Trial data reveal ensitrelvir's potent antiviral activity against COVID-19, offering a promising alternative to other treatments.
A recent phase 2 randomized controlled clinical trial published in The Lancet Infectious Diseases highlights ensitrelvir as a potential game-changer in the fight against COVID-19. This once-daily oral drug, developed by Shionogi, has already been administered to over 1 million individuals in Japan and Singapore, where it is registered for treating COVID-19. However, its effectiveness outside these countries remains under investigation.
The trial's objective was to compare ensitrelvir's antiviral effects with those of ritonavir-boosted nirmatrelvir (Paxlovid), the first oral antiviral approved by the US Food and Drug Administration (FDA) for COVID-19. While Paxlovid is widely used for mild-to-moderate COVID-19 cases, it carries drawbacks like high cost, numerous contraindications, and limited availability in low-income countries.
The open-label trial focused on low-risk outpatients aged 18 to 60 with early symptomatic COVID-19, recruited from Thai and Lao clinics. Researchers prioritized viral clearance rates to assess drug efficacy, as COVID-19 has become less severe, making traditional endpoints like hospitalization and death less frequent.
The study revealed that both ensitrelvir and ritonavir-boosted nirmatrelvir accelerated viral clearance. By day 3, viral densities were significantly lower in ensitrelvir patients (2.9-fold) and ritonavir-boosted nirmatrelvir patients (2.4-fold) compared to those receiving no treatment. By day 5, viral clearance was 82% faster with ensitrelvir and 116% faster with ritonavir-boosted nirmatrelvir. However, ensitrelvir was 16% slower in viral clearance compared to nirmatrelvir in a non-inferiority analysis.
Symptom resolution was also faster in the ensitrelvir group (32%) and ritonavir-boosted nirmatrelvir group (38%) compared to the untreated group. Viral rebound occurred in 7% of nirmatrelvir patients and 5% of ensitrelvir patients, with no severe disease cases reported.
This comparative in-vivo pharmacodynamic assessment confirms ensitrelvir's potent antiviral activity against COVID-19. A meta-analysis comparing ensitrelvir and ritonavir-boosted nirmatrelvir with other small-molecule drugs (remdesivir, molnupiravir, favipiravir, and ivermectin) demonstrated the largest antiviral effects in 1,157 Thai and Lao patients.
Ensitrelvir offers advantages over Paxlovid, including a lower pill burden (one pill daily) and a more pleasant taste. It may also be suitable for immunocompromised patients who take medications interacting with ritonavir. However, the threat of COVID-19 remains, especially for vulnerable populations, and the need for effective therapeutics persists.
Shionogi has submitted a new drug application (NDA) to the FDA for COVID-19 prevention, based on a phase 3 trial showing ensitrelvir's 67% reduced risk of COVID-19 infection post-exposure.
