Abstract
Orthoparamyxoviruses such as human parainfluenza virus type-3 (HPIV3), measles virus (MeV), and emerging henipaviruses pose a substantial threat to human health. We discovered an orally efficacious broad-spectrum non-nucleoside inhibitor of orthoparamyxovirus polymerases. However, here we found that tolerability in higher mammals was limited to 50 mg/kg b.i.d., close to the lowest efficacious dose. We report development of a clinical candidate analog, GHP-88310 (EIDD-3608), which combines improved oral efficacy with favorable tolerability in non-rodent species (ferrets and dogs), greatly expanding the therapeutic window. GHP-88310 had potent activity against the primary indication, HPIV3 and related respiroviruses, and the secondary indication, MeV and related morbilliviruses. In 7-day multi-dose tolerability studies, daily doses of 2,000 mg/kg were well-tolerated. Pharmacokinetic analysis revealed an altered plasma exposure profile after oral delivery of GHP-88310 compared to the original hit. In the HPIV3 cotton rat model, GHP-88310 significantly reduced viral load in the upper and lower respiratory tract when administered orally at 50 mg/kg twice daily. Therapeutic administration to ferrets infected with canine distemper virus (CDV), causing lethal measles-like disease, resulted in complete survival, significant reduction of primary viremia and shed viral load, and alleviated lymphocytopenia. Once-daily GHP-88310 was efficacious at respective 50 mg/kg and 150 mg/kg in the CDV ferret and HPIV3 cotton rat models. The compound was sterilizing against HPIV3 at pharmacokinetics-informed dynamic concentrations in disease-relevant human airway epithelium organoids. These results identify GHP-88310 as a candidate for urgently needed improved orthoparamyxovirus disease management.