Antifungal drugs: What brings the future?

Abstract

The high burden and growing prevalence of invasive fungal infections (IFIs), the toxicity and interactions associated with current antifungal drugs, as well as the increasing resistance, ask for the development of new antifungal drugs, preferably with a novel mode of action. Also, the availability of oral or once-weekly alternatives would enable ambulatory treatment resulting in an improved patient's comfort and therapy adherence. However, only one new azole and two new posaconazole-formulations were marketed over the last decade. This review focuses on the antifungal drugs in the pipeline undergoing clinical evaluation. First, the newest azole, isavuconazole, with its improved safety profile and reduction in DDIs, will be discussed. Moreover, there are two glucan synthase inhibitors (GSIs) in the antifungal pipeline: rezafungin (CD101), a long-acting echinocandin with an improved stability that enables once weekly administration, and SCY-078, an orally available GSI with efficacy against azole- and echinocandin resistant isolates. A new oral formulation of amphotericin B will also be presented. Moreover, the first representative of a new antifungal class, the orotomides, with a broad spectrum and no cross-resistance with current antifungal classes, will be discussed. Finally, an overview of other antifungals that are still in earlier clinical development phases, is provided.

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

“…Rezafungin (CD101; Cidara Therapeutics; Table 1) is a next-generation echinocandin in development that shares its mechanism of action, the inhibition of 1,3-β-d-glucan synthesis, with other members of this class [2]. It is a structural analog of anidulafungin with modifications resulting in increased stability and solubility.…”

“…A recently completed two-part phase II study of rezafungin compared two loading doses of rezafungin to caspofungin in the treatment of candidemia/invasive candidiasis (STRIVE; NCT02734862) followed by possible oral fluconazole step-down [2,15]. Rezafungin 400 mg for the first week, followed by 200 mg once weekly, was identified as the most effective dosing scheme, and is the regimen currently under investigation in the ongoing phase III invasive candidiasis study (ReSTORE; NCT03667690).…”

“…Polyenes achieve fungicidal activity by binding ergosterol in the cell membrane, resulting in increased permeability and the leakage of intracellular components, which subsequently leads to cell death ( Figure 1) [1,2]. Amphotericin B is the most clinically relevant polyene for invasive fungal infections, and maintains a broad spectrum of fungicidal activity, covering yeasts, moulds, and dimorphic fungi.…”

“…Despite these drawbacks, amphotericin B sees consistent clinical use as empiric coverage of invasive fungal infections until a more tolerable therapy or formulation can be identified. Similar to polyenes, azoles target ergosterol to achieve fungicidal activity [2,3]. They specifically inhibit ergosterol synthesis by inhibiting the lanosterol 14α-demethylase enzyme (Figure 1).…”

“…Azole enzyme inhibition is not entirely limited to fungal cells and the class is associated with cytochrome P450 inhibition driving dangerous drug-drug interactions and "off-target" side effects in some cases [4][5][6][7]. The class is also restricted by a wide range of significant toxicities, including hallucinations, Similar to polyenes, azoles target ergosterol to achieve fungicidal activity [2,3]. They specifically inhibit ergosterol synthesis by inhibiting the lanosterol 14α-demethylase enzyme (Figure 1).…”