Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19

N Engl J Med. 2024 Jan 18;390(3):230-241. doi: 10.1056/NEJMoa2301425.

Abstract

Background: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial.

Methods: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed.

Results: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate.

Conclusions: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • COVID-19 Drug Treatment / methods
  • COVID-19* / metabolism
  • COVID-19* / therapy
  • China
  • Coronavirus M Proteins / antagonists & inhibitors
  • Coronavirus M Proteins / metabolism
  • Coronavirus Protease Inhibitors* / administration & dosage
  • Coronavirus Protease Inhibitors* / adverse effects
  • Coronavirus Protease Inhibitors* / pharmacology
  • Coronavirus Protease Inhibitors* / therapeutic use
  • Double-Blind Method
  • Drug Combinations
  • Humans
  • Ritonavir / administration & dosage
  • Ritonavir / adverse effects
  • Ritonavir / pharmacology
  • Ritonavir / therapeutic use
  • SARS-CoV-2 / drug effects
  • Time Factors

Substances

  • Antiviral Agents
  • Coronavirus M Proteins
  • Coronavirus Protease Inhibitors
  • Ritonavir
  • Drug Combinations

Associated data

  • ClinicalTrials.gov/NCT05506176