An Update on SARS-CoV-2 Clinical Trial Results-What We Can Learn for the Next Pandemic

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 7 million lives worldwide, providing a stark reminder of the importance of pandemic preparedness. Due to the lack of approved antiviral drugs effective against coronaviruses at the start of the pandemic, the world largely relied on repurposed efforts. Here, we summarise results from randomised controlled trials to date, as well as selected in vitro data of directly acting antivirals, host-targeting antivirals, and immunomodulatory drugs. Overall, repurposing efforts evaluating directly acting antivirals targeting other viral families were largely unsuccessful, whereas several immunomodulatory drugs led to clinical improvement in hospitalised patients with severe disease. In addition, accelerated drug discovery efforts during the pandemic progressed to multiple novel directly acting antivirals with clinical efficacy, including small molecule inhibitors and monoclonal antibodies. We argue that large-scale investment is required to prepare for future pandemics; both to develop an arsenal of broad-spectrum antivirals beyond coronaviruses and build worldwide clinical trial networks that can be rapidly utilised.

Keywords: COVID-19; SARS-CoV-2; clinical trial; coronavirus; drug discovery; therapeutics.

Figure 1

The coronavirus life cycle and the mechanistic actions of antiviral drugs within the viral replication process, using SARS-CoV-2 as an example. The virus-cell membrane fusion was induced by the binding of spike protein to the host cellular receptor angiotensin-converting enzyme 2 (ACE2), together with the cell surface transmembrane serine protease 2 (TMPRSS2). Following viral entry, the release of the viral genome is followed by the immediate translation of viral proteins and the formation of the viral replication and transcription complex. The 3-chymotrypsin-like protease (CL^pro)/main protease (M^pro) and papain-like protease (PL^pro) cleave the virus polypeptide into 16 non-structural proteins. Structural glycoproteins are synthesised in the endoplasmic reticulum (ER) membrane for transit through the endoplasmic reticulum-to-Golgi intermediate compartment (ERGIC). Newly synthesised genomic RNA is encapsulated and buds into the ERGIC to form a virion. New virions leave the cell via lysosomes and are then able to infect new susceptible cells. SARS-CoV-2 infection activates the acid sphingomyelinase/ceramide system, resulting in the formation of ceramide-enriched membrane domains that serve viral entry and infection by clustering ACE2. The directly acting antivirals (DAA) mechanisms include the monoclonal antibodies that target the spike protein of the virus, M^pro inhibitor, nucleoside analogues, and RNA-dependent RNA polymerase (RdRp) inhibitor. The host-targeting antivirals (HTA) include the inhibitors of viral entry, functional inhibitors of acid sphingomyelinase activity (FIASMA), and inhibitors of viral glycoprotein processing. The immunomodulatory drugs modify the negative effects of an overreacting immune system, such as the interleukins and JAK ½ inhibitors. Adapted from “Coronavirus Replication Cycle”, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates, accessed on 20 April 2023.

Figure 2

COVID-19 disease progression and the windows of opportunities where antiviral drugs should be deployed. The directly acting antivirals (DAA) and host-targeting antivirals (HTA) are most effective for an intervention in the earlier course of the mild to moderate disease manifestation when viral load is increasing and detectable by RT-PCR. The immunomodulatory drugs are more potent in the later phase of the disease when the host immune response starts to develop as a response to the infection and the clinical manifestation starts to develop from severe to critical illness due to the risks of a cytokine storm. Adapted from “Time Course of COVID-19 Infection and Test Positivity”, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates, accessed on 20 April 2023.

Figure 3

Summary of compounds discussed in this review article, including directly acting antiviral (DAA), host-targeting antiviral (HTA), and immunomodulatory drugs. Therapeutics that received full approval and emergency use authorisation (EUA) for COVID-19 are marked in the table. FIASMA, Functional inhibitors of acid sphingomyelinase activity.