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
To the Editor:
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inhibition constant ≥9.2) and optimise delivery to the lungs while limiting systemic exposure (R. Sana and co-workers; unpublished results: abstract submitted to ERS International Congress, 2021).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.
The study was designed with separate data reporting for parts 1 and 2. Part 1 was a randomised, double-blind, placebo-controlled, multiple-ascending-dose trial conducted in the UK, Moldova and Ukraine. The study documents were approved by independent ethics committees at each site. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Patients provided informed consent. Hospitalised patients aged 18 to 80 years with PCR-confirmed symptomatic COVID-19 (symptoms for 3–14 days) who required supplemental oxygen to maintain saturation >90% were eligible; patients receiving JAK inhibitors or anti-interleukin-6 therapy were excluded (full inclusion/exclusion criteria: https://www.clinicaltrials.gov/ct2/show/NCT04402866). Patients were sequentially enrolled in three ascending-dose cohorts (n=6 active and 2 placebo per cohort) and received once-daily nezulcitinib 1 mg (day 1 loading dose 2 mg), 3 mg (day 1 loading dose 6 mg), or 10 mg (no loading dose) or matched placebo via inhalation (Aerogen Solo+Ultra nebuliser system, Galway, Ireland) for up to 7 days, with follow-up through day 28. Day 1 loading doses for nezulcitinib 1 mg and 3 mg were administered to rapidly achieve pseudo-steady state in the lung.
Peripheral blood arterial oxygen saturation (SaO2) was collected via pulse oximetry, and fraction of inspired oxygen (FIO2), vital signs, adverse events, and clinical status using an 8-point ordinal scale (OS) [11] were recorded daily through day 7 and on days 14, 21 and 28 and/or at hospital discharge. Physical examination and blood collection were performed on days 1 and 7; patient care-related laboratory evaluations through day 28 were included. Safety was assessed from vital signs, laboratory results, and treatment-emergent adverse events (TEAEs; coded per Medical Dictionary for Regulatory Activities v23.1). Plasma pharmacokinetic parameters were evaluated on days 1 and 7. The key pharmacodynamic outcome was change from baseline SaO2/FIO2 ratio; other clinical outcomes were considered exploratory.
A sample size of six active- and two placebo-treated patients per cohort was deemed appropriate to assess nezulcitinib safety and tolerability during dose escalation. Safety, SaO2/FIO2 ratio, and efficacy data were summarised as descriptive statistics using SAS v9.4 (SAS Institute, Cary, NC, USA).
25 patients enrolled (UK, 3; Ukraine, 4; Moldova, 18) and were randomised to receive nezulcitinib 1 mg (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. SaO2/FIO2 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 SaO2/FIO2 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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Acknowledgements
The authors and Theravance Biopharma, Inc., thank the patients and their families for their participation and Kyla Kennedy for clinical operations. Dave Singh, Robert Lord and Ashley Woodcock are supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC).
Footnotes
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.
Author contributions: D. Singh, E.J. Moran, R. Lord, G.D. Crater, A. Woodcock, B. Haumann and R. Saggar contributed to study design and interpretation. D. Singh, M. Bogus, V. Moskalenko and R. Lord enrolled patients, collected data and contributed to interpretation. D.L. Bourdet and N.D. Pfeifer performed pharmacokinetic analyses and contributed to data interpretation. J. Woo and E. Kaufman contributed to data interpretation. D.A. Lombardi, E.Y. Weng and T. Nguyen performed statistical analyses and contributed to data interpretation. All authors reviewed the manuscript critically for intellectual content and approved the final version for submission.
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.
Conflict of interest: M. Bogus is an employee of Arensia Exploratory Medicine SRL.
Conflict of interest: V. Moskalenko is an employee of Arensia Exploratory Medicine, LLC.
Conflict of interest: 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.
Conflict of interest: E.J. Moran is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc.
Conflict of interest: G.D. Crater is a former employee of Theravance Biopharma US, Inc., and owns shares in Theravance Biopharma, Inc.
Conflict of interest: D.L. Bourdet is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc.
Conflict of interest: N.D. Pfeifer is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc.
Conflict of interest: J. Woo is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc.
Conflict of interest: E. Kaufman is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc.
Conflict of interest: D.A. Lombardi is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc.
Conflict of interest: E.Y. Weng is a former employee of Theravance Biopharma US, Inc., and owns shares in Theravance Biopharma, Inc.
Conflict of interest: T. Nguyen is an employee of Theravance Biopharma US, Inc., and shareholder of Theravance Biopharma, Inc.
Conflict of interest: A. Woodcock reports fees from Theravance Biopharma, Inc., for consulting on the study design.
Conflict of interest: B. Haumann is a former employee of Theravance Biopharma UK Limited and shareholder of Theravance Biopharma, Inc.
Conflict of interest: 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.
- Received March 5, 2021.
- Accepted June 19, 2021.
- Copyright ©The authors 2021.
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