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Other oral antivirals under development for COVID-19

Earlier in this issue of TreatmentUpdate, we presented some information on molnupiravir. This drug is likely to become the first potent oral antiviral drug for the treatment of mild-to-moderate COVID-19. It is also possible that molnupiravir could become the first oral drug to be used as a form of post-exposure prophylaxis (PEP). If that happens, people who have been in close contact with someone diagnosed with COVID-19, such as people who live in the same household, may be prescribed molnupiravir in the future to prevent the onset or worsening of COVID-19. A clinical trial to explore this issue is underway.

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Other oral antivirals for SARS-CoV-2

Here are summaries of other oral antiviral drugs in development for the potential treatment of SARS-CoV-2:

Paxlovid (PF-07321332)

This antiviral is being developed by Pfizer. Paxlovid is a protease inhibitor that works against an enzyme of SARS-CoV-2 called main protease. Pfizer has several clinical trials of Paxlovid + a low dose of an older drug called ritonavir. The purpose of ritonavir is to slow the breakdown of Paxlovid and/or to boost levels of Paxlovid in the body. Studies underway with the Pfizer protease inhibitor will assess its ability to prevent worsening disease in people (with or without underlying conditions) who have early COVID-19. Preliminary analysis of the clinical trial suggests that the combination of Paxlovid + ritonavir is highly effective in people with mild to moderate COVID-19. Pfizer is also testing the combination of Paxlovid + ritonavir in people who live in the same household as someone diagnosed with COVID-19.

In the early to mid-1990s, ritonavir was tested as a treatment for HIV. Ritonavir works by interfering with an enzyme (called protease) used by HIV. Although ritonavir was lifesaving when used as part of combination treatment in people with HIV, it caused severe side effects at high doses, particularly diarrhea and nausea. In the late 1990s, infectious disease doctors repurposed ritonavir as a booster for some HIV drugs. In such cases, it was used at lower doses and was better tolerated by some people.

However, ritonavir also has many potential drug interactions—it can raise levels of other drugs, causing side effects or intensifying pre-existing side effects. Ritonavir can also lower levels of other drugs, increasing the risk of treatment failure for other drugs. Therefore, if ritonavir is used in people who are taking other medicines, particularly for underlying conditions, consultation with a pharmacist is important.

EDP-235

This antiviral is being developed by Enanta Pharmaceuticals. EDP-235 works by interfering with the main protease of SARS-CoV-2. This drug achieves high concentrations in the lungs in animal experiments and is effective against main protease from different variants of SARS-CoV-2. A phase I clinical trial is expected to start in early 2022.

S-217622

This antiviral is being developed by Shionogi Pharma. Compound S-217622 is an inhibitor of the SARS-CoV-2 main protease and is effective in experiments with animals. S-217622 is in a phase II/III clinical trial in participants with SARS-CoV-2 infection who have no or mild symptoms. The drug will be given once daily for five consecutive days.

Ensovibep (MP0420)

This antiviral is being developed by a company called Molecular Partners in cooperation with the pharmaceutical company Novartis. Ensovibep belongs to a class of compounds called DARPins (designed ankyrin repeat proteins). DARPins are small molecules that can mimic some of the function of antibodies. As DARPins are much smaller, they can reach more tissues. Molecular Partners has developed a DARPin that can simultaneously attach to three different parts of SARS-CoV-2. This property is useful, as the virus can change its structure from time to time, making it difficult for antibodies to attack SARS-CoV-2. By simultaneously binding to three different parts of the virus, researchers hope that ensovibep will be effective against a broad range of variants of SARS-CoV-2 and more effective at stopping the virus from infecting cells. The drug is in several clinical trials, including one phase II/III study.

PBI-0451

This antiviral is being developed by Pardes Biosciences. Compound PBI-0451 is a protease inhibitor that works against SARS-CoV-2 main protease. A randomized, double-blind, placebo-controlled phase I study is underway.

AT-527 (also known as RO7496998)

This antiviral is being developed by Atea Pharmaceuticals in cooperation with Hoffmann-La Roche. The drug has potent antiviral activity in lab experiments with cells and SARS-CoV-2. It works by interacting with an enzyme used by SARS-CoV-2-infected cells called RNA polymerase. In a phase II study called Moonsong, Atea reported disappointing results with AT-527 vs. placebo in participants with COVID-19. Most participants in Moonsong had mild symptoms and underlying conditions were not common. The drug might be more effective in patients who are sicker. Atea and Roche are trying to understand the results of Moonsong and how they may be used to influence the design of a phase III clinical trial called Morningsky.

—Sean R. Hosein

REFERENCES:

  1. Halford B. Pfizer unveils its oral SARS-CoV-2 inhibitor. Chemical and Engineering News. 7 April 2021.
  2. Pfizer. Pfizer starts global phase 2/3 EPIC-PEP study of novel COVID-19 oral antiviral candidate for post-exposure prophylaxis in adults. Press release. 27 September 2021.
  3. Pavan M, Bolcato G, Bassani D, et al. Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332. Journal of Enzyme Inhibition and Medicinal Chemistry. 2021 Dec;36(1):1646-1650.
  4. Pfizer. Pfizer’s Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death by 89% in Interim Analysis of Phase 2/3 EPIC-HR Study. Press release. 5 November 2021.
  5. Enanta. Enanta Pharmaceuticals presents new data for EDP-235, its lead oral protease inhibitor designed for the treatment of COVID-19, at the ISIRV–WHO Virtual Conference 2021. Press release. 19 October 2021.
  6. Shionogi. Notice regarding the initiation of a phase 2/3 clinical trial for a COVID-19 therapeutic agent in Japan. Press release. 28 September 2021.
  7. Rothenberger S, Walser M, Malvezzi F, et al. Multispecific DARPin therapeutics demonstrate very high potency against SARS-CoV-2 variants in vitro. Preprint. 26 May 2021.
  8. Anonymous. DARPins stack up as anti-COVID-19 agents. Nature Biotechnology. 2020 Dec;38(12):1369. 
  9. Novartis. Novartis and Molecular Partners announce start of EMPATHY clinical trial for ensovibep for the treatment of COVID-19. Press release. 27 May 2021.
  10. Atea. Atea Pharmaceuticals provides update and topline results for phase 2 MOONSONG Trial evaluating AT-527 in the outpatient setting. Press release. 19 October 2021.