COVID-19 Therapeutics Update: Efficacy and Safety

While the COVID-19 pandemic has gripped the world for over two years, several therapeutics have now been found to be efficacious in treating the SARS-CoV-2 virus. Unfortunately, many of them have undesirable side effects. These days, scientists are focused on determining mechanisms by which the virus spreads, investigating the causes of COVID-19, as well as developing treatments whose benefits outweigh the side effects.

Several of the therapies that have been beneficial in treating COVID-19 have also shown efficacy with other illnesses. However, only a few have received FDA approval (antiviral remdesivir and anti-inflammatory dexamethasone) or emergency use authorization (anti-inflammatory baricitinib and monoclonal antibodies casirivimab, imdevimab, bamlavinimab, and etesevimab).¹

Remdesivir inhibits RNA-dependent RNA polymerase, with RNA-dependent RNA polymerase being essential for replication of SARS-CoV-2.² The antiviral, having broad-spectrum antiviral activity against coronaviruses such as SARS-CoV and MERS-CoV, is typically used in patients who require supplemental oxygen.³ Remdesivir has proven to be highly effective in treating COVID-19. In a recent study, Garibaldi and associates,⁴ found that, in a population of over 43,000 COVID-19 patients, the condition of 74% of patients who received remdesivir improved within 28 days, with a median improvement time of seven days. 68.3% of the non-remdesivir receiving patients had improved conditions within 28 days, with a median improvement time of nine days. Although remdesivir is often a first-line antiviral for COVID-19 patients, it is not recommended for those with mild symptoms due to adverse events like hypoalbuminaemia, increased blood glucose, and thrombocytopenia.⁵

Dexamethasone, a corticosteroid and anti-inflammatory drug, operates by inhibiting the release of cytokines that cause hyperinflammation in COVID-19 patients.³ When administered, it has been shown to reduce mortality by 35% for ventilated patients and by 20% for other patients requiring supplemental oxygen. For patients who do not require ventilation or supplemental oxygen, though, there are no clear benefits of receiving dexamethasone. In addition, low doses of dexamethasone have been shown to be effective with those with severe COVID-19, but not with mild or moderate COVID-19. The combination of dexamethasone and remdesivir, however, has been shown to be effective with those with mild to moderate COVID-19. Adverse events that have been reported with dexamethasone include arrhythmias, headache, and dizziness. In fact, research presented at the American Heart Association Scientific Sessions 2021 found that those who received 6 mg/day dexamethasone were statistically more likely to have atrial fibrillation than those who did not receive corticosteroids.⁶

Baricitinib, another anti-inflammatory drug, operates by preventing cytokine release and SARS-CoV-2 cell entry via viral endocytosis. Baricitinib has been shown to reduce COVID-19 deaths by 20%.⁷ In a study of over 4000 patients, those who received usual care plus baricitinib (4 mg/day for 10 days until hospital discharge) were compared with those who received only usual care, which included treatment with dexamethasone, tocilizumab, or remdesivir, supplemental oxygen, and additional respiratory support. 12% of the patients who received baricitinib died within 28 days, as opposed to 14% of the usual care group, signifying a reduction of 13%. While baricitinib has not been shown to cause arrhythmias, it has other side effects, including hyperglycemia, infections, and thromboembolic events.

Monoclonal antibodies, like casirivimab, imdevimab, bamlavinimab, and etesevimab, operate by binding to the spike protein of SARS-CoV-2, minimizing virus entry into cells.¹ Administered as a single IV, monoclonal antibodies are used for those with mild to moderate COVID-19 who are at risk for developing severe COVID-19, namely senior citizens and those with chronic medical conditions. In a randomized, double-blind, placebo-controlled study that included over 300 people who tested positive for COVID-19, those who received 1200 mg casirivimab and imdevimab exhibited less progression from asymptomatic to symptomatic COVID-19 when compared to those who received the placebo (29% versus 42.3%, respectively). Those who received casirivimab and imdevimab also had fewer weeks showing COVID-19 symptoms compared to those who received the placebo (895.7 weeks versus 1637.4 weeks per 1000 participants, respectively) and lower viral loads (489.8 weeks versus 811.9 weeks per 1000 participants, respectively). In addition, 33.5% of those who received casirivimab and imdevimab had at least one adverse event, as opposed to 48.1% for those who received the placebo.⁸

Factors that exacerbate the spread of COVID-19 are still being discovered. For instance, researchers have found that human galectin-9 is elevated in those with severe COVID-19.⁹ In addition, they found that this lectin promotes the binding of the SARS-CoV-2 spike protein to angiotensin-converting enzyme 2 (ACE2), a transmembrane protein. This binding facilitates SARS-CoV-2 entry into human airway epithelial cells (AECs). Using in vitro means, these researchers found that SARS-CoV-2 infection of AECs increased with galectin-9 dosing, with an almost 30-fold increase at the highest concentration of galectin-9. Also, galectin-9 promoted the expression of several pro-inflammatory cytokines in AECs, including IL-6, IL-8, IL-17, EIF2, and TNFα.

All the COVID-19 drugs currently in use, either FDA approved or under emergency use authorization, have varying degrees of adverse effects, ranging from dizziness to arrhythmias. The monoclonal antibodies, while lacking side effects, are only recommended for those with mild to moderate COVID-19. More work needs to be done to develop therapies that effectively treat all phases of COVID-19, especially severe COVID-19, with minimal adverse events. In addition, identifying factors that promote the spread of COVID-19 continues to be a priority in order to develop therapies that address those factors.

References

1. LX Cubeddu et al. Antiviral and anti-inflammatory drugs to combat COVID-19: Effects on cardiac ion channels and risk of ventricular arrhythmias. Bioimpacts. 2022;12(1):9-20.

2.CJ Gordon et al. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem. 2020 May 15;295(20):6785-6797.

3. D. Liu et al. Adverse Cardiovascular Effects of Anti-COVID-19 Drugs. Front Pharmacol. 2021 Aug 25;12:699949.

4. BT Garibaldi et al. Real-World Effectiveness of Remdesivir in Adults Hospitalized With Coronavirus Disease 2019 (COVID-19): A Retrospective, Multicenter Comparative Effectiveness Study. Clinical Infectious Diseases. 15 December 2021.

5. Y Wang et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 16;395(10236):1569-1578.

6. Y Lee et al. Corticosteroids and the risk of atrial fibrillation in hospitalized COVID-19 patients. Presented at: AHA Scientific Sessions 2021; November 13-15, 2021. Poster P678.</>

7. E Mahase. Covid-19: Anti-inflammatory treatment baricitinib reduces deaths in patients admitted to hospital, finds trial. BMJ. 2022 Mar 3;376:o573.

8. MP O’Brien et al. Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial. JAMA. 2022 Feb 1;327(5):432-441.

9. L Du et al. Human Galectin-9 Potently Enhances SARS-CoV-2 Replication and Inflammation In Airway Epithelial Cells. bioRxiv. 2022 May 16;2022.03.18.484956.