ziresovir (AK0529) / Ark Biosci, Roche - LARVOL DELTA

Synthetic oxetanes in drug discovery: where are we in 2025? (PubMed, Expert Opin Drug Discov) - "While oxetanes feature famously in the taxol family, it was not until the recent approval of rilzabrutinib that they have been validated in a fully synthetic drug...The regulatory approval of rilzabrutinib and likely approval of ziresovir provide confidence in using oxetanes as important elements in drug design. While oxetanes have so far been incorporated primarily as pendant groups to optimize physicochemical properties, their use as scaffolding and binding elements presents an exciting opportunity. Enhanced synthetic accessibility to oxetane derivatives will expedite their inclusion in drug discovery campaigns."

Journal • Review • Oncology • Respiratory Diseases

Ziresovir: a potent, selective, and oral inhibitor of the respiratory syncytial virus fusion (F) protein (PubMed, Rev Esp Quimioter) - "When administered orally twice daily for 5 days, it produces a clear clinical improvement in bronchiolitis (signs and symptoms) and a decrease in viral load in the respiratory tract. This new antiviral is well tolerated with few adverse effects, but with the development of resistance during treatment in 11-18% of cases, especially at high doses."

Journal • Review • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Development of a HEp2-CDX Mouse Model With Sustained High RSV Viral Loads for Robust Antiviral Therapeutic Evaluation. (PubMed, J Med Virol) - "Furthermore, the addition of a clinical monoclonal antibody (nirsevimab) and an antiviral drug (ziresovir) showed strong antiviral activity within this animal model. These findings suggest that HEp2-CDX mice, which enable stable RSV infection and replication, serve as useful models for evaluating antiviral therapeutics."

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

Development and Optimization of a Novel Synthetic Route for 2,4-Diamine-quinazoline Containing Ziresovir: A Drug Candidate for the Treatment of Respiratory Syncytial Virus (RSV) Infection. (PubMed, ACS Omega) - "Finally, nucleophilic substitution of compound 19 with 3-amino-3-oxetanylmethylamine yields the target molecule, Ziresovir. This chromatography-free process offers practical advantages, offering a viable pathway for the production of Ziresovir and other quinazoline analogs."

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

Cholesterol-rich lipid rafts mediate endocytosis as a common pathway for respiratory syncytial virus entry into different host cells. (PubMed, Microbiol Spectr) - "Furthermore, reducing cholesterol levels using methyl-β-cyclodextrin, simvastatin, or terbinafine inhibited RSV infection. Notably, combining simvastatin with an RSV fusion protein inhibitor (AK0529) resulted in enhanced antiviral effects both in vitro and in vivo...By meticulously examining various RSV genotypes, we revealed shared mechanisms underlying viral entry, highlighting the significance of cholesterol regulation and its impact on infection inhibition. Our findings also demonstrate enhanced antiviral efficacy through a combined approach targeting both viral entry and cholesterol metabolism."

Journal • Infectious Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Viral Bronchiolitis in Infants in the Era of Targeted Therapies: What Now and What's Next? (PubMed, Pediatr Pulmonol) - "Understanding and addressing the causes of poor adherence to bronchiolitis guidelines is critical. Future research should aim to integrate evidence-based treatments with options for personalized adjustments. Updated guidelines should reflect emerging interventions and provide rational management pathways until robust evidence from new studies becomes available."

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

ArkBio's Ziresovir Included into Pediatric RSV Drug Priority List by WHO (PRNewswire) - "In the newly released 'Paediatric drug optimization for respiratory syncytial virus (PADO-RSV) meeting report' by Global Accelerator for Paediatric formulations (GAP-f), the World Health Organization (WHO) host network, ziresovir (10mg) has been included in the PADO-RSV priority list. Ziresovir, developed by Shanghai Ark Biopharmaceutical Co., Ltd. ('ArkBio'), is the first and only RSV antiviral drug to be included in the list. This is the first time WHO has included an anti-RSV drug developed from China in the paediatric drug optimization priority list."

Commercial • Respiratory Syncytial Virus Infections

The Lancet Child & Adolescent Health Publishes Phase III Trial and 24-Month Follow-Up Results of Ziresovir for RSV in Infants Under 6 Months (PRNewswire) - "The Lancet Child & Adolescent Health, a leading international journal in pediatric and adolescent medicine, has published the Phase III clinical trial results of ziresovir, a novel RSV-targeted antiviral drug developed by Shanghai Ark Biopharmaceutical Ltd. The article...presents detailed subgroup analysis of infants under six months of age, following the primary results published in The New England Journal of Medicine in September 2024....Ziresovir's Phase III results mark a significant milestone, representing the first clinical validation of an antiviral's efficacy in hospitalized infants ≤6 months, and demonstrating long-term benefits in reducing recurrent wheezing and asthma."

P3 data • Asthma • Infectious Disease

Efficacy and safety of ziresovir in hospitalised infants aged 6 months or younger with respiratory syncytial virus infection in China: findings from a phase 3 randomised trial with 24-month follow-up. (PubMed, Lancet Child Adolesc Health) - P3 | "Ziresovir had a favourable safety profile and was associated with a significant clinical benefit during the treatment period compared with placebo in patients aged 6 months or younger."

