The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis

Abstract

Aspergillus spp. infections remain a global concern, with ∼30% attributable mortality of invasive aspergillosis (IA). VT-1598 is a novel fungal CYP51 inhibitor designed for exquisite selectivity versus human CYP enzymes to achieve a maximal therapeutic index and therefore maximal antifungal efficacy. Previously, its broad-spectrum in vitro antifungal activity was reported. We report here the pharmacokinetics (PK) and pharmacodynamics (PD) of VT-1598 in neutropenic mouse models of IA. The plasma area-under-the-curve (AUC) of VT-1598 increased nearly linearly between 5 and 40 mg/kg after 5 days of QD administration (155 and 1033 μg*h/ml, respectively), with a further increase with 40 mg/kg BID dosing (1354 μg*h/ml). When A. fumigatus isolates with in vitro susceptibilities of 0.25 and 1.0 μg/ml were used in a disseminated IA model, VT-1598 treatment produced no decrease in kidney fungal burden at QD 10 mg/kg, intermediate decreases at QD 20 mg/kg and maximum or near maximum decreases at 40 mg/kg QD and BID. The PK/PD relationships of AUCfree/MIC for 1-log killing for the two strains were 5.1 and 1.6 h, respectively, similar to values reported for approved CYP51 inhibitors. In a survival study where animals were observed for 12 days after the last treatment, survival was 100% at the doses tested (20 and 40 mg/kg QD), and fungal burden remained suppressed even though drug wash-out was complete. Similar dose-dependent reductions in lung fungal burden were observed in a pulmonary model of IA. These data strongly support further exploration of VT-1598 for the treatment of this lethal mold infection.

Novel antifungal agents in clinical trials

“…and Rhizopus spp.) and endemic dimorphic fungi (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides posadasii, and C. immitis) [68][69][70] . In murine models of CNS coccidioidomycosis, VT-1598 treatment leads to improved survival and reduced fungal burden in brain tissue as compared to fluconazole.…”

Novel antifungal agents in clinical trials

“…and Rhizopus spp.) and endemic dimorphic fungi (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides posadasii, and C. immitis) [62][63][64] . In murine models of CNS coccidioidomycosis, VT-1598 treatment leads to improved survival and reduced fungal burden in brain tissue as compared to fluconazole.…”

Advances in anti-fungal therapies

“…and Rhizopus arrhizus [ 13 ]. VT-1598 also appears to have good efficacy in murine models of central nervous system coccidioidomycosis [ 14 ], cryptococcal meningitis [ 15 ] and invasive aspergillosis [ 16 ]. A phase I study of VT-1598 (NCT04208321) is currently listed to complete in mid-2021.…”