Antivirals in Patients with COVID-19
Since the beginning of the COVID-19 pandemic, clinicians and drug manufacturers have raced to find active antivirals to target SARS-CoV-2. Coronaviruses (and viruses in general) have always been difficult drug targets, compact genome, minimal cellular contents, and innate ability to mutate.1 In the current COVID-19 pandemic, many researchers repurposed antivirals that were already on the market, like lopinavir/ritonavir and oseltamivir. Others repurposed antivirals in the development pipeline, like remdesivir and molnupiravir. Lastly, additional antivirals like PF-07321332 were developed over the past 18 months explicitly to target SARS-CoV-2. While many antivirals have been trialed a year and a half into this pandemic, only remdesivir has made it through the FDA’s approval process. The fight against COVID-19 using antivirals is far from over though, with the US government recently investing $3 billion in antiviral development and creating the “Antiviral Program for Pandemics.”2 In this Expert Insight, I will review the antivirals that have come across my radar in the treatment of COVID-19 and their status.
Remdesivir is the only antiviral currently approved by the FDA for the treatment of COVID-19. It works by inhibiting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), an essential piece to viral replication. Remdesivir’s development started well before SARS-CoV-2’s introduction to the world, however. Research began as early as 2009, with pre-clinical work targeting hepatitis C and respiratory syncytial virus (RSV).3 It was then tested in clinical trials against Ebola in 2014. While the Ebola randomized controlled trial failed to show remdesivir having an impact on patient mortality, it did provide data on the safety of remdesivir in humans.4 In vitro work from 2017 showed that remdesivir has activity against coronaviruses.5 When COVID-19 hit, Gilead quickly initiated or donated supply to multiple clinical trials. Of those, the two most notable were ACTT-1 and SOLIDARITY. The FDA’s approval of remdesivir came largely based on the results of ACTT-1, where patients randomized to receive remdesivir recovered from COVID-19 in a median of 10 days compared to 15 days in the placebo arm.6 SOLIDARITY, on the other hand, failed to show a mortality benefit with remdesivir compared to standard of care (11.0% vs. 11.2%).7 I don’t consider these two studies to be contradictory however, as they were vastly different in design and measured outcomes. Remdesivir likely has a place in therapy in those early in their disease to reduce recovery time. It is currently only available in an intravenous formulation, which generally limits its use to hospitalized patients. Gilead is working on an inhaled formulation, currently in a phase 1 trial, that could potentially be administered in the outpatient setting.8
Similar to remdesivir, molnupiravir works by inhibiting SARS-CoV-2 RdRp. Molnupiravir is under development as an oral antiviral against COVID-19, with two phase 2/3 randomized trials, MOVe-OUT and MOVe-IN.9,10 In a press release, Merck announced the lack of benefit for molnupiravir in the inpatient setting, but there was enough evidence to move to the phase 3 portion of the outpatient clinical trial in patients with symptoms for ≤ 5 days.11 While we do not yet have published results, the U.S. government has procured approximately 1.7 million courses of molnupiravir in hopes that the outpatient clinical trial provides favorable outcomes.12
Favipiravir also comes in an oral formulation and inhibits SARS-CoV-2 RdRp in vitro. It has been licensed in Japan since 2014 for the treatment of influenza and has received attention for the treatment of COVID-19 since early 2020. A number of small heterogenous randomized controlled trials have been completed, with a meta-analysis showing mixed results.13 Favipiravir is currently being investigated in a larger outpatient clinical trial in the UK, PRINCIPLE.14
Umifenovir is an oral antiviral that blocks multiple stages of the viral life cycle, including fusion and exocytosis. It has been licensed for influenza treatment and prophylaxis in China since 2006 and Russia since the 1990s.15 Like favipiravir, the trials that have been completed thus far on its use in COVID-19 have been heterogeneous with mixed results, and recommendations for its use for COVID-19 treatment remain inconclusive.16
AT-527 is an oral antiviral that inhibits SARS-CoV-2 RdRp. It is not yet licensed in any country, but is currently undergoing phase 2 clinical trials in both the inpatient and outpatient settings.17,18
PF-07321332 is an orally administered protease inhibitor designed during the current pandemic specifically to inhibit the 3CL protease of SARS-CoV-2. Pfizer is also studying PF-07304814, another protease inhibitor originally discovered in 2003 for SARS-CoV-1. This compound can only be given intravenously (similar to remdesivir) however, so PF-07321332 has instead received the majority of attention since its reveal at the Spring American Chemical Society meeting earlier this year. PF-07321332 is currently undergoing phase 1 trials, with plans to hopefully ramp up to phase 2 and 3 trials by the end of the summer.19,20
Antivirals Not Recommended in Patients with COVID-19
Many medications have been repurposed for COVID-19 treatment in the past 18 months. Of those, potential antivirals that have been proven to not be effective for the treatment of COVID-19 include chloroquine, hydroxychloroquine, lopinavir/ritonavir, and oseltamivir.
