Developmental candidate GHP-88310/EIDD-3608 with high tolerability and oral efficacy in measles and respiratory paramyxovirus models
Lieber, C. M.; Wolf, J.; Govindarajan, M.; Yoon, J.; Sticher, Z. M.; Ruckel, C.; Leach, A.; Harrison, L.; Vyshenska, D.; Cruz, A.; Andrews, M.; Krueger, R.; Cox, R.; Painter, G. R.; Greninger, A. L.; Natchus, M. G.; Plemper, R. K.
Show 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 development of clinical candidate analog GHP-88310 (EIDD-3608), which combines improved oral efficacy with favorable tolerability in non-rodents (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 2,000 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 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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