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      A phase 2 multiple ascending dose study of the inhaled pan-JAK inhibitor nezulcitinib (TD-0903) in severe COVID-19

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          Abstract

          Severe coronavirus disease 2019 (COVID-19) is characterised by pneumonia with excessive systemic inflammation, referred to as a “cytokine storm” [1–3]. Dexamethasone treatment decreases mortality in patients with COVID-19 receiving respiratory support and is standard of care for severe COVID-19 [4, 5]. However, pulmonary inflammation, which drives COVID-19 morbidity and mortality [3], can persist despite corticosteroid use [6, 7]. Janus kinase (JAK) inhibition blocks signalling by many cytokines in diverse cell types, offering broad immunomodulation [8]. The oral JAK-1/2 inhibitor baricitinib combined with the antiviral remdesivir shows clinical efficacy in patients with severe COVID-19 [9]. Direct delivery of JAK inhibition to the lung via inhalation could overcome corticosteroid-resistant pulmonary inflammation [10], offering the potential for improved responses while minimising risk of excessive systemic immunosuppression. The novel inhaled pan-JAK inhibitor nezulcitinib (TD-0903) was designed to target all JAK isoforms (JAK1, JAK2, JAK3, TYK2; −log inhibition constant ≥9.2) and optimise delivery to the lungs while limiting systemic exposure (R. Sana and co-workers; unpublished results: abstract submitted to ERS International Congress, 2021). We report results from the completed part 1 of a 2-part phase 2 trial (NCT04402866) in hospitalised patients with severe COVID-19.

          Abstract

          The inhaled lung-selective pan-JAK inhibitor nezulcitinib appears generally well tolerated in hospitalised patients with severe #COVID-19, with trends for improved oxygenation and clinical status, shortened hospitalisation, and fewer deaths versus placebo https://bit.ly/35Xs1Rf

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          Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

          Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)
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            Remdesivir for the Treatment of Covid-19 — Final Report

            Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)
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              Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review

              The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19.
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                Author and article information

                Journal
                Eur Respir J
                Eur Respir J
                ERJ
                erj
                The European Respiratory Journal
                European Respiratory Society
                0903-1936
                1399-3003
                October 2021
                14 October 2021
                : 58
                : 4
                : 2100673
                Affiliations
                [1 ]Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundations Trust, Manchester, UK
                [2 ]Arensia Exploratory Medicine SRL, Timofei Moșneaga Republican Clinical Hospital, Chișinău, Moldova
                [3 ]Arensia Exploratory Medicine, LLC, Kyiv City Clinical Hospital #12, Kyiv, Ukraine
                [4 ]Oleksandrivska Kyiv City Clinical Hospital, Kyiv, Ukraine
                [5 ]Brovary Multidisciplinary Clinical Hospital, Brovary, Ukraine
                [6 ]University of Manchester, Manchester University NHS Foundations Trust, Manchester, UK
                [7 ]Theravance Biopharma US, Inc., South San Francisco, CA, USA
                [8 ]Theravance Biopharma UK Limited, London, UK
                Author notes
                Author information
                https://orcid.org/0000-0001-9008-2502
                Article
                ERJ-00673-2021
                10.1183/13993003.00673-2021
                8859971
                34210790
                08ca0c81-0d46-4c52-bee6-4415760b507e
                Copyright ©The authors 2021.

                This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions@ersnet.org

                History
                : 5 March 2021
                : 19 June 2021
                Funding
                Funded by: Theravance Biopharma Ireland Limited
                Funded by: Theravance Biopharma US, doi 10.13039/100013993;
                Award ID: medical writing support
                Categories
                Agora
                Research Letters

                Respiratory medicine
                Respiratory medicine

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