pimodivir (JNJ-3872) / J&J - LARVOL DELTA

Predictive modeling & mechanistic validation of synergistic pimodivir combinations for anti-influenza therapy via PB2cap affinity boost. (PubMed, NPJ Digit Med) - "This study introduces a machine learning framework to predict effective antiviral combinations for influenza A. It identifies Pimodivir with Epinephrine or L-Adrenaline as synergistic agents, confirmed by experiments demonstrating increased binding affinity and viral suppression. Multiple synergy scoring methods validate these drug combinations' potential, offering a strategic pathway for designing rational combination therapies against influenza and other RNA viruses."

Journal • Infectious Disease • Influenza • Respiratory Diseases

Antiviral Susceptibility of Influenza A(H5N1) Clade 2.3.2.1c and 2.3.4.4b Viruses from Humans, 2023-2024. (PubMed, Emerg Infect Dis) - "In the neuraminidase inhibition assay, all viruses displayed susceptibility to neuraminidase inhibitor antiviral drugs oseltamivir, zanamivir, peramivir, laninamivir, and AV5080...All viruses were susceptible to polymerase inhibitors baloxavir and tivoxavir and to polymerase basic 2 inhibitor pimodivir with 50% effective concentrations in low nanomolar ranges. Because drug-resistant viruses can emerge spontaneously or by reassortment, close monitoring of antiviral susceptibility of H5N1 viruses collected from animals and humans by using sequence-based analysis supplemented with phenotypic testing is essential."

Journal • Infectious Disease • Influenza • Respiratory Diseases

Study of Acute Uncomplicated Seasonal Influenza A in Adult Subjects (clinicaltrials.gov) - P2 | N=292 | Completed | Sponsor: Janssen Research & Development, LLC | Phase classification: P2b ➔ P2

Monotherapy • Phase classification • Infectious Disease • Influenza • Respiratory Diseases

The Evaluation of DNA-linked Inhibitor Antibody and AlphaScreen Assays for High-throughput Screening of Compounds Targeting the Cap-binding Domain in Influenza A Polymerase. (PubMed, Eur J Pharm Sci) - "Using a diverse set of substrates and compounds based on the previously described PB2 binder pimodivir, we thoroughly assessed the capabilities of these new methods...Notably, DIANA's ability to determine Ki values from a single-well measurement significantly enhances its practicality and efficiency in inhibitor screening. This research represents a significant step forward in the development of more efficient and scalable screening strategies, helping advance efforts in the discovery of antiviral drugs against influenza."

Journal • Infectious Disease • Influenza • Respiratory Diseases

Efficacy and Safety of Pimodivir Combined with Standard-of-care in Hospitalized and Non-hospitalized High-risk Adolescents and Adults with Influenza A Infection. (PubMed, J Infect Dis) - P3 | "Pimodivir + SoC showed no additional clinical benefit versus SoC treatment alone in hospitalized patients. Pimodivir + SoC demonstrated shorter TTR of influenza symptoms versus placebo + SoC in high-risk outpatients."

Journal • Infectious Disease • Influenza • Respiratory Diseases

Genotypic and phenotypic characterization of influenza A viral variants in study participants treated with pimodivir in the phase 2b TOPAZ study. (PubMed, Antivir Ther) - "Participants with acute uncomplicated influenza A treated with pimodivir in the TOPAZ study infrequently developed reduced susceptibility to pimodivir and combining pimodivir with oseltamivir further decreased the risk of reduced susceptibility development."

Journal • P2b data • Infectious Disease • Influenza • Respiratory Diseases

Preclinical Study of ZSP1273, a Potent Antiviral Inhibitor of Cap Binding to the PB2 Subunit of Influenza A Polymerase. (PubMed, Pharmaceuticals (Basel)) - "The inhibitory activity of ZSP1273 on RNA polymerase activity was 0.562 ± 0.116 nM (IC value), which was better than that of the clinical candidate compound VX-787 with the same target...Moreover, oseltamivir-resistant strains, baloxavir-resistant strains, and highly pathogenic avian influenza strains were also sensitive to ZSP1273...In conclusion, ZSP1273 is a highly effective anti-influenza A virus replication inhibitor, especially against multidrug-resistant strains. ZSP1273 is currently being studied in phase III clinical trials."

