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Pharmacokinetics, Safety, and Tolerability of the Isatoribine Oral Prodrug ANA975 in a Phase I Heakthy Volunteer Study
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Bradley Kerr, Anadys Pharmaceuticals Inc, San Diego, CA; Lisa Bauman, Stephen Webber, Alan Xiang, John Ng, Leo Kirkovsky, Darian Bartkowski, Kevin Steffy, Simon Fletcher, Robert Aust, Anadys Pharmaceuticals, Inc.,
San Diego, CA; Jeffrey Theiss, SunCoast Tox, San Diego, CA; Devron
Averett, Anadys Pharmaceuticals Inc, San Diego, CA
Purpose: In a proof-of-concept (POC) clinical study, intravenous (IV) infusion of the TLR7 agonist isatoribine 800mg once daily x 7 days to patients chronically infected with hepatitis C virus (HCV) yielded a significant reduction of plasma HCV RNA that correlated with induction of 2', 5'-oligoadenylate synthetase (OAS). Oral doses of isatoribine are poorly absorbed in multiple species. The prodrug ANA975 was developed to improve oral delivery of isatoribine to systemic circulation.
Methods: Toxicology studies, including GLP oral multiple-dose studies in cynomolgus monkeys, were performed to enable clinical studies. An open label, rising dose level, single-dose study in healthy volunteers was performed in the United Kingdom according to institutional and local regulatory requirements. Thirty-six subjects each received a single oral dose of ANA975 administered
as a 5mg/mL solution in the fasted state at doses of 400mg (n 6), 800mg (n 18), or 1200mg (n 12).
Results: Oral administration of ANA975 to monkeys resulted in efficient systemic delivery of isatoribine; the highest tolerated dose in monkey achieved plasma area-under-the-curve (AUC) values 6-13x higher than achieved with the 800mg IV dose in the clinical POC study. Monkeys showed a dose-related OAS induction in blood that persisted with once daily dosing for treatment periods up to at least 28 days.
Single oral doses of ANA975 were well tolerated by healthy volunteers. There were no serious adverse events (AEs) and no withdrawals from the study. A total of 15 AEs were reported by 13 of 36 subjects. All reported AEs were mild (13 events) or moderate (2 events) in severity. The Investigator considered 1 AE (mild transient increase in CPK at 800mg) to be possibly related to ANA975 and all other AEs to be unlikely related or not related to ANA975. There were no reports of gastrointestinal AEs or flu-like syndrome. ANA975 was rapidly and extensively converted to isatoribine, with isatoribine Cmax typically occurring within 1 hour post-dose. At the highest tested dose, which has an isatoribine
dose content of 988mg, plasma isatoribine AUC values (range 23-40, median 27mg*h/L) were similar to those observed in the clinical POC study with daily 1-hour IV infusions of isatoribine 800mg (first dose AUC range 19-38, median 24mg*h/L). The similarity of AUC values at comparable molar doses of oral ANA975 and IV isatoribine indicates that fractional oral absorption and conversion of ANA975 to isatoribine was very high.
Conclusion: ANA975 is an efficient oral prodrug that achieves plasma isatoribine exposures comparable to those previously shown to reduce plasma HCV RNA in chronically infected patients.
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