Innovative therapies for invasive fungal infections in preclinical and clinical development

ABSTRACT

Introduction

The incidence of life-threatening invasive fungal infections (IFIs) has increased significantly in recent years. Current therapeutic options for IFIs are limited. Only four major classes of antifungal agents are available to clinicians, namely polyenes, azoles, echinocandins, and flucytosine. These antifungals have particular drawbacks, including toxicity, drug-drug interactions, and increasing antifungal resistance. Consequently, there is an urgent need for new antifungals to combat IFIs.

Areas covered

This review illuminates new classes of synthetic antifungal drugs under preclinical and clinical investigations that have novel mechanisms of action; it also examines innovative strategies for the in vivo delivery of antifungal drugs.

Expert opinion

It is imperative to expand the pipeline of antifungals to tackle emerging fungal resistance against conventional antimycotic drugs, toxicity, and drug-drug interactions. This unmet medical need should not be underappreciated.

KEYWORDS:

• GPI biosynthesis inhibitor
• mitochondrial function disrupter
• novel antifungals
• pyrimidine biosynthesis inhibitor
• siderophore analog
• APX001
• olorofim
• T-2307
• antifungal resistance

Article highlights

• The incidence of invasive fungal infections (IFIs) has increased noticeably during the past decades and are associated with high mortality on a global scale.

• Only four major classes of antifungal agents are available for the treatment of IFIs; all have clear drawbacks which emphasizes the unmet clinical need for novel antifungals.

• Several antifungal agents with novel mechanisms of action are under preclinical and clinical development. Key novel antifungal agents are GPI biosynthesis inhibitors, pyrimidine biosynthesis inhibitors, and mitochondrial function disrupters.

• The GPI biosynthesis inhibitor APX001 is in phase II clinical trials. The pyrimidine biosynthesis inhibitor olorofim received Breakthrough Therapy designation from FDA in 2019 and a phase IIb clinical trial is ongoing. The mitochondrial function disrupter T-2307 has completed three phase I clinical trials by the end of 2019.

• Innovative strategies for in vivo delivery of antifungal drugs provide the possibility to lower unnecessary systemic exposure of/lower unnecessary systemic exposure of antifungals upon treatment of local infection.

• There are too few antifungal drugs in development to fulfill unmet clinical needs, further expansion of preclinical antifungal pipeline is imperative.

This box summarizes key points contained in the article.

Acknowledgments

We thank Dr. S. Krappmann for critical review and valuable comments on the manuscript and Dr. Matthias Tautz and Paul Günzel for assistance with the figure design. Figures in this manuscript were created using icons offered in the Mind the Graph platform (http://mindthegraph.com/) under a Creative Commons license.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

The work of A Beilhack is supported by a grant from the German Research Foundation (DFG) [DFG TRR124 A3].