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4th July 2022
The effectiveness of the anti-viral drug paxlovid in preventing the progression of COVID-19 remains even in those who have been adequately vaccinated against the virus according to the results of a real-world study by Israeli researchers.
Paxlovid consists of nirmatrelivir, a protease inhibitor against COVID-19 and ritonavir, which reduces the in vivo metabolism of nirmatrelivir. The published data for the drug (the EPIC-HR trial) suggested that treatment of symptomatic COVID-19 in patients at risk of progression to severe disease, results in an 89% lower risk compared to placebo. Nevertheless, the study was undertaken before omicron became the main circulating variant and therefore the generalisability of the study’s findings are potentially limited. Consequently, for the present study, the Israeli team decided to undertake a large, retrospective cohort study of high-risk COVID-19 patients, to assess the effectiveness of paxlovid at preventing progression to severe COVID-19 and subsequent death during the time when omicron was the predominant strain.
Using a large, national health service database, the researchers identified all adults (18 years and over) who tested positive for COVID-19 but restricted the search to those who would be suitable candidates for treatment with paxlovid, i.e., those who were older than 60 years, with a body mass index (BMI) greater than 30 and with co-morbidities including diabetes, hypertension and cardiovascular disease. However, unlike in the EPIC-HR trial, where those who had been vaccinated were excluded, for the present analysis, researchers included patients, regardless of their vaccination status. The main outcome of the study was a composite of severe COVID-19 or COVID-19-related mortality. For their analysis, the researchers included demographic and co-morbidity data and which were adjusted for in the analysis.
Paxlovid and progression of COVID-19
A total of 4,737 individuals with a mean age of 68.5 years (42.1% male) were treated with paxlovid and compared with 175,614 individuals who tested positive but who did not receive the drug. In total, 77.8% of those given paxlovid had adequate COVID-19 vaccination compared to 75% of those in the non-paxlovid group.
Overall, the primary outcome occurred in 39 individuals receiving paxlovid compared to 903 in those not given the drug. Paxlovid was therefore associated with a significantly lower risk of severe COVID-19 or mortality (hazard ratio, HR = 0.54, 95% CI 0.39 – 0.75). Moreover, among the whole cohort, having adequate COVID-19 vaccination, was also associated with a significantly lower risk of the primary outcome (HR = 0.20, 95% CI 0.17 – 0.22).
When the analysis was restricted to those diagnosed with COVID-19 when omicron was the main circulating variant, paxlovid was also associated with a greater reduction in the primary endpoint (HR = 0.43, 95% CI 0.64 – 0.85). Interestingly, among those given paxlovid and who were adequately vaccinated, there was still a significant reduction in the primary outcome (HR = 0.62, 95% CI 0.39 – 0.98) as well as among those not vaccinated (HR = 0.52, 95% CI 0.32 – 0.82).
The authors concluded that their study had demonstrated that in a real-world setting and during the period of time when omicron was the dominant variant, paxlovid was associated with a significant reduction in progression of COVID-19 and COVID-19-related mortality.
Najjar-Debbiny R et al. Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients Clin Infect Dis 2022
21st June 2022
According to the results of a press release from the manufacturer, Pfizer, paxlovid does not benefit patients who are either unvaccinated or vaccinated and who are deemed not at a high risk of severe complications such as hospitalisation or death if infected with COVID-19.
Paxlovid is a protease inhibitor antiviral therapy against COVID-19 and was developed to be taken orally, at the first sign of infection or at first awareness of an exposure. The early use of the drug could therefore help patients avoid severe illness and which might lead to hospitalisation or death, or avoid disease development following contact with an infected individual.
The June 2022 press release, follows on from the success of the results from an earlier trial, EPIC-HR, in which symptomatic, unvaccinated, non-hospitalised adults, at high risk for progression to severe COVID-19, were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelivir plus 100 mg of ritonavir (i.e., Paxlovid) or placebo every 12 hours for 5 days. The results of EPIC-HR were published in February 2022 and showed that treatment of symptomatic COVID-19 with paxlovid reduced the risk of progression to severe COVID-19 by 89% compared to placebo and without any major safety concerns. Based on these encouraging results, both the FDA and EMA approved the use of paxlovid for the treatment of mild-to-moderate COVID-19 in adults and children (12 years and older) who were deemed to be at high risk for progression to severe COVID-19, including hospitalisation or death.
