ibuzatrelvir (PF-07817883) / Pfizer - LARVOL DELTA

Structural insights into the nirmatrelvir-resistant SARS-CoV-2 Mpro L50F/E166A/L167F triple mutant-inhibitor-complex reveal strategies for next generation coronaviral inhibitor design. (PubMed, RSC Med Chem) - "One such variant harbors a triple mutation in Mpro, L50F/E166A/L167F, that displays decreased potency for nirmatrelvir (IC50 ∼ 850-1600 nM) and ibuzatrelvir while viral replication remained similar to that of the wildtype (WT) virus. A co-crystal structure reveals tight inhibitor binding that is stabilized by a network of hydrogen bonds formed by the mutated residues A166 and F167. This study provides the groundwork for optimized Mpro inhibitors against potential emerging variants of SARS-CoV-2, as well as strategies for broad-spectrum inhibitor design against variants of Mpro."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A Study to Learn About the Study Medicine Ibuzatrelvir in Adults With COVID-19 Who Are Severely Immunocompromised (clinicaltrials.gov) - P3 | N=300 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Novel Coronavirus Disease

A Study to Learn About the Study Medicine Ibuzatrelvir in Adults With COVID-19 Who Are Severely Immunocompromised (clinicaltrials.gov) - P3 | N=300 | Not yet recruiting | Sponsor: Pfizer

New P3 trial • Infectious Disease • Novel Coronavirus Disease

Silaproline-bearing nirmatrelvir derivatives are potent inhibitors of the SARS-CoV-2 main protease highlighting the value of silicon-derivatives in structure-activity-relationship studies. (PubMed, Eur J Med Chem) - "One of the two prochiral silaproline methyl groups occupies space in the S2 pocket that is unoccupied in Mpro:nirmatrelvir complex structures, highlighting the value of sila-derivatives in structure-activity-relationship (SAR) studies. The combined results highlight the potential of silicon-containing molecules for inhibition of Mpro and, by implication, other nucleophilic cysteine enzymes."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Potent, Pan-Coronavirus Antiviral Activity of the Novel 3CLpro Inhibitor ALG-097558 (CROI 2025) - "Against Omicron subvariants, ALG-097558 is 3- to 9-fold more active than nirmatrelvir (the 3CLpro inhibitor in Paxlovid™). Other 3CLpro inhibitors in clinical development such as ensitrelvir and ibuzatrelvir demonstrated greatly reduced antiviral activity against α-CoVs...Conclusions ALG-097558 demonstrates potent, pan-coronaviral activity in preclinical experiments and is uniquely positioned as a treatment option for SARS-CoV-2 infection and potential future coronavirus pandemics. After having demonstrated a favorable clinical safety and PK profile in Phase I, including ritonavir-free dosing, ALG-097558 warrants further evaluation in patients with COVID-19."

Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A Study to Learn if Study Medicines Called Cyclosporine and Clarithromycin Affect How the Body Processes the Other Study Medicine Called PF-07328948 in Healthy Adults (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Pfizer

New P1 trial

A Study to Learn How Renal Impairment Affects the Pharmacokinetics of PF-07817883. (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion • Infectious Disease • Novel Coronavirus Disease • Renal Disease

A Study to Learn If the Study Medicine Called Carbamazepine Changes How the Body Processes the Other Study Medicine Ibuzatrelvir in Healthy Adults (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion

A Study to Learn If the Study Medicine Called Carbamazepine Changes How the Body Processes the Other Study Medicine Ibuzatrelvir in Healthy Adults (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting

Enrollment closed

A Study to Learn About if the Study Medicine Called Ibuzatrelvir Changes How the Body Process the Other Medicine Dabigatran Etexilate in Healthy Adults (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: Pfizer | Recruiting ➔ Completed

Trial completion • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A Study to Learn How Renal Impairment Affects the Pharmacokinetics of PF-07817883. (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=28 ➔ 8 | Trial completion date: Oct 2025 ➔ Feb 2025 | Trial primary completion date: Oct 2025 ➔ Feb 2025

