Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study.

OBJECTIVES: To evaluate the effect of subcutaneous (s.c.) secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic progression in patients with psoriatic arthritis (PsA). METHODS: Adults (n=996) with active PsA were randomised 2:2:2:3 to s.c. secukinumab 300 mg or 150 mg with loading dose (LD), 150 mg without LD or placebo. All groups received secukinumab or placebo at baseline, weeks 1, 2 and 3 and then every 4 weeks from week 4. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 16. RESULTS: Significantly more patients achieved an ACR20 response at week 16 with secukinumab 300 mg with LD (62.6%), 150 mg with LD (55.5%) or 150 mg without LD (59.5%) than placebo (27.4%) (p CONCLUSION: S.c. secukinumab 300 mg and 150 mg with and without LD significantly improved clinical signs and symptoms and inhibited radiographic structural progression versus placebo at week 24 in patients with PsA. TRIAL REGISTRATION NUMBER: NCT02404350; Results

Promoting ecological solutions for sustainable infrastructure

Sustainable infrastructure needs ecological solutions – it’s time to work together! We, the participants of the IENE 2020 International Conference, acknowledge that: 1. We are facing a significant worldwide expansion of transportation networks; this is especially the case in countries with developing economies. 2. If no action is taken, this global expansion will entail a substantial increase in greenhouse gas emissions, wildlife mortality and landscape fragmentation and change, with devastating effects on climate, biodiversity and ecosystem services. 3. Globally, ecosystem services are estimated to yield more than the Gross World Product of 2019 (https://www.worldometers.info/gdp/). 4. Despite the development and implementation of environmental impact assessment legislation, many existing transportation infrastructure networks are not environmentally friendly. These impacts are far-reaching with a debt being paid daily through unnecessary risks extendable to human health and well-being. 5.The economic, social, and ecological consequences of biodiversity loss and the role of transportation infrastructure is increasingly acknowledged worldwide: •Conservation and restoration of ecological connectivity is a major flagship in the preparation of the upcoming United Nations “Post-2020 Global biodiversity framework” following the recognised failure of the Aichi Targets associated with the loss and fragmentation of natural habitats (Target 5) (https://www.cbd.int/gbo5). •The European Green Deal and the new European Biodiversity Strategy for 2030, adopted by the European Commission in May 2020, stresses the need to develop a resilient Trans-European Nature Network supported by ecological corridors allowing the free flow of genes and individuals (https://ec.europa.eu/info/sites/info/files/communication-annex-eu-biodiversity-strategy-2030_en.pdf). •The Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) states that since 1970, transportation infrastructure is an important driver of land use change and associated loss of terrestrial biodiversity (https://ipbes.net/global-assessment). •The World Economic Forum 2020 recognised that biodiversity loss is one of the major threats with ‘plausible higher than average impact’ on Global Economies (https://www.weforum.org/reports/the-global-risks-report-2020). 6.To ahieve sustainability, infrastructure development must be decoupled from its negative effect on biodiversity. This requires immediate, stringent action and shared responsibilities from all stakeholders. 7.Regional, national, and worldwide networks of experts, including researchers, practitioners, landscape designers, and managers, address such concerns through knowledge-sharing platforms that promote effective ecological solutions. 8.The scarcity of collective and coordinated efforts, such as joint decision-making processes involving environmental, transportation, energy, policy and financing agencies, is still a major obstacle to achieve sustainability in transportation infrastructure projects.Comissão Europeia. Programa LIFE. Projeto LIFE LINES (LIFE14 NAT/PT/001081

Secukinumab provides sustained low rates of radiographic progression in psoriatic arthritis: 52-week results from a phase 3 study, FUTURE 5.

OBJECTIVE: To evaluate the effect of secukinumab on radiographic progression through 52 weeks in patients with PsA from the FUTURE 5 study. METHODS: Patients with active PsA, stratified by prior anti-TNF use (naïve or inadequate response), were randomized to s.c. secukinumab 300 mg load (300 mg), 150 mg load (150 mg), 150 mg no load regimens or placebo at baseline, at weeks 1, 2 and 3 and every 4 weeks starting at week 4. Radiographic progression was assessed by change in van der Heijde-modified total Sharp score (vdH-mTSS; mean of two readers). Statistical analysis used a linear mixed-effects model (random slope) at weeks 24 and 52, and observed data at week 52. Assessments at week 52 included additional efficacy endpoints (non-responders imputation and mixed-effects models for repeated measures) and safety. RESULTS: The majority (86.6%) of patients completed 52 weeks of treatment. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS ⩽0.5) was 91.8, 85.2 and 87.2% in 300, 150 and 150 mg no load groups, respectively, at week 52. The change in vdH-mTSS from baseline to week 52 using random slope [mean change (s.e.)] was -0.18 (0.17), 0.11 (0.18) and -0.20 (0.18) in 300, 150 and 150 mg no load groups, respectively; the corresponding observed data [mean change (s.d.)] was -0.09 (1.02), 0.13 (1.39) and 0.21 (1.15). Clinical efficacy endpoints were sustained, and no new or unexpected safety signals were reported through 52 weeks. CONCLUSION: Secukinumab 300 and 150 mg with or without s.c. loading regimen provided sustained low rates of radiographic progression through 52 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02404350

Caveolin-1 protects B6129 mice against Helicobacter pylori gastritis.

Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the mucosa of the gastrointestinal tract. Chronic infection of gastric epithelial cells by Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC) where Cav1 is frequently down-regulated. However, the function of Cav1 in H. pylori infection and pathogenesis of GC remained unknown. We show here that Cav1-deficient mice, infected for 11 months with the CagA-delivery deficient H. pylori strain SS1, developed more severe gastritis and tissue damage, including loss of parietal cells and foveolar hyperplasia, and displayed lower colonisation of the gastric mucosa than wild-type B6129 littermates. Cav1-null mice showed enhanced infiltration of macrophages and B-cells and secretion of chemokines (RANTES) but had reduced levels of CD25+ regulatory T-cells. Cav1-deficient human GC cells (AGS), infected with the CagA-delivery proficient H. pylori strain G27, were more sensitive to CagA-related cytoskeletal stress morphologies ("humming bird") compared to AGS cells stably transfected with Cav1 (AGS/Cav1). Infection of AGS/Cav1 cells triggered the recruitment of p120 RhoGTPase-activating protein/deleted in liver cancer-1 (p120RhoGAP/DLC1) to Cav1 and counteracted CagA-induced cytoskeletal rearrangements. In human GC cell lines (MKN45, N87) and mouse stomach tissue, H. pylori down-regulated endogenous expression of Cav1 independently of CagA. Mechanistically, H. pylori activated sterol-responsive element-binding protein-1 (SREBP1) to repress transcription of the human Cav1 gene from sterol-responsive elements (SREs) in the proximal Cav1 promoter. These data suggested a protective role of Cav1 against H. pylori-induced inflammation and tissue damage. We propose that H. pylori exploits down-regulation of Cav1 to subvert the host's immune response and to promote signalling of its virulence factors in host cells

Secukinumab provides sustained improvement in signs and symptoms and low radiographic progression in patients with psoriatic arthritis: 2-year (end-of-study) results from the FUTURE 5 study.

OBJECTIVE: Secukinumab provided sustained efficacy, low radiographic progression and consistent safety over 52 weeks in patients with psoriatic arthritis (PsA) in the FUTURE 5 study. Here, we report 2-year (end-of-study) results from this study. METHODS: Adults with active PsA were randomised 2:2:2:3 to receive subcutaneous secukinumab 300 mg load (300 mg), 150 mg load (150 mg), 150 mg no load or placebo at baseline; weeks 1, 2, 3 and 4; and every 4 weeks thereafter. Secukinumab could be escalated from 150 mg to 300 mg starting at week 52, if active signs of disease were observed based on physician\u27s assessment. Assessments at week 104 (2 years) included clinical end points and radiographic damage (mean change in van der Heijde-modified total Sharp score (vdH-mTSS)). Safety analysis included all patients who received ≥1 dose of study medication. RESULTS: Of the 996 patients randomised, 783 patients (78.6%) completed 2 years of treatment. Improvement in clinical end points was sustained through 2 years. The vdH-mTSS (mean change (SD)) was 0.10 (1.74; 300 mg), 0.52 (2.66; 150 mg) and 0.41 (2.20; 150 mg no load) at 2 years. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS ≤0.5) at 2 years was 89.5% (300 mg), 82.3% (150 mg) and 81.1% (150 mg no load). CONCLUSION: Secukinumab with and without loading regimen provided sustained clinical efficacy and low radiographic progression through 2 years in patients with PsA. No new safety findings were reported. TRIAL REGISTRATION NUMBER: NCT02404350

Secukinumab provides sustained low rates of radiographic progression in psoriatic arthritis: 52-week results from a phase 3 study, FUTURE 5

Objective: To evaluate the effect of secukinumab on radiographic progression through 52 weeks in patients with PsA from the FUTURE 5 study. Methods: Patients with active PsA, stratified by prior anti-TNF use (naïve or inadequate response), were randomized to s.c. secukinumab 300 mg load (300 mg), 150 mg load (150 mg), 150 mg no load regimens or placebo at baseline, at weeks 1, 2 and 3 and every 4 weeks starting at week 4. Radiographic progression was assessed by change in van der Heijde-modified total Sharp score (vdH-mTSS; mean of two readers). Statistical analysis used a linear mixed-effects model (random slope) at weeks 24 and 52, and observed data at week 52. Assessments at week 52 included additional efficacy endpoints (non-responders imputation and mixed-effects models for repeated measures) and safety. Results: The majority (86.6%) of patients completed 52 weeks of treatment. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS ≤0.5) was 91.8, 85.2 and 87.2% in 300, 150 and 150 mg no load groups, respectively, at week 52. The change in vdH-mTSS from baseline to week 52 using random slope [mean change (s.e.)] was-0.18 (0.17), 0.11 (0.18) and-0.20 (0.18) in 300, 150 and 150 mg no load groups, respectively; the corresponding observed data [mean change (s.d.)] was-0.09 (1.02), 0.13 (1.39) and 0.21 (1.15). Clinical efficacy endpoints were sustained, and no new or unexpected safety signals were reported through 52 weeks. Conclusion: Secukinumab 300 and 150 mg with or without s.c. loading regimen provided sustained low rates of radiographic progression through 52 weeks of treatment

Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β

Abstract Human interleukin-1β (hIL-1β) is a pro-inflammatory cytokine involved in many diseases. While hIL-1β directed antibodies have shown clinical benefit, an orally available low-molecular weight antagonist is still elusive, limiting the applications of hIL-1β-directed therapies. Here we describe the discovery of a low-molecular weight hIL-1β antagonist that blocks the interaction with the IL-1R1 receptor. Starting from a low affinity fragment-based screening hit 1, structure-based optimization resulted in a compound (S)-2 that binds and antagonizes hIL-1β with single-digit micromolar activity in biophysical, biochemical, and cellular assays. X-ray analysis reveals an allosteric mode of action that involves a hitherto unknown binding site in hIL-1β encompassing two loops involved in hIL-1R1/hIL-1β interactions. We show that residues of this binding site are part of a conformationally excited state of the mature cytokine. The compound antagonizes hIL-1β function in cells, including primary human fibroblasts, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics