Pfizer's COVID-19 Pill Paxlovid Explained

Back in February of 2020, just weeks before the World Health Organization would declare that the then-novel coronavirus had become a pandemic, Dr. Anthony Fauci told the Washington Post that once a pandemic begins spreading from person to person in multiple countries, it's no longer possible to contain it. Rather, "you can only mitigate it," as he noted. At that time, the U.S. was still in what Dr. Fauci referred to as the "containment phase."

More than two years later, COVID-19 has been diagnosed more than 500 million times, with more than six million deaths recorded (per WHO) – and despite the launch of several vaccines, it turns out the virus is still a moving target. Now well past containment, we are deep into mitigation, with our current efforts focused on preventing severe illness and death to the extent possible. That goes a long way toward explaining the government's Test to Treat initiative, launched in March 2022 (via the U.S. Health and Human Services' Office of Assistant Secretary For Preparedness And Response (ASPR)). 

Test to Treat is aimed at getting those most at risk for serious illness immediate access to life-saving treatment upon testing positive, including two oral therapies whose development was funded in part by the Biden-Harris Administration, per an ASPR fact sheet. Paxlovid, developed by Pfizer, is one such therapy. Join us as we explain all that you need to know about Pfizer's pill to treat COVID-19.

In order to issue an EUA for a particular drug, the FDA must determine, among other things, that "based on the total amount of scientific evidence available including data from adequate and well-controlled clinical trials," it is "reasonable to believe" that the drug is effective at doing what it is claimed that it can do and that the "known and potential benefits ... outweigh the known and potential risks (via HHS/ASPR). Accordingly, before granting an EUA with regard to Paxlovid, the FDA had to determine that Paxlovid is effective and safe enough to justify its use — at least until a better drug comes along, or if currently unknown safety issues tip the balance. 

In the case of Paxlovid, the FDA has stated that the "primary data supporting" the EUA are from a "randomized, double-blind, placebo-controlled clinical trial studying Paxlovid for the treatment of non-hospitalized symptomatic adults with a laboratory confirmed diagnosis of [COVID-19]," per FDA. The study involved more than 2,000 adults diagnosed with COVID-19 who were at a known risk for progression to severe disease. Half were given Paxlovid; the other half, a placebo. The Paxlovid group had a less-than-1% rate of hospitalization and no deaths, compared with 6% in the placebo group — which translates to Paxlovid being 89% effective at reducing hospitalizations/deaths from COVID-19. Additionally, one of Paxlovid's known benefits is that it can be administered outside a hospital setting and therefore at a lower cost, according to Nature.

"All viruses, including SARS-CoV-2, the virus that causes COVID-19, have the same goal: invade our cells, use our cells' internal machinery to make copies of itself, and then release the newly made virus to infect more of our cells," according to Pfizer. Protease inhibitors are drugs that have been developed to interrupt this process by blocking certain enzymes that are required for this process to take place. 

Nirmatrelvir is a protease inhibitor that specifically targets the viral protease M^PRO, which "plays an essential role in viral replication" in all coronaviruses that are known to be capable of infecting humans, according the National Institutes of Health (NIH). At the same time, it has a "low likelihood of off-target activity," which means that it does not tend to attack anything but the viral protease that it was designed to target (unlike, say, chemotherapy), per this 2022 study published in the New England Journal of Medicine.

In Paxlovid, nirmatrelvir is taken in combination with the drug ritonavir, because ritonavir increases blood concentrations of nirmatrelvir to what the NIH refers to as "target therapeutic range" (per NIH). Accordingly, any side effects associated with nirmatrelvir that the FDA considered in granting its Emergency Use Authorization are those associated with nirmatrelvir taken in combination with ritonavir, as opposed to nirmatrelvir alone.

Just as the rapid development of vaccines against COVID-19 was made possible by the body of vaccine research that already existed prior to the identification of the novel coronavirus that causes COVID-19, Paxlovid stands on the shoulders of a significant body of existing scientific research relating to both of its active ingredients. 

First, starting in 2003, and in response to the outbreak of SARS — another illness caused by a coronavirus — Pfizer researchers had been trying to come up with a protease inhibitor that would be capable of stopping coronaviruses (in general) in their tracks by interrupting the process of viral replication (per NPR). Although Pfizer moved on to different challenges after the SARS outbreak was beaten back, the research already in progress took scientists a long way toward coming up with a protease inhibitor that could stop the novel coronavirus that causes COVID-19 from replicating in the human body.

