Novel Antiviral Shows Promising Results Against COVID -19

Nirmatrelvir (PF-07321332) is an orally administered antiviral agent targeting the SARS-CoV-2 3-chymotrypsin–like cysteine protease enzyme (Mpro). Mpro is an attractive antiviral target because it is essential in the viral replication cycle. Nirmatrelvir exhibited potent inhibition of Mpro activity and virus replication across a wide spectrum of coronaviruses in vitro. Phase 1 trial showed a clinically acceptable safety profile up to the highest dose and exposure evaluated (500 mg of nirmatrelvir plus 100 mg of ritonavir twice daily for 10 days).

Recently, Dr Jennifer Hammond and her team conducted a phase 2-3 trial, evaluating the safety and efficacy of nirmatrelvir plus ritonavir in nonhospitalized adults with mild-to-moderate Covid-19 at high risk for progression to severe disease.

The EPIC-HR trial (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) was a phase 2–3, double-blind, randomized, placebo-controlled trial. The researchers included a total of 2246 patients and randomized them to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer)(n=1120) or placebo (n=1126) every 12 hours for 5 days. They assessed safety outcomes along with Covid-19–related hospitalization or death from any cause through day 28 and viral load. The trial was designed to include about 3000 patients, but it was terminated at the time of a planned interim analysis by the data monitoring committee because the efficacy end point had been reached.

Key findings of the study:

• Upon planned interim analysis, the researchers noted that 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 among patients treated within 3 days after symptom onset.
• They further noted that the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths.
• They observed that the 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 (relative risk reduction, 88.9%).
• They noted that all 13 deaths occurred in the placebo group.
• They found that 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 log10 copies per millilitre when treatment was initiated within 3 days after the onset of symptoms.
• They reported a similar incidence of adverse events in both groups, with dysgeusia and diarrhoea common among the nirmaltrelvir plus ritonavir group (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%).

The authors concluded, "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."

In an accompanying editorial, Dr wrote, "Results from the interim analysis were consistent with those of the final analysis is reassuring; it has not been the case for every Covid-19 trial. Until we have a better idea of the potential for the emergence of resistance, we need to be good stewards of this medication. By limiting its use to those most likely to benefit, we can potentially prolong its useful life."

For further information:

DOI: 10.1056/NEJMoa2118542