Early results show baricitinib helps reduce COVID-19 recovery time
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Eli Lilly & Co. announced that its JAK inhibitor baricitinib, when combined with remdesivir, reduced the time to recovery in patients with COVID-19 compared with remdesivir alone.
According to a company press release, the finding comes as a result of Eli Lilly’s ongoing Adaptive COVID-19 Treatment Trial (ACTT-2), a phase 3, randomized double-blind, placebo-controlled study sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH.
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“We are pleased with these data from the ACTT-2 study," Patrik Jonsson, senior vice president of Eli Lilly and president of Lilly Bio-Medicines, said in the release. “There is an urgent need to identify COVID-19 treatments, and we will continue to work with NIAID to understand these data and next steps on baricitinib's role moving forward. We appreciate NIAID selecting baricitinib for inclusion in this important study and the participants, investigators and collaborators for the vital roles they played.”
To analyze the efficacy and safety of a 4 mg dose of baricitinib (Olumiant) alongside remdesivir in patients who are hospitalized with COVID-19, the ACTT-2 researchers recruited more than 1,000 patients. The primary endpoint was the reduction of recovery time compared with remdesivir alone.
The researchers defined recovery as the patient being well enough for hospital discharge, meaning the participant either no longer required supplemental oxygen or ongoing medical care in the hospital, or was no longer hospitalized at day 29.
According to the press release, patients treated with baricitinib in combination with remdesivir demonstrated an approximately 1-day reduction in median recovery time, compared with those who received remdesivir monotherapy. The study also met a secondary endpoint comparing patient outcomes at day 15 using an ordinal 8-point scale ranging from fully recovered to death.
According to Eli Lilly, an independent board is overseeing the trial and has met throughout its duration to review safety data. Additional analyses are ongoing to examine mortality and safety data, the press release said.
The NIAID is expected to publish the full results in a peer-reviewed journal.
“These findings from ACTT-2 are another step as we improve the care of these patients," Andre Kalil, MD, a professor at the University of Nebraska Medical Center and a principal investigator of the ACTT studies, said in the release. “These data may help us to better understand baricitinib's potential role in the treatment of COVID-19.”
Based on these data, Eli Lilly said it plans to discuss the potential for an emergency use authorization (EUA) with the FDA for 4 mg baricitinib as a treatment for patients hospitalized with COVID-19, as well as similar measures with other regulatory agencies. If approved, the company will request that the drug be made available commercially. In addition, Eli Lilly will “work with hospitals and governments to ensure patient access,” according to the release.
Regarding patients with rheumatoid arthritis who currently rely on the drug, the company said it will create an adequate supply and ensure it remains available in countries where it is approved.
In addition, Eli Lilly said it will review ACTT-2 data with the NIAID and determine if they have any impact on COV-BARRIER, the phase 3 randomized, double-blind, placebo-controlled study the company began in June to examine the efficacy and safety of baricitinib compared with background therapy among hospitalized adults with COVID-19 in the United States, Europe, Asia and Latin America.
“As a company, we've moved quickly to develop and evaluate medicines for patients for the prevention and treatment of COVID-19,” Daniel Skovronsky, MD, PhD, senior vice president and chief scientific officer for Eli Lilly, said in the press release. “These data allow us to better understand baricitinib's role in potentially improving outcomes for hospitalized COVID-19 patients, and we look forward to continuing this research alongside our other initiatives to combat COVID-19.”
Perspective
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David A. McLain, MD, FACP, FACR
The COVID-19 pandemic has revealed the surprising utility of anti-rheumatic drugs in this disease. Hydroxychloroquine was the first with studies and observations with positive and negative results. Anakinra has been found to be of help in cytokine storm that is associated with COVID-19. Tocilizumab has been approved in China and Italy for COVID-19 patients with severe infection with extensive lung disease and elevated IL-6 levels.
The use of baricitinib with an antiviral medication was predicted by artificial intelligence in a theoretical analysis published in The Lancet in April 2020. The authors examined the affinity and selectivity of all the approved drugs in their database to identify those with both antiviral and anti-inflammatory properties. Such drugs were predicted to be of particular importance in the treatment of severe cases of COVID-19 when the host inflammatory response becomes a major cause of lung damage and subsequent mortality.
Baricitinib was identified as a NAK (numb-associated kinase) inhibitor, with a particularly high affinity for AAK1, a pivotal regulator of clathrin-mediated endocytosis. Inhibiting this enzyme prevents the virus from entering cells, like in the lung. The authors suggested that this drug could be of use in countering SARS-CoV-2 infections, subject to appropriate clinical testing of the concept. The Adaptive COVID-19 Treatment Trial (ACTT-2) reported on here is clinical testing, and showed a 4-mg dose of baricitinib plus remdesivir in hospitalized patients with COVID-19 met the primary endpoint of reduction of time to recovery in comparison with remdesivir alone.
What about tofacitinib? Tofacitinib shows no detectable inhibition of AAK1, but it is being studied for other reasons in COVID-19 trials. There is no information about upadacitinib or filgotinib and COVID-19 that I could find. With all JAK inhibitors to date, an increase in herpesvirus infections are a concern. Interferon is one of the most powerful innate immune responses to prevent viral replication during the early phases of infection.
Transcription through the JAK–STAT signaling pathway (mainly mediated by JAK1 and JAK2), activated by interferons, leads to the upregulation of many interferon-controlled genes that quickly kill viruses in infected cells. Like many areas in medicine, this is one of those yin-yang situations with baricitinib having both pro- and antiviral mechanisms.
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