A novel 'fungerp' targeting refractory Candida urinary tract infections

SUMMARY Urinary tract infections (UTI) infections caused by azole-resistant Candida isolates are a growing problem and pose a medical challenge with a lack of optimal treatments. Currently, fluconazole is the antifungal of choice for Candida UTIs considering it achieves high concentrations in urine. However, the management of fluconazole-resistant Candida strains represents a growing problem because there are limited treatment options, as most currently available antifungal agents fail to attain adequate concentrations in urine. Although Candida albicans is the most encountered species in Candida UTIs, the incidence of non-albicans Candida species is increasing. The main concern with this progressive shift in epidemiology is that many of these species like Candida glabrata and Candida auris show reduced susceptibility or resistance to fluconazole and other antifungals, further complicating the treatment of patients with these infections. There is a clear need for a novel antifungal agent that can be administered orally, achieves high concentrations in urine, and has potent and broad antifungal activity against Candida strains, including those resistant to currently available antifungal options. Our research partner Scynexis has developed two novel triterpenoid antifungal compounds, otherwise known as ‘fungerps.’ The first, ixbrexafungerp (IBX), is FDA approved for two indications in the treatment of vulvovaginal candidiasis. The second, SCY-247, is in preclinical development with a planned IND. These compounds are broad-spectrum with potent activity against Candida species, Aspergillus fumigatus, and other molds. They are also well-tolerated, can be given orally, and have exposure in the genitourinary tract, but fail to achieve therapeutic levels in the bladder and urine. The goal of this program is to develop a novel fungerp ready for IND submission with the following drug attributes: 1) enhanced distribution into urine while retaining the distribution to renal tissues and anti-fungal potency achieved with IBX; 2) comparable or better potency (vs. IBX or SCY-247) against fluconazole-resistant C. auris, C. glabrata, C. parapsilosis, and C. albicans; 3) oral bioavailability and pharmacokinetic properties consistent with QD administration; 4) No new dose-limiting toxicology at the NOAELs for IBX or SCY-247; and 5) maintain or surpass the low DDI potential observed with IBX. This goal will be accomplished by bringing together long-standing academic and industry partners within a CETR landscape to rapidly optimize lead candidates and advance a preclinical development candidate through IND enabling and de-risking studies resulting in an IND application.