks, until year 3 or relapse (> 50% reduction in maximal PASI from core study baseline).

Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes.

Cyclic peptides extend the druggable target space due to their size, flexibility, and hydrogen-bonding capacity. However, these properties impact also their passive membrane permeability. As the "journey" through membranes cannot be monitored experimentally, little is known about the underlying process, which hinders rational design.

Advances in Ovarian Cancer Treatment Beyond PARP Inhibitors.

Ovarian cancer has become the largest cause of gynaecological cancer-related mortality. It is typically diagnosed at a late stage and has no effective screening strategy. Ovarian cancer is a highly heterogeneous disease that can be subdivided into several molecular subsets.

Genetic models of cleavage-reduced and soluble TREM2 reveal distinct effects on myelination and microglia function in the cuprizone model.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell-surface immunoreceptor expressed on microglia, osteoclasts, dendritic cells and macrophages. Heterozygous loss-of-function mutations in TREM2, including mutations enhancing shedding form the cell surface, have been associated with myelin/neuronal loss and neuroinflammation in neurodegenerative diseases, such as Alzheimer`s disease and Frontotemporal Dementia. Using the cuprizone model, we investigated the involvement of soluble and cleavage-reduced TREM2 on central myelination processes in cleavage-reduced (TREM2-IPD), soluble-only (TREM2-sol), knockout (TREM2-KO) and wild-type (WT) mice.

Valhidepsin Lipopeptides from : Structures, Biosynthesis, and Coregulation with FR900359 Production.

Microbial secondary metabolites continue to provide a valuable source of both chemical matter and inspiration for drug discovery in a broad range of therapeutic areas. Beyond this, the corresponding microorganisms represent a sustainable modality for biotechnological production of structurally complex molecules at the quantities required for drug development or even commercial manufacturing. , which has recently been reported as a producer of the pharmacologically highly important G inhibitor FR900359 (FR), represents such an example.

Systematic Evaluation of Local and Global Machine Learning Models for the Prediction of ADME Properties.

Machine learning (ML) has become an indispensable tool to predict absorption, distribution, metabolism, and excretion (ADME) properties in pharmaceutical research. ML algorithms are trained on molecular structures and corresponding ADME assay data to develop quantitative structure-property relationship (QSPR) models. Traditional QSPR models were trained on compound sets of limited size.

Distribution, Determinants and Normal Reference Values of Aortic Arch Width: Thoracic Aortic Geometry in the Framingham Heart Study.

Study Objective: Aortic arch geometry changes with age, including an increase in aortic arch width (AAW). High AAW is a predictor of incident adverse cardiovascular disease (CVD) events, but its distribution and determinants are unknown. We hypothesized that traditional CVD risk factors, in addition to age, are associated with increased AAW in community-dwelling adults.

A whole-genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors.

The natural compound Artemisinin is the most widely used antimalarial drug worldwide. Based on its cytotoxicity, it is also used for anticancer therapy. Artemisinin and its derivates are endoperoxides that damage proteins in eukaryotic cells; their definite mechanism of action and host cell targets, however, have remained largely elusive.

Molecular response in newly diagnosed chronic-phase chronic myeloid leukemia: prediction modeling and pathway analysis.

Tyrosine kinase inhibitor therapy revolutionized chronic myeloid leukemia treatment and showed how targeted therapy and molecular monitoring could be used to substantially improve survival outcomes. We used chronic myeloid leukemia as a model to understand a critical question: why do some patients have an excellent response to therapy, while others have a poor response? We studied gene expression in whole blood samples from 112 patients from a large phase III randomized trial (clinicaltrials gov. Identifier: NCT00471497), dichotomizing cases into good responders (BCR::ABL1 ≤10% on the International Scale by 3 and 6 months and ≤0.

A root cause analysis to identify the mechanistic drivers of immunogenicity against the anti-VEGF biotherapeutic brolucizumab.

Immunogenicity against intravitreally administered brolucizumab has been previously described and associated with cases of severe intraocular inflammation, including retinal vasculitis/retinal vascular occlusion (RV/RO). The presence of antidrug antibodies (ADAs) in these patients led to the initial hypothesis that immune complexes could be key mediators. Although the formation of ADAs and immune complexes may be a prerequisite, other factors likely contribute to some patients having RV/RO, whereas the vast majority do not.

