Ibuzatrelvir
Ibuzatrelvir is an investigational antiviral drug developed by Pfizer for the treatment of COVID-19. It is a second-generation oral SARS-CoV-2 main protease 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.
Mechanism of action
Ibuzatrelvir is an orally bioavailable SARS-CoV-2 main protease inhibitor that targets viral replication through reversible covalent interaction with the active site cysteine residue of the viral 3CL protease. 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.The drug has demonstrated pan-human coronavirus antiviral activity and favorable off-target selectivity profile in vitro and in preclinical studies.
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. 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.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. It is more metabolically stable and has fewer potential drug-drug interactions. 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.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.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.