VV116 noninferior to nirmatrelvir-ritonavir for COVID-19

Early administration of oral VV116 was noninferior to nirmatrelvir-ritonavir in shortening the time to sustained clinical recovery in individuals with mild-to-moderate COVID-19 who were at high risk for progression to severe disease, a phase III trial has shown. VV116 also had fewer safety issues than nirmatrelvir-ritonavir.

In the final analysis of the full analysis cohort, 378 participants in each arm achieved sustained clinical recovery. The estimated median time to sustained clinical recovery was 4 and 5 days for the respective VV116 and nirmatrelvir-ritonavir arms. The hazard ratio (HR) was 1.17, which indicates that the noninferiority of VV116 to nirmatrelvir-ritonavir was established. [N Engl J Med 2023;388:406-417]

Nirmatrelvir-ritonavir has been recommended by the WHO for the treatment of mild-to-moderate COVID-19 and has been authorized for emergency use by several countries. [N Engl J Med 2022;386:1397-1408; BMJ 2020;370:m3379] However, nirmatrelvir has limited access, and its efficacy is dependent upon ritonavir, which has been reported to have multiple drug-drug interactions. [Science 2021;374:1586-1593]

Another recommended treatment is remdesivir, but its intravenous administration limits its widespread use, the researchers added.

With the supply falling short of the global demand, more treatment options are warranted, the researchers stressed. “The administration of oral antiviral agents is feasible early in infection. Such therapies, if given promptly, could help mitigate hospitalization burden, facilitate post-exposure prophylaxis, and potentially minimize household transmission.”

The study included 822 symptomatic individuals (median age 53 years, 50 percent female) at high risk for progression to severe COVID-19 during the Omicron outbreak. Most participants (92 percent) had mild COVID-19, and three-quarters were fully vaccinated or boosted. They were randomized 1:1 to receive a 5-day course of either VV116 (600 mg Q12H on day 1 and 300 mg Q12H on days 2 through 5) or a combination of nirmatrelvir 300 mg and ritonavir 100 mg Q12H.

Secondary outcomes, safety

None died or progressed to severe COVID-19. Estimated median time from randomization to sustained resolution of COVID-19-related target symptoms was similar in both arms (7 days; HR, 1.06), as was the median time from randomization to a first negative SARS-CoV-2 test (7 days; HR, 0.99).

Through 28 days of follow up, VV116 recipients reported fewer adverse events (AEs) than those on nirmatrelvir-ritonavir (67 percent vs 77 percent), as well as fewer grade 3/4 AEs (3 percent vs 5 percent). The most frequently reported AEs (occurring in ≥5 percent of participants) with VV116 were dysgeusia (4 percent), hypertriglyceridaemia (11 percent), and hyperlipidaemia (3 percent). All were nonserious.

“Unlike nirmatrelvir-ritonavir … VV116 does not inhibit or induce major drug-metabolizing enzymes or inhibit major drug transporters, so interaction with concomitant medications is less likely,” noted the researchers.

More trials needed

As the study sample was limited to Chinese adults from a single geographic area infected with Omicron subvariants, the researchers called for further investigation in more heterogeneous populations with greater diversity of viral variants to ascertain the validity of the findings.

“Also, no conclusions can be made about the efficacy of VV116 for the prevention of progression to severe or critical COVID-19 or death, [as] no events occurred in either arm,” they said.