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Paxlovid Fails to Shorten COVID in Standard-Risk and Vaccinated At-Risk Patients

— Drug still likely to benefit higher-risk patients, experts pointed out

MedpageToday
 A photo of a Paxlovid blister pack laying on an N95 mask

Nirmatrelvir/ritonavir (Paxlovid) failed to shorten COVID-19 symptom duration among people at standard risk for severe COVID-19 and among vaccinated people with at least one risk factor for severe disease, according to final results of the phase II/III trial.

In vaccinated and unvaccinated patients with COVID-19 at standard risk for severe disease and in fully vaccinated people with at least one risk factor who took nirmatrelvir/ritonavir, the median time to alleviation of COVID-19 symptoms was 12 days, compared with 13 days in patients who took a placebo (P=0.60), reported Jennifer Hammond, PhD, development head of antivirals at Pfizer in Collegeville, Pennsylvania, and colleagues in the .

"The usefulness of nirmatrelvir-ritonavir in patients who are not at high risk for severe COVID-19 has not been established," the authors wrote.

There was a trend toward fewer hospitalizations and death among participants who took nirmatrelvir/ritonavir, where five (0.8%) of these participants were hospitalized for COVID-19 or died from any cause, compared with 10 (1.6%) of those in the placebo group through day 28 (95% CI −2.0 to 0.4). However, the difference did not reach statistical significance.

In a subgroup analysis of at-risk participants only, three (0.9%) of the participants receiving nirmatrelvir/ritonavir were hospitalized or died versus seven (2.2%) in the placebo group (95% CI -3.3 to 0.7).

In 2022, the drug's manufacturer Pfizer announced an updated interim analysis of the EPIC-SR that reached similar conclusions to these final results. Because of low rates of hospitalization in the study population, Pfizer ended enrollment in EPIC-SR at that time.

In contrast to EPIC-SR, the EPIC-HR trial that enrolled high-risk unvaccinated participants found that nirmatrelvir/ritonavir reduced hospitalization or death by 88%.

"What can we conclude from these two trials about nirmatrelvir-ritonavir for the treatment of COVID-19?" wrote Rajesh Gandhi, MD, and Martin Hirsch, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, in an .

"Clearly, the benefit observed among unvaccinated high-risk persons does not extend to those at lower risk for severe COVID-19," they noted. The EPIC-SR results add support to that nirmatrelvir/ritonavir is only indicated for in persons at high risk for disease progression, they said.

However, Gandhi and Hirsch also pointed out that although the EPIC-SR trial failed to show that nirmatrelvir/ritonavir shortened COVID-19 symptoms in vaccinated participants with at least one risk factor, the study enrolled only a small percentage of patients who were most likely to be hospitalized with COVID-19.

"Other than obesity, smoking, and hypertension, risk factors for severe COVID-19 were uncommon; for example, less than 2% of the participants had heart or lung disease," they wrote. Of note, only 5% of EPIC-SR enrollees were 65 years or older.

"As with many medical interventions, there is likely to be a gradient of benefit for nirmatrelvir–ritonavir, with the patients at highest risk for progression most likely to derive the greatest benefit," Gandhi and Hirsch commented.

About 26% of participants who received nirmatrelvir/ritonavir experienced an adverse event, similar to the 24.1% in the placebo group. The most commonly reported treatment-related adverse events among those who took nirmatrelvir/ritonavir were dysgeusia (5.8%) and diarrhea (2.1%). In participants receiving nirmatrelvir/ritonavir, 3.7% reported grade 3 or 4 adverse events versus 3.9% in the placebo group. No grade 5 adverse events occurred in the treatment group.

Of note, symptom rebound at day 14 occurred in 11.4% of participants treated with nirmatrelvir/ritonavir versus 16.1% in the placebo group. Viral load rebound at day 14 was similar between the 2 groups (4.3% in the nirmatrelvir/ritonavir group vs 4.1% in the placebo group).

The EPIC-SR trial included 1,296 participants who had confirmed COVID-19 and symptom onset within the previous 5 days. Participants were randomized 1:1 to receive either nirmatrelvir/ritonavir (n=654) or placebo (n=634). Participants recorded COVID-19 symptoms on a daily basis from day 1 through day 28.

The primary end point of the study was time to sustained alleviation of all targeted COVID-19 signs and symptoms. COVID-19-related hospitalization and death from any cause were also assessed through day 28. A total of 1,250 participants completed efficacy and safety follow-up assessments.

Of participants, 54% were women and the median age was 42 years. The majority of participants were white (78.5%) and 41.4% were Hispanic or Latino. Approximately 57% had been vaccinated for COVID-19, and about 50% had at least one risk factor for severe COVID-19. The most common comorbidity was hypertension (12.3%) and the most common risk factor was cigarette smoking (13.3%).

Most participants (72.5%) underwent randomization within 3 days after symptom onset. Adherence to nirmatrelvir/ritonavir -- defined as having taken at least 80% of the pills -- was nearly 95%.

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    Katherine Kahn is a staff writer at 鶹ý, covering the infectious diseases beat. She has been a medical writer for over 15 years.

Disclosures

The study was funded by Pfizer.

Hammond is an employee of Pfizer and reported holding stock options in Pfizer. Co-authors are employees of Pfizer or reported other ties to industry.

Gandhi and Hirsch reported no disclosures.

Primary Source

New England Journal of Medicine

Hammond J, et al "Nirmatrelvir for vaccinated or unvaccinated adult outpatients with COVID-19" New Engl J Med 2024; DOI: 10.1056/NEJMoa2309003.

Secondary Source

New England Journal of Medicine

Gandhi RT, Hirsch M "Treating acute COVID-19 -- final chapters still unwritten" New Engl J Med 2024; DOI: 10.1056/NEJMe2402224.