The decision to combine an effective protease inhibitor with a drug that is capable of keeping that protease inhibitor active in the body for as long as safely possible comes out of medical therapies that have been proven safe and successful since the late 1990s, per NPR and WebMD. Ritonavir was a logical choice for this because it has been in use since the 1990s. Once researchers began testing ritonavir-boosted nirmatrelvir, they quickly observed a "90% reduction in hospitalization" and "100% protection against death" (per NPR). 

"Paxlovid is usually very well-tolerated," according to Dr. Scott Roberts (via Yale Medicine). Common side effects include an impaired sense of taste, diarrhea, increased blood pressure, and muscle aches, but these are usually mild. The most commonly seen adverse events that were observed in the clinical study that found Paxlovid to be nearly 90% effective at preventing hospitalizations and deaths from COVID-19 were the first two mentioned above, according to the NIH. However, what may be most relevant here is that Paxlovid appears to have been better tolerated than the placebo given to the control group in the study, with fewer experimental subjects having discontinued the study than members of the control group. 

All of that being said, Paxlovid should never be prescribed for or taken by people with "uncontrolled or undiagnosed HIV-1 infection," because Paxlovid could lead to HIV-1 drug resistance, according to the FDA and the NIH. Nor should it be prescribed for or taken by anyone with a pre-existing liver disease or condition, including abnormal liver enzyme readings (which could indicate liver inflammation and other issues), because the ritonavir in the regimen directly impacts liver function. Additionally, Paxlovid should not be taken by anyone with severe kidney issues. In people with moderate kidney impairment, Paxlovid may be used, albeit at a reduced dose. 

Pregnant women are considered to have an increased risk for developing severe COVID-19, and are therefore encouraged to get vaccinated, per the CDC. Nevertheless, at this point in time, Paxlovid is not approved or emergency-authorized for use in pregnant women or lactating women, according to the CDC. The reason is that Paxlovid is so new that its use in pregnant and lactating women has not yet undergone complete clinical study regarding its safety and efficacy (per Precision Vaccinations). 

However, the NIH stated that the ritonavir component of Paxlovid has been used "extensively during pregnancy in people with HIV," suggesting that Paxlovid would present an "acceptable safety profile" for use during pregnancy. The agency also noted that "based on the mechanisms of action for both nirmatrelvir and ritonavir and the available animal data," they would not prohibit a pregnant patient from receiving treatment in the form of ritonavir-boosted nirmatrelvir "if the potential benefits outweighed the potential risks." Thus, depending on the status of any current research, it is possible (if not likely) that Paxlovid will become available for emergency-authorized use in pregnant women in the near future. 

In March 2022, the Biden-Harris Administration launched a new program in the fight against COVID-19 called Test to Treat (per the HHS). Under this program, an individual should be able to get tested, receive results, receive a prescription, and have it filled, all from a single location — "One-Stop Test to Treat" sites — of which there are to be hundreds nationwide, including at pharmacies and within health clinics and long-term care facilities.

Of course, seeking testing and treatment from one's own healthcare provider will remain an option, as always. In connection with this program, the Administration has been investing in developing COVID-19 treatments that can be taken in pill form. One of the treatments that has come out of that is Paxlovid.

Express Scripts Pharmacy (ESP) says that Paxlovid will be in short supply initially, with only 65,000 treatment courses having been made available to distribute when the Emergency Use Authorization was issued. However, Pfizer has committed to "supplying 10 million treatment courses by the end of June and a total of 20 million treatment courses in 2022." If you're eligible for Paxlovid and find that it isn't available, there is another emergency use-authorized COVID-19 pill. Made by Merck, it's called molnupiravir. In addition, there is also the option of taking remdesivir, the monoclonal antibody treatment that is available by IV only. 

Something we have learned over the last two-plus years is that approximately 30% of all COVID-19 cases may lead to the long-term post-viral syndrome known as "long COVID," according to a 2022 study published in the Journal of General Internal Medicine and WebMD. Healthline describes the most common symptoms of long COVID as "fatigue, cognitive dysfunction, and malaise." Symptoms of long COVID may persist for six months or even longer following initial recovery from an initial bout of COVID-19. 

A recent study published in the journal Cell suggested multiple potential factors that may contribute to one's developing long COVID. Since none of these factors (the presence of certain autoantibodies, a high viral load, Type 2 diabetes, and a previous infection with Epstein-Barr virus) are within our immediate control, it may be comforting to know that Paxlovid has shown promise as a therapy for treating long COVID. Granted, that promise is nothing more than a case study of a patient whose long COVID symptoms retreated after taking Paxlovid, per Reuters. That said, some of our most groundbreaking drugs ultimately arose out of an observation made with regard to a single patient, according to University of California, San Francisco medical professor Steven Deeks (via Reuters).