New Potential Treatment Shows Reductions in Symptomatic COVID-19

A new potential treatment emerged to prevent COVID-19 transmission within households, offering a potential breakthrough for a pharmaceutical category that has previously seen high-profile clinical setbacks. The SCORPIO-PEP (NCT05897541) trial results, published in the New England Journal of Medicine, reveal that ensitrelvir, an oral 3C-like protease inhibitor already approved for treatment in Japan, significantly reduces the risk of developing symptomatic COVID-19 when administered as postexposure prophylaxis to household contacts.¹

This success stands in contrast to previous attempts at prophylactic intervention using other established antivirals. For instance, a phase 2/3 trial evaluating nirmatrelvir–ritonavir did not find a statistically significant reduction in symptomatic infection risk when used as prophylaxis, despite that drug’s proven effectiveness as a treatment for patients already at high risk for severe disease. Although the nirmatrelvir–ritonavir trial showed numerical risk reductions of approximately 30% to 35%, those results failed to reach the threshold of statistical significance required to meet the primary end point.²

The Results of the SCORPIO-PEP Trial

In the ensitrelvir study, which involved more than 2000 household contacts across diverse geographic regions including the United States and Japan, the incidence of laboratory-confirmed COVID-19 by day 10 was just 2.9% in the ensitrelvir group compared with 9.0% in the placebo group. This represents a 67% relative risk reduction in the primary efficacy population, a finding that remained consistent even among older adults and individuals with risk factors for severe illness.¹

The trial's design emphasized the importance of promptness, requiring household contacts to begin their 5-day regimen within 72 hours of symptom onset in the original index patient. For pharmacists, this highlights a critical window for intervention that mirrors the 5-to-7-day requirement for starting current COVID-19 treatments to ensure efficacy.^1,3

“The benefits of ensitrelvir prophylaxis generally appeared to be consistent across most subgroups, including older adults and persons who had risk factors for severe disease,” the study authors wrote.¹ “The incidence of COVID-19 among household contacts who received placebo appeared to be lower in the United States than in Japan.”

Safety data from the SCORPIO-PEP trial indicated that the incidence of adverse events was similar between the ensitrelvir and placebo groups. The most common included headache, diarrhea, and nasopharyngitis, notably avoiding the frequent reports of dysgeusia, or metallic taste, that often complicate adherence to nirmatrelvir–ritonavir. One unique laboratory finding for ensitrelvir was a reversible decline in high-density lipoprotein cholesterol levels during the 5-day treatment period, though concentrations typically returned to baseline levels by day 15 and were not associated with any clinical events. This dose-related, temporary effect on lipid profiles is a specific point of interest for pharmacists monitoring long-term patient health.^1-3

“No new safety signals were identified with regard to the incidence of patient-reported adverse events as compared with the incidence reported with placebo,” the study authors wrote.¹ “Alterations in plasma HDL levels were reversible and not associated with clinical events.”

The Role of the Pharmacist

From a clinical management perspective, pharmacists must evaluate ensitrelvir’s mechanism of action and its associated safety profile. The drug targets the SARS-CoV-2 3C-like protease to halt viral replication, and the dosing schedule consists of a 375 mg loading dose on the first day followed by 125 mg daily for the subsequent 4 days.¹

However, its use warrants careful consideration of potential drug-drug interactions, as ensitrelvir is a moderately strong cytochrome P450 3A inhibitor. This pharmacological profile requires the same level of vigilance that pharmacists currently apply to nirmatrelvir–ritonavir, which is well-known for its extensive interaction list and the frequent need for medication reconciliation.

The potential introduction of an effective postexposure prophylactic comes at a time when the CDC and the FDA have authorized several antivirals for treatment but lack a cleared oral option for prevention. Although vaccines remain the primary defense against severe outcomes, they are not a total replacement for antiviral interventions, particularly for immunocompromised patients who may not mount a full immune response to vaccination.^1,3

Earlier reviews of the prophylactic arena explored various small-molecule candidates such as ivermectin and nitazoxanide, but many of these have lacked the robust, large-scale phase 3 evidence now provided for ensitrelvir. As SARS-CoV-2 continues to evolve and household secondary attack rates remain as high as 48% in the Omicron era, the ability of pharmacists to provide a proven oral prophylactic could significantly reduce the global burden of the disease.^1,4

READ MORE: COVID-19 Resource Center

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REFERENCES

1. Hayden FG, Shinkai M, Clark TW, et al. Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts. N Engl J Med. 2026;394(19):1905-1915. doi:10.1056/NEJMoa2509306

2. Hammond J, Yunis C, Fountaine RJ, et al. Oral Nirmatrelvir-Ritonavir as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2024;391(3):224-234. doi:10.1056/NEJMoa2309002

3. CDC. Types of COVID-19 treatment. February 5, 2026. Accessed May 14, 2026. https://www.cdc.gov/covid/treatment/index.html

4. Ben-Zuk N, Dechtman ID, Henn I, et al. Potential Prophylactic Treatments for COVID-19. Viruses. 2021;13(7):1292. Published 2021 Jul 2. doi:10.3390/v13071292