Fungal-WHAT? Updates to the WHO Antifungal Pipeline

Invasive fungal diseases (IFD) are becoming increasingly prevalent, with associated increases in morbidity and mortality from these pathogens. The World Health Organization (WHO) has a fungal pathogen priority list (FPPL) for helping guide research and development for agents capable of treating these areas of concern.¹ The WHO FPPL includes organisms ranked from critical (Cryptococcus neoformans, Aspergillus fumigatus, Candidozyma (Candida) auris, and C albicans) to high priority to medium priority and contains fungal pathogens across the spectrum from yeasts to molds to dimorphic fungi. As part of this global fight against IFD, the WHO tracks antifungals in preclinical and clinical pipeline and provides a list of these agents on their website.² This article will provide a concise review of updates and changes related to the novel molecules since the development of the WHO report in 2025.

ATI-2307 (T-203)

ATI-2307 is an aromatic diamidine that disrupts the mitochondrial membrane potential of susceptible fungal pathogens.³ ATI-2307 is notably active against Candida spp, including C auris and other azole-resistant isolates, and Cryptococcus spp, while demonstrating variable in vitro resistance to Aspergillus spp. and limited/no activity versus other filamentous fungi.^3-6 Activity of all novel antifungals are summarized in Table 1. Further development of ATI-2307 after completion of phase 1 trials was halted in 2022 with no further information available on future development.⁷

BAL2062(formerly GR-2397)

BAL2062 is a non-ribosomally synthesized cyclic hexapeptide that acts as a siderophore-like molecule with selective affinity for fungal cells.⁸ It has demonstrated in vitro activity versus key pathogens including notably azole-resistant Aspergillus spp and C glabrata, though lacks activity versus most other Candida spp including C albicans.⁸ BAL2062 demonstrated safety and tolerability during prior phase 1 studies.⁹ An initial phase 2 trial was previously terminated in 2019, but plans for future phase 2 trials were again announced in 2023. BAL2062 received Qualified infectious disease product (QIDP), Orphan Drug, and Fast Track designations for treatment of invasive aspergillosis.¹⁰

BSG005

BSG005 is a chemically modified nystatin-like molecule with broad antifungal activity against Candida spp, Aspergillus spp, Fusarium spp, Mucor spp, and Cryptococcus spp. In neutropenic murine models, BSG005 demonstrated concentration-dependent killing against several Candida spp and A fumigatus.¹¹ The proposed advantage to other polyene antifungals is a potential reduction in rates of nephrotoxicity, though published clinical data remain limited.¹² A phase 1a trial demonstrated safety in healthy volunteers (NCT04921254), with previous plans for a phase 1b study in patients with invasive fungal infections. However, further development was halted in April 2026 due to business reasons.^13-14

Fosmanogepix (APX001)

Fosmanogepix (formerly APX001) acts as a prodrug to manogepix, which inhibits glycosylphosphatidylinositol-anchored wall transfer protein (Gwt1). It has demonstrated activity against a wide range of fungal pathogens including notably azole- and echinocandin-resistant Candida spp (except C krusei and C kefyr), Cryptococcus, Aspergillus, Scedosporium, Fusarium, and some Mucorales isolates. A phase 2 study evaluating fosmanogepix in patients with invasive mold diseases included 20 patients in the mITT analysis, of which 40% had a successful response to therapy and an all-cause mortality rate at day 42 of 25%.¹⁵ Two phase 3 trials (NCT05421858, NCT06925321) are currently ongoing for patients with invasive mold infections and invasive candidiasis.^16-17 Fosmanogepix has been granted QIDP, Orphan Drug, and Fast Track designations for seven different indications.¹⁰

HRS9432

HRS9432 is a long-acting echinocandin antifungal, similar to rezafungin, intended for the treatment of invasive candidiasis.¹⁸ Phase 1 studies demonstrated safety and tolerability in healthy volunteers, with a phase 2 trial in patients with candidemia and/or invasive candidiasis (NCT06194201) underway.^18,19 Given its similarity to rezafungin, it is unclear what additional gaps HRS9432 will address in the treatment of invasive fungal infections.

