In December 2021, Pfizer announced the significantly positive study results of its COVID-19 antiviral Paxlovid. The study enrolled unvaccinated people at high-risk for serious illness, and it was hailed by infectious disease specialists and President Biden’s administration as a tool for accelerating the end of the pandemic.
“I think it is the beginning of a ‘game-changer,’” said Yale Medicine infectious disease specialist Scott Roberts, M.D. “It’s really our first efficacious oral antiviral pill for this virus. It shows clear benefit, and it really can prevent hospitalization and death in people who are at high risk.”
But there is currently public confusion about who should get a prescription for Paxlovid if they test positive for COVID-19.
To help our colleagues with coverage, we gathered a few resources and experts to call [see Q&A at bottom of this post] and spoke with Professor Jason Gallagher, Pharm.D., F.C.C.P., F.I.D.P., F.I.D.S.A., B.C.P.S., a pharmacist who specializes in infectious diseases and the director of Temple University’s post-graduate infectious disease pharmacy training program.
We wanted to begin by clarifying what Pfizer is studying and what experts understand about the results so far.
Pfizer said its July 2021 EPIC-HR (which stands for ‘Evaluation of Protease Inhibition for COVID-19 in High Risk patients) study of more than 2,000 patients found 0.8% who received Paxlovid were hospitalized or died during 28 days of follow-up compared to 6% of the patients who received placebo. This impressive result persuaded the Food and Drug Administration (FDA) in December to grant a temporary clearance, known as an emergency use authorization for Paxlovid in people at high risk for progression to severe COVID-19.
In August 2021, Pfizer began a second big trial of Paxlovid, called EPIC-SR (for ‘standard risk’ patients), according to ClinicalTrials.Gov. The original intent of this study was to look at people who were fully vaccinated and had at least one risk factor and people with no characteristics associated with risk of severe COVID-19 who were unvaccinated.
Following the December EUA approval for Paxlovid, Pfizer made changes in the EPIC-SR study and excluded people at high risk of COVID complications. It also was amended to allow enrollment of patients without risk factors for progression to severe COVID-19, whose last COVID-19 vaccination occurred more than 12 months earlier.
In mid -June, Pfizer reported disappointing results from the EPIC-SR study. The company said the primary goal of the study, which was a sustained alleviation of all symptoms for four consecutive days, was not met. Pfizer also said other secondary data points in the study failed to meet the threshold for statistical significance, although trends appeared positive.
So it’s not as clear how much benefit Paxlovid will provide to those considered to be at standard risk (meaning no underlying conditions and under the age of 65), especially if they followed federal recommendations last year about getting booster shots and are up to date on vaccinations against COVID-19. Major studies of Paxlovid, to date, have not sought to enroll people who have kept up to date on these shots.
Pfizer told AHCJ that analyses of the EPIC-SR data are ongoing, and final results will be made available via publication or presentation. Complete results from the trial are expected in the second half of 2022, a company spokesperson said. Pfizer still intends to file a new drug application (NDA) with the FDA for use of Paxlovid in what the company describes as “appropriate individuals at high risk of progression to severe illness.”
And Paxlovid has become more widely available this year [though availability is scarce in high vulnerability zip codes, according to the CDC], stories have emerged on social media about people experiencing a rebound in COVID-19 symptoms in the days after they took Paxlovid. See this excellent June 8 JAMA article which lays out the questions about a rebound in symptoms post the five-day course of Paxlovid.
With about 100,000 people a day testing positive for COVID-19, what does this latest news on a COVID-19 treatment mean for most Americans? How should reporters be covering Paxlovid? What new COVID-19 treatments are on the horizon if you aren’t at serious risk of illness? Professor Gallagher shares his thoughts on this topic in the Q&A below. This conversation was edited for clarity and brevity.
When Pfizer said that it decided to “cease enrollment” in its Paxlovid trial because of low hospitalization and death in people with standard risks of illness, what does this mean? Does that mean Paxlovid doesn’t have benefits if you have no risk factors for serious illness?
They [Pfizer] gave us, on the surface, something that is pretty significant, but I don’t know how to interpret the significance … because they didn’t release the data. We need more than their press release. These are the study [results] that we have all been waiting for…and it’s a non-significant difference in the non-high-risk population, which is more of who we treat. It could be that there is a risk-benefit in those who were vaccinated, but I want to see more of the data and not just the press release. I want to see under the hood. It would help guide what we do.
Is it fair to say that Paxlovid doesn’t seem to make much of a difference if you are vaccinated unless you are 65 and older or have one of the more than two dozen chronic health conditions that put you at high risk for hospitalization or death? [See the CDC list here that specifies COVID-19 severe illness risk factors]
Recommendations that have been made [to clinicians] are based on the ongoing EPIC-HR study, which was a home run. It [showed] a major benefit in those high-risk patients. We have been applying [those results] to different patient populations. It is okay for clinicians to make a decision on an individual basis, based on the patient in front of them but I so badly want to see the data instead of [the current state] of less informed decision making [on Paxlovid.]