Clinical • Journal • P3 data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

A Study to Confirm the Effectiveness and Safety of AK0529 in Treating RSV Infections in Hospitalized Infants (clinicaltrials.gov) - P3 | N=180 | Recruiting | Sponsor: Shanghai Ark Biopharmaceutical Co., Ltd.

New P3 trial • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Cost-effectiveness of anti-viral treatment for infants with RSV disease in the United Kingdom. (PubMed, Vaccine) - "Ziresovir is a cost-effective intervention for all infants hospitalised with RSV if priced below £430 per dose and strategies that exclusively treat high-risk- with CLD and CHD infants justify a higher price of £6558 and £9460 respectively. The outcomes are highly sensitive to the efficacy of Ziresovir and can be improved when the full results of the AIRFLO trial are available."

HEOR • Journal • Cardiovascular • Heart Failure • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Vaccine and therapeutic agents against the respiratory syncytial virus: resolved and unresolved issue. (PubMed, MedComm (2020)) - "Additionally, there have been notable progress in the realm of passive immunoprophylactic antibodies, with the monoclonal antibody nirsevimab receiving regulatory approval for the prevention of RSV infections in infants...This review delineates the advancements and challenges faced in vaccines and therapeutic agents targeting RSV. It aims to provide insights that will guide the development of effective preventive and control measures for RSV."

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

Ziresovir in Hospitalized Infants with Respiratory Syncytial Virus Infection. (PubMed, N Engl J Med) - P3 | "Ziresovir treatment reduced signs and symptoms of bronchiolitis in infants and young children hospitalized with RSV infection. No safety concerns were identified. (Funded by Shanghai Ark Biopharmaceutical; AIRFLO ClinicalTrials.gov number, NCT04231968.)."

Clinical • Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Thorough QT/QTc (TQT) Clinical Study to Evaluate the Effects of Ziresovir on Cardiac Repolarization in Healthy Subjects (clinicaltrials.gov) - P1 | N=32 | Not yet recruiting | Sponsor: Shanghai Ark Biopharmaceutical Co., Ltd.

New P1 trial

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

Cost-Effectiveness Analysis of Ziresovir in Hospitalized Children Aged 0 to 2 Years With Respiratory Syncytial Virus Infection (ISPOR 2024) - "Ziresovir has a significant cost-effective advantage over the conventional treatment for RSV infection in hospitalized children aged 0 to 2 years in China."

Clinical • Cost effectiveness • HEOR • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Safety and efficacy of AK0529 in respiratory syncytial virus-infected infant patients: A phase 2 proof-of-concept trial. (PubMed, Influenza Other Respir Viruses) - P2 | "Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score. NCT02654171."

Journal • P2 data • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

A Phase 3 Pivotal Study of Efficacy and Safety of Oral Ziresovir in RSV-Infected Hospitalized Infants (ISIRV-RSV 2022) - "Ziresovir is well tolerated with good safety profile in the infant patients. To our knowledge, this was the first successful pivotal phase 3 study for a direct anti-RSV drug in hospitalized infant patients."

Clinical • P3 data • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

AirFLO: A Study of AK0529 in Chinese Infants Hospitalized With RSV (clinicaltrials.gov) - P3 | N=311 | Completed | Sponsor: Ark Biosciences Inc. | Recruiting ➔ Completed | Trial completion date: May 2022 ➔ Feb 2022 | Trial primary completion date: Apr 2022 ➔ Jan 2022

Trial completion • Trial completion date • Trial primary completion date • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Ziresovir in Healthy Subjects (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Ark Biosciences Inc. | Recruiting ➔ Completed | Trial primary completion date: Oct 2021 ➔ Jun 2021

Trial completion • Trial primary completion date

A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Ziresovir in Healthy Subjects (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Ark Biosciences Inc.; Not yet recruiting ➔ Recruiting; Trial completion date: Jun 2021 ➔ Oct 2021; Trial primary completion date: Jun 2021 ➔ Oct 2021

Clinical • Enrollment open • Trial completion date • Trial primary completion date

AirFLO: A Study of AK0529 in Chinese Infants Hospitalized With RSV (clinicaltrials.gov) - P3; N=249; Recruiting; Sponsor: Ark Biosciences Inc.; Not yet recruiting ➔ Recruiting; Trial completion date: Dec 2021 ➔ May 2022; Trial primary completion date: Jun 2021 ➔ Apr 2022

Clinical • Enrollment open • Trial completion date • Trial primary completion date • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

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

A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Ziresovir in Healthy Subjects (clinicaltrials.gov) - P1; N=24; Not yet recruiting; Sponsor: Ark Biosciences Inc.

Clinical • New P1 trial

Discovery of Ziresovir as a Potent, Selective and Orally Bioavailable Respiratory Syncytial Virus Fusion Protein Inhibitor. (PubMed, J Med Chem) - "Ziresovir demonstrates single-digit nM EC50 potency against laboratory strains as well as clinical isolates of RSV in cellular assays, and more than one log viral load reduction in BALB/c mouse model of RSV viral infection. Ziresovir was proven to be a specific RSV F protein inhibitor by identification of drug resistant mutations of D486N, D489V, and D489Y in RSV F protein and the inhibition of RSV F protein-induced cell-cell fusion in cellular assays."

Journal