Developing a Novel Fungicidal Therapeutic to Treat Coccidioidomycosis

DESCRIPTION provided by applicant Coccidioidomycosis more commonly known as Valley Fever VF is an invasive fungal infection that is endemic to the warm dry climate found in the Southwestern United States Infection occurs when airborne spores of the pathogen enter the lungs The estimated annual incidence of this illness in the U S is about cases per year Although about of coccidioidomycosis cases are asymptomatic the remaining of patients manifest symptoms including self limiting sore throat fever cough fatigue and chest pain with some patients progressing to debilitating life threatening disseminated disease The self limiting symptoms can persist for weeks or months resulting in a substantial morbidity cost due to work lost and the costs of follow up physician appointments Moreover the annual economic burden in California alone from hospitalizations due to coccidioidomycosis is on average about $ million and the associated mortality rate for those patients hospitalized is Recently Amplyx Pharmaceuticals has in licensed the entire portfolio of potent Gwt inhibitors from Eisai Several of these compounds show good potency M g mL vs both C immitis and C posadasii over orally bioavailability in mouse and rat models low potential for drug drug interactions based on in vitro P assays no observable toxicity at plasma levels in rodents that should permit strong antifungal activity and strong i vivo efficacy data We plan to leverage the extensive structure activity relationships SAR elucidated by the chemistry team at Eisai to refine the properties of our andquot hitandquot compounds employing the following Specific Aims Aim Create a first generation library of at least analogues of hit compounds from Phase I Aim Characterize and select compounds for advancement by employing in vitro assays to assess a antifungal potency b target engagement c cytotoxicity d i in vitro PK PD Aim Characterize and select compounds for advancement by employing in vivo studies to assess a PK b maximum tolerated dose c reduction of fungal burden d improved survival in VF models PUBLIC HEALTH RELEVANCE Coccidioidomycosis commonly known as Valley Fever is an emerging fungal disease in the southwestern United States Once the disease has progressed it causes substantial morbidity with an annual burden of $ million in health care costs in California alone and has an associated mortality rate of patients who are hospitalized Current treatments are generally not curative so better therapeutics are urgently needed to treat this disease