Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects

Abstract

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25–800 mg. T1/2 was within 4.80–6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 omicron variants

“…Molnupiravir and Paxlovid were indicated for un-hospitalized cases with high risks for severe illness within 5 days after symptom onset and proved to be effective [ 12 , 13 ]. VV116 is an oral drug with robust anti-SARS-CoV-2 efficacy in preclinical studies and satisfactory safety, tolerability, and pharmacokinetic properties in healthy Chinese subjects [ 5 , 6 ]. In this study, VV116 significantly accelerated the viral shedding by 2–3 days when applied at the early stage of disease.…”

“…VV116 is a new effective oral nucleoside drug candidate against SARS-CoV-2, which could inhibit SARS-CoV-2 replication, lower viral RNA levels and infectious virus titres in vivo and in vitro , along with satisfying tolerability safety and pharmacokinetic profile in 3 phase 1 studies [ 5 , 6 ]. VV116 targets the conserved viral RdRp, and demonstrated potent antiviral activities against the omicron variant with an EC 90 of 0.30 μM, comparable to that of the original strain (EC 90 : 0.83 μM).…”

An update on inhibitors targeting RNA-dependent RNA polymerase for COVID-19 treatment: Promises and challenges

“…It has been demonstrated that VV116 showed potent activity against a panel of SARS-CoV-2 variants, including the Omicron variant [87] , [90] . In addition, VV116 exhibited satisfactory safety and tolerability in healthy subjects in phase I studies [89] . VV116 has been approved for the treatment of COVID-19 in Uzbekistan and is currently being investigated in phase II/III clinical trials in patients with COVID-19.…”

“…As a deuterated, tri-isobutyrate ester prodrug of the RDV parent nucleoside, VV116 is rapidly metabolized into the parent nucleoside (116-N1) in vivo. 116-N1 is intracellularly converted to the nucleoside triphosphate active form, which would interfere with the function of RdRp, thus inhibiting SARS-CoV-2 replication [89] . It has been demonstrated that VV116 showed potent activity against a panel of SARS-CoV-2 variants, including the Omicron variant [87] , [90] .…”

Synthesis and anti-SARS-CoV-2 activity of deuterated GS-441524 analogs

“…Notably, a deuterated, oral GS-441524 tri-isobutyrate ester prodrug (VV116) has entered phase III clinical trials for evaluating its efficacy against SARS-CoV-2 infection. [ [12] , [13] ] In this study, we synthesized different deuterated GS-441524 analogs at different position on the ribose and nucleobase moieties, and evaluated their efficacy against SARS-CoV-2 in vitro.…”