Olorofim (F901318)

Olorofim is an orotomide that inhibits dihydroorotate dehydrogenase within the pyrimidine biosynthesis pathway.^20-21 It has activity against molds that are generally resistant to other antifungals, including most Aspergillus species, Paecilomyces variotii, Scopulariopsis spp, Scedosporium spp, and Lomentospora prolificans. Clinical trials have shown promising results. In the FORMULA-OLS phase 2 trial in patients with IFD with limited treatment options, 58 of 202 patients receiving olorofim (28.7%) had day 42 overall response (primary outcome).²² Two phase 2 trials for coccidioidies infections and a phase 3 for invasive aspergillosis (OASIS) are currently active without results in clinicaltrials.gov (NCT07712484, NCT07385638, NCT05101187).^23-25 Olorofim has been granted orphan drug status for the treatment of coccidiomycosis, invasive aspergillosis, and infections caused by Lomentospora or Scedopsorium.

Opelconazole (PC945)

Opelconazole is a triazole antifungal in phase 3 clinical trials whose novelty is driven by dosage form.^20-21 Opelconazole is given by nebulized suspension and boasts direct delivery to the lungs, with proposed lessening of systemic toxicities. In the OPERA-S and OPERA-T clinical trials, opelconazole was evaluated for aspergillus prophylaxis/pre-emptive therapy in lung transplant vs. standard of care (SOC) and in refractory invasive aspergillosis vs. placebo, respectively.^26-27 All-cause mortality was 1.45% (1/69) vs. 6.06% (2/33) for opelconazole vs. SOC in OPERA-S.²⁶ OPERA-T was terminated early due to a recalculation of sample size and numerically higher mortality rate (36.8% (21/57) vs. 28.6% (8/28), respectively).²⁷ Prevalence of adverse events were comparable (41.54% vs. 36.36% and 64.29% vs. 66.67%, respectively), with most frequently reported ADE being atrial fibrillation, bronchopulmonary aspergillosis, bacterial pneumonia, and sepsis.^26-27 Globally, opelconazole may be a promising agent, especially for treatment of pulmonary aspergillosis, if production continues.

SF001/EL219

Turletricin (SF001/EL219) is a phase 2 polyene with proposed intravenous and oral dosage formulations.^21,28 With more selective binding to ergosterol and reduced cholesterol binding, SF001 is proposed to cause less systemic toxicity than traditional polyenes. In animal studies, SF001 has shown activity against Candida spp, aspergillosis, mucormycoses, coccidioidomycosis, and fusariosis with comparable results to liposomal amphotericin.^28-31 Clinical trials to date are limited, but two clinical trials for cryptococcal meningitis and early antifungal treatment are currently recruiting (NCT06666322, NCT07215273).^32-33 SF001 has been granted QIDP and Fast Track status for cryptococcal meningitis.

VT-1598

VT-1598 is a phase 1 tetrazole antifungal with selective inhibition of fungal CYP51.²¹ It has fairly broad spectrum of activity, with in vitro studies reporting coverage against Candida spp., Cryptococcus spp, molds, and dimorphic fungi.³⁴ In animal studies, VT-1598 has shown activity against Candida species, including fluconazole-resistant strains and C auris, aspergillosis, cryptococcal meningitis, coccidioidomycosis, and Rhizopus spp.^35-39 Clinical studies to date are limited, but one pharmacokinetic evaluation demonstrates promising safety results (NCT04208321).⁴⁰ VT-1598 has been granted QIDP, Fast Track, and Orphan Drug status for coccidioidomycosis.

Eyes on the Future

The future for antifungal therapies is bright with a multitude of novel agents on the horizon. These potential drug therapies have the potential to create treatment options for patients with limited alternatives due to resistance or tolerability. Despite the excitement surrounding the future of antifungals, continued efforts are required to progress these agents towards approval for clinical use.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied health care professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.

References

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2. World Health Organization. Antifungal preclinical and clinical pipeline review. April 2025.Accessed September 29, 2026.https://www.who.int/observatories/global-observatory-on-health-research-and-development/monitoring/antifungal-agents-in-development

3. Wiederhold NP. Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential. J Fungi (Basel). 2021;7(2):130. Published 2021 Feb 11. doi:10.3390/jof7020130

4. Gerlach ES, Altamirano S, Yoder JM, et al. ATI-2307 Exhibits Equivalent Antifungal Activity in Cryptococcus neoformans Clinical Isolates With High and Low Fluconazole IC₅₀. Front Cell Infect Microbiol. 2021;11:695240. Published 2021 Jun 23. doi:10.3389/fcimb.2021.695240

