Abstract
Scabies affects ∼400 million people annually, yet current therapies lack ovicidal activity, require repeat dosing, and are increasingly compromised by treatment failure and resistance. The absence of a single-application therapy capable of eliminating both motile mites and eggs represents one important limitation to effective disease control. We developed a mechanism-informed topical therapy combining abametapir, a metalloprotease inhibitor with ovicidal activity, and flavesone, a β-triketone with rapid miticidal effects, designed to target multiple parasite life stages through distinct, non-neurotoxic mechanisms. Using a porcine model that closely recapitulates human scabies, we assessed efficacy, pruritus reduction, and pharmacologic exposure after topical administration. In severe scabies, a single 4-hour treatment eradicated all live mites and eggs and reduced pruritus, outperforming a standard two-dose oral ivermectin regimen. Skin pharmacokinetics demonstrated rapid attainment of concentrations with exposure profiles, supporting single-dose efficacy despite shorter systemic half-lives than ivermectin. Together, this promising therapeutic combination may offer a simplified and potentially resistance-resilient approach to scabies management.