Arguing the Case for Clinical Testing of Baricitinib for COVID-19

The likelihood that therapeutic agents against SARS-CoV-2 can be identified quicker by repurposing currently available products has impelled medical sleuths across the globe to sift through an array of medications for actions that could be directed at recently elucidated vulnerabilities of the virus.

Justin Stebbing, MD, PhD, and colleagues at BenevolentAI, London UK described finding baricitinib, an agent approved for rheumatoid arthritis, by using artificial intelligence (AI) to search for candidates that might offer both antiviral and anti-inflammatory actions against SARS-CoV-2.

The investigators sought agents in particular that inhibited AP2-associated protein kinase 1 (AAK1), a regulator of the endocytosis through which viruses can enter cells. "Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles," Stebbing and colleagues explained.

Of 378 products that they found inhibited AAK1, 47 were approved for medical use and 6 of these inhibited AAK1 with high affinity. Among the candidates were oncology drugs that the investigators considered too dangerous to suggest for this application.

Baricitinib, 1 of the 6 with high AAK1 binding, is a janus kinase (JAK) inhibitor that also binds the cyclin G-associated kinase, another regulator of endocytosis. This agent, the investigators noted, inhibits AAK1 within its approved therapeutic plasma concentrations.

"We suggest it could be trialed, using an appropriate patient population with (COVID-19) acute respiratory disease, to reduce both the viral entry and the inflammation in patients," they indicated.

The proposition drew a critical response from 1 group of rheumatologists, who were not only familiar with use of the agent for rheumatoid arthritis but also practiced in Lombardy, Italy, within the first European epicenter of coronavirus disease 2019 (COVID-19). Favalli and colleagues expressed concern about potential adverse effects, including interfering with the action of interferon, if it is employed to prevent viral replication.

"The described mechanism affecting viral endocytosis mediated by 2 members of the numb-associated kinase family is one of the many unfamiliar effects of a relatively recent drug class, the real safety profile of which still remains to be definitively clarified," remarked Ennio Favalli, MD, Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy, and colleagues.

In response to their concern, Stebbing and colleagues pointed out that pegylated interferon is unlikely to be used for COVID-19. In addition, they clarified that they anticipate the timing of administering baricitinib would avoid early stages of the disease not requiring hospitalization, during which the virus is often cleared spontaneously. They suggest that with increased severity requiring hospitalization, "JAK-STAT pathway inhibition might be a potential strategy."

In a subsequent correspondence in The Lancet Infectious Diseases, Stebbing and colleagues addressed a concern with the drug, identified in the US Food and Drug Administration stipulated black-box warning, about potential for serious infection, including with pulmonary pathogens.

"The most significant side-effect seen over 4214 patient-years in the clinical trial programs used for European Medicines Agency registration was a small increase in upper respiratory tract infections," they indicated.

They argued, further, that baricitinib would be a good agent to use in combination therapy with an antiviral such as remdesivir--currently nearing control trial results for COVID-19—as it has minimal interaction with the drug metabolizing cytochrome-P450 enzymes.

Stebbing and colleagues close their case by claiming, "combinations of baricitinib with these direct-acting antivirals could reduce viral infectivity, viral replication, and the aberrant host inflammatory response."