Pfizer announced EUA application for Covid-19 drug ” Paxlovid, a combo drug of a novel SARS-CoV-2-3CL C30 Endopeptidase inhibitor also known by the experimental name PF-07321332, a Cysteine protease inhibitor, and older protease inhibitor ritonavir to treat HIV/AIDS , that was found to reduce the risk of hospitalization or death by 89% compared to placebo in non-hospitalized high-risk adults with COVID-19 in phase 2 trials AFTER JUST 4 WEEKS.
Pfizer reported 389 patients In the overall study population through Day 28, no deaths in patients who received PAXLOVID™ as compared to 10 deaths in patients who received placebo
.8% or 3 out of 389 of patients who received PAXLOVID™ were hospitalized through Day 28 following randomization (3/389 hospitalized with no deaths), compared to 7.0% of patients who received placebo and were hospitalized or died (27/385 hospitalized with 7 subsequent deaths).
It is worth to remind that age and comorbities play a major role in post Sarscov2 recovery prognosis. No age or underlying conditions/comorbities data was available for both groups.
Pfizer reported very limited info on side effects but mentioned rates of problems were similar between the groups around 20%. One of the concerns is related to longer term effects but as usual, the trial was recommended to be stopped early when “INTERIM results show such a clear benefit” while the data have not yet been published for outside review.
Older component in this combo is Ritonavir developed in 1980s for Treatment of HIV-1 infection per Pfizer serves to slow down metabolism of PF-07321332 to maintain higher circulating concentrations of the main drug.
Among previously reported ritonavir side effects are fatal pancreatitis and liver damage, arrhythmias with Prolongation of PR interval and 2nd- or third-degree AV block. use with caution in patients with structural heart disease, cardiac conduction abnormalities, ischemic heart disease or cardiomyopathies is recommended as these individuals may be at increased risk for cardiac conduction abnormalities. Contraindications for hypersensitivity (toxic epidermal necrolysis) were also previously noted with ritonavir use. Perhaps different dosages in this combo drug were used but not yet disclosed. Some expect to use Merck’s molnupiravir together with Paxlovid but since Merck's molnupiravir actually speeds up mutations it may contribute to resistance to Pfizer's Paxlovid.
The novel component PF-07321332 is a 3CLprotease inhibitor, a covalent cysteine protease inhibitor, binding directly to the cysteine (Cys145). As noted, Side effects were not investigated or reported in a one month long study, but concerns may include ones to related to its effects on coagulation().
PF-07321332 inhibits cysteine protease from the PA clan proteases that play coagulant role as they are involved in blood clotting cascade. As a cysteine protease inhibitor, it may disrupt coagulation and have blood thinning qualities leading to predisposition to internal bleedings. Several snake venoms also belong to PA clan proteases and interfere with blood clotting cascade. This is interesting in light of presence of neurotoxin like motifs noted earlier in the sarscov2 sequence related to snake venom neurotoxin superantigens.
Another major concern is cysteine protease inhibition SPECIFICITY as Cysteine proteases play roles in every aspect of physiology and development.
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