NeRRe Therapeutics (United Kingdom)

While several PROMs are used to assess IPF cough severity, none have been developed and validated to the standard needed to support regulatory approval of new drugs. We set out to develop and validate a simple PROM that could be completed by patients with IPF cough to support drug approval. Following literature review and expert interviews, a one question 11-point numerical rating scale (NRS, recall=24hrs) was tested in an observational study in IPF patients, including cognitive debriefing. This led to the addition of 2 severity questions at different times of the day (Early Morning, Rest of the Day) resulting in the 3-item IPF CSS (v2). Psychometric properties were evaluated qualitatively (37 interviews) and quantitatively (N=80) in the ORV-PF-01 study (<ext-link>NCT05185089</ext-link>). Analyses were done on mean weekly scores with a focus on the Daily (last 24 hours) question. Within subject, mean scores are stable and between subject variance is low (CV%=17.8%). Floor and ceiling score effects are minimal. Test-retest reliability is good (ICC 0.81 in stable patients) and scores respond to change during treatment. Known groups validity and construct validity is shown through correlation with other cough assessments (global ratings of status/change, Leicester Cough Questionnaire). Distribution-based methods show a group mean difference of -0.7 points is clinically meaningful, and anchor-based methods show the meaningful within subject change is -1.1 points. Findings were similar for the other 2 questions. The IPF CSS v2 is a simple, valid NRS PROM for assessing cough severity in IPF; clinically relevant differences and changes are defined.

We investigated orvepitant, a selective antagonist of the NK1 receptor, as a treatment for chronic cough in IPF. This phase 2, randomised, double blind, placebo-controlled, 2-period cross-over study tested orvepitant 10 mg and 30 mg once daily in patients with confirmed IPF. Treatment periods were 4-wks with a wash-out of 3-wks. Eligible subjects had a mean score of ≥5 on a 0-10 cough severity numerical rating scale (NRS) in the last 7 days of screening. Assessments included daily and periodic patient-reported outcome measures and cough frequency monitoring for efficacy, and safety tests. The primary endpoint was weekly mean of the Daily Cough Severity NRS at wk 4. 80 patients were randomised. There was a significant period effect due to a marked placebo response in Period A, hence both cross over (XO) and additional by period (PB) analyses are presented. At wk 4, Daily Cough Severity NRS scores decreased with orvepitant 30mg compared to placebo in both XO (-0.58 pts, p=0.054) and PB (-1.17 pts, p=0.009) analyses. There were also reductions in the cough frequency verbal rating scale (XO: -0.23, p=0.010; PB: -0.35, p=0.018) and urge to cough NRS (XO: -0.46, p=0.092; PB: -0.84, p=0.042) scores. Wk 2 findings were similar. Leicester Cough Questionnaire QoL scores were improved (XO: 1.24, p=0.025; PB:1.94, p=0.015) and more subjects reported their cough improved with orvepitant 30 mg (69%) than placebo (44%) on a global rating of change. The 10 mg dose was not different to placebo. Both doses were well tolerated with no safety concerns. Orvepitant 30 mg once daily improved multiple patient-reported measures of cough burden in patients with IPF.

Fibrotic tissues are characterized by excessive crosslinking between extracellular matrix (ECM) proteins, rendering them more resistant to degradation. Although increased crosslinking of ECM is thought to play an important role for progression of tissue fibrosis, enhanced ECM crosslinking has not yet been targeted therapeutically in systemic sclerosis (SSc). Here, we investigated the role of transglutaminase 2 (TG2), a central crosslinking enzyme, in the activation of SSc fibroblasts. We assessed TG2 expression and activity using TG2 staining, Western blotting, and TG2 activity assays. We inhibited TG2 in fibroblasts cultured under standard 2-dimensional conditions and in a 3-dimensional full-thickness equivalent skin model using monoclonal inhibitory anti-TG2 antibodies. TG2 expression was increased in the skin of patients with SSc compared with healthy controls, with levels particularly high in patients with SSc-associated interstitial lung disease. TG2 expression and TG2 activity were also increased in SSc dermal fibroblasts. Moreover, the levels of circulating TG2 in the plasma samples from SSc patients were increased versus samples from healthy controls. Anti-TG2 antibodies did not show consistent antifibrotic effects across different fibroblast cell lines under 2-dimensional culture conditions; however, anti-TG2 antibodies effectively reduced transforming growth factor β-induced dermal thickening, myofibroblast differentiation, and collagen accumulation in the 3-dimensional full-thickness model of human skin. We provide the first evidence, to our knowledge, that inhibition of TG2 might be a potential antifibrotic approach in SSc. Our findings have translational potential as anti-TG2 antibodies are currently evaluated in a phase II clinical trial in chronic allograft injury and would thus be available for clinical studies in SSc (ClinicalTrials.gov identifier: NCT04335578).

Objectives:To evaluate the safety, pharmacokinetics, and preliminary efficacy of NT-814, a dual neurokinin 1,3 antagonist, in postmenopausal women with vasomotor symptoms (hot flashes).Methods:We completed a double-blind, randomized, placebo-controlled trial in three US clinical research units in 76 postmenopausal women with moderate/severe hot flashes. Participants were randomized to 14 days of once-daily NT-814 or placebo within each of four sequential dose cohorts; 50, 100, 150, and 300 mg. Participants completed diaries of hot flash frequency and severity and waking due to night sweats before (baseline) and during treatment.Results:All prespecified efficacy parameters (24-h hot flash frequency and severity, frequency of waking due to night sweats) decreased in all groups (including placebo). Mean reduction from baseline at week 2 in moderate/severe hot flash frequency was 37% in the placebo group and, respectively, 24% (P = 0.048 vs placebo), 59% (P = 0.155), 84% (P < 0.001) and 66% (P = 0.022) in the 50 mg, 100 mg, 150 mg, and 300 mg NT-814 groups; in waking due to night sweats reduction was 20% (P = 0.059), 55% (P = 0.135), 81% (P < 0.001), and 63% (P = 0.031) in the NT-814 groups and 32% in the placebo group. The improvement with NT-814 ≥150 mg was also evident in the first week of treatment. The most common treatment-related adverse events were mild somnolence and headache, more frequently in the 300 mg group. Safety monitoring identified no concerns.Conclusions:Once-daily NT-814 (≥150 mg/d) resulted in a rapid, marked improvement in hot flashes and waking due to night sweats. No safety concerns were identified. Doses up to 300 mg were well tolerated.

Review Articles| October 01 2008 Augmentation of Organ-Associated NK Activity by BRMs: Association of NK Activity with Mononuclear Cell Infiltration Subject Area: Immunology and Allergy , Pathology and Cell Biology Robert H. Wiltrout; Robert H. Wiltrout aExperimental Therapeutics Section and Search for other works by this author on: This Site PubMed Google Scholar A.C. Denn, III; A.C. Denn, III bCellular and Molecular Immunology Section, Laboratory of Experimental Immunology, Biological Response Modifiers Program, NCI-FCRF, Frederick, Md., USA Search for other works by this author on: This Site PubMed Google Scholar Craig W. Reynolds Craig W. Reynolds bCellular and Molecular Immunology Section, Laboratory of Experimental Immunology, Biological Response Modifiers Program, NCI-FCRF, Frederick, Md., USA Search for other works by this author on: This Site PubMed Google Scholar Pathology and Immunopathology Research (1986) 5 (3-5): 219–233. https://doi.org/10.1159/000157015 Article history Published Online: October 01 2008 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Robert H. Wiltrout, A.C. Denn, III, Craig W. Reynolds; Augmentation of Organ-Associated NK Activity by BRMs: Association of NK Activity with Mononuclear Cell Infiltration. Pathology and Immunopathology Research 31 December 1986; 5 (3-5): 219–233. https://doi.org/10.1159/000157015 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsSurvey and Synthesis of Pathology Research Search Advanced Search Article PDF first page preview Close Modal This content is only available via PDF. 1986Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.