Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure

Approximately 3.3 billion people live with the threat of Plasmodium vivax malaria. Infection can result in liver-localized hypnozoites, which when reactivated cause relapsing malaria. This is the first demonstration of an enzyme-cleavable polymeric prodrug of tafenoquine (TQ) that addresses key requirements for a mass administration, eradication campaign: excellent subcutaneous bioavailability, complete parasite control after a single dose, improved therapeutic window compared to the parent oral drug, and low Cost of Goods Sold (COGS) at less than $1.50/dose. Liver-targeting and subcutaneous dosing resulted in improved liver:plasma exposure profiles, with increased efficacy and reduced Glucose 6-Phosphate Dehydrogenase (G6PD)-dependent hemotoxicity in validated preclinical models. A COGS and manufacturability analysis demonstrated global scalability, affordability, and the ability to redesign this fully synthetic polymeric prodrug specifically to increase global equity and access. Taken together, this polymer prodrug platform is a candidate for evaluation in human patients and shows potential for P. vivax eradication campaigns.