In recent times, the surge in the number of new coronavirus infections has caused a "shock wave" of severe illness in many places across the country. The medical and health systems are under great pressure. Qidian Cao is also worried about the health of his family and friends, fe

Structural modification of VV116

A research and development team led by researcher Shen Jingshan found that although remdesivir and GS-441524 can effectively inhibit the replication of the new coronavirus in in vitro experiments, their initial development goal was to target hepatitis C virus, so they are liver-targeting and may not be suitable for antiviral treatment of new coronavirus infection. After all, the lungs are the key.

Therefore, the R&D team began to structurally modify GS-441524 and finally screened out the “most qualified” candidate oral antiviral drug, which is VV116. Preclinical studies have shown that VV116 can also effectively inhibit the synthesis of new coronavirus RNA by targeting RNA-dependent RNA polymerase (RdRp), and has good oral bioavailability and safety , and is expected to become a safe and efficient oral anti-new coronavirus drug [2].

VV116 showed antiviral ability in the lungs in preclinical studies

Subsequent early clinical studies also confirmed that VV116 treatment is safe and well tolerated [3], and VV116 was used to treat early Omicron mutant infection. Treatment can significantly shorten the "detoxification time" of infected people [3] and support the subsequent phase III clinical study , which is the research that reached the top of NEJM. Moreover, this research was conducted during the peak of the epidemic in Shanghai from April to May 2022. It faced many difficulties, and success was particularly difficult. The

research was led by Academician Ning Guang and Professor Zhao Ren of Ruijin Hospital Affiliated to Shanghai Jiao Tong University and Professor Gaoyuan of Renji Hospital Affiliated to Shanghai Jiao Tong University, from April 4 to May 2022. It was a multi-center, single-blind (the researcher remained blind), randomized controlled phase III clinical trial (NCT05341609), which was carried out in 7 COVID-19 designated hospitals in Shanghai on the 2nd. It included 822 adult patients with mild to moderate COVID-19 who had high risk factors for progression.The enrolled patients in

were randomized into groups according to a 1:1 ratio. In the end, 771 patients received VV116 (n=384) or Paxlovid (n=387) (i.e., full analysis set/FAS population). The median age of the patients was 53 years old. Most of the cases were mild (92.1%), 75.7% had completed the full course of the new coronavirus vaccine or received a booster shot, and 77.3% received VV116 or Paxlovid treatment within 5 days of the onset of symptoms. The development of high-risk factors is shown in the table below.

Patients’ high-risk factors for progression

The primary endpoint of the study is the time from randomization to sustained clinical recovery, where sustained clinical recovery refers to all 11 new coronavirus-related target symptoms of the patient (such as fever, Cough, etc., see Table 2 for details) The total severity score drops to 0-1 (that is, all symptoms need to disappear, or only one symptom remains mild) ; Based on the course of infection with the Omicron mutant strain and the vaccination rate in Shanghai, the reference time for patients to achieve sustained clinical recovery is 5.5 days.

11 COVID-19-related "target symptoms"

secondary efficacy endpoints include the proportion of patients who progress to severe/critical illness or all-cause death by day 28, changes in COVID-19-related symptom scores and WHO clinical progress scale scores, the time to the disappearance of persistent symptoms, the time to nucleic acid negative conversion, etc. Adverse events (AE) and serious adverse events (SAE) are also evaluated in terms of safety.

According to the final analysis results published in this paper (as of August 18, 2022), in the FAS population, VV116 and Paxlovid treatment achieved non-inferiority in terms of time to sustained clinical recovery (HR=1.17, 95% CI: 1.02-1.36) , the situation of most predetermined subgroups of patients was also similar to that of the FAS population, and the median recovery time of patients in the VV116 group was shorter than that in the Paxlovid group (4 days vs. 5 days) .

The time to sustained clinical recovery after treatment with VV116 and Paxlovid

In addition, no patients in the two groups progressed to severe/critical illness or death. The median time for patients to disappear from persistent symptoms and for the first nucleic acid to turn negative was also 7 days. (HRs were 1.06/0.99 respectively); at each preset time point of the study (days 5, 7, 10, 14, and 28), the proportion of patients in the VV116 group whose symptoms were relieved (defined as the disappearance of all 11 target symptoms for 2 consecutive days) was mostly higher than that in the Paxlovid group (except on day 28).

The proportion of symptom relief in patients treated with VV116 and Paxlovid at different time points

In terms of safety, the incidence of all-grade AEs in the VV116 group was 67.4%, which was lower than 77.3% in the Paxlovid group, and the incidence of grade 3-4 AEs was also lower (2.6% vs. 5.7%) . In addition, from the perspective of drug characteristics, unlike Paxlovid as a compound preparation, which has many drug interactions (DDI), VV116 does not inhibit or induce major drug metabolizing enzymes or drug transporters, so the possibility of DDI is less likely to occur when combined with .

If there are any regrets about this study, it is that due to various reasons, the study was ultimately unable to be conducted with the optimal "double-blind double simulation method", and the effect of VV116 on preventing progression to severe disease and death was not fully evaluated (no events occurred in either group). These all need to be further evaluated in subsequent clinical studies.

But there is no doubt that the key clinical research results have reached the NEJM, which means that the clinical value of VV116 has been highly recognized by the academic community. This is also a milestone event in the research and development of new coronavirus innovative drugs in my country. We look forward to VV116 being approved for use as soon as possible to help the front line of the epidemic and save more lives!

References:

[1]Cao Z, Gao W, Bao H, et al. VV116 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19[J]. New England Journal of Medicine, 2022.

[2]Xie Y, Yin W, Zhang Y, et al. Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2[J]. Cell Research, 2021, 31(11): 1212-1214.

[3]Qian H, Wang Y, Zhang M, et al. Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects[J]. Acta Pharmacologica Sinica, 2022, 43: 3130-3138.

[4]Shen Y, Ai J, Lin N, et al. An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 omicron variants[J]. Emerging Microbes Infections, 2022, 11(1): 1518-1523.

Editor-in-charge丨Tan Shuo