SARS-CoV-2 Mpro inhibitor, nirmatrelvir, found to reduce COVID-19 progression and death

By Sangeeta PaulFeb 18 2022Reviewed by Aimee Molineux

In a recent study published in The New England Journal of Medicine, a team of researchers from Pfizer, United States (US), evaluated the efficacy and safety of nirmatrelvir in mild to moderate coronavirus disease 2019 (COVID-19) patients who were at high risk of progression to severe COVID-19 disease.

Recent studies have revealed that patients with certain pre-existing conditions (such as old age, smoking, diabetes, obesity, cardiovascular disease, and cancer) were at higher risk and twice likely to progress to severe COVID-19 and five times more vulnerable to death compared to those without these conditions. nirmatrelvir is an orally administered antiviral drug with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^pro) inhibitory activity.

In the current study, the team of researchers performed a randomized, double-blind, placebo-controlled phase two to three clinical trial to estimate the efficacy, effect on viral load, and safety data of nirmatrelvir plus ritonavir (enhancer of pharmacokinetics) in non-vaccinated, symptomatic, non-hospitalized COVID-19 patients who were at risk of severe COVID-19 disease progression from different countries.

Study design

Eligible patients were randomly assigned using an interactive response technology system to receive a 1: 1 ratio of nirmatrelvir (300 mg) plus ritonavir (100 mg) or a placebo every 12 hours for five days. The team estimated SARS-CoV-2 viral load in nasopharyngeal swabs through a reverse-transcriptase polymerase-chain-reaction (RT-PCR) assay. Endpoints for safety information of the drug including adverse events, serious adverse events, and adverse events resulting in trial drug or placebo discontinuation were assessed through day 34 and coded as per version 24.0 of Medical Dictionary for Regulatory Activities (MedDRA).

An interim analysis of the primary endpoints was performed based on sequential group design using a Lan–DeMets alpha-spending function with an O’Brien–Fleming stopping boundary.

Findings

The median age of the enrolled patients was 46 years, and the cohort comprised 51.1% male, 71.5% White, and 14% Asian patients. Among the patients with a relative risk of COVID-19 severe disease progression, the most common coexisting clinical features and comorbidities were body mass index (BMI) ≥ 25 (80.5%), smoking (39%), hypertension (32.9%), and two or more other features or coexisting parameters (61%). At randomization, the majority of enrolled patients (93.8%) had not received monoclonal antibodies for COVID-19 and within three days after symptoms onset, 66.3% received a trial drug or placebo.

The primary interim analysis highlighted that nirmatrelvir plus ritonavir recipients who initiated treatment within three days of symptoms onset had 0.77% COVID-19-related hospitalization or mortality by day 28 as compared to 7.01% in the placebo group with a reduction of relative risk by 89.1%.

In patients who initiated treatment within three days and five days of symptom onset but were not administered with monoclonal antibodies, 0.72% and 0.77% of the recipients, respectively, in the nirmatrelvir group were hospitalized or died due to COVID-19 compared to 6.45% and 6.31% in the placebo group through day 28. The event rates for COVID-19-related hospitalization by any cause for the nirmatrelvir and placebo groups treated within five days of symptom onset were 0.72% and 6.53%, respectively. Observed relative risk reduction by nirmatrelvir at three and five days of treatment initiation were 88.9% and 87.8%, respectively.

Post-inclusion of patients who have received or expected to receive a monoclonal antibody, the nirmatrelvir plus ritonavir and placebo treatment groups had 0.81% and 6.10% of COVID-19-related hospitalizations and death, respectively, by any cause.

The researchers illustrated that when treatment was initiated within three and five days of symptoms onset, the nirmatrelvir plus ritonavir group reduced SARS-CoV-2 viral load by adjusted mean of an additional 0.868±0.105 log₁₀ copies per ml and 0.695±0.085 log₁₀ copies per ml, respectively.

Similarly, on the inclusion of patients who have received or expected to receive monoclonal antibodies to treat COVID-19, nirmatrelvir plus ritonavir treatment reduced SARS-CoV-2 viral load by an additional 0.689±0.082 log₁₀ copies per ml at day five compared to the placebo.

Nirmatrelvir plus ritonavir and placebo recipients elicited similar adverse events incidents – 22.6% and 23.9%, respectively, during and after the treatment period. The proportion of most frequently observed events affecting approximately 1% of patients among the nirmatrelvir plus ritonavir treatment group were dysgeusia (5.6%), diarrhea (3.1%), increased fibrin D-dimer (1.9%), increased alanine aminotransferase (1.5%), headache (1.4%), decrease in creatinine and renal clearance (1.4%), nausea (1.4%), and vomiting (1.1%) while in the placebo group, the percentage of these events were 0.3%, 1.6%, 2.8%, 2.4%, 1.3%, 1.6%, 1.7%, and 0.8%, respectively. All adverse events were non-serious and graded 1 or 2.

Adverse events were more common in the nirmatrelvir plus ritonavir group (7.8%) as compared to the placebo (3.8%) with differences largely attributed to dysgeusia (4.5%) and diarrhea (1.3%) compared with the placebo (0.2% for both).

The researchers observed that the nirmatrelvir plus ritonavir group reported fewer adverse events of grade 3 or 4, fewer serious adverse events, and fewer adverse reactions causing discontinuation of drugs (4.1%, 1.6%, and 2.1%, respectively) compared to placebo recipients (8.3%, 6.6%, and 4.2%, respectively).

Most frequent adverse events reported in recipients of the nirmatrelvir plus ritonavir group were COVID-19-induced pneumonia, COVID-19, and reduced creatinine clearance (0.5%, 0.2%, and 0.2%, respectively) compared to the placebo recipients (3.3%, 0.7%, and 0.3%, respectively) with none of the adverse events associated with nirmatrelvir as per the investigators.

Of note, the researchers analyzed that in the nirmatrelvir group, no serious adverse event-induced death was observed, while in the placebo group 13 deaths occurred which were COVID-19-related.

Conclusion

The findings of this study demonstrated the remarkable efficacy of oral nirmatrelvir plus ritonavir treatment in symptomatic mild to moderate COVID-19 patients to reduce the progression to severe COVID-19 and reduce the viral load quickly.

Further, nirmatrelvir plus ritonavir is associated with fewer adverse events and is more likely to be effective against future SARS-CoV-2 variants.