Oral Nirmatrelvir Prevents Progression to Severe COVID-19 in High-Risk, Unvaccinated Outpatients

April 15, 2022

By Denise Baez

Treatment of symptomatic coronavirus disease 2019 (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, according to a study published in The New England Journal of Medicine.

The phase 2/3 EPIC-HR trial randomised symptomatic, unvaccinated, non-hospitalised adults with COVID-19 at high risk for progression to severe disease to receive either nirmatrelvir 300 mg plus ritonavir 100 mg or placebo every 12 hours for 5 days

Results of a planned interim analysis in 774 of the 1,361 patients in the full analysis population treated within 3 days after symptom onset was previously reported, and showed that the incidence of COVID-19-related hospitalisation or death by day 28 was lower in the nirmatrelvir group (3 of 389 [0.77%] patients) than in the placebo group (27 of 385 [7.01%] patients; relative risk reduction, 89.1%; P < .001). There were no deaths in the nirmatrelvir group compared with 7 deaths in the placebo group.

“Efficacy was maintained in the final analysis involving the 1,379 patients in the modified intention-to-treat population (relative risk reduction, 88.9%)”, reported Jennifer Hammond, PhD, Pfizer, Collegeville, Pennsylvania, and colleagues. “All 13 deaths occurred in the placebo group.”

The modified intention-to-treat population included patients whose treatment began within 3 days after the onset of COVID-19 signs and symptoms and excluded patients who at randomisation had received or were expected to receive monoclonal antibody treatment.

The most common pre-specified characteristics and coexisting conditions associated with a risk of progression to severe COVID-19 at baseline were a body mass index (BMI) ≥25, current smoking, and hypertension.

Results from subgroup analyses were consistent, regardless of age, sex, race, BMI, baseline serology status, viral load, coexisting conditions, or number of coexisting conditions at baseline.

The researchers also found that viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies/mL when treatment was initiated within 3 days after the onset of symptoms.

Any adverse event (AE) occurred in 22.6% of patients in the nirmatrelvir arm compared with 23.9% of patients in the placebo group. Serious AEs occurred in 1.6% and 6.6%, respectively, and AEs leading to treatment discontinuation occurred in 2.1% and 4.2%. Dysgeusia (5.6% vs 0.3%) and diarrhoea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo.

“A need exists for safe and effective oral COVID-19 treatments that can prevent the progression of infection to more severe disease, hospitalisation, and death; shorten the time to clinical recovery; and reduce the transmission rate,” the authors wrote. “Such treatments would help reduce current strains on healthcare systems, including overwhelmed hospital facilities, and lack of beds in intensive care units…Our data show that treatment with nirmatrelvir plus ritonavir early in COVID-19 illness can decrease progression to severe disease and quickly reduce SARS-CoV-2 viral load.:

The researchers noted that the concomitant use of nirmatrelvir plus ritonavir and certain drugs may result in potentially important drug interactions, and that such interactions need to be managed through dose reduction of the concomitant medication, use of an alternative concomitant medication, increased monitoring for AEs or concomitant medication drug levels, temporary discontinuation of concomitant medications, or avoidance of coadministration.

Reference: https://www.nejm.org/doi/full/10.1056/NEJMoa2118542

SOURCE: The New England Journal of Medicine