With the success of their drug in high-risk patients, Pfizer proceeded with EPIC-SR, a phase 2/3 trial entitled, Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR). This time, the trial was designed to evaluate efficacy and safety in patients with a confirmed diagnosis of COVID-19 infection and who were deemed to be at standard risk (i.e., having a low risk for either hospitalisation or death). Enrolled participants were randomised 1:1, to receive paxlovid or matching placebo orally twice daily for five days.
Paxlovid in low-risk patients
The latest press release provides an updated analysis of the results from the EPIC-SR trial. The trial’s primary endpoint was self-reported, sustained alleviation of all (COVID-19) symptoms for four consecutive days. In an earlier press release from December 2021, Pfizer reported that primary endpoint in EPIC-SR was not met although this was based on an analysis of only 45% of the trial’s planned enrolment. Based on an updated analysis of 1,153 patients enrolled through December 2021, the current press release re-affirms, the results of the earlier, interim analysis. The data show that there was a non-significant 51% relative risk reduction in the primary outcome and in a sub-group analysis of 721 vaccinated adults who had at least one risk factor for progression to severe COVID-19, there was also a 57% non-significant relative risk reduction in hospitalisation or death.
However, not all of the current data is negative. When performing an additional analysis of secondary endpoint data, treatment with Paxlovid resulted in a nominally significant 62% decrease in COVID-19-related medical visits per day across all patients, relative to placebo (p = 0.0228).
Following these results, the press release reports that Pfizer has decided to cease enrolment into EPIC-SR due to low rate of hospitalisation or death in the standard-risk population but will continue to evaluate treatment in populations with high unmet need.
9th November 2021
Paxlovid given within three days of symptom onset to patients with COVID-19 significantly reduced the risk of hospitalisation and death. These were the results of an interim analysis posted by the manufacturer, Pfizer.
Paxlovid is a combination of Pfizer’s experimental drug (PF-00835231) and ritonavir. Both are protease inhibitors, a class of anti-viral drugs that have been used in the treatment of viral infections such as HIV and hepatitis C. COVID-19 produces a protease termed Mpro, which is vital to viral replication, and PF-00835231 been been found to be a potent inhibitor of Mpro. According to the manufacturer, co-administration of PF-00835231 and a low dose of ritonavir helps slow the metabolism of PF-07321332 so that it remains active for a longer period of time and at higher concentrations to help combat the virus.
In a clinical study, Paxlovid was used for the treatment of adults infected with COVID-19 but who, at the time of their illness, were not deemed sufficiently unwell to require hospitalisation but who were, however, considered to be at a higher risk of developing more severe illness. The study, Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR), is a randomised, 1:1, double-blind study, in which individuals received paxlovid or placebo orally every 12 hours for 5 days. The primary outcome of the study was the proportion of participants with COVID-19 related hospitalisation or death from any cause between days 1 and 28 after randomisation.
According to a pre-specified interim analysis based on 1219 participants, there was an 89% reduction in risk of COVID-19-related hospitalisation or death from any cause compared to placebo, in patients treated within three days of symptom onset. Overall, 3/389 (0.8%) who received paxlovid were hospitalised through to day 28 and there were no deaths but among 385 participants assigned to placebo, 27/395 (7.0%) were hospitalised and there were 7 deaths and this difference compared with Paxlovid was statistically significant (p < 0.0001).
Among patients treated within 5 days of symptom onset, 1.0% of those given Paxlovid were hospitalised through to day 28 (6/607) compared with 6.7% (41/612) of those given placebo (p < 0.0001). Moreover, to date, there have been no deaths were reported in patients receiving Paxlovid and 10 deaths in the placebo group.
According to the press release, based on a recommendation of the independent data monitoring committee and after consultation with the FDA, Pfizer will cease further enrolment and submit the data for the FDA’s emergency use authorisation (EUA) as soon as possible.
Further trials with Paxlovid are on-going and the company will release these results in due course.
Source. Pfizer press release, 5/11/2021