PAXLOVID™ Oral Antiviral May 2023
Pfizer Inc. Paxlovid™ (nirmatrelvir, Bexovid, ritonavir, PF-07321332) is an Aprroved oral antiviral targeting the SARS-CoV-2 beta coronavirus to prevent COVID-19. Paxlovid is packaged with nirmatrelvir and ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor. Nirmatrelvir, a novel main protease (Mpro) inhibitor originating in Pfizer's laboratories, is specifically designed to block the activity of the SARS-CoV-2 Mpro, an enzyme the novel coronavirus needs to replicate. It is an analog of GC373, where the aldehyde covalent cysteine acceptor replaced a nitrile.
Paxlovid works intracellularly, inhibiting viral replication at a stage known as proteolysis, which occurs before viral RNA replication. Protease inhibitors bind to a viral enzyme, preventing the virus from replicating in the cell. A study published on March 29, 2023, concluded multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid).
Pfizer developed PF-07321332 by modifying PF-07304814 (Lufotrelvir), a covalent inhibitor. PF-07321332 is also a covalent inhibitor, but its warhead is a phosphate prodrug, a hydroxyketone. Paxlovid is co-administration with a low dose of ritonavir, a strong cytochrome P450 (CYP) 3A inhibitor, to slow the metabolism or breakdown of Paxlovid and to remain active in the body for more extended periods at higher concentrations to help combat the virus. In preclinical studies, PF-07321332 did not demonstrate evidence of mutagenic DNA interactions. However, Paxlovid has complex drug-drug interactions, primarily due to the ritonavir component.
Paxlovid became the first orally administered coronavirus-specific investigational protease inhibitor authorized under Emergency Use Authorization (EUA) for certain adults and children by the U.S. Food and Drug Administration (FDA) on Dec. 22, 2021. Then on Jan. 28, 2022, the European Medicines Agency (EMA) and European Commission granted Pfizer Europe MA EEIG marketing authorization EMEA/H/C/005973 for adults. As a result, effective from Feb. 10, 2022, Paxlovid was added as a first-line treatment option for patients with hospital-onset COVID infection in the United Kingdom (U.K.). The FDA issued its Approval on May 25, 2023.
The World Health Organization (WHO) made a strong recommendation on Apr. 22, 2022, for Paxlovid, for mild and moderate COVID-19 patients at the highest risk of hospital admission, calling it the best therapeutic choice for high-risk patients to date. Paxlovid treatment should be initiated within days of disease symptom onset, says the U.S. NIH and the U.S. Centers for Disease Control and Prevention (CDC) on Dec. 5, 2022. On Dec. 20, 2022, Pfizer Inc. announced that the U.S. FDA extended the review period for the New Drug Application (NDA) of PAXLOVID, which remains available to eligible U.S. patients under a EUA. On Feb. 1, 2023, the FDA issued a revised EUA #105.
Please see the EUA Prescribing Information available at fda.gov and COVID19oralRx.com. Chemical Formula: C23H32F3N5O4; DrugBank Accession Number DB16691; CAS Number 2628280-40-8; PubChem CID 155903259; Molecular Weight: 499.5. Contact COVID19Therapeutics@hhs.gov with any questions. To learn more, please visit New York-based Pfizer Inc. at www.Pfizer.com. (NYSE: PFE).
PAXLOVID Availability May 2023
As of May 2023, Paxlovid (Bexovid, nirmatrelvir, ritonavir) was authorized by about 65 countries, including Australia, Bahrain, Canada, China, Europe, Israel, Japan, Greece, Singapore, South Africa, South Korea, Switzerland, the United Kingdom, Malaysia, Ontario, Quebec, New Brunswick, the Philippines, Taiwan, Malaysia, and Mexico. Pfizer expects a 58% reduction in 2023-distribution-related revenues.
During the U.S. FDA Emergency Use Authorization, PAXLOVID™, there is no price to the patient; however, there may be related services fees. The original Paxlovid price without insurance was about $530. Additional Paxlovid price and discount information is posted at InstantRx™.
