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Pfizer has announced its investigational novel COVID-19 oral antiviral candidate, Paxlovid, has significantly reduced hospitalization and death, based on an interim analysis of the phase 2/3 EPIC-HR ( Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients ) randomized, double-blind study of non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness.

The scheduled interim analysis has shown an 89% reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset ( primary endpoint ); 0.8% of patients who received Paxlovid were hospitalized through day 28 following randomization ( 3/389 hospitalized with no deaths ), compared to 7.0% of patients who received placebo and were hospitalized or died ( 27/385 hospitalized with 7 subsequent deaths ).
The statistical significance of these results was high ( p less than 0.0001 ).

Similar reductions in COVID-19-related hospitalization or death were observed in patients treated within five days of symptom onset; 1.0% of patients who received Paxlovid were hospitalized through day 28 following randomization ( 6/607 hospitalized, with no deaths ), compared to 6.7% of patients who received a placebo ( 41/612 hospitalized with 10 subsequent deaths ), with high statistical significance ( p less than 0.0001 ).

In the overall study population through day 28, no deaths were reported in patients who received Paxlovid as compared to 10 ( 1.6% ) deaths in patients who received placebo.

Paxlovid is an investigational SARS-CoV-2 protease inhibitor antiviral therapy, specifically designed to be administered orally so that it can be prescribed at the first sign of infection or at first awareness of an exposure, potentially helping patients avoid severe illness which can lead to hospitalization and death.
PF-07321332 is designed to block the activity of the SARS-CoV-2-3CL protease, an enzyme that the coronavirus needs to replicate.
Co-administration with a low dose of Ritonavir helps slow the metabolism, or breakdown, of PF-07321332 in order for it to remain active in the body for longer periods of time at higher concentrations to help combat the virus.

PF-07321332 inhibits viral replication at a stage known as proteolysis, which occurs before viral RNA replication.
In preclinical studies, PF-07321332 did not demonstrate evidence of mutagenic DNA interactions.

If approved or authorized, Paxlovid, would be the first oral antiviral of its kind, a specifically designed SARS-CoV-2-3CL protease inhibitor.
Upon successful completion of the remainder of the EPIC clinical development program and subject to approval or authorization, it could be prescribed more broadly as an at-home treatment to help reduce illness severity, hospitalizations, and deaths, as well as reduce the probability of infection following exposure, among adults. It has demonstrated potent antiviral in vitro activity against circulating variants of concern, as well as other known coronaviruses, suggesting its potential as a therapeutic for multiple types of coronavirus infections.

The phase 2/3 EPIC-HR study began enrollment in July 2021. The phase 2/3 EPIC-SR ( Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients ) and EPIC-PEP ( Evaluation of Protease Inhibition for COVID-19 in Post-Exposure Prophylaxis ) studies, which began in August and September 2021 respectively, were not included in this interim analysis and are ongoing.

Phase 2/3 EPIC-HR study interim analysis

The primary analysis of the interim data set evaluated data from 1219 adults who were enrolled by September 29, 2021.
At the time of the decision to stop recruiting patients, enrollment was at 70% of the 3,000 planned patients from clinical trial sites across North and South America, Europe, Africa, and Asia, with 45% of patients located in the United States.
Enrolled individuals had a laboratory-confirmed diagnosis of SARS-CoV-2 infection within a five-day period with mild to moderate symptoms and were required to have at least one characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19. Each patient was randomized ( 1:1 ) to receive Paxlovid or placebo orally every 12 hours for five days.

Phase 2/3 EPIC-HR study safety data

The review of safety data has included a larger cohort of 1881 patients in EPIC-HR, whose data were available at the time of the analysis.
Treatment-emergent adverse events were comparable between Paxlovid ( 19% ) and placebo ( 21% ), most of which were mild in intensity.
Among the patients evaluable for treatment-emergent adverse events, fewer serious adverse events ( 1.7% vs. 6.6% ) and discontinuation of study drug due to adverse events ( 2.1% vs. 4.1% ) were observed in patients dosed with Paxlovid compared to placebo, respectively. ( Xagena )

Source: Pfizer, 2021

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