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  • The current antifungal pipeline contains several categories

    2024-04-23

    The current antifungal pipeline contains several categories of compounds at different stages of development [1], [9], [10], [96]. In Table 1 we summarize the most promising antifungal molecules that are in preclinical and in clinical development. Several compounds in the pipeline are derivatives of the azoles, echinocandins and polyenes and, therefore, they have the same mechanism of action targeting ergosterol biosynthesis, membrane disruption and oxytocin receptor synthesis (β-1,3-d-glucan synthesis), respectively. Isavuconazole, the most recently approved triazole, is being evaluated in two different phase 3 trials. The results from the first trial to assess the efficacy and safety of isavuconazole versus voriconazole for the treatment of invasive molds diseases caused by Aspergillus and other filamentous fungi (SECURE) have been recently reported. Results showed that isavuconazole was not inferior to voriconazole for the primary treatment of such disease and it was well tolerated compared with voriconazole, with fewer study drug-related adverse effects [129]. Isavuconazole is also currently in a second phase 3 clinical trial to evaluate its efficacy and safety of intravenous and oral formulations for the treatment of candidemia and invasive Candida infections (ACTIVE) [www.astellas.us]. VT1129 and VT1161 belong to a novel class of triazoles that were identified as part of an effort trying to find molecules with very low affinity to human CYP enzymes, including human CYP51. In vitro, VT1161 is about 1000-fold more selective for Candida CYP51 than for the human enzyme, while VT1129 is approximately 3000-fold more selective for the Cryptococcus isoforms over human [130]. VT1129 inhibits the growth of Cryptococcus neoformans and C. gattii, and in a mouse model of cryptococcal meningitis performed better than fluconazole. This molecule has been granted QIDP designation and orphan drug status by FDA and is in phase 1 clinical trials for the treatment of cryptococcal meningitis. VT1161 which is very effective against fluconazole-resistant Candida isolates is in phase 2b trials for the treatment of onychomycosis and recurrent vulvovaginal candidiasis [131]. SCY-078 is a novel β-1,3-glucan synthase inhibitor structurally different than the current echinocandins. It is a derivative from enfumafungin, a triterpene glycoside produced by fermentation of a Hormonema sp. [140]. SCY-078 shows activity against echinocandin-resistant isolates of Candida and Aspergillus[141], against non-Aspergillus molds comparable to that of echinocandins and also against Scedosporium prolificans, a resistant mold for which there are no good treatment options. It is also interesting the good activity against Paecilomyces variotii, fungi associated with disseminated infections (fungemia and peritonitis in patients undergoing peritoneal dialysis) [133]. It has received QIDP designation and its oral formulation is currently in phase 2 clinical trials for the treatment of invasive candidiasis, while its IV (intravenously) formulation is in phase 1. Novel semi-synthetic enfumafungin derivatives are been studied to improve antifungal potency and oral pharmacokinetic properties [142]. Biafungin (CD101) is a novel echinocandin that shows similar activity to caspofungin and anidulafungin against Aspergillus and Candida species, but its advantage lies in its pharmacokinetics. Its half-time life is about 4-fold longer (81h) than the half-time of anidulafungin (24h), the longest-acting echinocandin to date. Like other echinocandins, it shows few drug interactions and excellent safety profile. Biafungin has been granted QIDP designation and orphan drug status and it is currently in phase 2 clinical trials for the treatment of candidemia. Very interestingly, there are some new candidates that show either different modes of action from the currently marketed drugs, or that even have not been identified yet. T-2307 is a novel arylamidine that collapses fungal mitochondrial membrane compromising energy production for essential cellular processes [136]. Interestingly, this activity is specific to fungi as it seems to be due to the selective uptake of this drug by the high-affinity fungal specific Agp2 spermine-spermidine transporter. T-2307 underwent successful phase 1 trials for the treatment of candidiasis.