Orally available NOD2 agonist, HPX-612, for the treatment of visceral leishmaniasis

Project Summary We are developing the first orally available immunotherapy product, HPX-612, for the treatment of visceral leishmaniasis, a parasitic disease caused by Leishmania and transmitted by sandflies. Visceral leishmaniasis remains endemic in 65 countries worldwide, with over 4 million people impacted globally. Current treatment options require lengthy and painful injections and have significant limitations including low therapeutic index, severe side effects, acute cytotoxicity, high associated hospital costs and emergence of their resistance strains. Additionally, these treatments are often inaccessible to those living in the remote areas where Leishmania is prevalent. Leishmania infection is heavily dependent on host monocytes and macrophages as once the parasite enters the human body, it is engulfed by monocytes and macrophages where it inhibits macrophage activation and replicates. Recent studies have identified the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) as a critical regulator in the intracellular killing of Leishmania parasites. Further, NOD2 agonism in infected monocytes and macrophages provide a novel host-targeted therapeutic strategy that increases immunosurveillance via activation of the innate immune system that resolves leishmaniasis. HPX-612 is a novel lipid nanoparticle and potent innate immune stimulator that is comprised of the active pharmaceutical ingredient muramyl tripeptide phosphatidylethanolamine (MTP-PE), a NOD2 agonist with demonstrated clinical safety. MTP-PE is the active pharmaceutical ingredient in the EMA-approved intravenously delivered MepactÒ for non-metastatic osteosarcoma. HPX-612 has a demonstrated capacity to cross the gut- blood barrier creating a sustained NOD2 stimulation and potent pro-inflammatory conversion of monocytes and macrophages after oral dosing. When approved, HPX-612 will be delivered external to hospital settings and over longer time periods to efficiently combat visceral leishmaniasis in regions that need it most. Herein this application we will evaluate the preclinical pharmacokinetic profile of HPX-612, optimal posology, and confirmation of efficacy in a murine model of visceral leishmaniasis. These results will support the launch of HPX-612 into full-scale preclinical development for the treatment of leishmaniasis and a future Phase II application.