The federal Food and Drug Administration has granted emergency use authorization of Paxlovid (nirmatrelvir plus ritonavir), the first antiviral pill for the treatment of COVID-19. The December 22 authorization comes just in time, as the coronavirus Omicron variant is spreading rapidly throughout the United States, but supplies will initially be limited.
A day later emergency use was granted for a second drug from Merck.
"This authorization provides a new tool to combat COVID-19 at a crucial time in the pandemic as new variants emerge and [it] promises to make antiviral treatment more accessible to patients who are at high risk for progression to severe COVID-19," Dr. Patrizia Cavazzoni, director of the FDA's Center for Drug Evaluation and Research, stated in a news release, referring to the Pfizer drug.
Paxlovid, from Pfizer, is authorized for people aged 12 and up who test positive for SARS-CoV-2 (the coronavirus that causes COVID-19), have mild to moderate symptoms that started within the past five days, and are at high risk for progression to severe disease. Getting results within the five-day window could be a challenge, as rapid antigen self-tests are in short supply, and PCR test sites and labs are overwhelmed.
The FDA emphasized that Paxlovid should not be considered a substitute for vaccination. Nor is it authorized as pre-exposure prophylaxis for people who are at risk for exposure to SARS-CoV-2, as post-exposure prophylaxis for those who have recently been exposed to someone with the virus, or as treatment for people who already have severe disease.
"Paxlovid will be a true game-changer in every sense of the word," Dr. Monica Gandhi, director of the Center for AIDS Research at UCSF, told the Bay Area Reporter. "There are adults who remain unvaccinated who are at risk of severe COVID, and this five-day oral medication reduces their risk of hospitalization and death by 88% — almost the same protection afforded by the vaccines," Gandhi said. "There are those who are immunocompromised and still at risk of a severe breakthrough infection despite vaccination, and this medication will be essential to prevent them from progressing to severe disease."
Efficacy and safety for Paxlovid
Despite the availability of highly effective vaccines, there is currently no oral treatment for mild or moderate COVID-19. Monoclonal antibodies can prevent disease progression, but they require injection or IV infusion. Other medications, including remdesivir and dexamethasone, are used to treat hospitalized patients with severe disease.
Paxlovid is a SARS-CoV-2 protease inhibitor that interferes with an enzyme needed for viral replication. Like some HIV protease inhibitors, it is administered with a low dose of ritonavir to maintain higher drug levels in the body. It is taken as three tablets (two nirmatrelvir and one ritonavir) twice daily for five days.
The FDA authorization is supported by a clinical trial that enrolled more than 2,000 high-risk adults with COVID-19 in North and South America, Europe, Africa, and Asia. They had mild to moderate symptoms for no more than five days, were either age 60 or older or had at least one underlying condition associated with progression to severe illness, and had not been vaccinated or previously infected with SARS-CoV-2.
Participants who received Paxlovid within three days of developing symptoms had an 89% lower risk of hospitalization or death, and those treated within five days had an 88% lower risk. No Paxlovid recipients died, but nine given placebos did. The risk reduction reached 94% for people age 65 and older, the group with the highest risk for severe COVID-19 outcomes.
What's more, SARS-CoV-2 viral load on the final day of treatment was 10-fold lower in Paxlovid recipients compared with placebo recipients, according to Pfizer. The medication remains active against the Omicron variant, which has many mutations in its spike protein that reduce the effectiveness of vaccines and most monoclonal antibodies.
Paxlovid was generally safe and well tolerated. The most common adverse effects are dysgeusia (changes in taste), diarrhea, hypertension, and muscle aches. However, the ritonavir component can interact with many other medications, and doctors and pharmacists should be aware of the risk. Ritonavir raises levels of several classes of drugs, which can lead to more severe side effects.
According to the Paxlovid prescribing information, people taking HIV protease inhibitors boosted with ritonavir or cobicistat should continue their treatment and be monitored for increased side effects. Because ritonavir is active against HIV but is not sufficient to fully control it, people with unsuppressed or undiagnosed HIV who use Paxlovid run the risk of developing resistance to HIV protease inhibitors, which could limit their future treatment options.
Drug in short supply
Pfizer said it expects to produce 180,00 courses of Paxlovid this year and more than 120 million in 2022. White House press secretary Jen Psaki said at a news briefing that the government has purchased 10 million courses and will be prepared to distribute them around the country as soon as the supply is available.
Tens of thousands of courses of Paxlovid are currently ready for delivery, according to the Washington Post, but this will not be enough to make a dent in the growing number of people expected to become infected during the Omicron surge. At least 300,000 additional courses are expected in January and February.
Pfizer said it will offer worldwide access to Paxlovid through a tiered pricing approach based on the income level of each country. The company has also signed a voluntary license agreement with the Medicines Patent Pool to help expand access in 95 low- and middle-income countries.
The authorizations raise questions about the appropriate use of Paxlovid and other antiviral pills, including whether they should be available for everyone with early COVID-19 or only those at high risk for severe disease and whether they are suitable for vaccinated people with breakthrough infections, who were not included in the first clinical trial.
While issues of supply, availability and access remain to be worked out, experts lauded the authorization as a major advance in the battle against COVID-19.
"This authorization comes at a key moment as the nation and the world face climbing case counts and increased stress on health care systems," Dr. Daniel McQuillen, president of the Infectious Diseases Society of America, said in a statement. "IDSA urges the U.S. Department of Health and Human Services to develop a fair process for distribution of Paxlovid so that the benefits of this treatment can be equitably accessed by all who need it."
2nd drug authorized
Update: On December 23, the FDA granted emergency use authorization to a second antiviral pill, Merck's molnupiravir. Like Paxlovid, it is indicated for people with a positive SARS-CoV-2 test and mild to moderate COVID-19 symptoms that started within the past five days. However, the agency limited its use to adults at high risk for progression to severe COVID-19 who cannot use alternative authorized treatment options, including Paxlovid.
"Today's authorization provides an additional treatment option against the COVID-19 virus in the form of a pill that can be taken orally," Cavazzoni said. "Molnupiravir is limited to situations where other FDA-authorized treatments for COVID-19 are inaccessible or are not clinically appropriate and will be a useful treatment option for some patients with COVID-19 at high risk of hospitalization or death."
Molnupiravir is a nucleoside analogue, in the same broad class as some medications used to treat HIV. But it works differently, causing so many mutations in the SARS-CoV-2 genetic code that the virus can no longer replicate. In a clinical trial of nearly 1,500 participants, molnupiravir reduced the risk of hospitalization or death by 30% — much lower than Paxlovid's nearly 90% reduction. But mortality decreased substantially, with was just one death in the molnupiravir group compared with nine in the placebo group.
Treatment was well tolerated, with the most common adverse events being diarrhea, nausea, and dizziness. Unlike Paxlovid, molnupiravir is not administered with ritonavir, which is contraindicated with many other medications due to drug interactions. Molnupiravir also does not carry the same warnings to use with caution in people with liver or kidney disease. However, molnupiravir can potentially cause fetal harm and it is not recommended during pregnancy. The drug is not authorized for people under 18 because it may affect bone and cartilage growth. Another potential issue is that, by causing many viral mutations, molnupiravir could promote the emergence of new variants.
The major advantage of molnupiravir is initial availability. Merck indicated that hundreds of thousands of courses are ready to ship in the U.S., compared with the 180,000 courses of Paxlovid that Pfizer expects to produce this year. The federal government has agreed to purchase 3.1 million courses of molnupiravir and Merck says millions more are ready for worldwide distribution.
Updated, 12/23/21: This article has been updated to include FDA emergency use authorization for a second COVID pill.
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