In the News: New Oral Antiviral Drugs Added to the Armamentarium Against COVID-19

Lately, it seems like new developments concerning the COVID-19 pandemic have been flying around at a head-spinning pace. You’ve probably been bombarded with news of a highly contagious variant, sky-rocketing case numbers, or constantly evolving clinical guidance. One of the more encouraging developments is that oral antiviral drugs for COVID-19 have finally arrived. In late December 2021, the U.S. Food and Drug Administration (FDA) first granted Emergency Use Authorization (EUA) for Pfizer’s Paxlovid (nirmatrelvir/ritonavir) and then for Merck and Ridgeback Biotherapeutics’ molnupiravir, giving the drug makers the green light to begin distributing their products in the United States.1,2 While other COVID-19 treatment options exist, oral antiviral drugs are being touted as potential game changers since they can be used in the outpatient setting to keep patients out of the hospital (freeing up resources for sicker patients) and prevent death.3

Molnupiravir (Merck and Ridgeback Biotherapeutics)

In early October 2021, Merck and Ridgeback Biotherapeutics announced that their oral antiviral drug, molnupiravir, reduced the risk of hospitalization and death by about 50% in adults with mild to moderate COVID-19 and at least one risk factor for severe disease (e.g., obesity, age ≥ 60, diabetes, or heart disease).4 Their EUA application for molnupiravir included supporting data from the MOVe-OUT phase 3 clinical trial. This trial was stopped early after favorable results were revealed during a planned midpoint analysis.4-6 Interestingly, the full trial data submitted for FDA review suggested that molnupiravir wasn’t as effective as initially thought and only decreased the risk of hospitalization by about 30%.6 Some researchers have hypothesized that the differences could be due to the emergence of the Delta variant in the latter half of the trial or demographic differences between trial groups.6

An FDA advisory committee met on November 30, 2021 to discuss the available data for adults at high risk for severe infection (e.g., hospitalization and/or death) and decided by a narrow margin (a 13-10 vote) to recommend molnupiravir for emergency use.6,7 Much of the dissent among committee members had to do with how the drug works and its potential risks. Molnupiravir mimics viral RNA building blocks and inserts itself into viral RNA during replication which leads to errors, known as mutations. When enough mutations accumulate, the virus is unable to replicate any further – essentially killing off the virus and reducing disease severity.3,8,9 This mechanism is responsible for the therapeutic effects of molnupiravir, but might also be to blame for concerns about the drug’s potential to cause certain cancers, birth defects, or impaired growth; though, the FDA concluded that such risks are low.2,3,6,11

Rapid symptom recognition and diagnosis are essential for effective treatment – molnupiravir should be started within 5 days of symptom onset.8 In addition to starting treatment quickly, efficacy will also depend on adherence to the recommended regimen of four 200mg capsules (800mg per dose) by mouth every 12 hours for 5 days.2,9 Some experts are concerned about the potential for resistant or more transmissible variants to develop, especially if patients don’t finish the full 5-day course, since it’s possible (but unlikely) that a mutated virus could survive and be passed on to someone else.6,9,10

Presently, the benefits of molnupiravir are limited to cases of new onset, mild to moderate COVID-19 in high risk patients – one study found no benefit in giving the drug to already hospitalized patients.7 It hasn’t been authorized for use in patients under 18 years old or for use as a prophylactic measure.2 Molnupiravir isn’t recommended for use during pregnancy and those with reproductive potential are advised to use reliable contraception both during and after treatment.2 Molnupiravir is only authorized for non-hospitalized, high-risk COVID-19 positive adult patients when other FDA authorized treatment options are inaccessible or inappropriate.2

Overall, the drug appears to be generally well-tolerated – reported side effects include diarrhea, nausea, and dizziness and clinically significant drug interactions haven’t been identified.2,12

Merck was expected to manufacture 10 million courses of treatment by the end of 2021.5 The U.S. government agreed to buy 3.1 million treatment courses for about $700 per 5-day course — a fraction of the cost of infusion therapies being used to treat COVID-19.8 ,13

Paxlovid (Pfizer)

In early November 2021, Pfizer announced that their COVID-19 antiviral treatment, Paxlovid, reduced the risk of hospitalization or death by almost 90% in non-hospitalized, high-risk adults with COVID-19 when started within 3 to 5 days of symptom onset.14 This data comes from the EPIC-HR trial, which was stopped early due to Paxlovid’s extremely high rate of efficacy.14 Subsequently, Pfizer submitted the data to the FDA, who granted EUA on December 22, 2021 for the treatment of mild-to-moderate COVID-19 in adults and some children (at least 12 years old and weighing at least 88 lbs.) who are at high risk for hospitalization or death.1 Paxlovid wasn’t authorized for prophylactic use or for hospitalized patients.1

