A study published in Science Advances reports on the ability of baricitinib, a JAK/STAT pathway inhibitor, to inhibit viral entry and reduce inflammatory markers in coronavirus disease 2019 (COVID-19) patients, reducing mortality risk by 71% among patients with moderate-severe COVID-19 pneumonia. In addition, the study shows that baricitinib prevents the type-1 interferon (IFN) mediated increase in the expression of angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
In the study, a total of 83 patients were treated with baricitinib at the University of Pisa (n= 37; median age, 66 years), Italy, and Albacete Hospital (n = 46; median age, 81 years) between mid-March and mid-April 2020. All patients enrolled had an SaO2 < 94% at baseline but did not require mechanical ventilation. Baricitinib was administered at a dose of 4 mg/day for 14 days in conjunction with standard of care in Italy, and at lower doses of 2 or 4 mg/day for 3 to 11 days in the Spanish cohort because of age-related factors. Eighty-three controls were included in the study using propensity score matching systems. Most individuals received concomitant antiviral therapy with hydroxychloroquine and lopinavir/ritonavir, antibiotics, corticosteroids and low molecular weight heparin (LMWH).
Study data showed that primary composite-endpoint of death or invasive mechanical ventilation occurred in 14 (16.9%) patients in the baricitinib-treated group compared to 29 (34.9%) in the control group (P < 0.001). In the multivariate Cox-regression analysis adjusted for all the covariates included in the matching of the two cohorts, baricitinib was independently associated as a protective variable with the primary outcome (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.15-0.58; P < 0.001).
Meanwhile, the main toxicities observed in the cohorts were hepatic, infectious, gastrointestinal and cardiovascular. An elevation in plasma transaminases occurred in some patients and the continuation of baricitinib in some of these patients was possible with resolution of liver function abnormalities. “Apart from transaminitis, adverse events were difficult to ascribe to baricitinib due to rapidly evolving clinical/capacity constraints,” wrote Justin Stebbing, Imperial College, London, United Kingdom, and colleagues. “We did not observe any signs of coagulopathy or thrombosis caused by baricitinib in any of our patients, though this has been described as a potential toxicity associated with longer term use in rheumatoid arthritis. However, the majority were anti-coagulated with LMWH.”
Using organotypic 3D cultures of primary human liver cells, the researchers demonstrated that interferon-alpha-2 (IFNα2) significantly increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by >5-fold and exposure to therapeutically relevant concentrations of baricitinib (800 nM) fully abolished ACE2 induction by IFN-α2 and efficiently blocked the increased infectivity in cytokine treated 3D liver microtissues even beyond the levels observed in non-cytokine exposed samples. Further, RNA-Seq revealed gene response signatures associated with platelet activation were fully inhibited by baricitinib.
To evaluate the effects of baricitinib on replication and viral entry, the researchers analyzed viral loads at 4 hours post infection using baricitinib concentrations close to the relevant Kd values (100 nM). Super-resolution microscopy revealed anti-nucleocapsid protein immunoreactivity clusters throughout the infected samples. In contrast, virus signals were almost absent in baricitinib-treated samples, demonstrating that baricitinib efficiently blocked viral entry at nanomolar concentrations.
“This reveals mechanistic actions of a JAK-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivizes further randomized controlled trials,” the authors concluded.
Nonetheless, the authors acknowledged that the study was not a randomized trial comparing baricitinib to a placebo control group; thus, known and unknown confounding variables could have compromised the results. In addition, they noted that the small sample size in the baricitinib cohort could limit the overall statistical power. “Given these limitations, we eagerly await the completion of the baricitinib randomized trials that are currently ongoing,” the authors added.