Oral nirmatrelvir, the active protease inhibitor in Pfizer’s COVID-19 pill Paxlovid, was associated with an 89% lower risk of hospitalization or high-risk death among non-hospitalized adults with COVID-19, phase 2/3 clinical trials found.
The study, published in New England Journal of Medicine, included 2246 symptomatic, unvaccinated adults with confirmed COVID-19 who were at high risk of developing serious illness due to characteristics such as old age, smoking, cardiovascular disease, diabetes, obesity or cancer. Participants were registered in 343 locations around the world between July 16 and December 9, 2021.
Participants were randomized into two groups, with 1120 receiving Paxlovid (300 mg nirmatrelvir plus 100 mg ritonavir) and 1126 receiving placebo every 12 hours for five days. The results showed that Paxlovid reduced the risk of hospitalization or death by any cause by 89% for those who started treatment within three days of symptom onset and by 88% among those who started treatment within five days. The 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 inches Hhigh-RPatients), ”said lead author Jennifer Hammond, PhD, of Pfizer Infection. In the final analysis of all included patients, among those who started treatment ≤3 days from symptom onset and did not receive monoclonal antibodies (mAbs), 5/697 (0.72%) and 44/682 (6.45%) of the patients in PAXLOVID and placebo groups were hospitalized for COVID-19 or died of any cause during day 28, respectively. “
Among those who started 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 by 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 on day 5. Adverse reactions were similar between the two groups, with a frequency of possible adverse reactions of 22.6% with Paxlovid compared to 23.9% with placebo and serious adverse reactions of 1.6% versus 6.6%. The most common side effects were dysgeusia, diarrhea and vomiting.
“The Data Monitoring Committee conducted a planned preliminary analysis of the experimental data in November 2021,” Hammond said. “The statistical criteria required to meet predefined stop rules were very strict, and at the time we thought the probability of meeting these criteria was low. So when the Data Monitoring Committee recommended that further enrollment be stopped due to evidence of overwhelming efficiency, it was a truly remarkable moment – a very good surprise. “
Nirmatrelvir has been shown to be promising 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 may be resistant to treatments targeting the tip protein expressed on the surface of the virus,” Hammond said. “However, PAXLOVID acts intracellularly on the protease of SARS-CoV-2, which inhibits viral replication. Given the well-preserved nature of the protease enzyme, it is expected that PAXLOVID will maintain its efficacy against current and future variants of concern.”
Hammond noted that ritonavir is a pharmacokinetic enhancer that is used to slow down the metabolism of nirmatrelvir and may result in drug interactions that should be manageable given the short duration and low dose of treatment.
“Additional phase 2/3 clinical trials are underway with adults at standard risk (ie, low risk of hospitalization or death) to develop into serious illness, and in those who have been exposed to the virus through household contacts,” Hammond said. “We will share the final results after the completion of each of these surveys, which are expected later this year. We also plan to begin studying other population groups, such as children, and will share updates as we have them.”
IN DecemberPaxlovid was the first oral antiviral drug to receive an emergency use permit from the US Food and Drug Administration after the company announced unpublished temporary data from its Phase 2/3 trial in November.
The study provides guidance on how to distribute treatment, wrote Eric J. Rubin, MD, PhD, and Lindsey R. Baden, MD, in a associated editorial staff. They noted that the absolute risk reduction is greatest among patients with the highest risk, and that initiating treatment within five days of symptom onset is likely to be critical.
“It will be very important to evaluate patients individually as ritonavir interferes with the metabolism of many therapeutic agents, from anti-seizure to immunosuppressive to anticoagulant drugs,” they wrote. “And finally, until we have a better idea of the potential for the emergence of resistance, we must be good stewards of this drug. By limiting its use to those who are most likely to benefit from it, we can potentially extend its useful life. “