PAXLOVID SARS-CoV-2 Sublineages
Current coronavirus variants can be resistant to treatments and vaccines that work by binding to the spike protein found on the surface of the SARS-CoV-2 virus. PAXLOVID, however, works intracellularly by binding to the highly conserved Mpro (3CL protease) of the SARS-CoV-2 virus to inhibit viral replication. Nirmatrelvir has consistently shown in vitro antiviral activity against the following variants: Alpha, Beta, Delta, Gamma, Lambda, Mu, and Omicron. The U.S. NIH OpenData Portal reports nirmatrelvir (Paxlovid's main ingredient), excluding ritonavir, in vitro Therapeutic Activity against SARS-CoV-2 coronavirus variants, as does the U.K.'s CoVariants.
On March 29, 2023, Science published a study that found multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (Paxlovid), and encourages the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.
The JAMA Network published a study based in Japan on December 6, 2022, focused on the Incidence of Viral Rebound After Treatment With Nirmatrelvir-Ritonavir, which found viral rebound was uncommon in adults with COVID-19 after treatment with nirmatrelvir-ritonavir. A total of 13 studies involving 186,306 patients were identified in the final analysis published on Sept. 30, 2022. This research shows that the overall Odds Ration of rebound among COVID-19 patients in the Paxlovid vs. control group was 0.99 (95% CI, 0.28-3.57; I2 =59%), P =0.99.
The U.S. FDA acknowledged cases on May 4, 2022, stating it 'was aware of the reports of some patients developing recurrent COVID-19 symptoms after completing a treatment course of Paxlovid.'
PAXLOVID Drug Interactions
As of December 30, 2022, Medscape identifies 44 Paxlovid drug interactions. Pfizer confirms PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product and with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. Before prescribing ritonavir-boosted nirmatrelvir, clinicians should carefully review the patient's concomitant medications, including over-the-counter medicines, herbal supplements, and recreational drugs, says the U.S. NIH.
The FDA provided additional guidance on June 3, 2022, to help prescribers evaluate potential drug interactions when using Paxlovid therapy for COVID-19. Prescribers should review each patient's full list of medications and use other resources to evaluate for potential drug interactions in patients who take medications that are not included on the Fact Sheet or checklist at this time (a listing of additional resources is provided at the end of the checklist). Please see the updated Prescriber Patient Eligibility Screening Checklist for more information."
On Feb. 24, 2022, the NIH published 'Ritonavir-boosted nirmatrelvir (Paxlovid) has significant and complex drug-drug interaction potential, primarily due to the ritonavir component of the combination. Clinicians who are not experienced in prescribing ritonavir-boosted drugs should refer to resources such as the EUA fact sheet for ritonavir-boosted nirmatrelvir (Paxlovid) and the Liverpool COVID-19 Drug Interactions website for additional guidance.
The two active substances of the medicine, PF-07321332, and ritonavir, are available as separate tablets. The EMA confirmed: (1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; ritonavir.
Please see Full EUA Prescribing Information at COVID19oralRx.com.
PAXLOVID oral antiviral therapy prevents the SARS-CoV-2 virus from replicating in human host cells. When administered as an early-stage treatment, Paxlovid might prevent COVID-19–related hospitalization among persons with mild-to-moderate COVID-19 who are at risk for progression to severe disease, stated the U.S. CDC's MMWR published on Jun. 21, 2022. On Dec. 13, 2022, Original Research published by the Annals of Internal Medicines - Nirmatrelvir Plus Ritonavir for Early COVID-19 in a U.S. Health System - concluded the overall risk for hospitalization or death was already low (1%) after an outpatient diagnosis of COVID-19, but Paxlovid uses reduced this risk further.
The U.S. NIH stated on Feb 24, 2022, 'The EPIC-HR trial excluded pregnant and lactating individuals. Ritonavir has been used extensively during pregnancy in people with HIV, suggesting an acceptable safety profile during pregnancy. Based on the mechanisms of action for both nirmatrelvir and ritonavir and the available animal data, the Panel would not withhold ritonavir-boosted nirmatrelvir from a pregnant patient if the potential benefits outweighed the potential risks.'
Pfizer confirmed on Mar. 9, 2022; the EPIC-PEDS Phase 2/3 trial is an open-label, multicenter, single-arm study in approximately 140 pediatric participants under 18 years of age. Cohort 1 includes participants aged 6 to 17 weighing at least 88 lbs, and Cohort 2 includes those aged 6 to 17 weighing more than 44 lbs and less than 88 lbs.
