Oral Nirmatrelvir Highly Effective Against COVID-19 in Phase 2/3 Trial

Oral nirmatrelvir, the active protease inhibitor in Pfizer’s COVID-19 pill Paxlovid, was associated with an 89% lower risk for hospitalization or death among high-risk, non-hospitalized adults with COVID-19, phase 2/3 clinical trials found.

The study, published in the New England Journal of Medicine, included 2246 symptomatic, unvaccinated adults with confirmed COVID-19 who were at high risk for developing severe disease due to characterizations such as old age, smoking, cardiovascular disease, diabetes, obesity or cancer. Participants were enrolled at 343 sites around the world between July 16 and Dec. 9, 2021.

The participants were randomized into two groups, with 1120 receiving Paxlovid (300 mg of nirmatrelvir plus 100 mg of ritonavir) and 1126 receiving a placebo every 12 hours for five days. The results showed that Paxlovid reduced the risk of hospitalization or death from any cause by 89% for those who began treatment within three days of symptom onset and by 88% among those who began treatment within five days. Results were consistent across all subgroups.

“This is the first peer-reviewed publication looking at the final analysis of PAXLOVID (nirmatrelvir [PF-07321332] tablets and ritonavir tablets) in our Phase 2/3 study, EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients),” lead author Jennifer Hammond, PhD, of Pfizer told Contagion. “In the final analysis of all patients enrolled, among those who initiated treatment ≤3 days from symptom onset and did not receive monoclonal antibodies (mAbs), 5/697 (0.72%) and 44/682 (6.45%) of patients in the PAXLOVID and placebo groups, respectively, were hospitalized due to COVID-19 or died from any cause through Day 28.”

Among those who initiated treatment within five days of symptom onset, 8/1,039 (0.77%) in the Paxlovid group and 66/1,046 (6.31%) in the placebo group were hospitalized or died through Day 28.

“There were no deaths in patients treated with PAXLOVID, compared to 12 deaths in the placebo group,” Hammond said.

The study also found that the viral load was lower among those in the treatment group by a factor of 10 at Day 5. Adverse events were similar between the two groups, with a rate of any adverse events of 22.6% with Paxlovid compared to 23.9% with placebo and serious adverse events at 1.6% vs. 6.6%. The most common adverse events were dysgeusia, diarrhea, and vomiting.

“The Data Monitoring Committee conducted a planned interim analysis of the trial data in November 2021,” Hammond said. “The statistical criteria required to meet predefined stopping rules were very stringent, and at the time we thought the likelihood of achieving those criteria was low. So, when the Data Monitoring Committee recommended further enrollment be stopped due to evidence of overwhelming efficacy, it was a truly remarkable moment—a very good surprise.”

Nirmatrelvir has shown promise against all variants of concern, including Alpha, Delta and Omicron, with consistent in vitro antiviral activity.

“From what we know, current SARS-CoV-2 mutations can be resistant to treatments that target the spike protein expressed on the surface of the virus,” Hammond said. “However, PAXLOVID works intracellularly on the protease of SARS-CoV-2, which inhibits viral replication. Given the well conserved nature of the protease enzyme, it is expected that PAXLOVID will retain efficacy against current and future variants of concern.”

Hammond noted that ritonavir is a pharmacokinetic enhancer used to slow the metabolism of nirmatrelvir and may result in drug interactions, which should be manageable given the short duration and low dose of the treatment.

“Additional Phase 2/3 clinical trials are ongoing in adults at standard risk (i.e., low risk of hospitalization or death) of progressing to severe illness, and in those who have been exposed to the virus through household contacts,” Hammond said. “We will share the final results upon completion of each of these studies, anticipated later this year. We also plan to start studying other populations, such as children, and will share updates as we have them.”

In December, Paxlovid was the first oral antiviral to receive emergency use authorization from the U.S. Food and Drug Administration after the company announced unpublished interim data from its phase 2/3 trial in November.

The study provides guidance on how to distribute the treatment, Eric J. Rubin, MD, PhD, and Lindsey R. Baden, MD, wrote in an associated editorial. They noted that absolute risk reduction is greatest among patients at the highest risk and that initiating therapy within five days of symptom onset is likely to be critical.

“It will be very important to assess patients individually, since ritonavir interferes with the metabolism of many therapeutic agents, from antiseizure to immunosuppressive to anticoagulant medications,” they wrote. “And, finally, 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.”