NP339

Background: There is a clear clinical & economic need for improved therapeutic options (safety, efficacy, resistance) for the increasing problem posed by systemic Candida spp. infections. To address this, NovaBiotics has developed NP339, a fast-acting candidacidal cationic peptide active against all Candida species, including examples known to be insensitive/resistant to azoles. Methods: Antifungal susceptibility testing on >200 Candida spp. clinical isolates other clinically relevant yeasts and fungi was performed using CLSI Approved Standard M27-A3 & M38-A2. The impact of physiological salt and serum was determined as was the in vitro haemolytic & cytotoxic potential of NP339. Tolerability and activity of NP339 in vivo was determined in a murine model of acute candidiasis in which peptide in native & PEGylated forms were administered intravenously 60 min post-Candida spp. challenge with yeast burden determined 24 hours post challenge. Results: In all cases, Candida spp. isolates, including isolates known to be insensitive/resistant to azoles were rapidly killed (<=30 min), MIC100 range 1-256 µg/ml, median 2 µg/ml) following exposure to NP339. NP339 was also active against other clinically relevant yeasts & mould including Aspergillus spp., Fusarium spp. & Cryptococcus spp.). The primary mode of action of NP339 is membranolysis. No resistance (acquired or spontaneous) was observed (>60 passages). Activity of NP339 was not significantly inhibited by physiological salt concentrations or serum in vitro & parenterally administered peptide was well tolerated in vivo. PEGylated-NP339 successfully reduced fungal burden in a murine model of acute candidiasis (10mg/kg). Conclusion: NP339 is an effective, novel fungicidal cationic antimicrobial peptide & a promising candidate for the treatment of Candida & other serious yeast and mould infections. NP339 will be formulated for both intravenous & oral delivery. Further research shall asses the suitability of NP339 for co-administration with other antifungals.

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