Anti-brolucizumab immune response as one prerequisite for rare retinal vasculitis/retinal vascular occlusion adverse events.

In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals.

Mometasone/Indacaterol/Glycopyrronium (MF/IND/GLY) and MF/IND at Different MF Strengths versus Fluticasone Propionate/Salmeterol Xinafoate (FLU/SAL) and FLU/SAL+ Tiotropium in Patients with Asthma.

Background: Once-daily, single-inhaler mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY, an ICS/LABA/LAMA) and MF/IND (an ICS/LABA) via Breezhaler have been approved for the maintenance treatment of patients with asthma inadequately controlled with medium-or high-dose ICS or medium-or high-dose ICS/LABA treatment.

Objective: Once-daily (o.d.

Quantitative systems pharmacology model of GITR-mediated T cell dynamics in tumor microenvironment.

T cell interaction in the tumor microenvironment is a key component of immuno-oncology therapy. Glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) is expressed on immune cells including regulatory T cells (Tregs) and effector T cells (Teffs). Preclinical data suggest that agonism of GITR in combination with Fc-γ receptor-mediated depletion of Tregs results in increased intratumoral Teff:Treg ratio and tumor shrinkage.

Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions.

Multiple trans-synaptic complexes organize synapse development, yet their roles in the mature brain and cooperation remain unclear. We analyzed the postsynaptic adhesion protein LRRTM1 in the prefrontal cortex (PFC), a region relevant to cognition and disorders. LRRTM1 knockout (KO) mice had fewer synapses, and we asked whether other synapse organizers counteract further loss.

EFMC: Trends in Medicinal Chemistry and Chemical Biology.

Ground-breaking research in disease biology and continuous efforts in method development have uncovered a range of potential new drug targets. Increasingly, the drug discovery process is informed by technologies involving chemical probes as tools. Applications for chemical probes comprise target identification and assessment, as well as the qualification of small molecules as chemical starting points and drug candidates.

Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates.

In nonhuman primates (NHPs), adeno-associated virus serotype 9 (AAV9) vectorized gene therapy can cause asymptomatic microscopic injury to dorsal root ganglia (DRG) and trigeminal ganglia (TG) somatosensory neurons, causing neurofilament light chain (NfL) to diffuse into cerebrospinal fluid (CSF) and blood. Data from 260 cynomolgus macaques administered vehicle or AAV9 vectors (intrathecally or intravenously) were analyzed to investigate NfL as a soluble biomarker for monitoring DRG/TG microscopic findings. The incidence of key DRG/TG findings with AAV9 vectors was 78% (maximum histopathology severity, moderate) at 2-12 weeks after the dose.

Discovery of a novel, highly potent and orally bioavailable pyrrolidinone indole series of irreversible Myeloperoxidase (MPO) inhibitors.

Myeloperoxidase (MPO) is a heme-containing peroxidase from phagocytic cells, which plays an important role in the innate immune response. The primary anti-microbial function of MPO is achieved by catalyzing the oxidation of halides by hydrogen peroxide (HO). Upon activation of phagocytes, MPO activity is detectable in both phagosomes and extracellularly, where it can remain or transcytose into interstitial compartments.

Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology.

Hepatocytes are the main workers in the hepatic factory, managing metabolism of nutrients and xenobiotics, production and recycling of proteins, and glucose and lipid homeostasis. Division of labor between hepatocytes is critical to coordinate complex complementary or opposing multistep processes, similar to distributed tasks at an assembly line. This so-called metabolic zonation has both spatial and temporal components.

Meeting report of the 3rd European Biotransformation Workshop.

Challenges, strategies and new technologies in the field of biotransformation were presented and discussed at the 3rd European Biotransformation Workshop which was held in collaboration with the DMDG on 5-6 October 2022 in Amsterdam. In this meeting report we summarise the presentations and discussions from this workshop. The topics covered are listed below:Accelerator mass spectrometry (AMS) for the support of microtracer studiesBiotransformation of the novel myeloperoxidase inhibitor AZD4831 in preclinical species and humansAMS in biotransformation studies: unusual case studiesDiscussion on new FDA draft guidance and AMSMultimodal molecular imaging and ion mobility applications in drug discovery and developmentMetabolites in Safety Testing considerations for large molecules.