Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact

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Highlights

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Baricitinib at 4 mg/day/orally was given to 12 patients with moderate COVID-19.
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In baricitinib-treated patients no adverse events were recorded, after 2 weeks.
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Clinical and respiratory parameters significantly improved at 2 weeks.
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None of the baricitinib-treated patients required admission to ICU.
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Proper control group was missing; this is required to demonstrate the efficacy

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

Bin Cao, Yeming Wang, Danning Wen … (2020)

Abstract Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao 2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2) to the fraction of inspired oxygen (Fio 2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. Results A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group. Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. Conclusions In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.)

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Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Peter Richardson, Ivan Griffin, Catherine Tucker … (2020)

Given the scale and rapid spread of the 2019 novel coronavirus (2019-nCoV) acute respiratory disease, there is an immediate need for medicines that can help before a vaccine can be produced. Results of rapid sequencing of 2019-nCoV, coupled with molecular modelling based on the genomes of related virus proteins, 1 have suggested a few compounds that are likely to be effective, including the anti-HIV lopinavir plus ritonavir combination. BenevolentAI's knowledge graph is a large repository of structured medical information, including numerous connections extracted from scientific literature by machine learning. 2 Together with customisations bespoke to 2019-nCoV, we used BenevolentAI to search for approved drugs that could help, focusing on those that might block the viral infection process. We identified baricitinib, which is predicted to reduce the ability of the virus to infect lung cells. Most viruses enter cells through receptor-mediated endocytosis. The receptor that 2019-nCoV uses to infect lung cells might be ACE2, a cell-surface protein on cells in the kidney, blood vessels, heart, and, importantly, lung AT2 alveolar epithelial cells (figure ). These AT2 cells are particularly prone to viral infection. 3 One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1). Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles. 4 Figure The BenevolentAI knowledge graph The BenevolentAI knowledge graph integrates biomedical data from structured and unstructured sources. It is queried by a fleet of algorithms to identify new relationships to suggest new ways of tackling disease. 2019-nCoV=2019 novel coronavirus. AAK1=AP-2 associated kinase 1. GAK=cyclin g-associated kinase. JAK1/2=janus kinase 1/2. Of 378 AAK1 inhibitors in the knowledge graph, 47 have been approved for medical use and six inhibited AAK1 with high affinity. These included a number of oncology drugs such as sunitinib and erlotinib, both of which have been shown to inhibit viral infection of cells through the inhibition of AAK1. 5 However, these compounds bring serious side-effects, and our data infer high doses to inhibit AAK1 effectively. We do not consider these drugs would be a safe therapy for a population of sick and infected people. By contrast, one of the six high-affinity AAK1-binding drugs was the janus kinase inhibitor baricitinib, which also binds the cyclin G-associated kinase, another regulator of endocytosis. Because the plasma concentration of baricitinib on therapeutic dosing (either as 2 mg or 4 mg once daily) is sufficient to inhibit AAK1, we suggest it 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. 7

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Author and article information

Contributors

Fabrizio Cantini

Laura Niccoli

Daniela Matarrese

Emanuele Nicastri

Paolo Stobbione

Delia Goletti

Journal

Journal ID (nlm-ta): J Infect

Journal ID (iso-abbrev): J. Infect

Title: The Journal of Infection

Publisher: Published by Elsevier Ltd on behalf of The British Infection Association.

ISSN (Print): 0163-4453

ISSN (Electronic): 1532-2742

Publication date PMC-release: 23 April 2020

Publication date (Electronic): 23 April 2020

Affiliations

[1 ]Rheumatology Department, Azienda USL Toscana Centro, Hospital of Prato, Italy

[2 ]Azienda USL Toscana Centro, Hospital of Prato, Italy

[3 ]National Institute for Infectious Diseases, Lazzaro Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy

[4 ]Department of Epidemiology and Preclinical Research, “L. Spallanzani” National Institute for Infectious Diseases (INMI), IRCCS, Via Portuense 292, 00149 Rome, Italy

[5 ]AOS Antonio e Biagio e C. Arrigo, Rheumatology Unit – Alessandria, Italy

Author notes

[* ]Corresponding author: Fabrizio Cantini MD, Department of Rheumatology, Hospital of Prato, Italy; Phone: +39 0574 807578; Fax: +39 0574 802939; Mobile: +39 340 8075607. fbrzcantini@ 123456gmail.com

Article

Publisher ID: S0163-4453(20)30228-0

DOI: 10.1016/j.jinf.2020.04.017

PMC ID: 7177073

PubMed ID: 32333918

SO-VID: 3d267b8e-7b5a-4622-b796-b162557b4323

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Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact

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Novel Coronavirus Disease COVID-19

Most cited references 7

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

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