Developmental candidate GHP-88310/EIDD-3608 with high tolerability and oral efficacy in measles and respiratory paramyxovirus models

  • Sci Adv. 2026 May 22;12(21):eaef1594. doi: 10.1126/sciadv.aef1594.
Carolin M Lieber  1 ,  Josef D Wolf  1 ,  Mugunthan Govindarajan  2 ,  Jeong-Joong Yoon  1 ,  Zachary M Sticher  2 ,  Claire E Ruckel  1 ,  Alexander I Leach  1 ,  Lauren A Harrison  1 ,  Dariia Vyshenska  3 ,  Amalia A Cruz  2 ,  Meghan K Andrews  2 ,  Rebecca E Krueger  2 ,  Robert M Cox  1 ,  George R Painter  2 ,  Alexander L Greninger  3 ,  Michael G Natchus  2 ,  Richard K Plemper  1
Affiliations
  • 1. Center for Translational Antiviral Research, Georgia State University Institute for Biomedical Sciences, Atlanta, GA 30303, USA.
  • 2. Emory Institute for Drug Development, Emory University, Atlanta, GA 30322, USA.
  • 3. Virology Division, Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, WA 98195, USA.
PMID: 42172325 DOI: 10.1126/sciadv.aef1594
Abstract

Orthoparamyxoviruses, such as human parainfluenza virus type 3 (HPIV3) and measles virus (MeV), are a major health threat. We discovered an orally efficacious broad-spectrum inhibitor of orthoparamyxovirus polymerases. However, here, we found that tolerability in higher mammals was limited. We report the development of the clinical candidate analog GHP-88310 (EIDD-3608), which combines improved oral efficacy with favorable tolerability in nonrodents (ferrets and dogs). GHP-88310 was active against HPIV3, Sendai virus (SeV), MeV, and related canine distemper virus (CDV). In 7-day tolerability studies, daily doses of 2000 mg/kg were well tolerated. Pharmacokinetic analysis revealed altered plasma exposure of GHP-88310 compared to the original hit. In HPIV3-infected cotton rats, GHP-88310 lowered the respiratory tract viral load. Dosing of ferrets infected with CDV, causing lethal measles-like disease, resulted in complete survival, reduction of viremia and shed viral load, and alleviated lymphocytopenia. Once-daily GHP-88310 was efficacious in the CDV-ferret and HPIV3-cotton rat models. The compound was sterilizing against HPIV3 at physiological concentrations in human airway epithelium organoids.

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