Journal • Preclinical • Infectious Disease • Influenza • Respiratory Diseases

Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors. (PubMed, Molecules) - "II had lower structural adaptability to PB2 than VX-787. Our results provide helpful information regarding the structure-activity relationship for the design of novel PB2 inhibitors and a reference for the development of drugs containing 2,3-dihydro-imidazopyridine fragments."

Journal • Infectious Disease • Influenza • Respiratory Diseases

Virus-host interaction analysis in colorectal cancer identifies core virus network signature and small molecules. (PubMed, Comput Struct Biotechnol J) - "This analysis highlighted that temsavir, pimodivir, famotine, and bictegravir bind to each virus protein target, respectively. We also assessed the effect of drug binding using molecular dynamic simulations, which shed light on the modulatory effect of drug molecules on SLiM regions in viral targets. Hence, our systematic screening of virus-host networks revealed viral targets, which could be crucial for cancer therapy."

Journal • Colorectal Cancer • Cytomegalovirus Infection • Gastrointestinal Cancer • Oncology • Solid Tumor

Comparative assessment of RNA-dependent RNA polymerase (RdRp) inhibitors under clinical trials to control SARS-CoV2 using rigorous computational workflow. (PubMed, RSC Adv) - "In this study, all the known RdRp inhibitors were computationally targeted in the native form and their active form making the use of molecular docking, MM-GBSA and molecular dynamics (MD) simulations to find the top two of each nucleoside/nucleotide analogues and nonnucleoside/nonnucleotide analogues. The results showed ribavirin 5'-triphosphate and favipiravir ribonucleoside triphosphate (favipiravir-RTP) to be the top two nucleotide analogues while pimodivir and dihydropyrazolopyridinone analogue 8d were the top two nonnucleosides/non-nucleotide analogues."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections. (PubMed, Viruses) - "Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections."

Journal • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • IFNA1

Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors. (PubMed, Molecules) - "Molecular dynamics (MD) simulations of the docking complexes of our active compounds revealed that each compound had its own binding characteristics that differed from those of VX-787. Our active compounds have novel structures and unique binding modes with PB2 proteins, and are suitable to serve as lead compounds for the development of PB2 inhibitors. An analysis of the MD simulation also helped us to identify the dominant amino acid residues that play a key role in binding the ligand to PB2, suggesting that we should focus on increasing and enhancing the interaction between inhibitors and these major amino acids during lead compound optimization to obtain more active PB2 inhibitors."

Journal • Infectious Disease • Respiratory Diseases

Comprehensive Profiling of Mutations to Influenza Virus PB2 That Confer Resistance to the Cap-Binding Inhibitor Pimodivir. (PubMed, Viruses) - "We identified both known and novel resistance mutations not only in the previously implicated cap-binding and mid-link domains, but also in the N-terminal domain. Our complete map of pimodivir resistance thus enables the evaluation of whether new viral strains contain mutations that will confer pimodivir resistance."

Journal • Infectious Disease • Respiratory Diseases

Structural and Thermodynamic Analysis of the Resistance Development to Pimodivir (VX-787), the Clinical Inhibitor of Cap Binding to PB2 Subunit of Influenza A Polymerase. (PubMed, Molecules) - "We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors."

Clinical • Journal • Infectious Disease • Respiratory Diseases

Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir. (PubMed, Antiviral Res) - "A rare PB2 substitution H357N was identified in an A (H4N2) subtype poultry virus that displayed >100-fold reduced pimodivir susceptibility. Our findings demonstrate a broad inhibitory activity of pimodivir and expand the existing knowledge of amino acid substitutions that can reduce susceptibility to this investigational antiviral."

Journal • Infectious Disease • Respiratory Diseases

A Study to Evaluate the Efficacy and Safety of Pimodivir in Combination With the Standard-of-Care Treatment in Adolescent, Adult, and Elderly Non-Hospitalized Participants With Influenza A Infection Who Are at Risk of Developing Complications (clinicaltrials.gov) - P3; N=553; Terminated; Sponsor: Janssen Research & Development, LLC; Trial completion date: Apr 2021 ➔ Aug 2020; Recruiting ➔ Terminated; Trial primary completion date: Oct 2020 ➔ May 2020; Based on interim Analysis outcome being futile for FLZ3001; decision was taken to stop (early terminate) both FLZ3001/3002. There was no safety concern.

