Baricitinib as a potential drug for COVID-19: evidence from a multicenter trial and translational research studies

Fabrizio Cantini, Laura Niccoli, Carlotta Nannini: Rheumatology Department, Azienda USL Toscana Centro, Hospital of Prato, Italy; Daniela Matarrese: Sanitary Direction, Azienda USL Toscana Centro, Hospital of Prato, Italy; Massimo Edoardo Di Natale, Pamela Lotti: II Division of Internal Medicine, Azienda USL Toscana Centro, Hospital of Prato, Italy; Donatella Aquilini: Division of Infectious Diseases, Azienda USL Toscana Centro, Hospital of Prato, Italy; Giancarlo Landini, Barbara Cimolato: Department of Medical Specialties, Division of Internal Medicine, Azienda USL Toscana Centro, S.Maria Nuova Hospital, Florence, Italy; Massimo Antonio Di Pietro, Michele Trezzi: Division of Infectious Diseases, Azienda USL Toscana Centro, Hospital of Pistoia, Italy; Paolo Stobbione: Rheumatology Unit, AO SS. Antonio e Biagio e C. Arrigo, Alessandria, Italy; Gabriele Frausini: Division of Internal Medicine, Azienda Ospedaliera Ospedali Riuniti Marche Nord, Fano-Pesaro, Italy; Assunta Navarra: Clinical epidemiology Unit, National Institute for Infectious Diseases, Lazzaro Spallanzani (INMI), Rome, Italy; Emanuele Nicastri: Clinical Division of Infectious Diseases, INMI, Rome, Italy; Giovanni Sotgiu: Clinical Epidemiology and Medical Statistics Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; Linda Petrone, Elisa Petruccioli, Delia Goletti: Translational Research Unit, INMI, Rome, Italy

Using artificial intelligence baricitinib, an anti-Janus kinase inhibitor used for reumathoid arthritis, was shown to have a dual action on COVID-19 therapy including the inhibition of cytokine-release and SARS-CoV-2 endocytosis. Aims are to report the evidence of an observational, retrospective, longitudinal multicenter-study in consecutive-hospitalized patients with COVID-19 moderate-pneumonia to evaluate the 2-week effectiveness and safety of baricitinib combined with antivirals compared with the standard-of-care-therapy. We evaluated the mortality rate, ICU transfer, hospital discharge, improvement of respiratory parameters, adverse events (AEs) occurrence. Moreover, we investigated the in-vitro effects of baricitinib in modulating the SARS-CoV-2-specific response in blood samples from COVID-19 patients.

Clinical charts from 7 Italian hospitals were reviewed. Baricitinib-treated arm included consecutive-hospitalized patients, SARS-CoV-2 naso-pharingeal swab-positive with a moderate-pneumonia. Baricitinib 4mg/day was provided orally associated with lopinavir/ritonavir tablets 250 mg/bid for 2 weeks. Control-arm included all consecutive-hospitalized patients with moderate COVID-19 pneumonia treated with hydroxychloroquine and lopinavir/ritonavir. The off-label study was approved by the Hospital-Committee and Ethical-Committee of Toscana-Region (Code: BARIC-off; 17261). The in vitro study involved the use of whole blood from COVID-19 patients that was in vitro stimulated with SARS-CoV-2-peptides and control antigens with/without baricitinib. Cytokines/chemokines response was then evaluated by Luminex (Parere 60, Comitato Etico Spallanzani).

At baseline, 113 patients were in the baricitinib-arm, and 78 in the control-arm. The results indicate that the 2-week case fatality rate was significantly lower in the baricitinib-arm compared with controls [0% (0/113) vs 6.4% (5/78) (p-value: 0.010]. ICU admission was requested in 0.88% (1/113) vs 17.9% (14/78) patients in the baricitinib-arm compared to the control-arm (week 1, p-value: 0.019), (week 2, p-value: <0.0001). Discharge rate was significantly higher in the baricitinib-arm at week 1 [9.7% (11/113) vs 1.3% (1/78) (p-value: 0.039], and at week 2 [77.8% (88/113) vs 12.8% (10/78) (p:<0.0001)]. Clinical, laboratory and respiratory functions significantly improved. At discharge, the proportion of patients [positive to viral naso-pharingeal swabs was significantly lower [12.5% (11/88)] in the baricitinib-arm compared to the control-arm [40% (4/10)] (p-value: 0.043). No major AE were recorded. Moreover, the in vitro study involving blood samples from COVID-19 patients, showed that baricitinib significantly modulates SARS-CoV-2-specific response reducing the secretion of TH-1 cytokines and chemokines in a concentration-dependent manner. This effect was not observed in response to unrelated antigens as Cytomegalovirus.

These findings suggest that baricitinib is associated with beneficial clinical outcomes in terms of reduction of mortality and ICU transfer and improvement of clinical parameters. Moreover, a reduction in the viral load was found, as evaluated by the decreased number of patients with a positive viral nasopharyngeal swab at the end of therapy. Moreover baricitinib has an effect on the SARS-CoV-2-specific response that may be instrumental to explain the clinical effects observed. Randomized controlled trials are needed to support this encouraging evidence.