5. Wiederhold NP, Najvar LK, Jaramillo R, et al. The Novel Arylamidine T-2307 Demonstrates In Vitro and In Vivo Activity against Candida auris. Antimicrob Agents Chemother. 2020;64(3):e02198-19. Published 2020 Feb 21. doi:10.1128/AAC.02198-19

6. Mitsuyama J, Nomura N, Hashimoto K, et al. In vitro and in vivo antifungal activities of T-2307, a novel arylamidine. Antimicrob Agents Chemother. 2008;52(4):1318-1324. doi:10.1128/AAC.01159-07

7. Appili Therapeutics Reports Financial and Operational Resulted for Second Quarter of Fiscal Year 2023. Appili Therapeutics. November 10, 2022. Accessed October 1, 2026. https://appilitherapeutics.com/2022/11/10/appili-therapeutics-reports-financial-and-operational-results-for-second-quarter-of-fiscal-year-2023/

8. Shaw KJ. GR-2397: Review of the Novel Siderophore-like Antifungal Agent for the Treatment of Invasive Aspergillosis. J Fungi (Basel). 2022;8(9):909. Published 2022 Aug 27. doi:10.3390/jof8090909

9. Mammen MP, Armas D, Hughes FH, et al. First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults. Antimicrob Agents Chemother. 2019;63(11):e00969-19. Published 2019 Oct 22. doi:10.1128/AAC.00969-19

10. Basilea receives USD 39 million funding under BARDA agreement to continue to advance novel antifungals fosmanogepix and BAL2062. Basilea. July 8, 2025. Accessed October 1, 2026. https://www.basilea.com/news/news/basilea-receives-usd-39-million-funding-under-barda-agreement-to-continue-to-advance-novel-antifungals-fosmanogepix-and-bal2062

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12. Revolutionizing Antifungal Treatment. Biosergen. Accessed October 1, 2026. https://www.biosergen.net/research?6a712402_page=2

13. A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BSG005. ClinicalTrials.gov. Updated November 21, 2022. Accessed October 1, 2026. https://clinicaltrials.gov/study/NCT04921254

14. Biosergen Pauses Development of BSG005. Nasdaq. April 4, 2026. Accessed October 1, 2026.

15. Hodges MR, Tawadrous M, Cornely OA, et al. Fosmanogepix for the Treatment of Invasive Mold Diseases Caused by Aspergillus Species and Rare Molds: A Phase 2, Open-Label Study (AEGIS). Clin Infect Dis. 2025;81(5):e302-e309. doi:10.1093/cid/ciaf185

16. Phase 3 Efficacy and Safety Study of Fosmanogepix for the Treatment of Adult Participants With Candidemia and/or Invasive Candidiasis. ClinicalTrials.gov. Updated September 14, 2026. Accessed October 1, 2026. https://clinicaltrials.gov/study/NCT05421858

17. Phase 3 Efficacy and Safety Study of Fosmanogepix for the Treatment of Adult Participants With Invasive Mold Infections. ClinicalTrials.gov. Updated September 14, 2026. Accessed October 1, 2026. https://clinicaltrials.gov/study/NCT06925321

18. Yan X, Huang Y, Xie J, et al. Safety, tolerability, and pharmacokinetics of HRS9432(A) injection in healthy Chinese subjects: a phase-I randomized, double-blind, dose escalation, placebo-controlled study. Antimicrob Agents Chemother. 2024;68(7):e0052424. doi:10.1128/aac.00524-24

19. Trial of Intravenous HRS9432 in the Treatment of Subjects with Candidemia and/or Invasive Candidiasis. ClinicalTrials.gov. September 10, 2026. Accessed October 1, 2026. https://clinicaltrials.gov/study/NCT06194201

20. Hoenigl M, Sprute R, Egger M, et al. The antifungal pipeline: fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin. Drugs. 2021;81(15):1703-1729. doi: 10.1007/s40265-021-01611-0.

21. Johnson MD, Moore WJ. Current antifungals and the developing pipeline. Infect Dis Clin North Am. 2025 Mar;39(1S):e1-e31. doi: 10.1016/j.idc.2025.01.001.

