COVID-19-Directed Medications

Bamlanivimab With Etesevimab and Casirivimab With Imdevimab

Monoclonal antibodies were first conceived as a target for disease-causing pathogens in the early 1900s by Elie Metchnikoff. This idea led to the developmental theory of immunology, in which Metchnikoff was awarded the Nobel Prize for Physiology or Medicine in 1908. Additional discoveries and techniques through the 1990s led to the progressive improvement in using monoclonal antibodies, ultimately leading to multiple therapeutic uses in various diseases.

During the COVID-19 pandemic, renewed interest surrounded the use of monoclonal antibodies for treatment. After the SARS-CoV-2 genome was decoded, of the four major structural proteins identified, the surface spike protein was targeted to inhibit viral attachment and entry into human cells with the expectation of neutralizing the viral infection.

Two combination products—bamlanivimab with etesevimab, and casirivimab with imdevimab—are experimental monoclonal antibodies developed specifically to inhibit the SARS-CoV-2 coronavirus by binding to different but overlapping receptors (bamlanivimab/etesevimab) or nonoverlapping regions (casirivimab/imdevimab), thereby inhibiting the spike protein of the virus from attaching and gaining entry to the human cell. Both are administered intravenously, ideally within days of infection for maximum therapeutic benefit. With the relatively long half-life between 17 and 26 days, one dose administration is expected to be sufficient for COVID-19 treatment.

There are several ongoing clinical trials evaluating the safety and efficacy of these monoclonal antibodies. While many are providing initial results, none have yet established the safety and efficacy of SARS-CovC-2-specific monoclonal antibodies. Because of the variability and heterogeneity of the primary and secondary outcomes between all the trials, including four randomized controlled trials (RCTs), a metaanalysis was not performed. However, the most up-to-date data from the casirivimab/imdevimab studies suggest efficacy in reducing mortality and hospitalization.

As a result of the initial data gathered, all have received Emergency Use Authorizations from the FDA. However, the safety and efficacy of these therapeutics against COVID-19 has not been established, requiring further studies. The NIH COVID-19 Treatment Guidelines Panel and the Infectious Diseases Society of America (IDSA) recommend utilizing bamlanivimab/etesevimab or casirivimab/imdevimab to treat outpatients with mild-to-moderate COVID-19, who may be at a higher risk of developing more severe disease. The panel recommends against their use in hospitalized patients except in the context of a clinical trial.

Baricitinib

Baricitinib is a nonbiologic, small-molecule medication approved by the FDA in May 2018 for moderately to severely active rheumatoid arthritis (RA) after having an inadequate response to other RA treatments. The initial FDA application of baricitinib in April 2017 was declined due to safety concerns regarding thrombosis in the higher 4 mg dose, which ultimately led to only the 2-mg dose being approved the following year. As a disease-modifying antirheumatic drug (DMARD), it inhibits the intracellular Janus kinase (JAK) enzymes that modulate downstream cellular processes which are believed to be responsible for activation of inflammatory mediators in RA. With 80% bioavailability, baricitinib is an oral medication dosed at 2 mg daily in RA. About 50% of baricitinib is bound to plasma proteins, is hepatically metabolized via CYP3A4, and has a half-life of about 12 h. About 75% is excreted in the urine (69% as unchanged drug) and around 20% excreted in the feces (15% as unchanged drug). Baricitinib is not recommended in patients with severe hepatic impairment or moderate-to-severe renal impairment. As an immunomodulator, some potential side effects include upper respiratory tract infection, hypercholesterolemia, and other potential infection reactivations including herpes zoster, herpes simplex, urinary tract infections, and gastroenteritis.

As a JAK enzyme inhibitor, it is believed to help reduce viral entry while interfering with viral assembly completed within the host cell. This along with the ability of inhibiting various proinflammatory cytokines, thereby potentially reducing cytokine release syndrome in severely ill patients, made baricitinib an attractive study medication for COVID-19 infections. With 18 studies identified on https://ClinicalTrials.gov evaluating the use of baricitinib in COVID-19 infections, one of the higher impact clinical studies to date is the Adaptive COVID-19 Treatment Trial 2 (ACTT-2). The ACTT-2 trial is a multinational, randomized, placebo-controlled trial evaluating the time-to-clinical recovery in hospitalized patients who are administered baricitinib and remdesivir. Of the 1033 participants, half of those who received baricitinib had a shorter clinical recovery time versus placebo, specifically in patients requiring high-flow oxygen or noninvasive ventilation. There were no statistically significant differences in mortality between those who received baricitinib and remdesivir versus remdesivir alone. On November 19, 2020, the FDA issued an EUA for the use of baricitinib. The NIH COVID-19 Treatment Guidelines have specific recommendations regarding baricitinib’s use, stating there are insufficient data to recommend either for or against the use of baricitinib in combination with remdesivir for hospitalized patients, when corticosteroids can be used. Both NIH and IDSA guidelines suggest that baricitinib may be used in conjunction with remdesivir when corticosteroids cannot be used. Otherwise, baricitinib should only be used in the context of a clinical trial.