Paxlovid Postexposure Prophylaxis Not Found to Significantly Lower Risk of Symptomatic SARS-CoV-2
Paxlovid was the first oral drug approved by the FDA to treat Covid-19 in adults who do not require supplemental oxygen and who have an increased risk of progression to severe disease.
Image credit: JeromeCronenberger | stock.adobe.com
Findings from a Phase II/III study show postexposure prophylaxis with Paxlovid (nirmatrelvir–ritonavir; Pfizer) for five or 10 days failed to significantly lower the risk of symptomatic SARS-CoV-2 infection.1,2 Paxlovid was the first oral antiviral treatment for Covid-19 in adults to be approved by the FDA.3
“Implementation of postexposure prophylactic treatment for household contacts of persons with SARS-CoV-2 infection, as recommended for other infectious diseases, may help prevent transmission and decrease the burden of Covid-19,” the study authors wrote. “Such treatments should be effective, have an acceptable safety profile, and be easily accessible. To date, clinical trials of Covid-19 treatments, including a phase 3 trial of molnupiravir, have not shown a significant benefit of postexposure prophylaxis.”1
Paxlovid is comprised of the oral antiviral drugs nirmatrelvir and ritonavir, which must be taken together. The therapy is indicated to treat Covid-19 in adults who do not require supplemental oxygen and who have an increased risk of progression to severe disease. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease, whereas ritonavir is a pharmacokinetic enhancer with no activity against SARS-CoV-2 Mpro.
The randomized, double-blind, double-dummy, placebo-controlled trial (NCT05047601) analyzed the safety and efficacy of Paxlovid in asymptomatic, rapid antigen test–negative adults exposed to a household contact with Covid-19 within 96 hours prior to randomization. A total of 2736 participants, at least 18 years of age, were randomly assigned in a 1:1:1 ratio to receive Paxlovid (300 mg of nirmatrelvir and 100 mg of ritonavir) every 12 hours for five or for 10 days, or matching placebo for five or 10 days.
The trial’s primary endpoint was development of symptomatic SARS-CoV-2 infection confirmed via RT-PCR or rapid antigen testing, through 14 days in participants with a negative RT-PCR test at baseline. The trial’s key secondary endpoint was development of symptomatic, confirmed SARS-CoV-2 infection in patients with a high risk of progression to severe Covid-19.
A total of 921 individuals were randomly assigned to the five-day Paxlovid cohort, 917 were randomly assigned to the 10-day Paxlovid cohort, and 898 were randomly assigned to the placebo cohort. Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of patients in the five-day cohort, 2.4% of patients in the 10-day cohort, and 3.9% of patients in the placebo cohort.
“The incidence of symptomatic, confirmed SARS-CoV-2 infection by day 14 (primary end point) did not differ significantly between each nirmatrelvir–ritonavir group and the placebo group,” the study authors wrote.1
Risk reductions relative to placebo were 29.8% (95% confidence interval [CI], –16.7 to 57.8; P=0.17) in the five-day cohort group and 35.5% (95% CI, –11.5 to 62.7; P=0.12) in the 10-day cohort.
“Among the participants at high risk for progression to severe Covid-19, the incidence of symptomatic, RT-PCR– or rapid antigen test–confirmed SARS-CoV-2 infection by day 14 did not differ significantly between the 5-day or 10-day nirmatrelvir–ritonavir group (2.9% and 2.6%, respectively) and the placebo group (3.5%),” the study authors wrote.1
In terms of safety, incidence of adverse events (AEs) was similar across all three cohorts. The most commonly reported AE was dysgeusia, at rates of 5.9% and 6.8% of patients in the five- and 10-day cohorts, respectively, and in 0.7% in the placebo cohort.
“In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir–ritonavir did not result in a significant reduction in the risk of development of symptomatic SARS-CoV-2 infection among participants who were household contacts of persons with Covid-19 and initially had a negative RT-PCR or rapid antigen test,” the study authors concluded. “An important consideration when interpreting the results of the current trial is that it was conducted primarily during the period when omicron was the predominant circulating SARS-CoV-2 variant. Because of the continual mutation of the spike protein of SARS-CoV-2, the efficacy of monoclonal antibody products in treating or preventing Covid-19 may be negatively affected as new variants emerge.”1
References
1. Hammond J. et al. Oral Nirmatrelvir–Ritonavir as Postexposure Prophylaxis for Covid-19.
N Engl J Med 2024;391:224-234. DOI: 10.1056/NEJMoa2309002. Vol. 391 No. 3.
2. A Study of a Potential Oral Treatment to Prevent COVID-19 in Adults Who Are Exposed to Household Member(s) With a Confirmed Symptomatic COVID-19 Infection. ClinicalTrials.gov. May 6, 2024. Accessed July 19, 2023 https://clinicaltrials.gov/study/NCT05047601
3. FDA approves first oral antiviral for treatment of COVID-19 in adults. News release. US Food and Drug Administration. May 25, 2023. Accessed July 19, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-antiviral-treatment-covid-19-adults?utm_medium=email&utm_source=govdelivery
Merck Launches Phase III Trials of Once-Monthly Oral HIV PrEP Candidate MK-8527
July 14th 2025In the new EXPrESSIVE clinical trial program, Merck will evaluate MK-8527, a once-monthly, oral PrEP therapy, in populations at high risk of HIV-1 infection, including adolescent girls and women in sub-Saharan Africa.
Unifying Industry to Better Understand GCP Guidance
May 7th 2025In this episode of the Applied Clinical Trials Podcast, David Nickerson, head of clinical quality management at EMD Serono; and Arlene Lee, director of product management, data quality & risk management solutions at Medidata, discuss the newest ICH E6(R3) GCP guidelines as well as how TransCelerate and ACRO have partnered to help stakeholders better acclimate to these guidelines.
Baxdrostat Shows Significant Blood Pressure Reduction in Phase III BaxHTN Trial
July 14th 2025In the BaxHTN Phase III study, AstraZeneca’s baxdrostat demonstrated statistically significant and clinically meaningful reductions in systolic blood pressure in patients with uncontrolled or treatment-resistant hypertension.
New FDA Initiative Reveals Common Reasons for Drug Application Rejection
July 11th 2025By publishing more than 200 complete response letters, the FDA is offering new visibility into the issues that most often delay drug approvals, including safety concerns, trial design flaws, and manufacturing gaps.
Arcus’ Quemliclustat Earns Orphan Drug Designation as Phase III Pancreatic Cancer Trial Advances
July 11th 2025The FDA has granted orphan status to Arcus Biosciences’ CD73 inhibitor quemliclustat for metastatic pancreatic cancer, as the global PRISM-1 Phase III trial nears full enrollment following promising survival data from ARC-8.
