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VV116, GS-5245 for COVID
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Study Evaluating GS-5245 in Participants With COVID-19 Who Have a High Risk of Developing Serious or Severe Illness
Dec 2022
In this trial, early administration of oral VV116 was noninferior to nirmatrelvir–ritonavir in shortening the time to sustained clinical recovery in participants with mild-to-moderate Covid-19 who were at high risk for progression to severe disease. VV116 also had fewer safety concerns than nirmatrelvir–ritonavir.
Currently, nirmatrelvir–ritonavir8 is recommended by World Health Organization (WHO) guideline for treating mild-to-moderate Covid-19.9 Nirmatrelvir is an oral inhibitor of the SARS-CoV-2 3-chymotrypsin–like cysteine protease enzyme that can be dispensed at community pharmacies and has been authorized for emergency use by many countries. However, access to nirmatrelvir is limited worldwide, and its effectiveness depends on ritonavir,10 which has multiple drug–drug interactions warranting specialized assessment before prescription. Remdesivir is also recommended11 but needs to be administered intravenously, which limits its widespread use during the pandemic. Therefore, several oral analogues of remdesivir have been developed to address this issue, including GS-621763,12 ATV006,13 and VV116.14,15
VV116 is a deuterated remdesivir hydrobromide with oral bioavailability and potent activity against SARS-CoV-2 in studies in animals15 and satisfactory safety and side-effect profiles in phase 1 trials.16 A preliminary small-scale study has shown a shorter viral shedding time in patients with Covid-19 who received VV116 within 5 days after the first positive test than in those who received regular care.17 However, the efficacy of VV116 for clinical recovery, symptom resolution, and prevention of disease progression remains unknown, particularly as compared with nirmatrelvir–ritonavir. In addition, the safety profiles of VV116 have not been fully assessed. Here, we report the results of a phase 3 trial of VV116 as compared with nirmatrelvir–ritonavir for oral treatment of symptomatic participants at high risk for progression to severe Covid-19 during the omicron outbreak.
In light of the preliminary positive findings of a reduction in viral shedding time among patients with SARS-CoV-2 infection who were taking VV116,17 the current trial compared VV116 with nirmatrelvir–ritonavir to assess clinical end points and adverse events. This trial showed that in symptomatic adults hospitalized with mild-to-moderate Covid-19 who were at high risk for severe disease, a 5-day course of oral treatment with VV116 was noninferior to nirmatrelvir–ritonavir in shortening the time to sustained clinical recovery. This noninferiority in efficacy was seen in the full analysis population, the per-protocol population, and in participants who started treatment within 5 days after symptom onset. The point estimates of secondary end points also suggested that VV116 was better than or similar to nirmatrelvir–ritonavir with respect to the time to sustained symptom resolution and to a first negative SARS-CoV-2 test. No participants in either group died or had progression to severe or critical Covid-19. Participants in the VV116 group had a lower incidence of adverse events than those in the nirmatrelvir–ritonavir group.
The administration of oral antiviral agents is feasible early in infection. Such therapies, if given promptly, could help mitigate hospitalization burden, facilitate postexposure prophylaxis, and potentially minimize household transmission.
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