Vaccine shortages, public hesitancy to receive a vaccine, and emerging SARS-CoV-2 variants continue to impact health worldwide. The "elephant in the room," absent from public discourse, is that all these factors increase the odds that COVID-19 will become endemic with vaccine-resistant variant emergence. Ongoing vaccine and antiviral development will also continue to impact this pandemic going forward. Particularly needed at this time are oral antivirals to reduce infection severity and viral spread particularly in hard-to-reach communities worldwide.1 This article describes 2 antivirals seeking authorization in the United States and the world: Paxlovid (PF-07321332- ritonavir; Pfizer, New York) and Lageviro (molnupiravir; Merck, Kenilworth, New Jersey, and Ridgeback Biotherapeutics, Miami, Florida).

MOLNUPIRAVIR

Molnupiravir is a broad-spectrum antiviral that inhibits viral replication by a process known as "lethal mutagenesis." Molnupiravir disrupts SARS-CoV-2 genome replication via "error catastrophe" and prevents viral propagation by boosting accumulation of copying errors during viral RNA replication.1,2 Phase 1 studies in humans have demonstrated that molnupiravir is safe and tolerable, and phase 2/3 studies revealed that molnupiravir is effective in mild COVID-19. For subjects with moderate to severe COVID-19, molnupiravir has not been effective. The reduction in hospitalizations and death for persons with mild COVID-19 suggests that molnupiravir may become an important tool in the treatment of COVID-19. The ability of molnupiravir to weaken SARS-COV-2 replication in lung tissue and action as a mutagenizing agent via oral administration provides a path for antiviral treatment outside the hospital setting compared with approved intravenous remdesivir.3

In November 2021, the UK Medicines and Healthcare Products Regulatory Agency authorized molnupiravir for treatment of mild to moderate COVID-19 in adults with a positive diagnostic test and who have at least 1 risk factor for developing severe illness. This authorization was based on significant favorable findings during a planned interim analysis from the phase 3 MOVE-OUT clinical trial, which took place in more than 170 sites in Latin America, Europe, and Africa. This trial evaluated 800 mg of molnupiravir orally twice daily for 5 days in nonhospitalized, unvaccinated adult patients with laboratory-confirmed mild to moderate COVID-19 and symptom onset within 5 days of study randomization. Subjects also had to have at least 1 risk factor or comorbidity associated with severe outcomes. The data monitoring committee stopped the trial after interim analysis of results for 775 subjects revealed molnupiravir significantly reduced risk of hospitalization or death with safety events similar for both treatment and placebo arms. An earlier trial for hospitalized patients revealed that molnupiravir demonstrated no efficacy for this group.4-6

The ability of molnupiravir to target enzymes needed for virus replication and introduce errors in the viral genome was discovered by researchers at Emory University. DRIVE, a nonprofit LLC wholly owned by Emory, is an early-stage biotechnology company that focuses on the discovery and development of antiviral drugs for emerging infections, pandemic threats, and biodefense. Merck and Ridgeback Biotherapeutics are developing molnupiravir after licensing it from DRIVE. On October 11, 2021, Merck submitted the application for Emergency Use Authorization (EUA) to the US Food and Drug Administration.6 The US Food and Drug Administration Advisory Committee was scheduled to review on November 30, 2021 the EUA application for use of molnupiravir to treat mild to moderate COVID-19 with high risk of progression to severe illness, hospitalization, or death.7

PF-07321332/RITONAVIR

PF-07321332/ritonavir is an investigational SARS-CoV-2 protease inhibitor oral antiviral therapy, which can be prescribed at the first sign of infection or exposure. This agent blocks activity of the SARS-CoV-2-3CL protease, an enzyme the coronavirus requires to replicate. The combination of low-dose ritonavir slows the drug metabolism of PF-07321332, allowing the agent to remain active in a higher concentration for a longer period to inhibit viral replication.8

On November 5, 2021, Pfizer announced interim analysis results for PF-07321332/ritonavir from a phase 2/3 EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients). Data analysis of 1219 adults from clinical trial sites in North and South America, Europe, Africa, and Asia with 45% from the United States revealed significant reductions in hospitalization and death for nonhospitalized patients with COVID-19 with high risk of progression to severe illness. Subjects had a laboratory-confirmed COVID-19 infection within the first 5-day period with mild to moderate symptoms and least 1 factor associated with increased risk of developing severe illness from COVID-19. Each patient was randomized (1:1) to receive PF-07321332/ritonavir or placebo orally every 12 hours for 5 days.8

If the request for EUA is approved, PF-07321332/ritonavir (Paxlovid) would be the first SARS-CoV-2-3CL protease inhibitor that prevents the SARS-CoV-2 virus encoding of its own protease that it needs for replication. Rolling submissions for approval are ongoing at this time in the United Kingdom, Australia, New Zealand, and Korea, with additional submissions to other agencies around the world for authorization. In addition, emerging reports regarding the in vitro activity of PF-07321332/ritonavir suggests possible uses in the future for emerging variants and other types of coronavirus infections.8-11

GOING FORWARD

The continuing emergence of new antiviral agents for the prevention or treatment of COVID-19 will add complexity for the prescriber particularly in primary care. It is unclear how the administration of oral antivirals will fit into evolving treatment and prescribing algorithms. However, effective antiviral therapies are so needed, considering the low vaccination rates in the United States and in many areas of the world with continuing high morbidity and mortality associated with infection.5 Historically, use of antiviral monotherapies for other viruses has led to the development of resistance-an outcome that needs to be monitored for and, if possible, prevented. The seeming rapid drug approvals/authorizations during this pandemic have promoted increasing suspicion among patients fueling additional problems for the prescriber.5 The clinical nurse specialist must continue to educate when prescribing by providing evidence for every prescribed agent to reduce reliance on misleading information from social media. None of the therapies approved for use in this pandemic were developed overnight. Years of research underlie every agent in use at this time that enabled expedient and lifesaving drug and vaccine development for COVID-19.

Effective antiviral therapies are much needed, considering the low vaccination rates and continuing high morbidity and mortality associated with COIVD-19. Both Pfizer and Merck in 2021 entered into licensing agreements with the Medicines Patent Pool, a United Nations -supported nonprofit organization that makes medical treatments more accessible globally. These agreements will allow companies in 95 countries to manufacture antivirals for use for approximately 53% of the world's population. Under the agreement, Pfizer will not receive royalties on sales in low-income countries and will waive royalties in all countries that are included in the agreement as long as COVID-19 is a public health emergency. Merck agreed to a similar plan with the Medicines Patent Pool for molnupiravir, which will be available in 105 countries.12,13

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