The above antivirals are by no means an exhaustive list, as there are hundreds of medications currently in development or being studied across the world. More than 18 months into the current pandemic, of the above discussed antivirals, only remdesivir has proven to have an impact on COVID-19’s clinical course. However, the pipeline is full of potential oral (or inhaled) antiviral options that could bode well for initiating at first signs of symptom onset rather than awaiting hospitalization. While vaccine uptake will be the most important piece to curb the pandemic and vaccinations continue to increase worldwide, the development of antivirals for COVID-19 remains critical to treat those who have yet to be vaccinated or with breakthrough COVID-19 infections.
- Dolgin E. The race for antiviral drugs to beat COVID — and the next pandemic. Nature. 2021; 592:340-343.
- U.S. Department of Health & Human Services. (2021 Jun 17). Biden administration to invest $3 billion from American Rescue Plan as part of COVID-19 Antiviral Development Strategy [Press release]. https://www.hhs.gov/about/news/2021/06/17/biden-administration-invest-3-billion-american-rescue-plan-as-part-covid-19-antiviral-development-strategy.html.
- Gilead Sciences. Development of remdesivir. https://www.gilead.com/-/media/gilead-corporate/files/pdfs/covid-19/gilead_rdv-development-fact-sheet-2020.pdf (accessed 2021 Jul 4).
- Mulangu S, Dodd LE, Davey RT, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019; 381(24):2293-2303.
- Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017; 9(396):eaal3653.
- Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19 – final report. N Engl J Med. 2020; 383:1813-1826.
- WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID-19 – interim WHO Solidarity trial results. N Engl J Med. 2021; 384:497-511.
- ClinicalTrials.gov. Study in participants with early stage coronavirus disease 2019 (COVID-19) to evaluate the safety, efficacy, and pharmacokinetics of remdesivir administered by inhalation. https://clinicaltrials.gov/ct2/show/NCT04539262 (accessed 2021 Jul 4).
- ClinicalTrials.gov. Efficacy and safety of molnupiravir (MK-4482) in non-hospitalized adult participants with COVID-19 (MK-4482-002). https://clinicaltrials.gov/ct2/show/NCT04575597 (accessed 2021 Jul 4).
- ClinicalTrials.gov. Efficacy and safety of molnupiravir (MK-4482) in hospitalized adult participants with COVID-19 (MK-4482-001). https://clinicaltrials.gov/ct2/show/NCT04575584 (accessed 2021 Jul 4).
- Merck. (2021 Apr 15). Merck and Ridgeback Biotherapeutics Provide Update on Progress of Clinical Development Program for Molnupiravir, an Investigational Oral Therapeutic for the Treatment of Mild-to-Moderate COVID-19 [Press release]. https://www.merck.com/news/merck-and-ridgeback-biotherapeutics-provide-update-on-progress-of-clinical-development-program-for-molnupiravir-an-investigational-oral-therapeutic-for-the-treatment-of-mild-to-moderate-covid-19/.
- U.S. Department of Health & Human Services. (2021 Jun 9). Biden Administration announces U.S. government procurement of Merck’s investigational antiviral medicine for COVID-19 treatment [Press release]. https://www.hhs.gov/about/news/2021/06/09/biden-administration-announces-us-government-procurement-mercks-investigational-antiviral-medicine-covid-19-treatment.html.
- Hassanipour S, Arab-Zozani M, Amani B, et al. The efficacy and safety of Favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials. Sci Rep. 2021; 11:11022.
- Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE). https://www.principletrial.org/ (accessed 2021 Jul 5).
- Blaising J, Polyak SJ, Pécheur EI. Arbidol as a broad-spectrum antiviral: an update. Antiviral Res. 2014; 107:84-94.
- Huang D, Yu H, Wang T, et al. Efficacy and safety of umifenovir for coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis. J Med Virol. 2020; 93(1):481-490.
- ClinicalTrials.gov. Study to evaluate the effects of RO7496998 (AT-527) in non-hospitalized adult and adolescent participants with mild or moderate COVID-19 (MORNINGSKY). https://clinicaltrials.gov/ct2/show/NCT04889040 (accessed 2021 Jul 5).
- ClinicalTrials.gov. Safety and efficacy of AT-527 in subjects with moderate coronavirus disease (COVID-19). https://clinicaltrials.gov/ct2/show/NCT04396106 (accessed 2021 Jul 5).
- ClinicalTrials.gov. Study of PF-07321332 in healthy participants. https://clinicaltrials.gov/ct2/show/NCT04756531 (accessed 2021 Jul 6).
- Pfizer. (2021 Mar 23). Pfizer initiates phase 1 study of novel oral antiviral therapeutic agent against SARS-CoV-2 [Press release]. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-initiates-phase-1-study-novel-oral-antiviral.