The Biden administration and government agencies continue to push Pfizer’s COVID-19 emergency use authorization product, Paxlovid, even with insufficient new trial data showing effectiveness in the current population.
Pfizer’s initial clinical trial for Paxlovid in 2021, which earned it an emergency use authorization (EAU) by the FDA, seemed quite promising. Results showed a relative risk reduction of progression to severe COVID-19 at 89 percent. But after the unapproved Pfizer product hit the market with its EAU in tow, real-world studies came out quite differently.
Two studies between January and March 2022, using real-population-based data, showed many different results. In the first study published in Clinical Infectious Diseases in June 2022, the risk reduction was much smaller than in the initial 2021 trial (89 percent), coming in at 46 percent. Results from the second study, published in The New England Journal of Medicine in September, showed no evidence of avoidance of severe COVID-19 in adults younger than 65.
The EUA and push for use of Paxlovid continue despite falling efficacy rates, and the FDA hasn’t yet ordered Pfizer to produce a new randomized double-blind control clinical trial to confirm its efficacy in the current real-world population.
The Food and Drug Administration (FDA) has instead ordered Pfizer to test the effects of an additional course of its antiviral Paxlovid among people who experience a rebound of COVID-19 after treatment. When splashed across headlines that three high profile government officials, President Joe Biden, White House COVID-19 adviser Dr. Anthony Fauci, and most recently Centers for Disease Control and Prevention (CDC) Director Rochelle Walensky, all reported COVID rebound after taking Pfizer’s Paxlovid, marking a negative turn of events for the Pfizer drug.
But with treatment courses of Paxlovid at $530, and the U.S. government’s announcement on Dec. 13 of a new purchase of 3.7 million courses for around $2 billion in addition to its previous $5 billion purchase of 20 million courses of Paxlovid earlier this year, the drug remains quite profitable for Pfizer.
So what are the facts about Paxlovid we need to know?
What Is Paxlovid?
Paxlovid consists of two active drugs, nirmatrelvir and ritonavir. Nirmatrelvir is designed to inhibit viral replication and ritonavir is a protease inhibitor that was used for the treatment of HIV/AIDS.
Paxlovid is currently not approved by the FDA for any use, including for treatment of COVID-19, and is still being studied. Late in December 2021, the investigational medicine was granted emergency use authorization (EUA) in the U.S. by the FDA as a therapy to treat mild-to-moderate COVID-19 in adults and children 12 and older weighing at least 88 lb.
Currently, the safety and efficacy of Paxlovid in pediatric patients younger than 18 hasn’t been established and no data is available as clinical trials to date included adults 18 and older. Pfizer does mention that the authorized adult dosage is expected to result in a comparable outcome in patients 12 years of age and older weighing at least 88 pounds as observed in adults with similar body weight in the trials.
The data supporting the EUA was based on Paxlovid’s first clinical trial between July 16 and December 9, 2021, showing an 89 percent reduction in severe COVID-19 outcomes. This initial clinical trial was done on a very select group. Participants were symptomatic and COVID-positive, had at least one underlying medical condition with an increased risk of developing severe illness from COVID-19, and had no previous confirmed SARS-CoV-2 infection.
The first study from Israel, done between January and February using real population-based data was based on a more diverse group. 78 percent of participants had previous COVID-19 immunity from a prior SARS-CoV-2 infection, or were vaccinated, and estimated to be at high risk for progression to severe COVID-19. The outcome showed an overall risk reduction of 46 percent. It’s noted in the study that because Paxlovid isn’t recommended for use with several medical conditions and has complex drug-drug interactions, it may limit the drug’s use in high-risk patients.
The second study using real population-based data done between January and March 2022, tested results based on two age groups, 40-64 and 65 years of age or older. Results showed rates of severe COVID-19 outcomes were significantly lower in adults 65 years of age and older who received Paxlovid but there was no evidence of benefit found in adults under 65.
Pfizer’s most recent clinical trial reported in late April determined post-exposure prophylactic use. Eligible participants were again a very specific group; asymptomatic, had a negative screening SARS-CoV-2 antigen test result, exposed to a positive symptomatic individual, had not been infected with SARS-CoV-2 in the past 6 months, and had not received any SARS-CoV-2 vaccine within 6 months. Results were reported as not statistically significant, with the endpoint not met. Pfizer reported observed risk reductions of 32 percent (5-day course) and 37 percent reduction (10-day course).
So why in a matter of months, has Pfizer’s new “miraculous” medication, seemed to lose its staying power? What about new variants you may ask?
“Paxlovid is expected to be active against the Omicron variant and its sub-variants, although there is currently a lack of data on the clinical efficacy of Paxlovid against these variants,” the National Institutes of Health (NIH) states, while Pfizer also says the drug works against Omicron and backs up its claim with three laboratory-based studies.
Setting aside the evolving variants, there is currently no data to tell if Paxlovid is effective on the current population and to what degree it’s working with ever-evolving exposure and immunity. All clinical trials completed to date have had very select criteria. Having more clarity around the current murkiness of this drug sooner than later would be helpful for all, as since mid-April prescriptions for Paxlovid have surged to more than 160,000 per week, according to the CDC.
Side Effects and Contraindications
As with all pharmaceuticals, Paxlovid has potential side effects. Allergic reactions, hypersensitivity reactions, and anaphylaxis have been reported along with liver problems and a list of others. Dysgeusia, a taste disorder causing a sour, bitter, or metallic taste has also been reported. More recently cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported with ritonavir, a component of Paxlovid. Pfizer does warn that Paxlovid is still being studied, not many people have taken it, and it’s possible that all risks aren’t known at this time.
There is currently no human data on the use of Paxlovid during pregnancy and becoming pregnant during treatment is not currently recommended. It’s reported that it also may affect how birth control pills work.
Currently, the FDA lists 35 contraindicated drugs and herbal products, including anti-cancer drugs and St. John’s Wort that may cause serious or life-threatening side effects when taken with Paxlovid, as well as 94 additional drugs that should be avoided.
The NIH recommends, before prescribing Paxlovid, healthcare providers should counsel patients on all available COVID-19 treatment options and carefully review the patient’s medications, including over-the-counter medications, herbal supplements, and recreational drugs, to evaluate potential drug-drug interactions.
In the spring, doctors began reporting Paxlovid rebound. According to a CDC advisory, people who take Paxlovid for COVID-19 could experience a resurgence of the infection between two and eight days after initial recovery and have a recurrence in symptoms and again test positive for the virus.-
The CDC recommends patients experiencing Paxlovid rebound re-isolate for at least five days. There is currently limited information around the Paxlovid rebound although case reports show that most COVID-19 rebound occurrences are mild and there are currently no reports of severe disease.
A big part of the confusion around Paxlovid is the amount of contradictory messaging coming from Pfizer and government agencies.
On Pfizer’s Paxlovid website, there is “take it at your own risk”-type messaging embedded in their verbiage. For example, they state “there is limited information about the safety and effectiveness of using Paxlovid to treat people with mild-to-moderate COVID-19.” And yet White House officials are pushing it, criticizing doctors for being too hesitant to prescribe the drug, and most recently purchasing more courses of the drug.
The CDC states “there is limited real-world evidence on the benefit of Paxlovid according to vaccination status, age group, and underlying health conditions” but, in the same breath, states that Paxlovid should be prescribed to eligible adults to reduce the risk of COVID-19-associated hospitalization. They support this by pointing to a study using a large electronic health record data set using a Cox proportional hazards model to estimate a 51 percent reduced hospitalization rate. There is still no new randomized double-blind control clinical trial or real-world data to confirm this outcome.