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Journal ArticleDOI

Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues.

28 Jul 2021-Pharmaceuticals (Multidisciplinary Digital Publishing Institute)-Vol. 14, Iss: 8, pp 738-738
TL;DR: In this paper, a review of the development and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury.
Abstract: We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered.
Citations
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Journal ArticleDOI
TL;DR: In this article, a review of the possible mechanisms of the host response following SARS-CoV-2 infection and surveyed current research conducted by in-vitro, in vivo and human observations, as well as existing suggestions.

53 citations

Journal ArticleDOI
TL;DR: In this paper , a review of the possible mechanisms of the host response following SARS-CoV-2 infection and surveyed current research conducted by in vitro, in vivo and human observations, as well as existing suggestions.

53 citations

Journal ArticleDOI
TL;DR: The European Association for the Study of the Liver as mentioned in this paper provides a summary of the latest data on the impact of COVID-19 on the liver and issues guidance on the care of patients with chronic liver disease, hepatobiliary cancer, and previous liver transplantation.

33 citations

Journal ArticleDOI
TL;DR: Whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only is discussed, because the precise timing of treatment will be very important in future trials.
Abstract: During SARS-CoV-2 infection, the innate immune response can be inhibited or delayed, and the subsequent persistent viral replication can induce emergency signals that may culminate in a cytokine storm contributing to the severe evolution of COVID-19. Cytokines are key regulators of the immune response and virus clearance, and, as such, are linked to the—possibly altered—response to the SARS-CoV-2. They act via a family of more than 40 transmembrane receptors that are coupled to one or several of the 4 Janus kinases (JAKs) coded by the human genome, namely JAK1, JAK2, JAK3, and TYK2. Once activated, JAKs act on pathways for either survival, proliferation, differentiation, immune regulation or, in the case of type I interferons, antiviral and antiproliferative effects. Studies of graft-versus-host and systemic rheumatic diseases indicated that JAK inhibitors (JAKi) exert immunosuppressive effects that are non-redundant with those of corticotherapy. Therefore, they hold the potential to cut-off pathological reactions in COVID-19. Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. Yet, only baricitinib is recommended in first line for severe COVID-19 treatment by the WHO, as it is the only JAKi that has proven efficient to reduce mortality in individual randomized clinical trials (RCT), especially the Adaptive COVID-19 Treatment Trial (ACTT-2) and COV-BARRIER phase 3 trials. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19. We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules.

26 citations

Journal ArticleDOI
27 Nov 2021-Viruses
TL;DR: In this article, the authors review the diversity of strategies that viruses have evolved to interfere with JAK-STAT signaling, stressing the relevance of this pathway as a putative antiviral target.
Abstract: Modulation of the antiviral innate immune response has been proposed as a putative cellular target for the development of novel pan-viral therapeutic strategies. The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway is especially relevant due to its essential role in the regulation of local and systemic inflammation in response to viral infections, being, therefore, a putative therapeutic target. Here, we review the extraordinary diversity of strategies that viruses have evolved to interfere with JAK-STAT signaling, stressing the relevance of this pathway as a putative antiviral target. Moreover, due to the recent remarkable progress on the development of novel JAK inhibitors (JAKi), the current knowledge on its efficacy against distinct viral infections is also discussed. JAKi have a proven efficacy against a broad spectrum of disorders and exhibit safety profiles comparable to biologics, therefore representing good candidates for drug repurposing strategies, including viral infections.

25 citations

References
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Journal ArticleDOI
TL;DR: Approaches used for drug repurposing (also known as drug repositioning) are presented, the challenges faced by the repurpose community are discussed, and innovative ways by which these challenges could be addressed are recommended to help realize the full potential of drugRepurposing.
Abstract: Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.

