COVID-19 is the third coronavirus disease in the past 20 years after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). While the two predecessors caused severe mortality, they did not cause a pandemic. In contrast, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) triggered a pandemic, and to date has caused nearly 765 million confirmed cases, including nearly 20 million estimated deaths, according to the latest WHO releases. Vaccines and monoclonal antibody (mAb) treatments for COVID-19 became available within a year of the pandemic. However, there is a substantial need for more effective therapies to treat unvaccinated and immunocompromised patients and those whose vaccine immunity has declined over time.
Early in the pandemic, doctors used azithromycin and hydroxychloroquine as possible COVID-19 treatments for hospitalized patients based on in vitro evidence of their synergistic effect on SARS-CoV-2 infection. Subsequently, clinical trials found this combination to be ineffective. Similarly, the US NIH Panel did not specify recommendations for empirical antimicrobials. Azithromycin, however, remained as a treatment given initial AI data that it inhibits viral protease at doubled doses. Instead, it recommended the timely use of supplemental oxygenation and high-flow nasal cannula in patients with ARDS.
Early drug repurposing efforts targeted nucleotide prodrugs, such as remdesivir, AT-527, favipiravir, and molnupiravir. However, only three antivirals have received full Emergency Use Authorization (EUA) approval from the United States Food and Drug Administration (US-FDA), namely remdesivir, molnupiravir and nirmatrelvir. Preclinical characterization of remdesivir for other coronaviruses, human pharmacokinetic and safety evaluation in a failed clinical study for Ebola virus, all acquired before the onset of the COVID-19 pandemic, have enabled rapid progression of remdesivir. A Phase 3 study among patients in outpatient settings showed that administering remdesevir within seven days of symptom onset reduced the risk of hospitalization by 87%.
Therefore, its approval was also extended to high-risk outpatients. The Phase 1b/2a study for inhaled remdesivir and preclinical evaluation of an oral remdesivir-based prodrug is currently underway. Another randomized phase 3 trial evaluated ivermectin, metformin and fluvoxamine, all repurposed drug candidates, for the early treatment of COVID-19 in overweight or obese adults. Previous pivotal efficacy and clinical studies found that molnupiravir provided no clinical benefit in hospitalized COVID-19 patients. In contrast, the MOVE-OUT outpatient study showed that treatment started within five days of symptom onset reduced the risk of hospitalization or death.
As a result, molnupiravir was granted a US EUA in late 2021 for the treatment of mildly to moderately ill COVID-19 patients at high risk of progression to severe disease. However, an outpatient study has suggested that molnupiravir might increase the evolution of SARS-CoV-2 in immunocompromised individuals. Multiple initiatives have been undertaken in the United States to identify candidate agents that could be repurposed as COVID-19 drugs. For example, the Bill and Melinda Gates Foundation launched the Therapeutics Accelerator in March 2020, in which they took a three-way approach to testing approved drugs, examining drug libraries, and evaluating small molecules and including mAbs.
Encouragingly, apilimod, a PIKfyve kinase inhibitor developed for the treatment of autoimmune diseases, is being tested for COVID-19 in clinical trials. Similarly, several clinical trials are underway for camostat mesylate, a transmembrane protease serine 2 (TMPRSS2) inhibitor, an approved treatment for chronic pancreatitis in Japan. Among the anti-inflammatory and immunomodulatory drugs, dexamethasone, a corticosteroid, baricitinib, a Janus kinase (JAK) inhibitor, and tocilizumab have received FDA approval. Among mAb therapies, casirivimab with imdevimab and bamlanivimab with etesevimab, Sotrovimab, Bebtelovimab, Tixagevimab-cilgavimab have received FDA approval. However, as the coronavirus continues to evolve, changes in the spike protein have led to the withdrawal of EUAs for all mAb therapies due to loss of efficacy.
Between declining vaccine uptake and decreasing efficacy of mAbs as SARS-CoV2 mutates, there is a need for new, safe and effective anti-COVID therapies for population-level spread and the potential to reduce the resistance development. Researchers must accelerate the search for small-molecule candidates that would mechanistically target the conserved region of SARS-CoV2 and not become ineffective among mutant strains. To be prepared for another pandemic, a large repository of small molecules that have already progressed through early preclinical and clinical evaluation is needed to develop drugs, such as remdesivir, developed in a short two-year time frame.
More importantly, research efforts should continue to advance the development of antivirals for other pathogens, including coronaviruses, in preparation for the next pandemic.
- By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific publications
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