Emerging Antifungal Agents for the Management of Invasive Fungal Infections

Over the past few decades, the world has faced growing challenges in treating invasive fungal infections. Increasing resistance, expanding high-risk populations, and the limited number of effective drugs have created a need for new antifungal agents.

Until now, standard antifungal therapy has relied on three main classes: azoles (voriconazole, posaconazole, isavuconazole), echinocandins (caspofungin, micafungin, anidulafungin), and amphotericin B. While effective, these drugs have significant limitations:

• Azoles are associated with numerous CYP-mediated interactions and hepatotoxicity.

• Amphotericin B is nephrotoxic and requires parenteral administration.

• Echinocandins have a limited spectrum of activity and are also available only intravenously.

New Antifungals

After more than 20 years of stagnation, several promising antifungal agents are now in late-stage clinical development.

1. Fosmanogepix (Manogepix)

Fosmanogepix is a prodrug converted in the body to manogepix, an inhibitor of the Gwt1 enzyme. This disrupts the synthesis of GPI-anchored proteins in the fungal cell wall, compromising virulence and growth. It has broad-spectrum activity, including resistant strains of Candida spp., Aspergillus spp., Fusarium spp., and some Mucorales. In phase II trials, it showed good tolerability and 80% efficacy in treating invasive candidiasis. It is being developed in both oral and parenteral formulations.

2. Ibrexafungerp

The first antifungal from the triterpenoid class, ibrexafungerp inhibits 1,3-β-D-glucan synthesis, similar to echinocandins but at a different binding site, reducing cross-resistance. It is approved for vulvovaginal candidiasis and, in phase III trials, has shown efficacy against invasive candidiasis and aspergillosis. Advantages include oral administration and good tissue penetration. Oral and parenteral formulations are in development. However, as a CYP3A4 substrate, it carries potential for drug interactions. Animal studies suggest teratogenic risk, so in women of childbearing potential it must be prescribed with mandatory contraception.

3. Olorofim

A member of the novel orotomide class, olorofim inhibits the enzyme dihydroorotate dehydrogenase (DHODH), disrupting pyrimidine synthesis. Its activity is limited to molds (Aspergillus spp., Lomentospora, Scedosporium), but it shows exceptional potential in multidrug-resistant infections. Clinical trials demonstrate safety and potential use for infections resistant to all other therapies. As a CYP3A4 substrate, it may interact with other drugs.

4. Opelconazole

This new triazole has been optimized for inhaled administration, designed for the treatment of pulmonary aspergillosis. Inhaled delivery achieves high local concentrations in the lungs with minimal systemic exposure and side effects. Although inhaled, as a CYP3A4 substrate it still carries a potential for drug interactions.

5. Rezafungin

A second-generation echinocandin, rezafungin has an extended half-life, allowing once-weekly dosing. It demonstrates strong activity against Candida spp. (including C. auris) and Aspergillus spp., and is being tested for prophylaxis in immunocompromised patients. Phase II data show good tolerability and high efficacy.

6. Oral Formulation of Amphotericin B

An oral formulation of amphotericin B is currently under clinical investigation for the treatment of cryptococcal meningitis. Compared to parenteral amphotericin B, the oral formulation has the potential for reduced nephrotoxicity and electrolyte disturbances. Amphotericin B retains its broad spectrum of activity, covering Candida spp., Aspergillus spp., Mucorales, and Cryptococcus.

Conclusion

The development of these new antifungals marks a significant step forward in the management of invasive fungal infections. With novel mechanisms of action, availability in both oral and parenteral formulations, pharmacokinetic advantages, and broad activity spectra, their anticipated arrival on the market will be of great importance to clinical practice.

Find the full article in Pharmaca, Issue 2–2025.

References

• Hoenigl M, et al. The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin. Drugs. 2021 Oct;81(15):1703-1729. doi:10.1007/s40265-021-01611-0. PMID: 34626339; PMCID: PMC8501344.

• Vanbiervliet Y, et al. Correction: Review of the novel antifungal drug olorofim (F901318). BMC Infect Dis. 2024 Dec 12;24(1):1395. doi:10.1186/s12879-024-10295-2. Erratum for: BMC Infect Dis. 2024 Nov 7;24(1):1256. doi:10.1186/s12879-024-10143-3. PMID: 39668372; PMCID: PMC11636042.

• Boulware DR, et al. Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial. Clin Infect Dis. 2023 Dec 15;77(12):1659–1667. doi:10.1093/cid/ciad440.