Since age is considered a risk factor, should a 77-year-old woman in good health, without any underlying health conditions, and vaccinated and boosted for COVID-19 take Paxlovid if she tests positive?
Until the data exists that tells us not to give it to her, then my answer is yes. It wouldn’t surprise me [however if we learn] that for vaccinated people that this doesn’t benefit them.
What about these stories of Paxlovid rebound? I have seen some unscientific reports on Twitter that estimate as many as 40% of people experience a rebound in symptoms, but this Mayo Clinic study says less than 1% experience a rebound. How worried should people be about it, and does the rebound mean that some people need a longer course of Paxlovid?
I think people are looking at Paxlovid like it is an antibiotic. Like, “I will take it, and I will get better and feel great.” This [drug] isn’t penicillin for pneumonia, it’s an antiviral, and we don’t know enough about the pathogenicity of the virus to know exactly what the best duration is [in terms of how long to take it.]
What are a few other treatment options for non-hospitalized patients with COVID-19?
In pill form, there is molnupiravir [made by Merck]. That hasn’t been shown to be as effective as Paxlovid. There is the antiviral Remdesivir, [made by Gilead Sciences], but that must be given as an infusion and the need for three doses is challenging. There are monoclonal antibodies [bebtelovimab made by Eli Lilly, and Evusheld, made by AstraZeneca, for pre-exposure prevention of COVID-19 in those who are immune-compromised but is not authorized for treatment].
Is there anything else in terms of outpatient treatments in the pipeline? Any new treatments that might be used for those with a standard risk of illness?
Nothing in the near term that excites me. It is getting harder to generate data because more people are vaccinated and that means showing the effect is going to be harder. For high-risk unvaccinated patients, there is no way that placebo should be used [because it wouldn’t be ethical]. [See this June 13 story in Nature which lays the growing challenges with clinical trials to test COVID-19 treatments]
Where do you think we are with the progress of treatments at this point in the pandemic?
It is easy to get caught up in the nuances and negatives. I do think we are in a pretty good spot right now. We would have done a lot two years ago for any of these therapies. I think the most concerning thing right now is that because the virus keeps changing, it will impact [the effectiveness of] monoclonal antibodies [as a treatment.]
Resources on treatments in the pipeline
- The New York Times COVID-19 drug treatment tracker
- Recovery trial: an ongoing therapeutics trial led by the University of Oxford
- Biotechnology Industry Organization COVID-19 therapeutics pipeline tracker
- FDA’s Coronavirus treatment acceleration program dashboard
- National Institute of Health’s accelerating COVID-19 therapeutics prioritized for testing
Federal resources on Paxlovid
- FDA Updates on Paxlovid for Health Care Providers
- FDA Fact Sheet for Healthcare Providers
- ClinicalTrials.gov webpage for: EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19
- Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR)
- Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment — California, December 2021–May 2022 MMWR Early Release (CDC)
- This report draws from the experiences of patients in the Kaiser Permanente system. Researchers affiliated with the giant health system wrote that “symptoms experienced by patients with COVID-19 rebound after treatment with Paxlovid are milder than those experienced during the primary infection (3–5) and are unlikely to lead to hospitalization.”
Media-friendly experts to contact (Source: Infectious Diseases Society of America)
- George Diaz, M.D., F.I.D.S.A., clinical specialist, infectious diseases, Providence Regional Medical Center, clinical assistant professor, Washington State University College of Medicine. Contact: (425) 297-5234
- Jason Gallagher, PharmD, F.C.C.P., F.I.D.P., F.I.D.S.A., B.C.P.S., clinical specialist, infectious diseases, Temple University Hospital, clinical professor, Temple University School of Pharmacy. Contact: firstname.lastname@example.org
- Benjamin A. Miko, M.D., assistant professor, infectious diseases, Columbia University Medical Center. Contact: (212) 305-8039
- Kimberly Scarsi, PharmD, M.S., F.C.C.P., B.C.P.S., professor, College of Pharmacy, University of Nebraska Medical Center Ambulatory Clinical Pharmacist, University of Nebraska Medical Center. Contact: email@example.com
- Amy Hirsch Shumaker, Pharm.D., B.C.P.S., clinical specialist, infectious disease, VA Northeast Ohio Healthcare System senior clinical instructor, Case Western Reserve University, School of Medicine. Contact: 216-791-3800
- Melanie Thompson, M.D., founder and principal investigator, AIDS Research Consortium of Atlanta, past chair, HIV Medicine Association. Contact: (404) 874-3102