Chemistry:Ibuzatrelvir

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Ibuzatrelvir (also known as PF-07817883) is an investigational antiviral drug developed by Pfizer for the treatment of COVID-19.[1] It is a second-generation oral SARS-CoV-2 main protease (Mpro) inhibitor designed to improve upon the limitations of nirmatrelvir, the active antiviral component of Paxlovid, which is currently the only oral antiviral approved by the FDA for COVID-19 treatment.[2][3][4]

Mechanism of action

Ibuzatrelvir is an orally bioavailable SARS-CoV-2 main protease (Mpro) inhibitor that targets viral replication through reversible covalent interaction with the active site cysteine residue (Cys145) of the viral 3CL protease.[5][6][7] Like nirmatrelvir in Paxlovid, this orally active drug candidate is designed to target viral main proteases through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease.[6]

The drug has demonstrated pan-human coronavirus antiviral activity and favorable off-target selectivity profile in vitro and in preclinical studies.[5]

Development

Background

Ibuzatrelvir's design is derived from the structural framework of nirmatrelvir and exhibits extensive antiviral activity against coronaviruses in vitro, demonstrating efficacy in a mouse-adapted SARS-CoV-2 model following oral administration.[8] Pfizer announced ibuzatrelvir as a second-generation SARS-CoV-2 Mpro drug candidate, which has received fast-track status and has successfully completed Phase 2 clinical trials.[6]

Advantages over Paxlovid

Ibuzatrelvir offers several advantages over its predecessor, particularly that it doesn't have the drug-drug interactions that prevent many people with COVID-19 from taking Paxlovid.[2][9] It is more metabolically stable and has fewer potential drug-drug interactions.[6][8] Additionally, participants in ibuzatrelvir's Phase 2 clinical trial did not report "Paxlovid mouth," the unpleasant metallic taste side effect commonly associated with Paxlovid treatment.[2]

Clinical trials

Phase 2b trial

A phase 2b, double-blind, randomized clinical trial enrolled US adults aged 18 to <65 years with symptomatic COVID-19 and no risk factors for severe disease. Participants were randomized 1:1:2:2 to receive 100, 300, or 600 mg ibuzatrelvir or placebo orally twice daily for 5 days.[10][11][12]

The study involved 240 participants with COVID-19 and demonstrated that ibuzatrelvir led to greater viral load reduction compared with placebo. All 3 tested doses were generally well tolerated.[13]

Phase 3 trial

Pfizer has begun Phase 3 clinical trials of ibuzatrelvir.[2] The Phase 3 trial of ibuzatrelvir is expected to provide valuable insights into how this new treatment compares to existing options in reducing disease severity.[14][15]

Safety profile

Ibuzatrelvir is an orally bioavailable SARS-CoV-2 Mpro inhibitor with demonstrated in vitro antiviral activity and low potential for safety concerns, including drug-drug interactions.[11]

Regulatory status

As of September 2025, ibuzatrelvir remains an investigational drug undergoing clinical development. The compound has received fast-track status from regulatory authorities.[6]

See also

References

  1. ↑ "A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19". Journal of Medicinal Chemistry 67 (16): 13550–13571. August 2024. doi:10.1021/acs.jmedchem.3c02469. PMID 38687966. 
  2. ↑ 2.0 2.1 2.2 2.3 "Pfizer readies its next-generation COVID-19 antiviral". Chemical & Engineering News. 28 June 2024. https://cen.acs.org/pharmaceuticals/drug-discovery/Pfizer-readies-next-generation-COVID/103/i6. 
  3. ↑ "A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (Mpro) of SARS-CoV-2 and MERS-CoV". JACS Au 4 (8): 3217–3227. August 2024. doi:10.1021/jacsau.4c00508. PMID 39211604. 
  4. ↑ "Fixing the Achilles Heel of Pfizer's Paxlovid for COVID-19 Treatment". Journal of Medicinal Chemistry 67 (14): 11656–11661. July 2024. doi:10.1021/acs.jmedchem.4c01342. PMID 38967233. 
  5. ↑ 5.0 5.1 "Ibuzatrelvir (PF-07817883)". https://www.medchemexpress.com/ibuzatrelvir.html. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (Mpro) of SARS-CoV-2 and MERS-CoV". JACS Au 4 (8): 3217–3227. 2024. doi:10.1021/jacsau.4c00508. PMID 39211604. 
  7. ↑ "Fixing the Achilles Heel of Pfizer's Paxlovid for COVID-19 Treatment". Journal of Medicinal Chemistry 67 (14): 11656–11661. 25 July 2024. doi:10.1021/acs.jmedchem.4c01342. PMID 38967233. 
  8. ↑ 8.0 8.1 "Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents". Biomolecules 14 (7): 797. 4 July 2024. doi:10.3390/biom14070797. PMID 39062511. 
  9. ↑ "Pfizer readies its next-generation COVID-19 antiviral". C&EN Global Enterprise 103 (6): 31–32. 2025. doi:10.1021/cen-10306-cover3. https://pubs.acs.org/doi/10.1021/cen-10306-cover3. 
  10. ↑ "Virologic Response and Safety of Ibuzatrelvir, A Novel SARS-CoV-2 Antiviral, in Adults With COVID-19". Clinical Infectious Diseases 80 (3): 673–680. 17 March 2025. doi:10.1093/cid/ciae529. PMID 39486089. 
  11. ↑ 11.0 11.1 "Virologic Response and Safety of Ibuzatrelvir, A Novel SARS-CoV-2 Antiviral, in Adults With COVID-19". Clinical Infectious Diseases 80 (3): 673–680. 17 March 2025. doi:10.1093/cid/ciae529. PMID 39486089. PMC 11912966. https://academic.oup.com/cid/article/80/3/673/7863440. 
  12. ↑ Pfizer (12 September 2024). A PHASE 2B, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL GROUP, DOSE RANGING STUDY TO EVALUATE VIROLOGICAL RESPONSE AND SAFETY OF ORAL PF-07817883 IN NON-HOSPITALIZED SYMPTOMATIC ADULT PARTICIPANTS WITH COVID-19 (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT05799495. 
  13. ↑ "Virologic Response and Safety of Ibuzatrelvir, A Novel SARS-CoV-2 Antiviral, in Adults With COVID-19". Clinical Infectious Diseases 80 (3): 673–680. 2025. doi:10.1093/cid/ciae529. PMID 39486089. 
  14. ↑ "Pfizer Launched Phase 3 Trial for Ibuzatrelvir, New Oral Antiviral for COVID-19 Treatment". 24 December 2024. https://www.contagionlive.com/view/pfizer-launched-phase-3-trial-for-ibuzatrelvir-a-new-oral-antiviral-for-covid-19-treatment. 
  15. ↑ Pfizer (8 September 2025). AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 3, DOUBLE-BLIND, 2-ARM STUDY TO INVESTIGATE ORALLY ADMINISTERED IBUZATRELVIR COMPARED WITH PLACEBO IN NON-HOSPITALIZED SYMPTOMATIC ADULT AND ADOLESCENT PARTICIPANTS WITH COVID-19 WHO ARE AT HIGH RISK OF PROGRESSING TO SEVERE ILLNESS (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT06679140. 



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