Under the terms of the head license agreement between Pfizer and MPP, announced on November 16, 2021, qualified generic medicine manufacturers worldwide that are granted sub-licenses will be able to supply PF-07321332 in combination with ritonavir to 95 countries, covering up to approximately 53% of the world's population. This agreement was expanded on March 17, 2022, to include 35 companies. Beximco Pharma markets Paxlovid under the brand name Bexovid, initially in Bangladesh. Manila confirmed on March 10, 2022, that it authorized Bexovid for those aged 12 and above.
Paxlovid News 2023
May 2, 2023 - The COmpany announced Paxlovid revenues were approximately $8 billion, down 58% from 1Q 2022 results.
March 29, 2023 - "Despite Paxlovid's proven success in blunting COVID-19 symptoms, the long-term consequences of its widespread use in speeding up resistance are unknown," said S. Arad Moghadasi, co-author of the study and a University of Minnesota Medical School graduate student. "Drugs with the highest barriers to resistance are likely to prove more effective and have longer-term durability."
February 1, 2023 - The U.S. FDA published a revised EAU.
November 24, 2022 - The U.S. CDC published: Paxlovid Associated with Decreased Hospitalization Rate Among Adults with COVID-19 — United States, April–September 2022
August 24, 2022 - The NEJM published an ORIGINAL ARTICLE: Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge. CONCLUSIONS - Among patients 65+ years, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir. But there is no evidence of benefit found in younger adults.
July 19, 2022 - Iowa based Hy-Vee, Inc. announced all Hy-Vee Pharmacy locations across its eight-state region now offer test-to-treat COVID-19 services using the COVID-19 antiviral, PAXLOVID.
July 14, 2022 - The Lancet Infectious Disease published a Correspondence - Paxlovid in patients who are immunocompromised and hospitalized with SARS-CoV-2 infection. Paxlovid prescription within 5 days of diagnosis had a faster clearance of viral load as measured by ORF1ab viral gene replication (appendix p 3) and a shorter time to viral elimination in patients who are immunocompromised (13·67 days [5·84] vs 19·17 days [5·87], p=0·022; appendix pp 6,7). In addition, the correlation between the timing of paxlovid initiation and viral elimination is linear.
July 6, 2022 - The EMA published Paxlovid clinical data update: ((1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide / Ritonavir) EMEA/H/C/005973/0000.
June 14, 2022 - Pfizer Inc. announced pre-specified secondary endpoint resulted in a nominally significant 62% decrease in COVID-19-related medical visits per day across all patients, relative to placebo; In a sub-group analysis, a non-significant 57% reduction in hospitalizations and death was observed in PAXLOVID-treated vaccinated patients with at least one risk factor for severe COVID-19; Pfizer ceased enrollment into the EPIC-SR trial due to low rate of hospitalization or death in the standard-risk population; and will continue to evaluate treatment in populations with high unmet need. It also said Paxlovid did not have a significant impact on high-risk people who have been vaccinated.
June 6, 2022 - Pfizer Inc. announced it would further strengthen its commitment to U.S. manufacturing with a $120 million investment at its Kalamazoo, Michigan, facility, enabling U.S.-based production in support of its COVID-19 oral treatment, PAXLOVID.
June 2, 2022 - According to findings published in the peer review journal Clinical Infectious Diseases, both Paxlovid and adequate COVID-19 vaccination status were associated with a significant decrease in the rate of severe COVID-19 or mortality with adjusted HR 0.54 (95% CI, 0.39-0.75) and 0.20 (95% CI, 0.17-0.22), respectively. And Paxlovid appears to be more effective in older patients, immunosuppressed patients, and patients with underlying neurological or cardiovascular disease (interaction p-value <0.05 for all). No significant interaction was detected between Paxlovid treatment and COVID-19 vaccination status. Despite the shown effectiveness, it should be noted that Paxlovid is not recommended in several medical 6 conditions and has complex drug-drug interactions due to the ritonavir component of the combination.
