By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has issued another emergency use authorization (EUA) for a new COVID-19 treatment. The EUA was issued for baricitinib in combination with remdesivir for treating hospitalized COVID-19 patients who require supplemental oxygen.1 Baricitinib (Olumiant) is a kinase inhibitor that targets the intracellular signaling pathway of cytokines. It was approved in 2018 for moderate to severe active rheumatoid arthritis. Remdesivir is an antiviral agent that was approved in October 2020.
Baricitinib/remdesivir should be used to treat suspected or laboratory-confirmed COVID-19 in hospitalized adults and pediatric patients ≥ age 2 years who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).1,2
The recommended dose for baricitinib in adults and pediatric patients (≥ age 9 years) is 4 mg orally once daily for 14 days of total treatment or until hospital discharge, whichever happens first.2 The dose for pediatric patients (age 2 to 9 years) is 2 mg. For patients who cannot swallow an oral medication, baricitinib can be given as an oral dispersion, by gastrostomy tube, or nasogastric tube. The dose can be adjusted for reduced renal function and interrupted because of low absolute lymphocytic count, absolute neutrophil count, or elevated liver aminotransferases. Because of a drug-drug interaction with organic anion transporter 3 inhibitors (i.e., probenecid), the dose of baricitinib should be lowered. Remdesivir is administered by intravenous infusion for 10 days. Baricitinib is available as 1 mg and 2 mg tablets.
Baricitinib/remdesivir appeared to be more effective than remdesivir alone in shortening recovery time and improving clinical status in hospitalized COVID-19 patients who require supplemental oxygen.2,4
Based on animal studies, baricitinib poses a potential embryo-fetal toxicity. Therefore, potential benefit must justify potential risk when used during pregnancy.2 The combination is not recommended for patients on dialysis, those with end-stage renal disease, or those with acute renal injury.
The rationale for coupling baricitinib with remdesivir is to modulate the dysregulated inflammatory response associated with COVID-19. The clinical evidence supporting the EUA was a randomized, double-blind, placebo-controlled trial sponsored by the National Institute of Allergy and Infectious Diseases (Adaptive COVID-19 Treatment Trial 2, ACTT-2).2,4 Hospitalized subjects were COVID-19-positive and exhibited at least one of the following: radiographic evidence of infiltrates, SpO2 ≤ 94% on room air, requirement for supplemental oxygen, or requirement for mechanical ventilation. Subjects were randomized to baricitinib/remdesivir (n = 515) or placebo plus remdesivir (n = 518). The primary efficacy endpoint was time to recovery within 29 days after randomization. Recovery was defined as: discharged with no limitation on activities, discharged with limitation and/or requiring home oxygen, or hospitalized but not requiring oxygen and no longer requiring medical care. A key secondary outcome was change in clinical status according to an 8-point ordinal scale on day 15 based mainly on need for hospitalization and need for oxygen.
The median times to recovery were seven days for baricitinib/remdesivir vs. eight days for remdesivir alone. This represented a 15% faster recovery (P = 0.047).2 Patients on noninvasive ventilation or high-flow oxygen recovered after a median 10 days vs. 18 days for remdesivir alone.4 Other findings associated with those randomized to baricitinib/remdesivir included: 26% more likely to have a better clinical status (P = 0.044) and lower risk of death or noninvasive ventilation/high-flow oxygen or invasive mechanical ventilation by day 29 (23% vs. 28%; P = 0.039).2 Mortality at day 29 was numerically lower for baricitinib/remdesivir (4.7% vs. 7.1%) but did not reach statistical significance. The adverse event (AE) profiles for baricitinib/remdesivir generally were similar to remdesivir alone, although AEs leading to discontinuation of the study drug and serious AEs were less frequent with the combination (7% vs. 12%) and (15% vs. 20%).2,4
Baricitinib/remdesivir provides measurable benefit to certain hospitalized patients with COVID-19 who require supplemental oxygen, especially those receiving high-flow oxygen or noninvasive ventilation. Currently, there are no recommendations from the Infectious Diseases Society of America or the National Institutes of Health (NIH) for baricitinib/remdesivir.5,6 Current NIH COVID-19 treatment guidelines recommend dexamethasone with or without remdesivir as options for patients hospitalized and requiring supplemental oxygen or oxygen delivery through a high-flow device or noninvasive ventilation, and dexamethasone alone for patients requiring invasive mechanical ventilation or ECMO.6 Dexamethasone has been reported to reduce 28-day mortality among patients receiving either invasive mechanical ventilation or oxygen alone (29.3% vs. 41.4%).7 Baricitinib/remdesivir provides another therapeutic option in this COVID-19 population.
- U.S. Food & Drug Administration. Coronavirus (COVID-19) update: FDA authorizes drug combination for treatment of COVID-19. Nov. 19, 2020.
- U.S. Food & Drug Administration. Frequently asked questions on the emergency use authorization for Olumiant (baricitinib) in combination with Veklury (remdesivir) for treatment of mild to moderate COVID-19. Nov. 19, 2020.
- Eli Lilly and Company. Fact sheet for healthcare providers. Emergency use authorization (EUA) of baricitinib. November 2020.
- Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N Engl J Med 2020; Dec 11;NEJMoa2031994. doi: 10.1056/NEJMoa2031994. [Online ahead of print].
- Infectious Diseases Society of America. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Last updated Dec. 2, 2020.
- National Institutes of Health. Therapeutic management of patients with COVID-19. Last updated Dec. 3, 2020.
- RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with COVID-19 - Preliminary report. N Engl J Med 2020; Jul 17;NEJMoa2021436. doi: 10.1056/NEJMoa2021436. [Online ahead of print].