Therapeutics Treat Patients Who Test Positive for COVID-19
Monoclonal antibodies and emerging agents may avert severe illness, especially for high-risk individuals.
Although vaccines remain the best preventive strategy for COVID-19, there is still a need for therapies to help avert progression to severe illness, especially for high-risk patients.
Monoclonal Antibodies
Monoclonal antibodies (mAbs) have the potential to prevent and treat COVID-19 by binding to an epitope in the SARS-CoV-2 spike protein to neutralize the virus. It is expected such therapies that directly target SARS-CoV-2 would have the greatest effect earlier in the disease course when pathogenesis is primarily driven by viral replication. Therefore, treatment should be started as soon as possible in those who test positive. Three anti–SARS-CoV-2 mAbs have received emergency use authorizations (EUAs) for mild to moderate COVID-19 in those who are at high risk for progression (see the Table1). Tixagevimab and cilgavimab (Evusheld) is a fourth anti–SARS-CoV-2 mAb under EUA for COVID-19. However, it is only authorized as pre-exposure prophylaxis for immunocompromised patients who may not mount an adequate immune response to vaccination or those with a history of severe adverse reactions to available vaccines.2 Its efficacy against the omicron variant is being determined.
Bamlanivimab and etesevimab are neutralizing mAbs that bind to different but overlapping, epitopes of the spike protein.3 A phase 3 trial in 1035 patients showed a 4.8% absolute risk reduction (ARR) in death or hospitalization in those who received the combination compared with a placebo.4 They are the only mAbs available for younger pediatric patients, including neonates, largely based on pharmacokinetic studies. However, efficacy may vary based on the dominant circulating strain.3
Casirivimab and imdevimab are recombinant mAbs that bind to nonoverlapping epitopes of the spike protein. Also known as the cocktail REGEN-CoV, a single intravenous infusion was associated with a 2.2% ARR in death or hospitalization compared with a placebo.1,5 REGEN-COV, a combination of the mAbs casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with COVID 2019 (COVID-19 REGEN-CoV is also available as a subcutaneous injection, which has the propensity to increase access and administration to outside clinic and hospital settings. However, 1-hour monitoring is still required).
Sotrovimab is a pan-sarbecovirus mAb that has demonstrated a 4.5% ARR in death or hospitalizations compared with a placebo.6 Sotrovimab is expected to a have a higher barrier to resistance, because it targets an epitope that lies outside the rapidly evolving motif and thus could retain activity against emerging variants of concern.7 In a study evaluating in vitro neutralizing activity of anti–SARS-CoV-2 mAbs, sotrovimab was the only agent authorized for treatment that has retained activity against the omicron variant.8
Emerging Agents
Although mAbs represent a milestone in COVID-19 management, because of challenges in accessibility, administration, and monitoring requirements, new oral antivirals such as molnupiravir nirmatrelvir, and ritonavir (Paxlovid) are welcome interventions to prevent disease progression.
Molnupiravir is a prodrug that introduces transcription errors into viral RNA to impair SARS-CoV-2 replication. Results from a phase 3 trial in 1433 patients showed a 3% ARR in death and hospitalizations with molnupiravir compared with the placebo (95% CI, –5.9 to –0.1).9 Paxlovid is a protease inhibitor that also targets viral replication. Results from a phase 2/3 trial in 2246 patients showed a death or hospitalization rate of 0.8% with Paxlovid compared with 6.3% for the placebo when administered within 5 days of symptom onset.10 Paxlovid contains ritonavir to slow nirmatrelvir’s metabolism via cytochrome P450 inhibition. However, that also makes it prone to drug interactions requiring pharmacists to be very vigilant upon dispensing. Both agents have been issued an EUA to be initiated as soon as possible after diagnosis and within 5 days of symptom onset to prevent progression in high-risk patients with mild to moderate COVID-19.10,11 Paxlovid is authorized in patients aged 12 years and older weighing at least 40 kg. However, molnupiravir is not recommended in children or pregnant women, because of the potential risk of embryofetal toxicity and impaired bone and cartilage growth seen in nonclinical studies. There are no available data to support the use of Paxlovid during pregnancy.10,11
Repurposing existing drugs is another approach to identify potential agents for COVID-19. Fluvoxamine is the first of many repurposed agents that has shown a mortality benefit.12 As an oral selective serotonin reuptake inhibitor and an alpha-1 receptor (S1R) agonist, a potential mechanism against COVID-19 is via S1R’s regulation of cytokine production in response to inflammatory triggers. Results from an adaptiveplatform trial in 1497 patients showed a 5% ARR inhospitalizations with fluvoxamine compared with the placebo.12
Conclusion
The therapeutic management of COVID-19 has evolved with our understanding of its clinical course of infection. As studies continue to emphasize the importance of early intervention in mild to moderate disease, pharmacists should remain up-to-date on information regarding therapies used to control, prevent, and treat COVID-19 infection.
Sara Lee, PharmD, is a PGY2 infectious diseases pharmacy resident at New York-Presbyterian Hospital in New York, New York.
REFERENCES
1. Taylor PC, Adams AC, Hufford MM, de la Torre I, Winthrop K, Gottlieb RL. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol. 2021;21(6):382-393. doi:10.1038/s41577-021-00542-x
2. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. Updated December 16, 2021. Accessed December 19, 2021. https://www.covid19treatmentguidelines.nih.gov
3. Dougan M, Nirula A, Azizad M, et al; BLAZE-1 Investigators. Bamlanivimab plus etesevimab in mild or moderate COVID-19. N Engl J Med. 2021;385(15):1382-1392. doi:10.1056/NEJMoa2102685
4. Fact sheet for health care providers emergency use authorization (EUA) of REGEN-CoV (casirivimab and imdevimab). FDA. Updated November 2021. Accessed December 19, 2021. https://www.fda.gov/media/145611/download
5. Gupta A, Gonzalez-Rojas Y, Juarez E, et al; COMET-ICE Investigators. Early treatment for COVID-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med. 2021;385(21):1941-1950 doi:10.1056/NEJMoa2107934
6. Kabinger F, Stiller C, Schmitzová J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021;28(9):740-746. doi:10.1038/s41594-021-00651-0
7. Merck and Ridgeback’s investigational oral antiviral molnupiravir reduced the risk of hospitalization or death by approximately 50 percent compared to placebo for patients with mild or moderate COVID-19 in positive interim analysis of phase 3 study. Merck. News release. October 1, 2021. Accessed November 6, 2021. https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/
8. Merck and Ridgeback’s molnupiravir, an oral COVID-19 antiviral medicine, receives first authorization in the world. Merck. News release. November 4, 2021. Accessed December 19, 2021. https://www.merck.com/news/merck-and-ridgebacks-molnupiravir-an-oral-covid-19-antiviral-medicine-receives-first-authorization-in-the-world/
9. Reis G, dos Santos Moreira-Silva EA, Silva DCM, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2022;10(1):e42-e51 doi:10.1016/S2214-109X(21)00448-4
10. Hirshberg JS, Cooke E, Oakes MC, Odibo AO, Raghuraman N, Kelly JC. Monoclonal antibody treatment of symptomatic COVID-19 in pregnancy: initial report. Am J Obstet Gynecol. 2021;225(6):688-689. doi:10.1016/j.ajog.2021.08.025
The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.
