In a recent study published in the NEJM, researchers presented the results of a phase III randomized controlled trial (RCT) of oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral VV116. They conducted this trial during the recent outbreak caused by the new SARS-CoV-2 variant Omicron (B.1.1.529), which had a higher immunity-evading potential.

Study: VV116 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19. Image Credit: angellodeco/Shutterstock


The World Health Organization (WHO) recommends nirmatrelvir–ritonavir for mild-to-moderate coronavirus disease 2019 (COVID-19) treatment. Consequently, this oral drug combination that inhibits SARS-CoV-2 3-chymotrypsin–cysteine protease enzyme received emergency use authorization (EUA) across multiple countries.

However, there is a need for more COVID-19 drugs that could substitute remdesivir because several factors limit its widespread use. First, its intravenous administration limits its extensive use during the current pandemic. Second, its component, ritonavir, has drug–drug interactions which studies have not extensively assessed but require assessment before the prescription.

Currently, available oral analogs of remdesivir are GS-621763, VV116, and ATV006. VV116, a deuterated remdesivir hydrobromide, showed good oral bioavailability and anti-SARS-CoV-2 activity in preclinical trials.

In its phase I clinical trials, the drug showed a favorable safety profile and fewer side effects. It also reduced viral shedding time in patients who received treatment within five days of testing COVID-19-positive. However, VV116 efficacy with respect to clinical recovery, symptom(s) resolution, and preventing COVID-19 progression compared with nirmatrelvir–ritonavir remains unknown.

About the study

In the present multicenter clinical drug trial, researchers screened 997 participants between April 4 and May 2, 2022, but randomized 822 symptomatic participants at high risk of developing severe COVID-19 into a 1:1 ratio using an interactive Web response system. Accordingly, of 771 participants who received any of the two drugs throughout the follow-up duration of 28 days, 384 and 387 received VV116 and nirmatrelvir–ritonavir, respectively, and they constituted the full-analysis population at baseline.

The trial executioners ensured that all the site staff, including researchers involved in endpoint drug assessments except those who dispensed the trial drugs directly, remained blinded to drug assignment groups until unblinding in May 2022. However, study participants remained blinded to their drug assignment throughout the study.

Notably, the team obtained all study participants from seven hospitals in Shanghai, China, between April 4, 2022, and May 2, 2022. The recipients of oral VV116 received 600 mg and 300 mg of the drug every 12 hours on Day 1 and every 12 hours during Days 2 to 5, respectively. Likewise, recipients of oral nirmatrelvir–ritonavir received 300 and 100mg of nirmatrelvir and ritonavir every 12 hours for five days, respectively.

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The study participants were all adults with mild-to-moderate COVID-19 and a minimum of one risk factor, such as age above 60, which made them prone to developing severe COVID-19.

The WHO clinical progression scale had scores ranging between zero to 10, whereas total symptom scores ranged between zero and 33, with higher scores indicating greater severity for all 11 targeted COVID-19 symptoms. The study investigators assessed these scores before the trial-drug dispensation. They continued these assessments until Day 28 of the study or resolution of targeted symptoms (or sustained clinical recovery), whichever was earlier.

The team considered the first day of the two-consecutive-day period when all COVID-19 target symptoms alleviated to a total symptom score of zero or one as the event date. The data cutoff date for primary drug efficacy analysis was May 13, 2022, whereas the final study analysis ended by August 18, 2022. Furthermore, the team determined adverse events and serious adverse events, i.e., the safety profile of VV116, and actively monitored and reported their emergence or worsening till day 28.

The statistical analyses worked on the hypothesis that VV116 would be non-inferior to nirmatrelvir–ritonavir concerning sustained recovery from COVID-19. However, due to a shortage of data on the time of clinical recovery during the Omicron wave, they used a reference duration of five and a half days.

They maintained the lower boundary while doing the computations for the 95% confidence interval (CI) for the hazard ratio (HR) of the primary endpoint analysis >0.8, estimated with the Cox proportional-hazards model. Likewise, they used the Kaplan–Meier method to estimate the average time to sustain COVID-19 clinical recovery and 95% CI. The noninferiority margin corresponded to 6.875 days taken for sustained clinical recovery from COVID-19, and a minimum of 724 events ensured 85% statistical power.

Study findings

The median age of the study participants was 53 years, and around 50% were women. Over 92% had mild COVID-19, and one-third were COVID-19 vaccinated. The HR for the time to sustained clinical recovery was 1.17 in VV116 recipients vs. the nirmatrelvir–ritonavir group, which established the noninferiority of VV116. Its five-day oral treatment shortened the time to sustained clinical recovery in all population groups, including the full-analysis and the per-protocol population, and even in participants who began VV116 treatment within five days of COVID-19 symptom onset.

Even in many prespecified subgroups, the HR point estimates were more than one, irrespective of gender, age, and vaccination status. In addition, participants in the VV116 group had a lower incidence of adverse events than those in the nirmatrelvir–ritonavir group. Most importantly, VV116 did not inhibit or induce any major drug-metabolizing enzymes or drug transporters, so interaction with concomitant medications was also less likely compared to the recipients of nirmatrelvir–ritonavir.


Overall, VV116 had a favorable safety profile, and its early oral administration was non-inferior to nirmatrelvir–ritonavir, thus, reducing the time to sustained clinical recovery from mild-to-moderate COVID-19 in all study participants.

Future trials should further investigate the occurrence of transient dysgeusia and the incidence of dyslipidemia in participants receiving nirmatrelvir–ritonavir and some VV116 recipients. Although this adverse reaction is frequent in patients who use ritonavir for a longer duration, such as human immunodeficiency virus (HIV)-infected patients; yet, the researchers advocated further investigation of the possible effect(s) of nirmatrelvir or VV116 on lipid metabolism.

Journal reference:
  • VV116 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19, Z. Cao, W. Gao, H. Bao, H. Feng, S. Mei, P. Chen, Yueqiu Gao, Z. Cui, Q. Zhang, X. Meng, H. Gui, W. Wang, Y. Jiang, Z. Song, Y. Shi, J. Sun, Y. Zhang, Q. Xie, Y. Xu, G. Ning, Yuan Gao, and R. Zhao, NEJM 2022, doi: 10.1056/NEJMoa2208822

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Coronavirus, Coronavirus Disease COVID-19, covid-19, Cysteine, Drugs, Dysgeusia, Dyslipidemia, Efficacy, Enzyme, HIV, immunity, Immunodeficiency, Metabolism, Omicron, Pandemic, Preclinical, Remdesivir, Respiratory, Ritonavir, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Virus

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Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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