Ensitrelvir Versus Nirmatrelvir in COVID-19 Viral Clearance

Key Takeaways

• Both 5-day oral antiviral regimens were associated with faster oropharyngeal SARS-CoV-2 clearance than no study drug, and nirmatrelvir showed the faster signal head to head.
• The trial enrolled low-risk adult outpatients early in illness and used a virologic endpoint measured from day 0 through day 5.
• Viral rebound was reported in both antiviral groups.

In the PLATCOV phase 2 trial, ensitrelvir accelerated oropharyngeal SARS-CoV-2 clearance but was 16% slower than ritonavir-boosted nirmatrelvir in direct comparison. The phase 2 randomized study evaluated oral antivirals in low-risk outpatients with early symptomatic COVID-19 rather than hospitalized populations. Investigators used serial oropharyngeal sampling to compare virologic activity across active treatment groups and a no-study-drug comparator. The comparison included adults aged 18-60 years enrolled within 4 days of symptom onset in Thailand and Laos.

The study was an open-label, phase 2, randomized, controlled, adaptive pharmacometric platform trial conducted in hospital acute respiratory infection clinics in Thailand and Laos. Eligible participants were low-risk adults aged 18-60 years with symptoms for less than 4 days at enrollment. Oral ensitrelvir and oral ritonavir-boosted nirmatrelvir were each given for 5 days, alongside a no-study-drug comparator within the platform. The primary endpoint was the oropharyngeal SARS-CoV-2 viral clearance rate from day 0 to day 5 in the modified intention-to-treat population, estimated with a Bayesian hierarchical linear model using log10 viral densities from standardized paired oropharyngeal swab eluates.

Between March 17, 2023, and April 21, 2024, 604 of 903 enrolled patients were concurrently assigned to the three comparison groups. Those groups included 202 patients receiving ensitrelvir, 207 receiving ritonavir-boosted nirmatrelvir, and 195 receiving no study drug. Median estimated SARS-CoV-2 clearance half-lives were 5.9 hours with ensitrelvir, 5.2 hours with nirmatrelvir, and 11.6 hours with no study drug, with IQRs of 4.0-8.6, 3.8-6.6, and 8.1-14.5 hours. Compared with no study drug, ensitrelvir was 82% faster, with a 95% credible interval of 61-104. Against ritonavir-boosted nirmatrelvir, ensitrelvir was 16% slower, with a 95% credible interval of 5-25, and the head-to-head virologic comparison favored nirmatrelvir.

Viral rebound was reported in both antiviral groups, occurring in 15 of 207 patients, or 7%, with nirmatrelvir and 10 of 202, or 5%, with ensitrelvir. The between-group comparison for rebound had a p value of 0.45. Investigators also noted that a within-platform individual patient data meta-analysis of 1157 patients found nirmatrelvir and ensitrelvir had the largest antiviral effects among unblinded small-molecule drugs. The authors interpreted the findings as showing that both antivirals accelerated oropharyngeal SARS-CoV-2 viral clearance. They also described ensitrelvir as an effective alternative to currently available antivirals in treating COVID-19.