Nirmatrelvir Plus Ritonavir: first orally available antiviral treatment for COVID-19

The global pandemic, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is ongoing. Although numerous effective vaccines have been developed, the treatment options are still limited.

New antiviral agents are required to prevent Covid-19 disease progression to hospitalization or death. One of the most promising biological targets in SARS-CoV-2 is its main protease (Mpro) which is highly conserved in coronaviruses with low mutation rates. It cleaves polyproteins to produce shorter non-structural proteins that play an essential role in viral replication.

A potent SARS-CoV-2 Mpro inhibitor, Nirmatrelvir, was identified as the first orally available antiviral treatment for COVID-19. It binds directly to the SARS-CoV-2 Mpro active site, reversibly inhibiting the protease activity, hence preventing viral replication. To maximise its therapeutic effect, co-administration of nirmatrelvir with another antiviral agent, ritonavir, was suggested. Ritonavir is a CYP3A inhibitor that slows down nirmatrelvir’s metabolism, increasing its circulatory half-life and efficacy.

A co-packaged combination of nirmatrelvir and ritonavir under the trade name (Paxlovid) is being developed by Pfizer. Paxlovid is intended for the treatment and post-exposure prophylaxis of COVID-19. It was first authorized in the USA for emergency use to treat mild-to-moderate COVID-19 in adults and paediatric patients at high risk of progression to severe COVID-19 (including hospitalization or death). Subsequent authorizations of Paxlovid were received in the UK (31 December 2021), Australia (20 January 2022), the EU (28 January 2022), and Canada (January 2022).

These authorizations were under conditional approval schemes where the regulatory agencies awaited further data on Paxlovid. The recommended dosage of Paxlovid is 300mg nirmatrelvir (taken as two 150mg tablets) and 100mg Ritonavir (one 100mg tablet) taken together twice daily for 5 days with or without food. Ideally, treatment should be started as soon as possible after diagnosis with COVID-19 and within the first 5-days of symptom onset. Patients with moderate kidney dysfunction (eGFR > ≥ 30 to < 60 mL/min) would need to adjust the dose to Nirmatrelvir 150mg with Ritonavir 100mg twice daily for 5 days. Those with severe kidney dysfunction (including those with end-stage renal disease under hemodialysis) should not take it.

Two groups of patients for whom Paxlovid is contraindicated are:
– Those taking drugs highly dependent on CYP3A for clearance where elevated concentrations are associated with serious and life-threatening reactions.
– Those receiving potent CYP3A inducers where significant reductions in nirmatrelvir and ritonavir.

plasma concentrations may result in potential loss of virologic response and possible resistance.
Ongoing phase II/III clinical trials continue to collect data on nirmatrelvir plus ritonavir in treating COVID-19.

One of the therapeutic trials where nirmatrelvir plus ritonavir efficacy was assessed is the EPIC-HR trial (NCT04960202). This trial was a randomized, double-blind, placebo-controlled, phase II/III trial where the patients’ eligibility was assessed according to the following criteria:
– Laboratory confirmed SARS-CoV-2 infection.
– COVID-19 symptom onset ≤ 5 days prior to randomization.
– Had at least one risk factor for progression to severe COVID-19 (diabetes, chronic lung or kidney disease, cardiovascular disease, immunosuppression, hypertension, cancer, and being overweight (BMI >25kg/m2) or being ≥ 60 years of age). Those with prior COVID-19 infection or vaccination were excluded.

A total of 2246 patients were randomised in a 1:1 ratio to receive either nirmatrelvir 300mg plus ritonavir 100mg or a placebo administered orally every 12 hours for 5 days. Their median age was 46 years. Most patients were white (71.5%) and had a high BMI (> 25kg/ m2).
Those patients treated within 3 days of symptom onset who at baseline did not receive nor were expected to receive COVID-19 mAb treatment were called the mITT (modified intention-to-treat) population.

Planned interim analysis of data from 774 patients in the mITT population showed a significantly lower rate of incidence of COVID-19-related hospitalizations and any-cause death through day 28, with nirmatrelvir plus ritonavir rather 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%.
The final efficacy results of EPIC-HR were consistent with those from the planned interim analysis, with relative risk reduction of 88.9%Patients treated within 5 days of symptom onset had a relative risk reduction of 87.8% through day 28. Estimated event rates were 9.78% versus 6.40% (difference – 5.63%; 95% CI -7.21 to 4.03%; p<0.001).

Another phase II/III clinical trial, EPIC-SR (NCT05011513), was conducted in a non-hospitalized, standard-risk population with laboratory-confirmed SARS-CoV-2 infection. It included unvaccinated adults (at standard risk of progressing to severe illness – low risk of hospitalization or death) and vaccinated adults with at least one risk factor for progressing.
Patients were randomised to receive either nirmatrelvir plus ritonavir or a placebo every 12 hours for 5 days. In the interim analysis, although the symptoms were not alleviated, there was a 70% reduction in hospitalization and a ≈ 10-fold decrease in viral load with nirmatrelvir plus ritonavir relative to placebo. The final follow-on analysis was consistent with the results from the interim analysis; 0.7% of nirmatrelvir plus ritonavir recipients were hospitalized following randomization, compared to 2.4% of placebo recipients (p=0.051), with no deaths in either group.

Nirmatrelvir plus ritonavir appear to be generally well-tolerated in adult patients with symptomatic COVID-19; however, the safety data available is limited and therefore is not absolute. The most common adverse event of any causality in nirmatrelvir plus ritonavir recipients were dysgeusia, diarrhea, hypertension, and myalgia. Adverse events related to the study drug occurred in 7.8% of nirmatrelvir plus ritonavir recipients versus 3.8% of placebo recipients.