Paxlovid is a combination of two drugs packaged together and is the first oral antiviral specifically designed to inhibit the activity of SARS-CoV-2 main protease, an enzyme that’s critical for viral replication.14.15 Its key component, nirmatrelvir, is given along with low dose ritonavir, a drug historically used with other protease inhibitors in HIV.1,14 Here, ritonavir helps slow the breakdown of nirmatrelvir, so it can attain therapeutic concentrations high enough to adequately fight the virus.1,14 A typical Paxlovid course consists of three tablets (two 150mg nirmatrelvir tablets and one 100mg ritonavir tablet) taken together by mouth twice daily for 5 days.1,15

Like molnupiravir, Paxlovid should be initiated within 5 days of symptom onset and is similarly well-tolerated.1 More common side effects include loss of taste, diarrhea, hypertension, and muscle aches.1 To date, there isn’t any evidence suggesting that Paxlovid causes human DNA mutations.14

Paxlovid has limitations, though, and in some cases should be used more cautiously (or not at all). It isn’t recommended for use in patients with severe renal or hepatic impairment, requires renal dose adjustments, and should be used cautiously in patients with liver abnormalities since ritonavir can worsen hepatic function.1,15 Patients’ medications should be carefully screened before starting treatment, especially when combined with medications that induce or are metabolized by CYP3A, due to the potential for clinically significant and serious drug interactions.15

The U.S. government originally agreed to acquire 10 million courses of treatment with a price tag of $530 per course – about 25% less than that of molnupiravir.16-18 In early January 2022, they doubled their order to purchase a total of 20 million courses.19 It’s expected that the first 10 million treatment courses will be available by June 2022.19 Pfizer expects to produce up to 120 million courses of treatment in 2022.16,17

Distribution & Availability

The U.S. Department of Health and Human Services (HHS) will oversee equitable allocation of these medications to state health departments and some federally funded health clinics.20,21 The health departments will make the drugs available to dispensing sites in their state.20,21 Dispensing sites might include some pharmacies, doctors’ offices, clinics, hospitals, urgent care centers, and local health departments.20,21 Accessibility and availability will vary by state, since different states have different supply allocations and distribution plans.20.21 These drugs aren’t expected to be widely available at first.20,21 Initially, only 300,000 courses of molnupiravir and 65,000 courses of Paxlovid were made available to state health departments.20,21

A list of COVID-19 therapeutic dispensing sites can be viewed here.

Bottom Line

The prospect of having oral antivirals targeted against COVID-19 is definitely exciting and data from initial trials is encouraging. Early identification of COVID-19 infections in high-risk patients and improved access to these prescription-only medications will be essential for the widespread success of both treatments. These drugs aren’t going to be magic pills that make COVID-19 disappear, but may serve to help reduce the severity of disease, hospitalizations, and death in high-risk individuals. Once readily available, these drugs could be invaluable tools in the armamentarium to fight the COVID-19 pandemic.

Written by:

John Corrigan, PharmD

Clinical Pharmacist, OnePoint Patient Care

References

  1. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19. December 22, 2021. Accessed December 27, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
  2. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 in Certain Adults. December 23, 2021. Accessed December 27, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-oral-antiviral-treatment-covid-19-certain
  3. Lang K. Molnupiravir vs. COVID-19: Will the drug live up to the hype? Medical News Today. October 14, 2021. Accessed October 20, 2021. https://www.medicalnewstoday.com/articles/molnupiravir-vs-covid-19-will-the-drug-live-up-to-the-hype
  4. Merck and Ridgeback’s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study. Merck. October 1, 2021. Accessed October 20, 2021. https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/
  5. Merck and Ridgeback Announce Submission of Emergency Use Authorization Application to the U.S. FDA for Molnupiravir, an investigational Oral Antiviral Medicine, for the Treatment of Mild-to-Moderate COVID-19 in at Risk Adults. Merck. October 11, 2021. Accessed October 20, 2021. https://www.merck.com/news/merck-and-ridgeback-announce-submission-of-emergency-use-authorization-application-to-the-u-s-fda-for-molnupiravir-an-investigational-oral-antiviral-medicine-for-the-treatment-of-mild-to-moderate-c/
  6. Kozlov M. Merck’s COVID pill loses its lustre: what that means for the pandemic. Nature. December 13, 2021. Accessed December 29, 2021. https://www.nature.com/articles/d41586-021-03667-0
  7. Food and Drug administration. FDA to Hold Advisory Committee Meeting to Discuss Merck and Ridgeback’s EUA Application for COVID-19 Oral Treatment. October 14, 2021. Accessed October 29,2021. https://www.fda.gov/news-events/press-announcements/fda-hold-advisory-committee-meeting-discuss-merck-and-ridgebacks-eua-application-covid-19-oral
  8. Willyard C. How antiviral pill molnupiravir shot ahead in the COVID drug hunt. Nature. Updated October 9, 2021. Accessed October 29, 2021. https://www.nature.com/articles/d41586-021-02783-1
  9. Browne G. Merck’s Antiviral Could Be Just What Covid Was Waiting for. Wired. November 1, 2021. Accessed November 3, 2021. https://www.wired.com/story/merck-covid-antiviral-drug-molnupiravir/
  10. Haseltine W. Supercharging New Viral Variants: The Dangers of Molnupiravir (Part 1). Forbes November 1, 2021. Accessed November 3, 2021. https://www.forbes.com/sites/williamhaseltine/2021/11/01/supercharging-new-viral-variants-the-dangers-of-molnupiravir-part-1/?sh=751538f6b15a
  11. Haseltine W. Harming Those Who Receive It: The Dangers of Molnupiravir (Part 2). Forbes. November 2, 2021. Accessed November 3, 2021. https://www.forbes.com/sites/williamhaseltine/2021/11/02/harming-those-who-receive-it-the-dangers-of-molnupiravir-part-2/?sh=48f1a82e1490
  12. Food and Drug Administration. Fact Sheet For Healthcare Providers: Emergency Use Authorization for Molnupiravir. December 23, 2021. Accessed December 27, 2021. https://www.fda.gov/media/155054/download
  13. Mishra M. U.S government to buy $1 billion more worth of Merck’s COVID-19 pill. Reuters. November 9, 2021. Accessed December 30, 2021. https://www.reuters.com/world/us/us-government-buy-14-mln-more-courses-mercks-covid-19-pill-2021-11-09/
  14. Pfizer’s Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Deaht by 89% in Interim Analysis of Phase 2/3 EPIC-HR Study. Pfizer. November 5, 2021. Accessed November 5, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate
  15. Food and Drug Administration. Fact Sheet For Healthcare Providers: Emergency Use Authorization for Paxlovid. December 22, 2021. Accessed December 27, 2021. https://www.fda.gov/media/155050/download
  16. Robbins R. Pfizer Says Its Antiviral Pill Is Highly Effective in Treating Covid. New York Times. November 5, 2021. Accessed November 5, 2021. https://www.nytimes.com/2021/11/05/health/pfizer-covid-pill.html?auth=login-email&login=email
  17. Pfizer Receives U.S. FDA Emergency Use Authorization for Novel COVID-19 Oral Antiviral Treatment. Pfizer. December 22, 2021. Accessed December 30,2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-receives-us-fda-emergency-use-authorization-novel
  18. Manas M. U.S. to buy 10 mln courses of Pfizer’s COVID-19 pill for $5.3 bln. Reuters. November 18, 2021. Accessed January 3, 2022. https://www.reuters.com/business/healthcare-pharmaceuticals/us-govt-buy-10-mln-courses-pfizers-covid-19-pill-529-bln-2021-11-18/ 
  19. Maddipatla M, Hunnicutt T. Pfizer to supply U.S. with 10mln more courses of COVID-19 pills. Reuters. January 4, 2022. Accessed January 11, 2022. https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-supply-10-mln-additional-courses-covid-19-pill-us-govt-2022-01-04/ 
  20. Department of Health & Human Services. Molnupiravir (MK-4482). Public Health Emergency. December 23, 2021. Accessed January 3, 2022 https://www.phe.gov/emergency/events/COVID19/investigation-MCM/molnupiravir/Pages/default.aspx
  21. Department of Health & Human Services. Paxlovid (nirmatrelvir/PF-07321332 and ritonavir). Public Health Emergency. December 22, 2021. Accessed January 3, 2022. https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Paxlovid/Pages/default.aspx

Updated 1/28/22

 

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