22. Evaluate F901318 (Olorofim) treatment of invasive fungal infections in participants lacking treatment options (FORMULA-OLS). ClinicalTrials.gov. Updated July 10, 2024. Accessed September 29, 2026. https://clinicaltrials.gov/study/NCT03583164

23. A phase II randomized study to evaluate measures for endpoint derivation in patients with progressive or refractory disseminated coccidioidomycosis treated with olorofim plus baseline standard of care or placebo plus baseline standard of care (COCCIMETRICS). ClinicalTrials.gov. Updated September 22, 2026. Accessed September 30, 2026. https://clinicaltrials.gov/study/NCT07712484

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26. An Open-label Safety Study of PC945 (Opelconazole) Prophylaxis or Pre-emptive Therapy Against Pulmonary Aspergillosis in Lung Transplant Recipients (OPERA-S). ClinicalTrials.gov. Updated April 30, 2026. Accessed September 30, 2026.https://clinicaltrials.gov/study/NCT05238116.

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28. Marr K. Turletricin (EL219.SF001), a novel, once weekly, non-nephrotoxic polyene takes a novel clinical development approach. Elion Therapeutics. April 18, 2026. Accessed September 30, 2026. https://eliontx.com/wp-content/uploads/2026/04/Elion-ESCMID_final_APR2026.pdf

29. Youssef EG, Gebremariam T, Gu Y, et al. Efficacy assessments of EL219, a next-generation polyene antifungal, in immunosuppressed mice infected with drug-sensitive and drug-resistant Aspergillus isolates. Antimicrob Agents Chemother. 2026;70(1):e0140025. doi: 10.1128/aac.01400-25.

30. Lepak AJ, VanScoy B, Rubino C, Ambrose PG, Andes DR. In vivo pharmacodynamic characterization of a next-generation polyene, SF001, in the invasive pulmonary aspergillosis mouse model. Antimicrob Agents Chemother. 2024;68(3):e0163123. doi: 10.1128/aac.01631-23.

31. Gebremariam T, Gu Y, Patterson H, et al. Efficacy assessments of SF001, a next-generation polyene antifungal, in a neutropenic mouse model of invasive fusariosis. Antimicrob Agents Chemother. 2025;69(5):e0180224. doi: 10.1128/aac.01802-24.

32. Platform Trial for Cryptococcal Meningitis (PLATFORM-CM). ClinicalTrials.gov. Updated July 27, 2026. Accessed September 30, 2026.https://clinicaltrials.gov/study/NCT06666322.

33. Phase 2 EL219 versus liposomal amphotericin B or voriconazole for early antifungal therapy. ClinicalTrials.gov. Updated September 25, 2026. Accessed September 30, 2026.https://clinicaltrials.gov/study/NCT07215273.

34. Break TJ, Desai JV, Healey KR, et al. VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice. J Antimicrob Chemother. 2018;73(8):2089-2094. doi: 10.1093/jac/dky170.

35. Garvey EP, Sharp AD, Warn PA, et al. The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis. Med Mycol. 2020;58(4):505-513. doi: 10.1093/mmy/myz092.

36. Wiederhold NP, Lockhart SR, Najvar LK, et al. The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris. Antimicrob Agents Chemother. 2019;63(3):e02233-18. doi: 10.1128/AAC.02233-18.

37. Garvey EP, Sharp AD, Warn PA, Yates CM, Schotzinger RJ. The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis. J Antimicrob Chemother. 2018;73(10):2815-2822. doi: 10.1093/jac/dky242.

38. Wiederhold NP, Shubitz LF, Najvar LK, et al. The Novel Fungal Cyp51 Inhibitor VT-1598 Is Efficacious in Experimental Models of Central Nervous System Coccidioidomycosis Caused by Coccidioides posadasii and Coccidioides immitis. Antimicrob Agents Chemother. 2018;62(4):e02258-17. doi: 10.1128/AAC.02258-17.

39. Wiederhold NP, Patterson HP, Tran BH, et al. Fungal-specific Cyp51 inhibitor VT-1598 demonstrates in vitro activity against Candida and Cryptococcus species, endemic fungi, including Coccidioides species, Aspergillus species and Rhizopus arrhizus. J Antimicrob Chemother. 2018;73(2):404-408. doi: 10.1093/jac/dkx410.

40. Safety and pharmacokinetics of VT-1598. ClinicalTrials.gov. Updated July 26, 2024. Accessed September 30, 2026.https://clinicaltrials.gov/study/NCT04208321.