Drugs in Clinical Development for Fungal Infections

Abstract

Despite increasing rates of invasive fungal infections being reported globally, only a single antifungal drug has been approved during the last decade. Resistance, toxicity, drug interactions and restricted routes of administration remain unresolved issues. This review focuses on new antifungal compounds which are currently in various clinical phases of development. We discuss two azoles with a tetrazole moiety that allows selective activity against the fungal CYP: VT-1161 for Candida infections and VT-1129 for cryptococcal meningoencephalitis. We also discuss two glucan synthesis inhibitors: CD101, an echinocandin with an increased half-life, and SCY-078 with oral bioavailability and increased activity against echinocandin-resistant isolates. Among the polyenes, we discuss MAT023, an encochleated amphotericin B formulation that allows oral administration. Two novel classes of antifungal drugs are also described: glycosylphosphatidylinositol inhibitors, and the leading drug APX001, which disrupt the integrity of the fungal wall; and the orotomides, inhibitors of pyrimidine synthesis with the leading drug F901318. Finally, a chitin synthesis inhibitor and progress on human monoclonal antifungal antibodies are discussed.

In Vivo Pharmacokinetics and Pharmacodynamics of APX001 against Candida spp. in a Neutropenic Disseminated Candidiasis Mouse Model

“…and oral (p.o.) broad-spectrum antifungal agent in clinical development for the treatment of invasive fungal infections (9,12). The active moiety APX001A inhibits the inositol acyltransferase in fungal GPI biosynthesis but not the human homolog, Pig-W (12).…”

“…Therefore, antifungal drugs with novel mechanisms of action which lack cross-resistance to existing antifungals are desirable for the treatment of invasive fungal infections. APX001, the methyl-phosphate prodrug of the active moiety APX001A, is a first-in-class broad-spectrum antifungal agent for the treatment of invasive fungal infections, including species resistant to existing antifungal drug classes (9)(10)(11). APX001A inhibits the fungal enzyme Gwt1 that is part of the glycosylphosphatidylinositol (GPI) biosynthesis pathway (12).…”

Exploration of Antifungal Potential of Carbohydrate‐Tethered Triazoles as CYP450 Inhibitors

“…Each currently used class has both strengths and weaknesses in terms of efficacy and safety. Moreover, since 2006 no new class of antifungals have been approved and the last decade has acclaimed only a single antifungal drug . Azole molecules have been refined during the past 30 years and have come up as triazole molecule .…”

“…Moreover, since 2006 no new class of antifungals have been approved and the last decade has acclaimed only a single antifungal drug. [5] Azole molecules have been refined during the past 30 years and have come up as triazole molecule. [6] Triazoles are any heterocyclic compound containing a five membered ring with two carbon and three nitrogen atoms.…”

APX001 Pharmacokinetic/Pharmacodynamic Target Determination against Aspergillus fumigatus in an In Vivo Model of Invasive Pulmonary Aspergillosis

“…date (12)(13)(14). APX001A inhibits the fungal enzyme Gwt1 of the glycosylphosphatidylinositol (GPI) biosynthesis pathway by preventing inositol acylation during synthesis of GPI-anchored proteins (15).…”