Current Status and Progress in Developing Drugs to Treat Coronavirus Disease 2019 (COVID-19)

Introduction

Since first emerging in late 2019, the novel coronavirus known as SARS-CoV-2 has spread rapidly worldwide, causing a pandemic of coronavirus disease 2019 (COVID-19). While vaccines are helping to bring the pandemic under control, development of effective drug treatments remains an urgent public health priority. This article reviews the current status and progress of drug development research focused on treating COVID-19.

Repurposed Antivirals and Other Drugs

In the early stages of the pandemic before virus-specific therapies could be developed, clinicians and researchers turned to existing drugs that might have antiviral activity against SARS-CoV-2. Some of the most promising repurposed drugs evaluated have included:

- Remdesivir: An antiviral originally developed to treat Ebola virus, remdesivir interferes with viral RNA replication and was shown to modestly shorten recovery time in hospitalized COVID-19 patients in clinical trials. It was granted emergency use authorization by the FDA.

- Dexamethasone: A corticosteroid, dexamethasone demonstrated a mortality benefit in hospitalized patients requiring oxygen or mechanical ventilation in a large UK clinical trial. However, it is not recommended for non-hospitalized or mild disease cases.

- Convalescent plasma: Collected from recovered Coronavirus Treatment Drugs patients, convalescent plasma contains antibodies that may help the immune system fight infection. Data on effectiveness is limited and results have been inconsistent across studies.

- Hydroxychloroquine and chloroquine: These antimalarial drugs received significant attention early on but were found to have no benefit or possibly increase risks based on larger, higher quality clinical trials. Most major studies of them have now been discontinued.

Monoclonal Antibody Treatments

Another strategy involves development of laboratory-produced monoclonal antibody therapies targeting the SARS-CoV-2 virus. The goal is to generate antibodies that can block viral entry or replication. Some leading monoclonal antibody treatment candidates include:

- Bamlanivimab: Developed by Eli Lilly, bamlanivimab received emergency use authorization from the FDA in November 2020 based on an interim analysis finding it reduced COVID-19 related hospitalizations and ER visits in high-risk patients with mild-moderate disease.

- REGN-COV2: This combination monoclonal antibody cocktail from Regeneron was granted emergency authorization in November 2020 for non-hospitalized COVID-19 patients at high risk of severe illness. It was part of the treatment received by then-President Trump.

- Sotrovimab: Developed by GlaxoSmithKline and Vir Biotechnology, sotrovimab targets a conserved epitope on the SARS-CoV-2 spike protein and has demonstrated high in vitro potency against current variants of concern. In March 2021, it received emergency use authorization from the FDA based on interim clinical trial results.

Oral Antiviral Pill Candidates

One of the highest priorities in COVID-19 drug development is researching oral antiviral pills that could be easily administered outside of a medical setting to treat early disease. This could help speed recovery and reduce hospitalizations. Leading oral antiviral candidates in clinical trials include:

- Molnupiravir: An investigational oral antiviral agent being jointly developed by Ridgeback Biotherapeutics and Merck, molnupiravir works by introducing errors into the viral genome to stop replication. Phase 3 trials are currently underway.

- PF-07321332: This protease inhibitor developed by Pfizer appears highly effective at suppressing SARS-CoV-2 replication in early stage clinical studies. Phase 2/3 trials continue to evaluate its efficacy and safety as a potential oral treatment.

- AT-527: Developed by Atea Pharmaceuticals and Roche, AT-527 is an orally administered direct-acting antiviral currently being studied in Phase 2 and Phase 3 clinical trials. It aims to inhibit the viral RNA polymerase essential for SARS-CoV-2 replication.

Variants and New Candidates

Continued evolution of new SARS-CoV-2 variants underscores the need for multiple therapeutics that maintain effectiveness as the virus mutates. Some therapies in research pipelines specifically target features of variants of concern. For example, Celltrion is developing an injectable anti-RBD monoclonal antibody cocktail with in vitro activity against variants. Overall, dozens of companies worldwide remain engaged in COVID-19 drug discovery and clinical evaluation efforts.

While vaccination programs have brought hope, developing effective treatments remains crucial considering gaps in global vaccine access. Research is advancing multiple therapeutic strategies, including antivirals, monoclonal antibodies, and hyperimmune therapies. Repurposed drugs have offered an early bridge, but newer agents under investigation focus directly on SARS-CoV-2. Large clinical trials continue to evaluate multiple promising candidates and demonstrate their ability to improve outcomes when used early in infection. Continued progress through 2021 and beyond is expected to expand options to fight COVID-19 worldwide.

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