lumicitabine (JNJ-64041575) / J&J - LARVOL DELTA

A Phase 2a Study to Evaluate Orally Administered ALS-008176 in Adults Hospitalized With a Respiratory Syncytial Virus (clinicaltrials.gov) - P2 | N=9 | Completed | Sponsor: Alios Biopharma Inc. | Phase classification: P2a ➔ P2

Phase classification • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

A Phase 2a Study to Evaluate ALS-008176 in the Virus Challenge Model (clinicaltrials.gov) - P2 | N=62 | Completed | Sponsor: Alios Biopharma Inc. | Phase classification: P2a ➔ P2

Phase classification • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Systematic Review of the Efficacy and Safety of RSV-Specific Monoclonal Antibodies and Antivirals in Development. (PubMed, Rev Med Virol) - "Results from 59 studies were extracted, covering efficacy and safety data on six mAbs (motavizumab, motavizumab-YTE, nirsevimab, ALX-0171, suptavumab, clesrovimab) and 12 AV therapies (ALN-RSV01, RSV604, presatovir, MDT-637, lumicitabine, IFN-α1b, rilematovir, enzaplatovir, AK0529, sisunatovir, PC786, EDP-938). Moving forward, passive immunisation and treatment options for RSV infection will play a significant role in reducing the health burden of RSV, complementing recent advancements in vaccine development. TRIAL REGISTRATION: PROSPERO registration: CRD42022376633."

Journal • Review • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • IFNA1

Lumicitabine, an orally administered nucleoside analog, in infants hospitalized with respiratory syncytial virus (RSV) infection: Safety, efficacy, and pharmacokinetic results. (PubMed, PLoS One) - P1, P2 | "This contrasts with the findings of the previous RSV-A adult challenge study where significant antiviral activity was noted, without incidence of neutropenia. Trial registration ClinicalTrials.gov Identifier: NCT02202356 (phase 1b); NCT03333317 (phase 2b)."

Journal • PK/PD data • Hematological Disorders • Infectious Disease • Neutropenia • Respiratory Diseases • Respiratory Syncytial Virus Infections

Nucleoside analogs for management of respiratory virus infections: mechanism of action and clinical efficacy. (PubMed, Curr Opin Virol) - "The COVID-19 pandemic has accelerated the development of nucleoside analogs to treat respiratory virus infections, with remdesivir being the first compound to receive worldwide authorization and three other nucleoside analogs (i.e. favipiravir, molnupiravir, and bemnifosbuvir) in the pipeline...We also mention trials of favipiravir and lumicitabine, for influenza and respiratory syncytial virus, respectively. Besides, we outline how nucleoside analogs interact with the polymerases of respiratory viruses, to cause lethal virus mutagenesis or disturbance of viral RNA synthesis. In this way, we aim to convey the key findings on this rapidly evolving class of respiratory virus medication."

Journal • Review • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Nitro-Activated Nucleobase Exchange in the Synthesis of 2'-Fluoro-2'-Deoxyribonucleosides. (PubMed, J Org Chem) - "Nitration of lumicitabine, a 2'-fluoro-2'-deoxycytidine class antiviral agent, and its 2'-fluoro-2'-deoxyuridine precursor produce the same 5-nitro-2'-fluoro-2'-deoxyuridine. Under Vorbrüggen conditions, 5-nitrouracil serves as the leaving nucleobase and enables exchange with pyrimidine and purine nucleobases to anomeric 2'-fluoro-2'-deoxyribonucleosides in favor of β-anomers generally. The strategy is also applied in the isotopic labeling of 2'-fluoro-2'-deoxyuridines."

Journal

4'-Modified Nucleosides for Antiviral Drug Discovery: Achievements and Perspectives. (PubMed, Acc Chem Res) - P=N/A, P3 | "Currently, seven 4'-modified nucleoside drug candidates such as azvudine (also known as FNC), islatravir, censavudine, balapiravir, lumicitabine, AL-335, and 4-azidothymidine have progressed into clinical stages for treating viral infections. FNC cured the COVID-19 disease in almost all patients and showed better therapeutic efficacy than remdesivir. In this Account, we provide an overview of 4'-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure-activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery."

