VV116 vs. Nirmatrelvir-Ritonavir Against COVID-19

Tholkappian R, NIT Durgapur

Nirmatrelvir is an oral inhibitor of the SARS-CoV-2’s, 3-chymotrypsin–like cysteine protease, while VV116 is a deuterated remdesivir hydro-bromide with potent activity against SARS-CoV-2. Nirmatrelvir-ritonavir was used to treat COVID-19 of low to moderate severity. However, its production could not meet the global supply demands. VV116 is one such oral analog of Nirmatrelvir-Ritonavir developed by Xie et al. 2021, to address this demand issue that has shown similar therapeutic efficacy.

Technical details:

During the B.1.1.529 variant outbreak, a phase III, noninferiority, observer-blinded, randomized controlled trial was conducted with the approval of the National Human Genetic Resources Committee, China. Adults with less than severe symptoms of COVID-19 but with a high risk of progression received a 5-day course of either VV116 or nirmatrelvir–ritonavir. The primary endpoint was the time required to sustain clinical recovery through day 28. Sustained clinical recovery refers to the alleviation of all COVID-19-related target symptoms with a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, where higher scores indicate greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of >0.8 indicated noninferiority (hazard ratio of >1 indicates a shorter time to sustain clinical recovery with VV116 than with nirmatrelvir–ritonavir).

822 participants underwent randomization, and 771 received either of the oral antiviral agents. VV116 was given to 384 participants, while nirmatrelvir–ritonavir to 387 participants. In the final analysis, there were no appreciable differences between the two groups in the time to sustained symptom resolution (a score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) or a first negative SARS-CoV-2 test. By day 28, neither group’s participants had experienced death or a progression to severe COVID-19. The incidence of adverse events in the VV116 group (67.4%) was lower than in the nirmatrelvir–ritonavir group (77.3%).

Limitations:

The trial reported several limitations of this trial. Firstly, it was not reported as a double-blind, double-dummy design (neither the participants nor the investigators are aware of which individuals are being administered the experimental medication and which are receiving a placebo). That was because the placebo tablet for nirmatrelvir–ritonavir was not available before the trial began owing to the Omicron outbreak.

The trial involved Chinese adults infected with omicron subvariants in a single geographic area, so the results required validation in more heterogeneous populations with a greater diversity of viral variants. Symptoms could have returned after two consecutive days without no symptoms.

The WHO ordinal scale used to evaluate outcomes wasn’t ideal for detecting differences among participants with mild COVID-19. Furthermore, the degree of VV116’s efficacy cannot be conclusively determined, because no adverse event occurred in either of the two groups. Also, SARS-CoV-2 rebound after nirmatrelvir–ritonavir treatment wasn’t recognized until the release of the Centers for Disease Control and Prevention advisory on May 24, 2022.

Conclusion

Fewer adverse events occurred in the VV116 group when compared to the nirmatrelvir–ritonavir group. Nirmatrelvir–ritonavir had drug-drug interactions with multiple other medications. VV116 on the other hand did not inhibit or induce major drug-metabolizing enzymes or inhibit major drug transporters and thus interacting with concomitant medications is less likely in that context. The possible effect of both antiviral agents on lipid metabolism still requires further investigation. Among adults with mild-to-moderate COVID-19 who were at risk for progression, VV116 was non-inferior to nirmatrelvir–ritonavir concerning the time to sustained clinical recovery, with fewer safety concerns.

References:

1. Cao, Z., Gao, W., Bao, H., Feng, H., Mei, S., Chen, P., Gao, Y., Cui, Z., Zhang, Q., Meng, X., Gui, H., Wang, W., Jiang, Y., Song, Z., Shi, Y., Sun, J., Zhang, Y., Xie, Q., Xu, Y., … Zhao, R. (2023). Vv116 versus nirmatrelvir–ritonavir for oral treatment of covid-19. New England Journal of Medicine, 388(5), 406–417. https://doi.org/10.1056/NEJMoa2208822
2. Xie, Y., Yin, W., Zhang, Y., Shang, W., Wang, Z., Luan, X., Tian, G., Aisa, H. A., Xu, Y., Xiao, G., Li, J., Jiang, H., Zhang, S., Zhang, L., Xu, H. E., & Shen, J. (2021). Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2. Cell Research, 31(11), 1212–1214. https://doi.org/10.1038/s41422-021-00570-1

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