Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

INTRODUCTION: Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. METHODS: This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks. RESULTS: GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of - 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. CONCLUSION: Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.

Psoriasis is thought to be caused by problems with the immune system, including possibly receptor-interacting protein kinase 1 (RIPK1), which plays an important role in the development of inflammation. A previous study suggested that the drug, GSK2982772, which interferes with RIPK1, might improve symptoms in patients with psoriasis. This study examined whether higher doses of GSK2982772 than previously studied would be beneficial for patients with psoriasis. The study found that the severity of psoriasis was similar in patients treated with GSK2982772 for 12 weeks as in those who did not receive the drug, indicating that GSK298772 did not improve psoriasis.

Study to Explore the Association of the Renin-Angiotensin System and Right Ventricular Function in Mechanically Ventilated Patients.

BACKGROUND: Right ventricular (RV) dysfunction is associated with pulmonary vasoconstriction in mechanically ventilated patients. Enhancing the activity of angiotensin-converting enzyme 2 (ACE2), a key enzyme of the renin-angiotensin system (RAS), using recombinant human ACE2 (rhACE2) could alleviate RAS-mediated vasoconstriction and vascular remodeling. METHODS: This prospective observational study investigated the association between concentrations of RAS peptides (Ang II or Ang(1-7)) and markers of RV function, as assessed by echocardiography (ratio of RV to left ventricular end-diastolic area, interventricular septal motion, and pulmonary arterial systolic pressure (PASP)). RESULTS: Fifty-seven mechanically ventilated patients were enrolled. Incidence rates of acute cor pulmonale (ACP) and pulmonary circulatory dysfunction (PCD) were consistent with previous studies. In the 45 evaluable participants, no notable or consistent changes in RAS peptides concentration were observed over the observation period, and there was no correlation between Ang II concentration and either PASP or RV size. The model of the predicted posterior distributions for the pre- and post-dose values of Ang II demonstrated no change in the likelihood of PCD after hypothetical dosing with rhACE2, thus meeting the futility criteria. Similar results were observed with the other RAS peptides evaluated. CONCLUSIONS: Pre-defined success criteria for an association between PCD and the plasma RAS peptides were not met in the mechanically ventilated unselected patients.

An open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of GSK2586881 in participants with pulmonary arterial hypertension.

Preclinical and early clinical studies suggest that angiotensin-converting enzyme type 2 activity may be impaired in patients with pulmonary arterial hypertension (PAH); therefore, administration of exogenous angiotensin-converting enzyme type 2 (ACE2) may be beneficial. This Phase IIa, multi-center, open-label, exploratory, single-dose, dose-escalation study (NCT03177603) assessed the potential vasodilatory effects of single doses of GSK2586881 (a recombinant human ACE2) on acute cardiopulmonary hemodynamics in hemodynamically stable adults with documented PAH who were receiving background PAH therapy. Successive cohorts of participants were administered a single intravenous dose of GSK2586881 of 0.1, 0.2, 0.4, or 0.8 mg/kg. Dose escalation occurred after four or more participants per cohort were dosed and a review of safety, tolerability, pharmacokinetics, and hemodynamic data up to 24 h postdose was undertaken. The primary endpoint was a change in cardiopulmonary hemodynamics (pulmonary vascular resistance, cardiac index, and mean pulmonary artery pressure) from baseline. Secondary/exploratory objectives included safety and tolerability, effect on renin-angiotensin system peptides, and pharmacokinetics. GSK2586881 demonstrated no consistent or sustained effect on acute cardiopulmonary hemodynamics in participants with PAH receiving background PAH therapy (N = 23). All doses of GSK2586881 were well tolerated. GSK2586881 was quantifiable in plasma for up to 4 h poststart of infusion in all participants and caused a consistent and sustained reduction in angiotensin II and a corresponding increase in angiotensin (1-7) and angiotensin (1-5). While there does not appear to be a consistent acute vasodilatory response to single doses of GSK2586881 in participants with PAH, the potential benefits in terms of chronic vascular remodeling remain to be determined.

Effects of Recombinant Human Angiotensin-Converting Enzyme 2 on Response to Acute Hypoxia and Exercise: A Randomised, Placebo-Controlled Study.

