In a recent study posted to the medRxiv* preprint server, researchers reported the findings of the phase 2a part of a phase 2/3 study that assessed the safety and efficacy of Ensitrelvir among patients with asymptomatic or mild-to-moderate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Japan.
Studies have reported that SARS-CoV-2 shedding can persist for 10 days after the onset of symptoms among patients with asymptomatic, mild, or moderate coronavirus disease 2019 (COVID-19). Consistently high SARS-CoV-2 titers not only affect the COVID-19 severity but also facilitate SARS-CoV-2 transmission to close contacts.
Vaccination has been pivotal in curbing the COVID-19 pandemic; however, breakthrough COVID-19 infections have been reported in vaccinated individuals. Thus, from a general population standpoint, rapid reduction of SARS-CoV-2 titers among the infected individuals is important for controlling the pandemic, in addition to vaccines.
Ensitrelvir (S-217622) is a newly discovered and orally administered SARS-CoV-2 3C-like protease inhibitor which has demonstrated anti-SARS-CoV-2 efficacy in animals during in vitro and in vivo trials. In addition, the drug has been proven safe in a previous Phase 1 trial.
About the study
In the present study, researchers reported the safety and efficacy of Ensitrelvir among 69 Japanese patients with asymptomatic, mild, or moderate SARS-CoV-2 infections in Phase 2a part of a randomized, phase 2/3 clinical study, conducted between 28 September 2021, and 1 January 2022.
Some patients were excluded from the analysis if they deviated from the protocol, if they did not receive the test drug, if they discontinued the study due to consent withdrawal or COVID-19 progression, or if they tested negative in the reverse transcription-polymerase chain reaction (RT-PCR) analysis. As a result, 47 patients were randomized to receive orally a five-day course of Ensitrelvir in either of the therapeutic regimens: 375 mg on day 1 followed by 125 mg regularly (n=16), 750 mg on day 1 followed by 250 mg regularly (n=14)) or placebo (n=17). These participants comprised the intention-to-treat (ITT) population.
The ITT population was analyzed and follow-up assessments were performed for 28 days. The primary outcome of the study comprised alterations in the SARS-CoV-2 titers and the RT-PCR-measured SARS-CoV-2 ribonucleic acid (RNA) levels among the participants. The average time of SARS-CoV-2 clearance was noted for all the groups. In addition, the treatment-emergent adverse events (TEAEs) of Ensitrelvir were noted to determine its tolerability.
The participants were 20-to-65-year-old and most of them were males. Out of 47 patients, 40 patients and 7 patients had mild or moderate, and asymptomatic COVID-19, respectively. Most patients (42/47) had Delta (variant) infections whereas the remaining (5 patients) were infected by the Omicron variant. Most patients (38/47) had received COVID-19 vaccinations.
SARS-CoV-2 titers were reduced till day 4 and stable thereafter till day 21 among all participants. The titers were substantially lower among participants in the 125 mg group [mean (standard deviation)] was 0.9 (0.3)] and the 250 mg group [0.9 (0.2)] compared to the placebo-treated group [1.7 (1.2)]. The change in viral titers from baseline up to day 4 was larger in the 125 mg group [-2.4 (1.4)] and 250 mg group [-2.8 (1.2)] compared to the placebo-treated group [-1.5 (0.7)].
SARS-CoV-2 RNA levels expressed as log10 copies/mL were substantially lower among participants in the 250 mg group compared to the placebo-treated group on the fourth day [4.0 (0.77) versus 5.1 (1.1)]. The change in SARS-CoV-2 RNA levels from baseline on the fourth day was substantially greater among participants in the 125mg group [-2.7 (1.1) difference from the placebo, -1.4] and 250 mg group [-2.8 (1.3), the difference from placebo -1.5] compared to the placebo group [-1.27 (1.23)] Similar trends of greater changes in SARS-CoV-2 RNA titers were observed among the treatment groups compared to the placebo-treated group on the sixth day in the 125 mg group and 250 mg groups and on the ninth day in the 125 mg group.
The number of patients with SARS-CoV-2-positive titers reduced over time till day 21 in the 125 mg and 250 mg groups. On the fourth day, 26.7%, and 14.3% of participants demonstrated positive SARS-CoV-2 titers in the 125 mg group and the 250 mg group, respectively, which were substantially lower compared to the placebo-treated group (71.4%). Of note, on the sixth day, none of the 125 mg group participants demonstrated SARS-CoV-2-positive titers compared to the placebo group (30.8%).
The average time duration for SARS-CoV-2 clearance or the first SARS-CoV-2-negative titer was substantially lesser in the 125 mg group (61 hours) and the 250 mg group (63 hours) compared to the placebo-treated group (111 hours). Notably, SARS-CoV-2 clearance was observed among all the participants of the 125 mg group and the 250 mg group within 120 hours.
TEAEs were reported in 11 (52%), 16 (70%), and 9 (38%) of the participants in the 125 mg, 250 mg, and placebo groups, respectively, such as reduced high-density lipoprotein (HDL) and increased iron and total bilirubin levels. However, none of the TEAEs were severe or permanent.
Overall, the study findings showed that Ensitrelvir caused rapid SARS-CoV-2 clearance and was well tolerated among individuals with asymptomatic, mild, or moderate COVID-19.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.