Journal • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • CD4

Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro. (PubMed, Molecules) - "Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from -50 µM % to -176 µM % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations."

Journal • Preclinical • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

[VIRTUAL] Expedient synthesis of nucleoside analogues by activation and replacement of pyrimidine nucleobases: Application for synthesis of radio-labeled lumicitabine via Vorbrüggen transglycosylation (ACS-Sp 2021) - "This synthetic method was applied to the production of radioisotope-labeled Lumicitabine (ALS-8176, 4) by activation of a pyrimidine nucleobase via substitution of the electron-withdrawing group at the 5-position of the uracil ring of the 2-deoxyuridine analogues, followed by replacement of the activated uracil with a 14C-labeled uracil (Vorbrüggen reaction with BSA/TMSOTf), producing a high specific activity 14C tracer in respectable radiochemical yield, thus demonstrating the utility of the method for the production of a complex nucleoside analogues. The results will be presented."

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

A Phase 1 Study to Evaluate the Effect of the Organic Anion Transporter Inhibitor Probenecid on the Pharmacokinetics of JNJ-64041575 in Healthy Adults (clinicaltrials.gov) - P1; N=18; Completed; Sponsor: Janssen-Cilag International NV; Recruiting ➔ Completed

Trial completion • Biosimilar

A Crossover Study to Assess the Drug-drug Interaction of Acid Reducing Agent(s) on the Pharmacokinetics of a Single Oral Dose of Lumicitabine (JNJ-64041575) in Healthy Adult Participants (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Janssen Research & Development, LLC

New P1 trial • Biosimilar • Chronic Kidney Disease • Renal Disease

STEP: Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Oral Lumicitabine Regimens in Hospitalized Adult Participants Infected With Human Metapneumovirus (clinicaltrials.gov) - P2b; N=90; Not yet recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Nov 2019 ➔ Oct 2020

Trial completion date • Biosimilar

Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered ALS-008176 Regimens in Adult Participants Hospitalized With Respiratory Syncytial Virus (clinicaltrials.gov) - P2b; N=114; Recruiting; Sponsor: Janssen Research & Development, LLC; Suspended ➔ Recruiting

Enrollment open • Biosimilar

A Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered Lumicitabine (JNJ-64041575) Regimens in Hospitalized Infants and Children Aged 28 Days to 36 Months Infected With Respiratory Syncytial Virus (clinicaltrials.gov) - P2; N=7; Terminated; Sponsor: Janssen Research & Development, LLC; N=180 ➔ 7; Trial completion date: Apr 2019 ➔ Mar 2018; Suspended ➔ Terminated; Trial primary completion date: Apr 2019 ➔ Mar 2018; Sponsor Decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Biosimilar

A Long-term Follow-up Study to Evaluate the Impact of Lumicitabine on the Incidence of Asthma and/or Wheezing in Infants and Children With a History of Respiratory Syncytial Virus Infection (clinicaltrials.gov) - P2; N=7; Completed; Sponsor: Janssen Research & Development, LLC; Active, not recruiting ➔ Completed

Clinical • Trial completion • Asthma • Infectious Disease • Respiratory Diseases

Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans. (PubMed, J Antimicrob Chemother) - "The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients."

Journal • Immunology • Infectious Disease • Pediatrics

Potent in vitro activity of β-D-4'-chloromethyl-2'-deoxy-2'-fluorocytidine against Nipah virus. (PubMed, Antiviral Res) - "However, further cytotoxicity testing in primary cells and bone marrow progenitor cells indicated cytotoxicity at higher concentrations of ALS-8112. Our results warrant the evaluation of lumicitabine against NiV infection in relevant animal models."

Journal • Preclinical

A Study of ALS-008176 in Infants and Children Hospitalized with RSV (clinicaltrialsregister.eu) - P2; N=120; Sponsor: Janssen-Cilag International NV

Clinical • Clinical data • New P2 trial