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). Enhancing ACE2 activity using GSK2586881, a recombinant form of human ACE2, could be beneficial in diseases such as ARDS but may blunt the hypoxic pulmonary vasoconstriction (HPV) response and potentially impact systemic and tissue oxygenation. This study aimed to evaluate the effect of GSK2586881 0.8 mg/kg on HPV response in healthy adult volunteers during exercise under hypoxic conditions. METHODS: In this phase I, randomised, double-blind (sponsor open) study, GSK2586881 or placebo was administered as a single intravenous (IV) dose in a two-period crossover design. Treatment periods were separated by a washout period of 3-14 days. The primary endpoint was change from baseline in pulmonary artery systolic pressure (PASP) measured by echocardiography. Secondary endpoints included RAS peptides and oxygen saturation. RESULTS: Seventeen adults aged 18-40 years were randomised to treatment. There were no clinically relevant differences (defined as a reduction of ≥ 5 mmHg) in change from baseline in PASP between GSK2586881 and placebo. GSK2586881 was well tolerated, with no serious adverse events, no worsening of hypoxaemia and no evidence of immunogenicity. The study was terminated early after review of the data, which showed that the predefined success criteria had not been met. Following GSK2586881 administration, levels of the RAS peptide angiotensin II decreased while angiotensin (1-7) increased, as expected, indicating that GSK2586881 was pharmacologically active. CONCLUSIONS: A single IV dose of GSK2586881 0.8 mg/kg was well tolerated but did not impact the acute HPV response in healthy volunteers.

Pharmacologic targeting of the ATX/LPA axis attenuates bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease with a dismal prognosis and a largely unknown etiology. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for extracellular production of lysophosphatidic acid (LPA), a bioactive phospholipid. LPA has numerous effects in most cell types, signaling through at least 6 receptors (LPAR) exhibiting wide spread distribution and overlapping specificities. The ATX/LPA axis has been suggested as a therapeutic target in different chronic inflammatory and fibroproliferative disorders, including pulmonary fibrosis. In this report, we examined head-to-head the efficacy of a potent inhibitor of ATX (PF-8380), that has not been tested in pulmonary fibrosis models, and an antagonist of LPAR1 (AM095) in bleomycin (BLM)-induced pulmonary fibrosis. Both compounds abrogated the development of pulmonary fibrosis and prevented the distortion of lung architecture, exhibiting qualitative and quantitative differences in different manifestations of the modeled disease.

Healthcare utilization and direct costs of non-infectious comorbidities in HIV-infected patients in the USA.

OBJECTIVE: To estimate the incremental healthcare utilization and costs associated with common non-infectious comorbid conditions among commercially and Medicaid-insured HIV-infected patients in the US. METHODS: US administrative claims were used to select adult HIV patients with chronic kidney disease (CKD), cardiovascular disease (CVD) events, or fracture/osteoporosis, three common comorbidities that have been associated with HIV and HIV treatment, between 1 January 2004 and 30 June 2013. Propensity score matched controls with no CKD, no CVD events, and no fracture/osteoporosis were identified for comparison. All-cause healthcare utilization and costs were reported as per patient per month (PPPM). RESULTS: The commercial cohort comprised 381 CKD patients, 624 patients with CVD events, and 774 fracture/osteoporosis patients, and 1013, 1710, and 2081 matched controls, respectively; while the Medicaid HIV cohort comprised 207 CKD and 271 CVD cases, and 516 and 735 matched controls, respectively. There was insufficient Medicaid data for fracture analyses. Across both payers, HIV patients with CKD or CVD events had significantly higher healthcare utilization and costs than controls. The average incremental PPPM costs in HIV patients with CKD were $1403 in the commercial cohort and $3051 in the Medicaid cohort. In those with CVD events, the incremental costs were $2655 (commercial) and $4959 (Medicaid) for HIV patients compared to controls (p < .001). CONCLUSIONS: The results suggested a considerable increase in healthcare utilization and costs associated with CKD, CVD and fracture/osteoporosis comorbidities among HIV patients in the past decade. Because these conditions have been associated with treatment, it is critical to consider their impact on costs and outcomes when optimizing patient care.

Correction to "Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma".

[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma.

Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.

Magma reservoir dynamics at Toba caldera, Indonesia, recorded by oxygen isotope zoning in quartz.

Quartz is a common phase in high-silica igneous rocks and is resistant to post-eruptive alteration, thus offering a reliable record of magmatic processes in silicic magma systems. Here we employ the 75 ka Toba super-eruption as a case study to show that quartz can resolve late-stage temporal changes in magmatic δ18O values. Overall, Toba quartz crystals exhibit comparatively high δ18O values, up to 10.2‰, due to magma residence within, and assimilation of, local granite basement. However, some 40% of the analysed quartz crystals display a decrease in δ18O values in outermost growth zones compared to their cores, with values as low as 6.7‰ (maximum ∆core-rim = 1.8‰). These lower values are consistent with the limited zircon record available for Toba, and the crystallisation history of Toba quartz traces an influx of a low-δ18O component into the magma reservoir just prior to eruption. Here we argue that this late-stage low-δ18O component is derived from hydrothermally-altered roof material. Our study demonstrates that quartz isotope stratigraphy can resolve magmatic events that may remain undetected by whole-rock or zircon isotope studies, and that assimilation of altered roof material may represent a viable eruption trigger in large Toba-style magmatic systems.

Transforming Growth Factor Beta Gene Signatures are Spatially Enriched in Keloid Tissue Biopsies and Ex vivo-Cultured Keloid Fibroblasts.

The keloid lesion is recognised as a spatially heterogeneous mass both in cellular and acellular composition and biological activity. Here, we have utilised a bioinformatic approach to determine whether this spatial heterogeneity is also evident at the molecular level and to identify key upstream regulators of signalling pathways enriched in the lesion in a spatially-restricted manner. Differentially expressed genes (20% change, p < 0.05) obtained from microarray datasets derived from whole keloid biopsies and ex vivo-cultured keloid fibroblasts, both from distinct regions of the keloid lesion (leading edge, centre, and top) have been analysed to show that the TGFß family plays a significant but spatially dependent role in regulation of keloid gene expression. Furthermore, we have identified additional upstream signalling molecules involved in driving keloid biology and provide information on therapeutic targets whose modulation might be expected to lead to significant therapeutic efficacy.

Development of Autotaxin Inhibitors: An Overview of the Patent and Primary Literature.

The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is implicated in a variety of human disease states including angiogenesis, autoimmune diseases, cancer, fibrotic diseases, inflammation, neurodegeneration, and neuropathic pain, among others. As a result, ATX-LPA has become of significant interest within both the industrial and the academic communities. This review aims to provide a concise overview of the development of novel ATX inhibitors, including the disclosure of the first ATX clinical trial data.

Comparison of "Word" vs. "Picture" Version of the Free and Cued Selective Reminding Test (FCSRT) in Older Adults.

BACKGROUND: This study examined the psychometric relationship between the Word and Picture versions of the Free and Cued Selective Reminding Test (FCSRT) and developed an equation for score conversion. METHODS: 187 participants were administered the FCSRT-Picture and FCSRT-Word on two visits using a randomized counterbalanced design. RESULTS: Participants had a mean age of 82.1 (sd=5.4) and mean education of 14.5 (sd=3.3) years. Mean FCSRT-Picture Free Recall score (mean 33.0, range: 17-44) was 7.9 points higher than the Word score (mean 25.1, range: 3-43). The Picture and Word FCSRT correlations for Free Recall and Total Recall were r=0.56, p<0.01 and r=0.46, p<0.01, respectively. DISCUSSION: The Picture and Word versions of the FCSRT were moderately associated in a sample of cognitively normal older adults. The score mean differences and variability between FCSRT-Picture and FCSRT-Word indicate that their scores should not be considered equivalent.

Discovery of novel non-carboxylic acid 5-amino-4-cyanopyrazole derivatives as potent and highly selective LPA1R antagonists.

High throughput screening (HTS) of our chemical library identified 3-alkylamino-2-aryl-5H-imidazo[1,2,b]pyrazol-7-carbonitrile 1 as a potent antagonist of the LPA1 receptor (LPA1R). Further evaluation of this class of compounds indicated that LPA1R antagonist activity originated from the degradation of the parent molecule in DMSO during the assay conditions. Here, we describe the isolation and characterization of the degradation products and their LPA1R antagonist activity. We further profiled these novel non-carboxylic acid LPA1R antagonists and demonstrated their inhibition of LPA-induced proliferation and contraction of normal human lung fibroblasts (NHLF).

Development of lysophosphatidic acid pathway modulators as therapies for fibrosis.

Lysophosphatidic acid (LPA) is a class of bioactive phospholipid that displays a wide range of cellular effects via LPA receptors, of which six have been identified (LPAR1-6). In serum and plasma, LPA production occurs mainly by the hydrolysis of lysophosphatidylcholine by the phospholipase D activity of autotaxin (ATX). The involvement of the LPA pathway in driving chronic wound-healing conditions, such as idiopathic pulmonary fibrosis, has suggested targets in this pathway could provide potential therapeutic approaches. Mice with LPAR1 knockout or tissue-specific ATX deletion have demonstrated reduced lung fibrosis following bleomycin challenge. Therefore, strategies aimed at antagonizing LPA receptors or inhibiting ATX have gained considerable attention. This Review will summarize the current status of identifying small-molecule modulators of the LPA pathway. The therapeutic utility of LPA modulators for the treatment of fibrotic diseases will soon be revealed as clinical trials are already in progress in this area.

Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.