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease • Renal Disease

A Study to Learn About a Study Medicine Called Ibuzatrelvir in Adult and Adolescent Patients With COVID-19 Who Are Not Hospitalized But Are at Risk For Severe Disease (clinicaltrials.gov) - P3 | N=2330 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A Study to Learn About if the Study Medicine Called Ibuzatrelvir Changes How the Body Process the Other Medicine Dabigatran Etexilate in Healthy Adults (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Virologic Response and Safety of Ibuzatrelvir, a Novel SARS-CoV-2 Antiviral, in Adults With COVID-19. (PubMed, Clin Infect Dis) - P2 | "All 3 ibuzatrelvir doses were associated with robust antiviral activity and an acceptable safety profile, supporting continued clinical development."

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

A Study to Learn About if the Study Medicine Called Ibuzatrelvir Changes How the Body Process the Other Medicine Dabigatran Etexilate in Healthy Adults (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: Pfizer

New P1 trial • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A Study to Learn If the Study Medicine Called Carbamazepine Changes How the Body Processes the Other Study Medicine Ibuzatrelvir in Healthy Adults (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Learn About a Study Medicine Called Ibuzatrelvir in Adult and Adolescent Patients With COVID-19 Who Are Not Hospitalized But Are at Risk For Severe Disease (clinicaltrials.gov) - P3 | N=2330 | Not yet recruiting | Sponsor: Pfizer

New P3 trial • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Replication Capacity and Susceptibility of Nirmatrelvir-Resistant Mutants to Next-Generation Mpro Inhibitors in a SARS-CoV-2 Replicon System. (PubMed, Antiviral Res) - "Using a subgenomic SARS-CoV-2 replicon system, we studied the RNA replication capacity of nirmatrelvir (NTV)-resistant mutants and their susceptibility to next-generation Mpro inhibitors, including ibuzatrelvir (ITV), ensitrelvir (ETV), and ML2006a4. ML2006a4 demonstrated the most effective suppression across most mutants (S144A, E166V, S144A+L50F, E166A/V+L50F, L167F+L50F, and E166A+L167F+L50F). Thus, ML2006a4 represents an attractive investigational candidate against clinically relevant NTV-resistant SARS-CoV-2 mutants."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A Study to Learn If the Study Medicine Called Carbamazepine Changes How the Body Processes the Other Study Medicine Ibuzatrelvir in Healthy Adults (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Pfizer

New P1 trial

A Study to Learn How Renal Impairment Affects the Pharmacokinetics of PF-07817883. (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Novel Coronavirus Disease • Renal Disease

A Study to Learn About How Loss of Liver Function Affects the Blood Levels of the Study Medicine Called PF-07817883. (clinicaltrials.gov) - P1 | N=21 | Completed | Sponsor: Pfizer | N=16 ➔ 21

Enrollment change • Hepatology • Infectious Disease • Novel Coronavirus Disease

A Study to Learn How Renal Impairment Affects the Pharmacokinetics of PF-07817883. (clinicaltrials.gov) - P1 | N=28 | Not yet recruiting | Sponsor: Pfizer

New P1 trial • Infectious Disease • Novel Coronavirus Disease • Renal Disease

A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (Mpro) of SARS-CoV-2 and MERS-CoV. (PubMed, JACS Au) - "It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with Mpro of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A Study to Learn About How Loss of Liver Function Affects the Blood Levels of the Study Medicine Called PF-07817883. (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Pfizer | Recruiting ➔ Completed | N=40 ➔ 16 | Trial completion date: Oct 2024 ➔ Jun 2024 | Trial primary completion date: Oct 2024 ➔ Jun 2024

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Hepatology • Infectious Disease • Novel Coronavirus Disease

Oral Main Protease (Mpro) inhibitors for the treatment of COVID-19 (ACS-Fall 2024) - "The discovery and characterization of orally bioavailable inhibitors of the SARS-CoV-2 main protease (Mpro) as potential treatments for COVID-19 will be described. This will include nirmatrelvir, the ritonavir-boosted, antiviral component of PAXLOVIDTM, and ibuzatrelvir, a second generation Mpro inhibitor with improved metabolic stability, and based on in vitro studies, low potential for perpetrator drug-drug interactions when used as a single agent."

Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases