lufotrelvir (PF-07304814) / Pfizer - LARVOL DELTA

Development of a highly sensitive luciferase assay for intracellular evaluation of coronavirus Mpro activity. (PubMed, Front Microbiol) - "Additionally, the system proved suitable for evaluating and screening of antiviral compounds, including lufotrelvir, GC376, Nirmatrelvir, X77, MG-101, and the potential inhibitor Cynaroside. The ICMP system is not only an invaluable tool for the detection of live coronaviruses, but also for the discovery of antivirals against current and future pandemic coronaviruses."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Discovery and development of COVID-19 vaccines and therapeutics: nonclinical perspectives. (PubMed, J Toxicol Sci) - "Likewise, a comprehensive nonclinical safety assessment was conducted for the therapeutic candidates, lufotrelvir (PF-07304814) and nirmatrelvir (PF-07321332). The development and regulatory review of BNT162b2 and Paxlovid was enabled through close collaboration of the pharmaceutical industry with regulatory agencies and public health organizations. This experience highlights approaches that could be adopted for pandemic preparedness including risk-based investment strategies, conduct of activities in parallel that normally are conducted sequentially, quick kill decisions, simultaneous evaluation of multiple candidates, and use of flexible, established vaccine platforms."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

PF-07304814 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial) (clinicaltrials.gov) - P3 | N=58 | Terminated | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Suspended ➔ Terminated; The agent was withdrawn from development by the manufacturer after being placed on clinical hold by the US FDA.

Trial termination • Infectious Disease • Novel Coronavirus Disease

Molecular docking and MD simulations reveal protease inhibitors block the catalytic residues in Prp8 intein of Aspergillus fumigatus: a potential target for antimycotics. (PubMed, J Biomol Struct Dyn) - "Molecular docking shows that two FDA-approved drugs, i.e. Lufotrelvir and Remdesivir triphosphate efficiently interact with Prp8 intein from the assortment of 212 protease inhibitors. Per-residue decomposition analysis confirms the importance of F: block R802, V803, and Q807 binding pocket in intein splicing domain towards recognition of inhibitors, along with active site residues through strong hydrogen bonds and hydrophobic contacts. However, in vitro and in vivo assays are required to confirm the inhibitory action on Prp8 intein splicing; which may pave the way for the development of new antifungals for A. fumigatus.Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease

TICO: ACTIV-3: Therapeutics for Inpatients With COVID-19 (clinicaltrials.gov) - P3 | N=2753 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Active, not recruiting ➔ Completed

Trial completion • Infectious Disease • Novel Coronavirus Disease

Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19. (PubMed, Open Forum Infect Dis) - P1b | "PF-07304814-the prodrug (lufotrelvir) and its active moiety (PF-00835231)-is a potent inhibitor of the SARS-CoV-2 3CL protease. Clinical Trials Registration. ClinicalTrials.gov NCT04535167."

Journal • PK/PD data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Self-Assembly Properties of an Amphiphilic Phosphate Ester Prodrug Designed for the Treatment of COVID-19. (PubMed, J Pharm Sci) - "PF-07304814 is a water-soluble phosphate ester prodrug of a small molecule inhibitor for the SARS CoV-2 3CL protease designed for the treatment of COVID-19...The observed solubilization could help extend the drug product shelf-life and in use stability through inhibition of precipitation, without the need for solubilizing excipients. The work presented in this manuscript provides a roadmap for the characterization of prodrug self-assembly and highlights the potential for prodrug modifications to enhance solubility of both active ingredients and impurities and to extend drug product shelf-life."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Crystal structures of main protease (M) mutants of SARS-CoV-2 variants bound to PF-07304814. (PubMed, Mol Biomed) - "Patterns for PF-07304814 to bind with these investigated M mutants and the wild-type M are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of M mutants when bound to an inhibitor."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Structural basis of main proteases of HCoV-229E bound to inhibitor PF-07304814 and PF-07321332. (PubMed, Biochem Biophys Res Commun) - "Further, we compared the crystal structures of multiple coronavirus M complexes with PF-07321332 or PF-07304814 to illustrate the differences in the interaction of Ms, and found that the inhibition mechanism of lower pathogenic coronavirus M was more similar to that of moderately pathogenic coronaviruses. Our structural studies provide new insights into drug development for low pathogenic coronavirus M, and provide theoretical basis for further optimization of both inhibitors to contain potential future coronaviruses."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

PF-07304814 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial) (clinicaltrials.gov) - P3 | N=58 | Suspended | Sponsor: University of Minnesota

New P3 trial • Infectious Disease • Novel Coronavirus Disease

Review of preclinical data of PF-07304814 and its active metabolite derivatives against SARS-CoV-2 infection. (PubMed, Front Pharmacol) - "PF-07304814 is a phosphate ester prodrug of PF-00835231 that is rapidly metabolized into the active metabolite PF-00835231 by alkaline phosphatase (ALP) and then suppresses SARS-CoV-2 replication by inhibiting M. PF-07304814 increased the bioavailability of PF-00835231 by enhancing plasma protein binding (PPB). Prodrugs, nanotechnology and salt form drugs may solve this problem. In this review, we focus on the preclinical data of PF-07304814 and its active metabolite derivatives to hopefully provide knowledge for researchers to study SARS-CoV-2 infection."

Journal • Preclinical • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Safety, Tolerability, and Pharmacokinetics of Intravenous Doses of PF-07304814, a Phosphate Prodrug Protease Inhibitor for the Treatment of SARS-CoV-2, in Healthy Adult Participants. (PubMed, Clin Pharmacol Drug Dev) - "Studies on targeted antivirals for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing pandemic, are limited. A daily, 24-hour continuous infusion of 270 to 350 mg is expected to maintain PF-00835231 concentration at steady state/above effective antiviral concentrations. Further studies exploring lufotrelvir efficacy in patients with coronavirus disease 2019 are ongoing."

Journal • PK/PD data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

TICO: ACTIV-3: Therapeutics for Inpatients With COVID-19 (clinicaltrials.gov) - P3 | N=2753 | Active, not recruiting | Sponsor: University of Minnesota | N=10000 ➔ 2753

Enrollment change • Infectious Disease • Novel Coronavirus Disease

TICO: ACTIV-3: Therapeutics for Inpatients With COVID-19 (clinicaltrials.gov) - P3 | N=10000 | Active, not recruiting | Sponsor: University of Minnesota | Trial completion date: Jul 2022 ➔ Jul 2023

Trial completion date • Infectious Disease • Novel Coronavirus Disease

Structural Basis of Main Proteases of Coronavirus Bound to Drug Candidate PF-07304814. (PubMed, J Mol Biol) - "A detailed analysis of these crystal structures complemented by comprehensive comparison defined the key structural determinants essential for inhibition and illustrated the binding mode of action of Ms from different coronaviruses. In view of the importance of M for the medications of SARS-CoV-2 infection, insights derived from the present study should accelerate the design of pan-coronaviral main protease inhibitors that are safer and more effective."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Study to Investigate the Mass Balance, Metabolism, and Excretion of [14C]-PF-07304814 in Healthy Participants (clinicaltrials.gov) - P1; N=5; Completed; Sponsor: Pfizer; Recruiting ➔ Completed

Clinical • Trial completion

Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19. (PubMed, Nat Commun) - "Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Study to Investigate the Mass Balance, Metabolism, and Excretion of [14C]-PF-07304814 in Healthy Participants (clinicaltrials.gov) - P1; N=5; Recruiting; Sponsor: Pfizer; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

Study to Investigate the Mass Balance, Metabolism, and Excretion of [14C]-PF-07304814 in Healthy Participants (clinicaltrials.gov) - P1; N=5; Not yet recruiting; Sponsor: Pfizer

