Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

Abstract

Background Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M pro ) inhibitor with potent pan–human-coronavirus activity in vitro. Methods We conducted a phase 2–3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19–related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. Results A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19–related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of −5.81 percentage points (95% CI, −7.78 to −3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of −0.868 log 10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. Conclusions Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202 .)

Nirmatrelvir Plus Ritonavir: First Approval

“…Final efficacy results from EPIC-HR were consistent with those from the planned interim analysis [ 24 ]. In the full mITT population ( n = 697 and 682 in the nirmatrelvir plus ritonavir and placebo groups, respectively), Kaplan-Meier estimated event rates for COVID-19-related hospitalization or any-cause death through day 28 were 0.72% with nirmatrelvir plus ritonavir versus 6.53% with placebo (difference − 5.81%; 95% CI − 7.78 to − 3.84%; p < 0.001), corresponding to a relative risk reduction of 88.9%.…”

“…Nirmatrelvir plus ritonavir was effective in reducing the risk of progression to severe COVID-19 in non-hospitalized, symptomatic adults (≥ 18 years) at high risk for progression to severe COVID-19 in the randomized, double-blind, placebo-controlled, phase II/III EPIC-HR trial (NCT04960202) [ 24 ]. To be eligible for enrolment in EPIC-HR, patients had laboratory-confirmed SARS-CoV-2 infection, COVID-19 symptom onset ≤ 5 days prior to randomization, and at least one risk factor for progression to severe COVID-19.…”

“…At randomization, a minority of patients (6.2%) received or were expected to receive COVID-19 monoclonal antibody (mAb) treatment. The EPIC-HR modified intention-to-treat (mITT) population included all patients treated within 3 days of symptom onset who, at baseline, did not receive nor were expected to receive COVID-19 mAb treatment [ 24 ]. In a planned interim analysis of data from 774 patients in mITT population (primary efficacy analysis), the incidence of COVID-19-related hospitalization or any-cause death through day 28 was significantly lower with nirmatrelvir plus ritonavir than with placebo (0.77% vs 7.01%) [difference −6.32%; 95% CI −9.04% to −3.59%; p < 0.001], corresponding to a relative risk reduction of 89.1% [ 10 , 24 ].…”

Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2

“…Molnupiravir, an inhibitor of the RNA-dependent RNA polymerase of SARS-CoV-2, and nirmatrelvir 39 , an inhibitor of the main protease (also called 3CLpro) of SARS-CoV-2, have been authorized for emergency use by the FDA to treat COVID-19. In addition, S-217622, another inhibitor of 3CLpro, is currently in clinical trials 37,40 .…”

The Potential of Intentional Drug Development

“…Investigators now report in the Journal the first small-molecule antiviral agent designed specifically to inhibit SARS-CoV-2. 2 The active component, nirmatrelvir, is an inhibitor of the SARS-CoV-2 3-chymotrypsin–like cysteine protease enzyme, one of two essential proteases encoded by the virus. Protease inhibitors have a record of success in treating viral infections that dates from their introduction for the treatment of HIV.…”