Assessment of Brd4 inhibition in idiopathic pulmonary fibrosis lung fibroblasts and in vivo models of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of high unmet medical need. Although bromodomain (Brd) and extra terminal domain isoforms have recently been implicated in mediating inflammatory and oncologic indications, their roles in lung fibrosis have not been comprehensively assessed. We investigated the role of Brd on the profibrotic responses of lung fibroblasts (LFs) in patients with rapidly progressing IPF and a mouse bleomycin model of lung fibrosis. The enhanced migration, proliferation, and IL-6 release observed in LFs from patients with rapidly progressing IPF are attenuated by pharmacologic inhibition of Brd4. These changes are accompanied by enhanced histone H4 lysine5 acetylation and association of Brd4 with genes involved in the profibrotic responses in IPF LFs as demonstrated using chromatin immunoprecipitation and quantitative PCR. Oral administration of 200 mg/kg per day Brd4 inhibitor JQ1 in a therapeutic dosing regimen substantially attenuated lung fibrosis induced by bleomycin in C57BL/6 mice. In conclusion, this study shows that the Brd4 inhibitor JQ1, administered in a therapeutic dosage, is capable of inhibiting the profibrotic effects of IPF LFs and attenuates bleomycin-induced lung fibrosis in mice. These results suggest that Brd4 inhibitors may represent a novel therapy for the treatment of rapidly progressing IPF.

Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.

The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFß was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.

Targeting the epithelial cells in fibrosis: a new concept for an old disease.

Fibrosis, which affects millions of individuals worldwide, is a leading cause of organ failure. For 40 years myofibroblasts have been recognized to be the key cellular players in fibrosis. Currently, several pharmaceutical targets are under investigation that may contribute to the activation of myofibroblasts. Recent preclinical and clinical evidence suggests that other components in the fibrotic microenvironment can trigger myofibroblast activation, providing new targets for pharmaceutical intervention. Epithelial cells may represent the most promising cellular phenotype that could be exploited in the design of new anti-fibrotic medicines through their paracrine action on myofibroblasts. The present review briefly highlights this hypothesis and discusses some interesting related pharmacological targets.

BET bromodomain proteins mediate downstream signaling events following growth factor stimulation in human lung fibroblasts and are involved in bleomycin-induced pulmonary fibrosis.

Epigenetic alterations, such as histone acetylation, regulate the signaling outcomes and phenotypic responses of fibroblasts after growth factor stimulation. The bromodomain and extra-terminal domain-containing proteins (Brd) bind to acetylated histone residues, resulting in recruitment of components of the transcriptional machinery and subsequent gene transcription. Given the central importance of fibroblasts in tissue fibrosis, this study sought to determine the role of Brd proteins in human lung fibroblasts (LFs) after growth factor stimulation and in the murine bleomycin model of lung fibrosis. Using small interfering RNA against human Brd2 and Brd4 and pharmacologic Brd inhibitors, this study found that Brd2 and Brd4 are essential in mediating the phenotypic responses of LFs downstream of multiple growth factor pathways. Growth factor stimulation of LFs causes increased histone acetylation, association of Brd4 with growth factor-responsive genes, and enhanced transcription of these genes that could be attenuated with pharmacologic Brd inhibitors. Of note, lung fibrosis induced after intratracheal bleomycin challenge in mice could be prevented by pretreatment of animals with pharmacologic inhibitors of Brd proteins. This study is the first demonstration of a role for Brd2 and Brd4 proteins in mediating the responses of LFs after growth factor stimulation and in driving the induction of lung fibrosis in mice in response to bleomycin challenge.

Comparing the differential effects of LPA on the barrier function of human pulmonary endothelial cells.

Lysophosphatidic acid (LPA) is a class of bioactive lyso-phospholipid that mediates most of its biological effects through a family of G protein-coupled receptors of which six have been identified. The role of the LPA pathway in driving chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) has gained considerable academic and industry attention. Modulation of the pulmonary artery endothelial barrier function by the LPA1 receptor has been shown to drive pulmonary fibrosis in murine models of disease. The purpose of this study was (i) to assess the effect of LPA on the barrier function of human pulmonary arterial (HPAEC) and microvascular (HMVEC) endothelial cells and (ii) to identify the LPA receptor subtype(s) responsible for changes in human pulmonary endothelial cell permeability using LPA receptor antagonists and siRNA technology. Analysis of the LPA receptor subtype expression demonstrated predominant expression of LPA2 and LPA6 receptor subtypes in both HPAECs and HMVECs. HPAECs also exhibit low expression of LPA1, LPA3, and LPA4 receptor subtypes. Treatment of cells with increasing concentrations of LPA caused loss of barrier function in HPAECs but not HMVECs, despite both cell types exhibiting very similar LPA receptor expression profiles. The LPA-mediated loss of barrier function in HPAECs appears to be independent of the LPA1 receptor and likely to be mediated via the LPA6 receptor although we cannot exclude an additional role for the LPA2 and LPA4 receptors in mediating these effects. These results suggest cell-specific mechanisms exist in human pulmonary endothelial cells to permit regulation of barrier function downstream of LPA receptors. More importantly, our data indicate that selective LPA1 receptor antagonism may be insufficient for therapeutic use in pulmonary diseases where impaired endothelial barrier function is related to disease initiation and progression.