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Developmental candidate GHP-88310/EIDD-3608 with high tolerability and oral efficacy in measles and respiratory
Carolin M Lieber1, Josef D Wolf1, Mugunthan Govindarajan2
1Center for Translational Antiviral Research, Georgia State University Institute for Biomedical Sciences, Atlanta, GA 30303, USA.
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.
Insights
A new drug candidate, GHP-88310, shows broad-spectrum efficacy against orthoparamyxoviruses like HPIV3 and MeV. It offers improved oral delivery and tolerability in mammals, representing a promising antiviral treatment.
Area of Science:
- Virology
- Drug Discovery
- Antiviral Therapeutics
Background:
- Orthoparamyxoviruses, including human parainfluenza virus type 3 (HPIV3) and measles virus (MeV), pose significant health risks.
- Previous broad-spectrum orthoparamyxovirus polymerase inhibitors showed limited tolerability in higher mammals.
Purpose of the Study:
- To develop a clinical candidate analog with improved oral efficacy and favorable tolerability for treating orthoparamyxovirus infections.
- To evaluate the efficacy and safety of GHP-88310 (EIDD-3608) in preclinical models.
Main Methods:
- GHP-88310 was tested for activity against HPIV3, Sendai virus (SeV), MeV, and canine distemper virus (CDV).
- Tolerability was assessed in ferrets and dogs over 7 days.
- Pharmacokinetic analysis was performed.
- Efficacy was evaluated in HPIV3-infected cotton rats and CDV-infected ferrets.
- In vitro activity was assessed using human airway epithelium organoids.
Main Results:
- GHP-88310 demonstrated broad-spectrum activity against multiple orthoparamyxoviruses.
- The compound was well-tolerated at high doses (2000 mg/kg) in nonrodents.
- GHP-88310 reduced viral load in the respiratory tract of HPIV3-infected cotton rats.
- In CDV-infected ferrets, GHP-88310 led to complete survival, reduced viremia and viral shedding, and alleviated lymphocytopenia.
- The compound exhibited sterilizing activity against HPIV3 in human airway organoids.
Conclusions:
- GHP-88310 is a promising clinical candidate with improved oral efficacy and tolerability for orthoparamyxovirus infections.
- The drug candidate effectively treats lethal measles-like disease and HPIV3 infections in relevant animal models.
- GHP-88310 shows potential as a broad-spectrum antiviral agent against dangerous paramyxoviruses.
