Hope on the Horizon: Novel Fungal Treatments in Development

Abstract

The treatment of invasive fungal infections remains challenging due to limitations in currently available antifungal therapies including toxicity, interactions, restricted routes of administration, and drug resistance. This review focuses on novel therapies in clinical development, including drugs and a device. These drugs have novel mechanisms of action to overcome resistance, and some offer new formulations providing distinct advantages over current therapies to improve safety profiles and reduce interactions. Among agents that target the cell wall, 2 glucan synthesis inhibitors are discussed (rezafungin and ibrexafungerp), as well as fosmanogepix and nikkomycin Z. Agents that target the cell membrane include 3 fourth-generation azoles, oral encochleated amphotericin B, and aureobasidin A. Among agents with intracellular targets, we will review olorofim, VL-2397, T-2307, AR-12, and MGCD290. In addition, we will describe neurapheresis, a device used as adjunctive therapy for cryptococcosis. With a field full of novel treatments for fungal infections, the future looks promising.

Keywords: antifungal drugs; invasive fungal infections; novel treatment; review.

Figure 1.

Mechanism of action and target sites of the novel antifungals. The antifungal compounds currently in development have several novel mechanisms of action or new formulations to (1) improve efficacy or reduce toxicity and (2) target different sites in the cell wall, cell membrane, and also intracellular targets. DHODH, dihydroorotate dehydrogenase; IPC, inositol phosphorylceramide.

Figure 2.

Novel antifungals with spectrum of activity. New antifungal compounds show extensive spectrum of activity to overcome resistant fungi; however, several gaps still remain. *MGCD290: Potent activity in combination with azoles and/or echinocandins. ABA, aureobasidin A; CAMB, encochleated amphotericin B; FOSMANO, fosmanogepix; GSI, glucan synthase inhibitor; IBREXA, ibrexafungerp; NIKZ, nikkomycin Z; REZA, rezafungin.

Figure 3.

Stage of clinical development of the novel antifungals. New antifungal compounds are currently in several stages of development. Most have advanced to phase 2 or 3, but a few still remain in phase 1 or preclinical development. VL-2397 had early termination of phase 2 trial, and there are currently no ongoing trials. AR-12 and MGCD290 have no ongoing trials.