June 1, 2022 - A non-peer-review Research Article based on data from Israel: Oral Nirmatrelvir and Severe Covid-19 Outcomes During the Omicron Surge, concluded - Nirmatrelvir therapy was associated with a 67% reduction in Covid-19 hospitalizations and an 81% reduction in Covid-19 mortality in patients 65 years and above. However, no significant benefit in avoidance of severe Covid-19 outcomes was shown in younger adults.
April 29, 2022 - Pfizer Inc said a large trial found that Paxlovid was not effective at preventing coronavirus infection in people living with someone infected with the virus.
April 11, 2022 - Taiwan's Central Epidemic Command Center announced that it had signed a purchase contract with Pfizer for 700,000 courses of Paxlovid.
March 22, 2022 - Pfizer Inc. announced today an agreement with UNICEF to supply up to 4 million treatment courses of PAXLOVID to 95 low- and middle-income countries, pending authorization or approval.
March 17, 2022 - The Medicines Patent Pool announced that it had signed agreements with 35 companies to manufacture the generic version of Paxlovid that can be supplied in 95 low- and middle-income countries.
February 8, 2022 - Pfizer, Inc. confirmed multiple studies demonstrating that the in vitro efficacy of nirmatrelvir, the active main protease inhibitor of Paxlovid, is maintained against the SARS-CoV-2 variant Omicron. Taken together, these in vitro studies suggest that Paxlovid has the potential to maintain plasma concentrations many-fold times higher than the amount required to prevent Omicron from replicating in cells.
February 4, 2022 - MIT Technology reported: How Pfizer made an effective anti-covid pill.
January 28, 2022 - The European Commission issued authorization to Pfizer Europe MA EEIG.
January 27, 2022 - The EMA Committee recommended authorizing Paxlovid for treating COVID-19 in certain adults; the first COVID-19 oral antiviral recommended in the E.U.
January 20, 2022 - The Australian Government welcomed the Therapeutic Goods Administration's provisional approval of the first oral Paxlovid® (nirmatrelvir + ritonavir).
January 18, 2022 - Pfizer Inc. announced results from multiple clinical studies demonstrating the in vitro efficacy of nirmatrelvir, the active main protease inhibitor of PAXLOVID, is maintained against the SARS-CoV-2 virus variant known as Omicron.
January 17, 2022 - The Honourable Filomena Tassi, Minister of Public Services and Procurement, announced Canada has received an initial shipment of 30,400 treatment courses of PAXLOVID, with 120,000 more expected by the end of March 2022.
January 11, 2022 - The Philippines Food and Drug Administration granted a compassionate special permit for Bexovid, the first generic version of Pfizer's Paxlovid.
January 10, 2022 - The EMA announced 'Should the additional data submitted with the conditional marketing authorization application be sufficient to conclude that the benefits of Paxlovid outweigh its risks in the treatment of COVID 19, the EMA will liaise closely with the European Commission to fast track the decision granting a conditional marketing authorization in all E.U. and the EEA Member States.'
December 26, 2021 - The Times of Israel announced the Health Ministry authorized Paxlovid.
December 22, 2021 - The U.S. FDA announced a EUA was issued for Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) for the treatment of mild-to-moderate COVID-19 in adults and certain pediatric patients with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
December 22, 2021 - Pfizer Inc. announced a new agreement with the United Kingdom government to supply an additional 2.5 million treatment courses of its investigational candidate PAXLOVID™, subject to local authorization. This brings the total amount of treatment courses to 2.75 million.
December 16, 2021 - The EMA advised that Paxlovid should be administered as soon as possible after a diagnosis of COVID-19 and within five days of the start of symptoms. The EMA issued this advice to support national authorities who may decide on the possible early use of the medicine before marketing authorization. If authorized, PAXLOVID could be prescribed as an at-home treatment to high-risk patients at the first sign of infection, potentially helping patients avoid severe illness, which can lead to hospitalization and death. PAXLOVID is also being studied in adults at risk of progressing to severe illness and adults exposed to the virus through household contacts.
December 14, 2021 - Pfizer Inc. announced the final results from its Phase 2/3 EPIC-HR trial analysis. These results were consistent with the interim analysis announced in November 2021, showing PAXLOVID significantly reduced the risk of hospitalization or death for any cause by 89% compared to placebo in nonhospitalized, high-risk adult patients with COVID-19 treated within three days of symptom onset. In addition, in a secondary endpoint, PAXLOVID reduced the risk of hospitalization or death for any cause by 88% compared to placebo in patients treated within five days of symptom onset, an increase from the 85% observed in the interim analysis.