Clinical • New P1 trial

Antiviral treatment of COVID-19: An update. (PubMed, Turk J Med Sci) - "The main drug groups include inhibitors of viral entry into the human cell (convalescent plasma, monoclonal antibodies, nanobodies, mini proteins, human soluble ACE-2, camostat, dutasteride, proxalutamide, bromhexin, hydroxychloroquine, umifenovir nitazoxanid, niclosamide, lactoferrin), inhibitors of viral proteases (lopinavir/ritonavir, PF-07321332, PF-07304814, GC376), inhibitors of viral RNA (remdesivir, favipiravir, molnupiravir, AT-527, merimepodib, PTC299); inhibitors of host proteins supporting virus (plitidepsin, fluvoxamine, ivermectin) and agents supporting host natural immunity (Interferons)...Additional studies are needed to define the role of remdesivir, favipiravir, interferons, ivermectin, dutasteride, proxulutamide, fluvoxamine, bromhexine, nitazoxanide and niclosamid in the treatment of COVID-19. Finally, the results of phase trials are waited to learn whether or not the newer agents such as molnupiravir, PF-07321332, PF-07304814, plitidepsin and AT-527..."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332. (PubMed, J Enzyme Inhib Med Chem) - "The chemical structure of PF-07321332, the first orally available Covid-19 clinical candidate, has recently been revealed by Pfizer. In the present work, we exploited Supervised Molecular Dynamics (SuMD) simulations to elucidate the key features that characterise the interaction between this drug candidate and the protease, emphasising similarities and differences with other structurally related inhibitors such as Boceprevir and PF-07304814. The structural insights provided by SuMD will hopefully be able to inspire the rational discovery of other potent and selective protease inhibitors."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

First-In-Human Study To Evaluate Safety, Tolerability, And Pharmacokinetics Following Single Ascending And Multiple Ascending Doses of PF-07304814 In Hospitalized Participants With COVID-19. (clinicaltrials.gov) - P1b; N=26; Completed; Sponsor: Pfizer; Recruiting ➔ Completed; N=72 ➔ 26

Clinical • Enrollment change • Trial completion • Infectious Disease • Novel Coronavirus Disease

Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection. (PubMed, Curr Opin Virol) - "Here we review first-generation SARS-CoV-2 3CLpro inhibitors PF-07304814, GC-376, and CDI-45205 that are being delivered either by injection or inhalation due to their low intrinsic oral bioavailability. In addition, PF-07321332 is now emerging as a promising second-generation clinical candidate for oral delivery. A key challenge to the development of novel 3CLpro inhibitors is the poor understanding of the predictive value of in vitro potency toward clinical efficacy, an issue complicated by the involvement of host proteases in virus entry. Further preclinical and clinical validation will be key to establishing 3CLpro inhibitors as a bona fide class for future SARS-CoV-2 therapeutics for both hospitalized and outpatient populations."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

"Preclinical data of PF-00835231 SARS-CoV-2 3CLpro inhibitor and its phosphate prodrug PF-07304814 presented by Pfizer. Live from #HatfieldMedChem21 @RSC_BMCS" (@Cortellis)

Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Pfizer Initiates Phase 1 Study of Novel Oral Antiviral Therapeutic Agent Against SARS-CoV-2 (Businesswire) - "Pfizer Inc. (NYSE: PFE) announced today that it is progressing to multiple ascending doses after completing the dosing of single ascending doses in a Phase 1 study...The Phase 1 trial is a randomized, double-blind, sponsor-open, placebo-controlled, single- and multiple-dose escalation study in healthy adults evaluating the safety, tolerability and pharmacokinetics of PF-07321332....The structure of PF-07321332, together with the pre-clinical data, will be shared in a COVID-19 session of the Spring American Chemical Society meeting on April 6. Pfizer is also investigating an intravenously administered investigational protease inhibitor, PF-07304814, which is currently in a Phase 1b multi-dose trial in hospitalized clinical trial participants with COVID-19."

Preclinical • Review • Trial status • Infectious Disease • Novel Coronavirus Disease