Review

. 2021 Oct;81(15):1703-1729.

doi: 10.1007/s40265-021-01611-0. Epub 2021 Oct 9.

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin

Martin Hoenigl^#^{1

2

3}, Rosanne Sprute^#^{4

5

6}, Matthias Egger⁷, Amir Arastehfar⁸, Oliver A Cornely^{4

5

6

9}, Robert Krause⁷, Cornelia Lass-Flörl¹⁰, Juergen Prattes⁷, Andrej Spec¹¹, George R Thompson 3rd¹², Nathan Wiederhold¹³, Jeffrey D Jenks^{14

15

16}

Affiliations

¹ Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria. hoeniglmartin@gmail.com.
² Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, USA. hoeniglmartin@gmail.com.
³ Clinical and Translational Fungal-Working Group, University of California San Diego, La Jolla, San Diego, CA, USA. hoeniglmartin@gmail.com.
⁴ Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
⁵ Chair Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
⁶ German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.
⁷ Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
⁸ Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
⁹ Clinical Trials Centre Cologne (ZKS Köln), University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
¹⁰ Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
¹¹ Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MI, USA.
¹² Division of Infectious Diseases, Departments of Internal Medicine and Medical Microbiology and Immunology, University of California Davis Medical Center, Sacramento, CA, USA.
¹³ Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹⁴ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, USA.
¹⁵ Clinical and Translational Fungal-Working Group, University of California San Diego, La Jolla, San Diego, CA, USA.
¹⁶ Division of General Internal Medicine, Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, USA.

^# Contributed equally.

PMID: 34626339
PMCID: PMC8501344
DOI: 10.1007/s40265-021-01611-0

Review

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin

Martin Hoenigl et al. Drugs. 2021 Oct.

. 2021 Oct;81(15):1703-1729.

doi: 10.1007/s40265-021-01611-0. Epub 2021 Oct 9.

Authors

Affiliations

¹ Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria. hoeniglmartin@gmail.com.
² Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, USA. hoeniglmartin@gmail.com.
³ Clinical and Translational Fungal-Working Group, University of California San Diego, La Jolla, San Diego, CA, USA. hoeniglmartin@gmail.com.
⁴ Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
⁵ Chair Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
⁶ German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.
⁷ Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
⁸ Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
⁹ Clinical Trials Centre Cologne (ZKS Köln), University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
¹⁰ Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
¹¹ Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MI, USA.
¹² Division of Infectious Diseases, Departments of Internal Medicine and Medical Microbiology and Immunology, University of California Davis Medical Center, Sacramento, CA, USA.
¹³ Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹⁴ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, USA.
¹⁵ Clinical and Translational Fungal-Working Group, University of California San Diego, La Jolla, San Diego, CA, USA.
¹⁶ Division of General Internal Medicine, Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, USA.

^# Contributed equally.

PMID: 34626339
PMCID: PMC8501344
DOI: 10.1007/s40265-021-01611-0

Abstract

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.

PubMed Disclaimer

Conflict of interest statement

MH has received research funding from Gilead, Astellas, Pfizer, Merck, Scynexis, F2G, Pulmocide and Amplyx. RS has nothing to disclose. ME has nothing to disclose. AA has nothing to disclose. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, and Seres; honoraria for lectures from Abbott, Al-Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, and Pfizer; payment for expert testimony from Cidara; participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, and Shionogi; a pending patent currently reviewed at the German Patent and Trade Mark Office; other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, and Wiley. RK has nothing to disclose. CLF reports grants, consulting fees, support for travel to meetings and payment for lectures including service on speakers bureaus from Gilead Sciences, Astellas Pharma, Merck Sharp and Dahme, Basilea, and Angelini. JP has nothing to disclose. AS has received grant funding from Astellas and Mayne, and consulting fees from Scynexis and Mayne. GRT has received honoraria from Amplyx, Cidara, Mayne Pharma, Pfizer, and Scynexis. NW has received research funding from Astellas, bioMerieux, Cepheid, Covance, F2G, and Sfunga, and has served on an advisory board for Mayne Pharma. JDJ has received research funding from Astellas, Pfizer, and F2G.

Figures

**Fig. 1**
Mechanism of action of novel antifungal drugs discussed in this review. *DHODH* dihydroorotate dehydrogenase

**Fig. 2**
Activity of the new antifungal drugs in the pipeline against most common fungal pathogens

**Fig. 3**
Timetable of clinical trials evaluating fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin. IV intravenous

See this image and copyright information in PMC

References

1. Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SCA, Dannaoui E, Hochhegger B, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19(12):e405–e421. doi: 10.1016/S1473-3099(19)30312-3. - DOI - PMC - PubMed
1. Hoenigl M, Salmanton-García J, Walsh TJ, Nucci M, Neoh CF, Jenks JD, et al. Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology. Lancet Infect Dis. 2021;21(8):e246–e257. doi: 10.1016/S1473-3099(20)30784-2. - DOI - PubMed
1. Salmanton-GarcÍa J, Koehler P, Kindo A, Falces-Romero I, GarcÍa-RodrÍguez J, RÁČil Z, et al. Needles in a haystack: extremely rare invasive fungal infections reported in FungiScope®—Global Registry for Emerging Fungal Infections. J Infect. 2020;81(5):802–815. doi: 10.1016/j.jinf.2020.08.015. - DOI - PubMed
1. Jenks JD, Seidel D, Cornely OA, Chen S, van Hal S, Kauffman C, et al. Voriconazole plus terbinafine combination antifungal therapy for invasive Lomentospora prolificans infections: analysis of 41 patients from the FungiScope® registry 2008-2019. Clin Microbiol Infect. 2020;S1198-743X(20)30037-9. - PubMed
1. Arastehfar A, de Almeida Júnior JN, Perlin DS, Ilkit M, Boekhout T, Colombo AL. Multidrug-resistant Trichosporon species: underestimated fungal pathogens posing imminent threats in clinical settings. Crit Rev Microbiol. 2021:1–20. - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- H1 Connect - Access expert opinions and insights on biomedical research.
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin

Affiliations

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical