key: cord-0871468-ou27fr8z
authors: Singh, Dave; Bogus, Maxim; Moskalenko, Valentyn; Lord, Robert; Moran, Edmund J.; Crater, Glenn D.; Bourdet, David L.; Pfeifer, Nathan D.; Woo, Jacky; Kaufman, Elad; Lombardi, David A.; Weng, Emily Y.; Nguyen, Tuan; Woodcock, Ashley; Haumann, Brett; Saggar, Rajeev
title: A phase 2 multiple ascending dose study of the inhaled pan-JAK inhibitor nezulcitinib (TD-0903) in severe COVID-19
date: 2021-10-14
journal: Eur Respir J
DOI: 10.1183/13993003.00673-2021
sha: 761a24b0668fbdb7c7e916fc226b3685e2624836
doc_id: 871468
cord_uid: ou27fr8z

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

Data are shown as mean±SD or n (%), unless otherwise specified. # : one patient discontinued the study due to subsequent negative PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was replaced but included in analyses as available data permitted. ¶ : includes heparins, enoxaparin, bemiparin and nadroparin. + : including patients who received ⩾1 dose of study drug analysed as treated. § : including all randomised patients analysed as randomised (intent-to-treat population). ƒ : the patient who discontinued the study due to negative PCR test for SARS-CoV-2 was known to be alive but with unknown clinical status at day 28. Thus, this patient was not counted as alive and respiratory failure-free and was not included in analyses of ordinal scale (OS) on days 7 and 28. ## : for patients who died or were still hospitalised on day 28, a time to discharge of 28 days was assigned. ¶ ¶ : 8-point OS: 1, not hospitalised, no limitations on activities; 2, not hospitalised, but with limitation on activities and/or requiring home oxygen; 3, hospitalised, not requiring supplemental oxygen and no longer requiring ongoing medical care (including hospitalisation for infection control); 4, hospitalised, not requiring supplemental oxygen but requiring ongoing medical care (whether related or not to coronavirus disease 2019 (COVID-19)); 5, hospitalised, requiring supplemental oxygen; 6, hospitalised, on noninvasive ventilation or high-flow oxygen devices; 7, hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 8, death. IQR: interquartile range; S aO 2 /F IO 2 : ratio of oxygen saturation measured by pulse oximetry to fraction of inspired oxygen; TEAE: treatment-emergent adverse event. (n=6), 3 mg (n=7), 10 mg (n=6), or placebo (n=6). One patient receiving nezulcitinib 3 mg was discontinued due to a negative SARS-CoV-2 PCR screening test returned after randomisation and was replaced per protocol. Baseline data, concomitant medications, TEAEs and clinical outcomes are summarised in table 1. Mean body mass index and proportion of men were lower in patients receiving placebo versus nezulcitinib, and mean age was lower in patients receiving placebo or nezulcitinib 10 mg versus nezulcitinib 1 mg or 3 mg. Almost all patients (92%) received dexamethasone; three (12%) received remdesivir. The majority of TEAEs were mild to moderate and resolved by end of study, with no apparent dose relationship. Serious TEAEs occurred in five patients through day 28, including COVID-19 progression in one placebo-treated patient; acute respiratory distress syndrome (ARDS) and fatal multiple organ dysfunction syndrome (MODS) in one placebo-treated patient; ARDS and fatal cardiac arrest in one placebo-treated patient; acute respiratory failure, ventricular fibrillation, and fatal MODS in one nezulcitinib 1 mg-treated patient; and ischaemic stroke in one nezulcitinib 3 mg-treated patient. No serious TEAEs were considered related to study treatment by the investigator. One patient receiving nezulcitinib 10 mg discontinued treatment on day 4 due to elevated alanine aminotransferase that resolved without consequence. No other changes in vital signs or laboratory safety measures, including creatinine and haematologic parameters, were attributed to treatment. On day 7, mean systemic levels of inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) and lung injury marker soluble receptor for advanced glycation end products (sRAGE) were lower versus baseline in patients treated with nezulcitinib 3 mg and 10 mg (range: hsCRP, 52%-75% reduction; sRAGE, 54%-83% reduction) versus placebo (41% increase and 37% reduction, respectively). The mean steady state maximal plasma concentration of nezulcitinib at the highest dose was 19.0 ng·mL −1 , well below levels predicted to produce systemic JAK inhibition.

At baseline, all patients received supplemental oxygen via nasal prongs or mask (OS 5). During the 7-day treatment period, three (50%) placebo-treated patients progressed to invasive mechanical ventilation (OS 7), but no nezulcitinib-treated patient declined in clinical status. After day 7, one patient treated with nezulcitinib 1 mg and two placebo-treated patients died (OS 8; nezulcitinib 1 mg-treated patient on day 23 and placebo-treated patients on days 11 and 14), whereas clinical status remained stable or improved through day 28 in all patients treated with nezulcitinib 3 mg or 10 mg. S aO 2 /F IO 2 ratio improved from baseline to day 7, proportion of patients alive and respiratory failure-free at day 28 was higher and mean time to hospital discharge was shorter in patients treated with nezulcitinib versus placebo (table 1) .

This is the first clinical trial of an inhaled JAK inhibitor for COVID-19 treatment. Once-daily inhaled nezulcitinib for 7 days was generally well tolerated in patients with severe COVID-19. There were trends towards improvement in S aO 2 /F IO 2 ratio, respiratory failure-free survival at day 28, and mean time to hospital discharge in patients treated with nezulcitinib versus placebo. Overall mortality was 33% in placebo-treated patients versus 5% in nezulcitinib-treated patients. The small size of this early-phase clinical trial and consequent baseline differences in clinical characteristics limited evaluation of efficacy through between-group comparisons and formal control for potential confounders. Nevertheless, the low mortality and pattern of earlier clinical recovery with nezulcitinib versus placebo treatment suggests promise for targeting cytokine-driven pulmonary inflammation in patients with severe COVID-19 through pan-JAK inhibition. Notably, JAK inhibition may have additive anti-inflammatory effects in combination with corticosteroid treatment [10, 12] , which almost all patients in the study received, and, thus, inhaled nezulcitinib may complement dexamethasone for treatment of patients with COVID-19.

Based on all evidence, inhaled nezulcitinib 3 mg was advanced for further evaluation in part 2, a larger (n≈200) double-blind, placebo-controlled parallel-group phase 2 study in hospitalised COVID-19 patients requiring supplemental oxygen (OS 5-6) (NCT04402866).

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This study was registered at Clinicaltrials.gov with identifier NCT04402866. Theravance Biopharma (and its affiliates) will not be sharing individual de-identified participant data or other relevant study documents. Conflict of interest: D. Singh reports personal fees from Theravance Biopharma during the conduct of the study; and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Theravance Biopharma and Verona outside this work. M. Bogus is an employee of Arensia Exploratory Medicine SRL. V. Moskalenko is an employee of Arensia Exploratory Medicine, LLC. R. Lord reports an independent grant from Vertex Pharmaceuticals for an investigator-initiated study on gastro-oesophageal reflux, honoraria from the Manchester Adult CF Centre for speaking at a conference and travel awards from the European CF Society and British Thoracic Society. E.J. Moran is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc. G.D. Crater is a former employee of Theravance Biopharma US, Inc., and owns shares in Theravance Biopharma, Inc. D.L. Bourdet is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc. N.D. Pfeifer is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc. J. Woo is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc. E. Kaufman is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc. D.A. Lombardi is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc. E.Y. Weng is a former employee of Theravance Biopharma US, Inc., and owns shares in Theravance Biopharma, Inc. T. Nguyen is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc. A. Woodcock reports fees from Theravance Biopharma, Inc., for consulting on the study design. B. Haumann is a former employee of Theravance Biopharma UK Limited and shareholder of Theravance Biopharma, Inc. R. Saggar is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc. Support statement: The study was funded by Theravance Biopharma Ireland Limited. Medical writing and editorial support were provided by Judith M. Phillips, of AlphaBioCom, LLC, and funded by Theravance Biopharma US, Inc. Funding information for this article has been deposited with the Crossref Funder Registry.