November 18, 2021 - Pfizer Inc. announced an agreement with the U.S. government to supply 10 million treatment courses of PAXLOVID™ (PF-07321332; ritonavir), subject to regulatory authorization beginning later this year and concluding in 2022.
November 16, 2021 - Pfizer Inc. announced it is seeking Emergency Use Authorization for its investigational oral antiviral candidate, PAXLOVID™ (PF-07321332; ritonavir), for the treatment of mild to moderate COVID-19 in patients at increased risk of hospitalizations or death.
November 16, 2021 - Pfizer Inc. and the Medicines Patent Pool announced the signing of a voluntary license agreement for Pfizer's COVID-19 oral antiviral treatment candidate PF-07321332.
November 10, 2021 - The journal Nature published an article: COVID antiviral pills: what scientists still want to know.
November 8, 2021 - The BMJ published an article: Commenting on the PAXLOVID announcement, England's health and social care secretary, Sajid Javid, said, "If approved, this could be another significant weapon in our armory to fight the virus alongside our vaccines and other treatments, including molnupiravir, which the U.K. was the first country in the world to approve this week."
November 5, 2021 - Pfizer Inc. announced its investigational novel COVID-19 oral antiviral candidate, PAXLOVID™, significantly reduced hospitalization and death, based on an interim analysis of the Phase 2/3 EPIC-HR randomized, double-blind study of nonhospitalized adult patients with COVID-19. They are at high risk of progressing to severe illness.
October 5, 2021 - Australia announced the TGA had granted provisional determination to Pfizer Australia concerning a new combination medicine containing PF-07321332 and ritonavir to treat adult patients with symptomatic, confirmed coronavirus infection. The granting of an interim judgment means that the TGA has decided that Pfizer Australia is now eligible to apply for provisional registration of this treatment in the Australian Register of Therapeutic Goods.
September 27, 2021 - Pfizer Inc. announced the start of the Phase 2/3 EPIC-PEP study to evaluate the investigational novel oral antiviral candidate PF-07321332, co-administered with a low dose of ritonavir, for the prevention of COVID-19 infection. This Phase 2/3 trial is part of a global clinical research program. It enrolls individuals at least 18 years old and live in the same household as those with a confirmed symptomatic SARS-CoV-2 infection.
September 1, 2021 - Pfizer Inc. shared that the first participant has been dosed in a pivotal Phase 2/3 clinical trial to evaluate the safety and efficacy of PF-07321332.
April 7, 2021 - Chemical & Engineering News published: Pfizer unveils its oral SARS-CoV-2 inhibitor.
March 23, 2021 - Pfizer Inc. announced that it is progressing to multiple ascending doses after completing the dosing of single ascending doses in a Phase 1 study in healthy adults to evaluate the safety and tolerability of an investigational, novel oral antiviral therapy for SARS-CoV-2, the virus that causes COVID-19. This Phase 1 trial is being conducted in the United States.
Paxlovid Clinical Trials
Clinical Trial: NCT04960202 - Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer)
The Phase 2/3 EPIC-PEP trial is a randomized, double-blind, placebo-controlled study and will enroll up to 2,660 healthy adult participants aged 18 and older. Participants will be randomly assigned (1:1:1) to receive PF-07321332/ritonavir or placebo orally twice daily for 5 or 10 days. The primary objective will assess safety and efficacy to prevent confirmed SARS-CoV-2 infection and its symptoms through Day 14. PF-07321332 is an oral antiviral SARS-CoV-2-3CL protease inhibitor, which has an encouraging preclinical profile, including potent in vitro antiviral SARS-CoV-2 and broad coronavirus activity. Results from the Phase 1 clinical trial demonstrated that PF-07321332 was safe and well-tolerated.
A Phase 1, double-blind, sponsor open, single, and multiple ascending dose study evaluates the safety, tolerability, and pharmacokinetics of PF-07321332 in healthy participants.
For more information on the EPIC Phase 2/3 clinical trials for PAXLOVID, visit clinicaltrials.gov.