====== 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 [[pharmaceutical_companies:pfizer|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. ===== Authorizations ===== * 22 December 2021: EUA(([[https://www.fda.gov/media/155049/download]])) 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 approval(([[https://www.gov.uk/government/news/oral-covid-19-antiviral-paxlovid-approved-by-uk-regulator]])) 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.((https://covid-vaccine.canada.ca/info/regulatory-decision-summary-detail.html?linkID=RDS00904)) ===== Clinical Trials ===== 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. \\ || NCT04960202 | EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19 || ||NCT05047601 | A Post-Exposure Prophylaxis Study of PF-07321332/Ritonavir in Adult Household Contacts of an Individual With Symptomatic COVID-19 || || NCT05011513 | Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR) || || NCT05032950 | Drug-Drug Interaction Study to Estimate the Effect of PF-07321332/Ritonavir and Ritonavir on Midazolam in Healthy Participants || || NCT04962022 |Drug-Drug Interaction Study Assessing Effect of Itraconazole on PF-07321332/Ritonavir in Healthy Participants || || NCT04909853 | Renal Impairment Study of PF-07321332 Boosted With Ritonavir in Adult Participants With Renal Impairment and in Healthy Participants With Normal Renal Function || || NCT05005312 | Study to Estimate the Effects of Hepatic Impairment on the Pharmacokinetics (PK) of PF-07321332 || || NCT05129475 | Food Effect Study to Evaluate the Effect of High-Fat Meal on the Relative Bioavailability of PF-07321332 Boosted With Ritonavir in Healthy Adult Participants || || NCT05064800 | PF-07321332/Ritonavir and Ritonavir on Dabigatran Study in Healthy Participants || ==== Press Releases ==== 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.((November 5, 2021 | Pfizer | [[https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate|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]])) 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 ===== 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."((Blackwell, T. (2022, January 25). //Pfizer anti-COVID pill’s dangerous interaction with common drugs will narrow its benefit, experts say.// National Post; Postmedia Network Inc. https://archive.ph/hfU0L)) ===== Articles in Medical Journals ===== [[https://www.bmj.com/content/375/bmj.n2611|Editorial: Safety and efficacy of antivirals against SARS-CoV-2]] \\ [[https://link.springer.com/article/10.1007/s13238-021-00883-2|Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332]] \\ [[https://www.tandfonline.com/doi/full/10.1080/14756366.2021.1954919|Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332]] \\ [[https://www.mdpi.com/1422-0067/22/17/9124|Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations]] \\ [[https://www.sciencedirect.com/science/article/pii/S1879625721000407|Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection]] \\ [[https://www.biorxiv.org/content/10.1101/2021.11.04.467077v1.abstract|The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern]] \\ [[https://www.science.org/doi/full/10.1126/science.abl4784|An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19]] \\ [[https://pubs.rsc.org/en/content/articlelanding/2021/cc/d1cc03953a/unauth|Computational simulations on the binding and reactivity of a nitrile inhibitor of the SARS-CoV-2 main protease†]] \\ ===== In the News ===== [[https://www.bmj.com/content/375/bmj.n2602.full|Covid-19: UK stockpiles two unapproved antiviral drugs for treatment at home]] \\ [[https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate|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]] \\ [[https://markets.businessinsider.com/news/stocks/pfizer-s-covid-19-franchise-could-push-revenue-past-100b-in-2022-analyst-1030999039|SVB Leerink analyst Geoffrey Porges forecasts Paxlovid revenues of $95 million in 2021, $24 billion in 2022, and $33 billion in 2023.]] \\ [[https://www.pharmaceutical-technology.com/features/paxlovid-pfizer-covid-19-pill/ | Paxlovid: what we know about Pfizer’s Covid-19 pill]]. \\ [[https://www.bloomberg.com/news/articles/2022-02-03/drug-maker-merck-s-antiviral-covid-pill-fumble-gives-pfizer-17-billion-win|Merck’s Covid Pill Fumble Gives Pfizer Potential $17 Billion Win]] ===== Sales ===== || **Country** | **Doses Secured** | **Price** | **Date** || ||Canada | 1,000,000 | ??? | 3 Dec 2021 || ||USA | 10,000,000 | $5.29 billion | 18 Nov 2021 || ||UK | 250,000 | ??? | Nov 2021 || ||Israel | tens of thousands | ??? | 15 Nov 2021 || ||USA | 10,000,000 | ??? | 04 Jan 2022 || 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