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Trial termination • Infectious Disease • Respiratory Diseases • PCR

Novel influenza polymerase PB2 inhibitors for the treatment of influenza A infection. (PubMed, Bioorg Med Chem Lett) - "Exploration of the chemical space of known influenza polymerase PB2 inhibitor Pimodivir, was performed by our group. We synthesized and identified compounds 16a and 16b, two novel thienopyrimidine derivatives displaying anti-influenza A activity in the single digit nanomolar range in cell culture. Binding of these unique compounds in the influenza polymerase PB2 pocket was also determined using molecular modeling."

Journal • Infectious Disease

A Study to Evaluate the Efficacy and Safety of Pimodivir in Combination With the Standard-of-Care Treatment in Adolescent, Adult, and Elderly Hospitalized Participants With Influenza A Infection (clinicaltrials.gov) - P3; N=334; Terminated; Sponsor: Janssen Research & Development, LLC; N=600 ➔ 334; Trial completion date: Apr 2021 ➔ Apr 2020; Recruiting ➔ Terminated; Trial primary completion date: Apr 2021 ➔ Mar 2020; Study terminated early (date of study termination decision: 28 August 2020) as a result of the outcome of the pre-planned Interim Analysis.

Clinical • Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Infectious Disease • PCR

A Study of Orally Administered Pimodivir in Adult Participants With Renal Impairment (clinicaltrials.gov) - P1; N=29; Terminated; Sponsor: Janssen-Cilag International NV; N=48 ➔ 29; Recruiting ➔ Terminated; Strategic decision to stop pimodivir phase 1 studies

Clinical • Enrollment change • Trial termination • Chronic Kidney Disease • Renal Disease

A Study of Orally Administered Pimodivir in Adult Participants With Renal Impairment (clinicaltrials.gov) - P1; N=48; Recruiting; Sponsor: Janssen-Cilag International NV; Trial completion date: Jul 2020 ➔ Nov 2020

Trial completion date • Chronic Kidney Disease • Renal Disease

One hundred years after the 1918 pandemic: new concepts for preparing for influenza pandemics. (PubMed, Curr Opin Infect Dis) - "Despite the progress in pandemic preparedness, gaps remain including important scientific questions, adequate resources and most importantly, the ability to rapidly deliver highly effective vaccines."

Journal • Infectious Disease

Antivirals targeting the polymerase complex of influenza viruses. (PubMed, Antiviral Res) - "Encouragingly, several new compounds which inhibit the polymerase of influenza viruses have recently been shown to have enhanced pre-clinical and clinical effectiveness compared to the neuraminidase inhibitors, the mainstay of influenza antiviral therapy over the last two decades. In this review we focus on four compounds which inhibit polymerase function, baloxavir marboxil, favipiravir, pimodivir and AL-794 and discuss their clinical and virological effectiveness, their propensity to select for resistance and their potential for future combination therapy with the most commonly used neuraminidase inhibitor, oseltamivir."

Journal • Review • Infectious Disease

A Study of Orally Administered Pimodivir in Adult Participants With Hepatic Impairment (clinicaltrials.gov) - P1; N=42; Completed; Sponsor: Janssen-Cilag International NV; Recruiting ➔ Completed

Clinical • Trial completion

A Phase 2 Study of Pimodivir (JNJ-63623872) in Combination with Oseltamivir in Elderly and NonElderly Adults Hospitalized with Influenza A Infection: OPAL study. (PubMed, J Infect Dis) - "No apparent relationship was observed between pimodivir pharmacokinetics and age. Our data demonstrate the need for a larger study of pimodivir in addition to oseltamivir to test whether it results in a clinically significant decrease in time-to-influenza symptom alleviation and/or the frequency of influenza complications."

Clinical • Combination therapy • Journal • P2 data • Infectious Disease

Advances in respiratory virus therapeutics - A meeting report from the 6th isirv Antiviral Group conference. (PubMed, Antiviral Res) - "Updates were presented on several influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies including nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting."

Journal • Review • Infectious Disease • Novel Coronavirus Disease