2,365 citations

Journal ArticleDOI
Carly G. K. Ziegler, Samuel J. Allon, Sarah K. Nyquist, Ian M. Mbano1, Vincent N. Miao, Constantine N. Tzouanas, Yuming Cao2, Ashraf S. Yousif3, Julia Bals3, Blake M. Hauser3, Blake M. Hauser4, Jared Feldman4, Jared Feldman3, Christoph Muus5, Christoph Muus4, Marc H. Wadsworth, Samuel W. Kazer, Travis K. Hughes, Benjamin Doran, G. James Gatter6, G. James Gatter5, G. James Gatter3, Marko Vukovic, Faith Taliaferro7, Faith Taliaferro5, Benjamin E. Mead, Zhiru Guo2, Jennifer P. Wang2, Delphine Gras8, Magali Plaisant9, Meshal Ansari, Ilias Angelidis, Heiko Adler, Jennifer M.S. Sucre10, Chase J. Taylor10, Brian M. Lin4, Avinash Waghray4, Vanessa Mitsialis11, Vanessa Mitsialis7, Daniel F. Dwyer11, Kathleen M. Buchheit11, Joshua A. Boyce11, Nora A. Barrett11, Tanya M. Laidlaw11, Shaina L. Carroll12, Lucrezia Colonna13, Victor Tkachev7, Victor Tkachev4, Christopher W. Peterson13, Christopher W. Peterson14, Alison Yu7, Alison Yu15, Hengqi Betty Zheng13, Hengqi Betty Zheng15, Hannah P. Gideon16, Caylin G. Winchell16, Philana Ling Lin16, Philana Ling Lin7, Colin D. Bingle17, Scott B. Snapper7, Scott B. Snapper11, Jonathan A. Kropski10, Jonathan A. Kropski18, Fabian J. Theis, Herbert B. Schiller, Laure-Emmanuelle Zaragosi9, Pascal Barbry9, Alasdair Leslie19, Alasdair Leslie1, Hans-Peter Kiem13, Hans-Peter Kiem14, JoAnne L. Flynn16, Sarah M. Fortune4, Sarah M. Fortune5, Sarah M. Fortune3, Bonnie Berger6, Robert W. Finberg2, Leslie S. Kean4, Leslie S. Kean7, Manuel Garber2, Aaron G. Schmidt3, Aaron G. Schmidt4, Daniel Lingwood3, Alex K. Shalek, Jose Ordovas-Montanes, Nicholas E. Banovich, Alvis Brazma, Tushar J. Desai, Thu Elizabeth Duong, Oliver Eickelberg, Christine S. Falk, Michael Farzan20, Ian A. Glass, Muzlifah Haniffa, Peter Horvath, Deborah T. Hung, Naftali Kaminski, Mark A. Krasnow, Malte Kühnemund, Robert Lafyatis, Haeock Lee, Sylvie Leroy, Sten Linnarson, Joakim Lundeberg, Kerstin B. Meyer, Alexander V. Misharin, Martijn C. Nawijn, Marko Nikolic, Dana Pe'er, Joseph E. Powell, Stephen R. Quake, Jay Rajagopal, Purushothama Rao Tata, Emma L. Rawlins, Aviv Regev, Paul A. Reyfman, Mauricio Rojas, Orit Rosen, Kourosh Saeb-Parsy, Christos Samakovlis, Herbert B. Schiller, Joachim L. Schultze, Max A. Seibold, Douglas P. Shepherd, Jason R. Spence, Avrum Spira, Xin Sun, Sarah A. Teichmann, Fabian J. Theis, Alexander M. Tsankov, Maarten van den Berge, Michael von Papen, Jeffrey A. Whitsett, Ramnik J. Xavier, Yan Xu, Kun Zhang 
28 May 2020-Cell
TL;DR: The data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.

1,911 citations

Journal ArticleDOI
TL;DR: RAAS Inhibitors in Patients with Covid-19 show low levels of renin–angiotensin-converting enzyme 2 levels and activity in humans, but the effects are still uncertain.
Abstract: RAAS Inhibitors in Patients with Covid-19 The effects of renin–angiotensin–aldosterone system blockers on angiotensin-converting enzyme 2 levels and activity in humans are uncertain. The authors hy...

1,687 citations

Journal ArticleDOI
TL;DR: Baricitinib plus remdesivir was superior to remdes Vivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation.
Abstract: Background Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. Methods We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. Results A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). Conclusions Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

1,301 citations

Journal ArticleDOI
TL;DR: It is suggested that baricitinib could be trialled, using an appropriate patient population with 2019-nCoV acute respiratory disease, to reduce both the viral entry and the inflammation in patients, using endpoints such as the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia.

1,170 citations