WHO assessment of the preclinical antifungal pipeline. Evaluating innovation and preparedness in the face of emerging fungal threats

Life-threatening invasive and mucosal fungal infections are a major, increasingly complex global health problem. Among all population groups, individuals who are immunocompromised face the greatest risk of contracting such infections, and the size of these global populations is growing at a swift pace. Climate change also affects the dynamics of fungal infections. Commercially available antifungal drugs often have a narrow-spectrum activity and below-optimal safety profile. Drug resistance to antifungals is also rising, and the use of fungicides in agriculture plays a role in resistance development. In this Review, we aim to provide an overview of the current preclinical research and development landscape of antifungal agents and to critically assess the extent to which current efforts address fungal priority pathogens according to the WHO priority list. We identified 22 programmes in the preclinical pipeline, including 13 for novel agents, four exploring new routes of administration, two investigating new formulations of existing antifungals, and three repurposed monoclonal antibody programmes. These preclinical programmes are at the initial stages (with nine [40·9%] of 22 programmes in the earliest preclinical stage) and insufficiently mature to enter robust clinical developmental stages, requiring comprehensive safety characterisation before advancement. Thus, there is a crucial need to develop novel antifungal agents with improved potency, broad-spectrum activity, and enhanced safety profiles and pharmacological features.