Nirmatrelvir/ritonavir combo antiviral yields EPIC results for hospitalization, deaths

A new oral COVID-19 antiviral therapy comprising nirmatrelvir and ritonavir substantially slashes the risk of hospitalization or death compared with placebo in nonhospitalized adults with COVID-19 who are at high risk of developing severe illness, according to final analysis of the EPIC-HR* study. 

The findings came hot on the heels of molnupiravir — another investigational oral antiviral against COVID-19 that is jointly developed by Merck and Ridgeback — which has recently just cleared the FDA advisory panel in early December to be considered for authorization.

The new combination oral antiviral therapy, developed by Pfizer, contains the SARS-CoV-2-3CL protease inhibitor nirmatrelvir and the HIV antiretroviral, ritonavir. Nirmatrelvir blocks the SARS-CoV-2-3CL protease enzyme needed for viral replication while ritonavir prevents the breakdown of nirmatrelvir.

Through 28 days of follow-up, the combination antiviral therapy significantly reduced the risk of COVID-19-related hospitalization or all-cause death by 89 percent compared with placebo in high-risk patients who received the treatment within 3 days of symptom onset (0.7 percent vs 6.5 percent; p<0.0001), consistent with the interim results released a month earlier. 

In a secondary analysis of patients treated within 5 days of symptom onset, the risk reduction was similarly high at 88 percent (rate, 0.8 percent vs 6.3 percent; p<0.0001). 

When stratifying the analysis by age, the researchers found that the relative risk reduction with the combination antiviral therapy was as high as 94 percent in those aged ≥65 years (rate, 1.1 percent vs 16.3 percent for combination antiviral therapy vs placebo; p<0.0001) — which represent one of the patient groups at high risk of hospitalization or death.

In the overall population, there were no deaths among the patients treated with the combination antiviral therapy while 12 have died in the placebo group by day 28.

Among a subset of patient with available data on SARS-CoV-2 viral load at baseline and day 5 (n=499), the combination antiviral therapy led to a 10-fold reduction in viral load (change, -0.93 log₁₀ copies/mL) compared with placebo. This shows that the therapy has robust activity against the virus, which according to experts, represents “the strongest viral load reduction reported to date for an oral COVID-19 agent.”

“Emerging variants of concern, like Omicron, have exacerbated the need for accessible treatment options for those who contract the virus,” said Pfizer’s Chairman and CEO, Albert Bourla, in a company statement. “[These findings] provide further corroboration that our oral antiviral candidate, if authorized or approved, could have a meaningful impact on the lives of many … patients around the world.”

The implications are huge — for one, having such an effective antiviral pill means that fewer people would develop severe illness from COVID-19 and prevent hospitals from getting overwhelmed. In addition, it is taken orally and thus provides a more accessible option for outpatients to recover — unlike remdesivir which is given intravenously for hospitalized patients.    

Already, there is indication that nirmatrelvir has the potential to maintain robust activity against the Omicron variant. Based on preliminary findings from in vitro biochemical assay, nirmatrelvir has shown potent inhibition of the 3CL protease of Omicron, in addition to other existing variants of concerns including alpha, beta, delta, gamma, lambda, and mu. 

Further in vitro antiviral studies on Omicron are currently underway, according to researchers.

Participants in the phase II/III EPIC-HR study were 2,246 adults with mild to moderate SARS-CoV-2 infection diagnosed within 5 days, who were randomized 1:1 to the oral combination antiviral therapy or placebo twice a day at 12 hours interval for 5 days. All patients had at least one risk factor associated with an increased risk of progressing to severe illness.

The rates of treatment-emergent adverse events (TRAEs) were similar between the antiviral and the placebo groups (23 percent vs 24 percent)—most of which, according to the researchers, were mild in intensity. Patients treated with the combination antiviral therapy had fewer serious AEs (1.6 percent vs 6.6 percent) and AEs leading to drug discontinuation (2.1 percent vs 4.2 percent) compared with placebo.

“If authorized or approved, this potential treatment could be a critical tool to help quell the pandemic,” said Bourla.

Not a silver bullet

Nonetheless, as impressive as the findings were for the oral antiviral in high-risk outpatients with COVID-19, Bourla warned that while it serves as an important additional tool in the fight against COVID-19, it should not replace vaccines.

Vaccines remain the primary frontier to prevent people from getting infected by SARS-CoV-2 in the first place, according to Bourla. The goal is not to get sick, rather than to get sick and then hope for a medicine that will save you, he said.

In another separate study (EPIC-SR**) which included unvaccinated COVID-19 cases at standard risk starting the combination antiviral therapy within 5 days of COVID-19 diagnosis also reduced the risk of hospitalization or death, this time by 70 percent (rate, 0.7 percent vs 2.4 percent; p=0.051).

This interim analysis of the phase II/III EPIC-SR trial included 673 adults with mild to moderate SARS-CoV-2 infection diagnosed within 5 days. Unlike the above EPIC-HR trial, the EPIC-SR enrolled unvaccinated adults low risk of hospitalization or death (considered as standard-risk population), in addition to vaccinated cases at high risk. Randomization and dosing was similar to that of EPIC-HR.

The primary outcome of self-reported, sustained relief of all symptoms for four days in a row, though, was not met in the interim analysis.

Is it for every one?

Unlike molnupiravir which works by introducing mutations into the viral genome, nirmatrelvir/ritonavir interferes with the processing of certain viral proteins into a functional form.

While nirmatrelvir/ritonavir might not come with the potential risk of genomic mutation of the human cells, experts raised concerns about potential drug-drug interactions with ritonavir contained in the combination therapy. Many commonly used drugs including those to treat heart conditions and pain should not be used together with ritonavir.

Nonetheless, experts believed that in time to come, doctors might find ways to work around this issue and understand when and to whom can it be given.

On 22nd Dec, the US FDA has granted emergency use authorization for the use of nirmatrelvir/ritonavir in high-risk COVID-19 patients, making it the first oral antiviral to be conferred such status by the FDA.

 

*EPIC-HR: Evaluation of Protease Inhibition for COVID-19 in High-Risk patients

**EPIC-SR: Evaluation of Protease Inhibition for COVID-19 in Standard-Risk patients