PAXLOVID™ (PF-07321332; ritonavir)

Paxlovid is a novel, COVID-19, oral, antiviral candidate. PAXLOVID™ is a SARS-CoV-2-3CL protease (an enzyme that the coronavirus needs to replicate) inhibitor, which originated in Pfizer’s laboratories. It may have efficacy as a prophylaxis and/or outpatient treatment. 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.

• 22 December 2021: EUA¹⁾ in the USA for patients 12 years of age and older weighing at least 40 kg with mild-to-moderate COVID-19, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
• 31 December 2021: UK MHRA grants approval²⁾ to Pfizer’s oral antiviral for Covid-19 for mild to moderate COVID-19 infected patients who are at an increased risk of developing severe disease.
• 16 January 2022: Canada’s health regulator has approved Paxlovid.³⁾

The Phase 2/3 EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) 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, began in August and September 2021 respectively.

On Friday, November 5, 2021, Pfizer issued a stunningly optimistic press release for a new drug, stating “overwhelming efficacy” and a risk reduction of 89% for hospitalization and death from COVID-19.⁴⁾ The press release claimed that after 28 days there were 0 deaths in the treatment arm and 10 in the placebo arm, with 41 vs. 6 hospitalizations.

Adverse events in the PAXLOVID group (≥1%) that occurred at a greater frequency (≥5 subject difference) than in the placebo group were dysgeusia (6% and <1%, respectively), diarrhea (3% and 2%), and hypertension (1% and <1%), and myalgia (1% and <1%). The proportions of subjects who discontinued treatment due to an adverse event were 2% in the PAXLOVID group and 4% in the placebo group.

The National Post reported that a component of the drug can “interact dangerously with a slew of commonly used medications, pumping up the potency of blood thinners, heart-arrhythmia therapies, epilepsy drugs and others. And the patients targeted for its use – those most at risk of serious COVID disease because of age and other health issues – are also the people most likely to be taking those 'contraindicated' medications.”⁵⁾

Editorial: Safety and efficacy of antivirals against SARS-CoV-2
Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332
Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332
Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations
Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection
The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern
An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19
Computational simulations on the binding and reactivity of a nitrile inhibitor of the SARS-CoV-2 main protease†

Covid-19: UK stockpiles two unapproved antiviral drugs for treatment at home
PFIZER’S NOVEL COVID-19 ORAL ANTIVIRAL TREATMENT CANDIDATE REDUCED RISK OF HOSPITALIZATION OR DEATH BY 89% IN INTERIM ANALYSIS OF PHASE 2/3 EPIC-HR STUDY
SVB Leerink analyst Geoffrey Porges forecasts Paxlovid revenues of $95 million in 2021, $24 billion in 2022, and $33 billion in 2023.
Paxlovid: what we know about Pfizer’s Covid-19 pill.
Merck’s Covid Pill Fumble Gives Pfizer Potential $17 Billion Win

An Alternate View

Note that there is no peer-reviewed article available describing the clinical trial and its results, nor is there even an FDA Briefing Document that I (JMG) can find for review. Literally everything we know about this medication so far has come from Pfizer, largely thru press releases and other communications.

For a somewhat jaundiced view of this medication see

https://joelshirschhorn.substack.com/p/paxlovid-what-we-should-know-about?r=1tk31&utm_campaign=post&utm_medium=web