A Second-Generation Oral SARS-CoV‑2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19
At the start of the decade, amidst the SARS-CoV-2 pandemic, there was a huge amount of interest in the rapid development and delivery of antiviral therapeutics to those in need. Among others,[ doi.org/10.1126/science.abo7201] Pfizer rose to this challenge with a colossal effort [doi.org/10.1126/science.abl4784, doi.org/10.1021/acscentsci.3c00145] involving teams across the globe to deliver nirmatrelvir, an orally bioavailable covalent inhibitor of the SARS-CoV-2 main protease (MPro), which gained emergency use authorisation from the FDA in 2021 as part of Paxlovid: their flagship treatment for SARS-CoV-2 infection.
A dose of Paxlovid consists of nirmatrelvir (300 mg) and ritonavir (100 mg),[www.paxlovidhcp.com/dosing] the latter acting as a CYP inhibitor and PK booster for nirmatrelvir, allowing acceptable free drug levels in the blood following the given dose. Although the plasma clearance of nirmatrelvir is attenuated, the inclusion of ritonavir in the therapy precludes a significant portion of the patient population due to renal impairment and/or reliance on other drugs which would otherwise lead to drug-drug interactions (DDIs). In this paper, researchers from Pfizer present their efforts toward an API that displays a reduced plasma clearance rate and does not require co-dosing of ritonavir. This was achieved with their clinical candidate: PF-07817883 (“ibuzatrelvir”), now in phase 1 and 2 trials for the treatment of COVID-19.
This new inhibitor has a much lower lipophilicity (logD = 0.9, compared to nirmatrelvir: logD = 1.9), and a key spot of metabolism: the fused dimethyl-cyclopropane, has been removed. Both contribute to the better PK profile of ibuzatrelvir compared to nirmatrelvir.
The inhibitor was shown to have pan-coronavirus MPro activity, tested against SARS-CoV-1, SARS-CoV-2, MERS-CoV and HCoV-229E. All translated well to cell antiviral models, with MERS-CoV as the outlier; the authors noted an inverse enzyme -> cell dropoff for MERS-CoV. This is likely to be due to the way that the biochemical IC50 was calculated, and the peculiar dimerization kinetics of MERS-CoV MPro in-vitro.[doi.org/10.1074/jbc.M115.651463, doi.org/10.1371/journal.pone.0144865] The inhibitor was shown to also have in-vivo efficacy against SARS-CoV-2 in a mouse model. For example, after an oral dose of 500 mg/kg BID (aiming for a consistent free blood level of ~3x EC90), a x2.7 log decrease in lung viral titre was observed 4 days post-infection.
One of the major challenges of developing viral protease inhibitors, particularly those with a covalent mode of action, is the risk of selectivity vs human/host proteases. Candidate protease inhibitors are thus routinely screened against protease panels. Unfortunately, ibuzatrelvir also appears to be a potent inhibitor of human cathepsins K and S, with IC50 values of 21 nM and 33 nM, respectively. So this is a liability that must be closely managed, going forward.