Invasive fungal infections cause a range of severe diseases in humans. During the COVID-19 pandemic, COVID-19 associated pulmonary aspergillosis and mucormycosis have been among the most serious complications. The rapid global spread of the multidrug-resistant yeast Candida auris is an example of how fungal infections can challenge health systems and our limited understanding of fungi. Despite the severity of invasive fungal infections, the field has been perennially neglected in terms of research funding and to this day, diagnostic and therapeutic options remain sorely insufficient. The global burden of fungal infections is unknown because of difficulties in diagnosing these infections.
In late 2022, WHO published the first fungal priority pathogens list, promoting attention to highly neglected pathogens. The WHO list comes at a time when new antifungal drugs, including rezafungin, ibrexafungerp, olorofim, and fosmanogepix, are reaching advanced trial stages or are being approved by regulatory bodies, after the drug pipeline had been almost empty for many years.
Rezafungin is a new echinocandin that has a long half-life of around 133 hours that allows for less frequent dosing. On March 22, 2023, the US Food and Drug Administration (FDA) approved rezafungin injection for the treatment of candidaemia and invasive candidiasis in patients 18 years of age or older who have limited or no alternative treatment options. Rezafungin showed non-inferiority to the older echinocandin caspofungin in the ReSTORE trial and was compared to oral antifungal drugs to treat Candida, Aspergillus, and Pneumocystis infections in allogeneic bone marrow transplant recipients in the ReSPECT trial, which results were presented at the recent ECCMID meeting in Copenhagen in April. Rezafungin performance in the field in patients with a variety of fungal infections not considered in the trials will provide answers to the breadth of its potential use.
Ibrexafungerp is a triterpenoid antifungal and first non-azole agent approved by the US FDA for the treatment of vaginal yeast infections (Candida spp). Preliminary results of the efficacy of ibrexafungerp in seven patients with urinary tract infections in the two single arm FURI (assessing efficacy and safety of ibrexafungerp in patients with a documented fungal disease intolerant or refractory to standard of care antifungal treatment) and CARES (evaluating the efficacy, safety, tolerability of oral ibreaxfungerp in patients with a documented Candida auris infection) trials presented at ECCMID showed complete response in 86% of patients. The real place of ibrexafungerp in the antifungal arsenal will be clearer when the SCYNERGIA trial (use in combination with voriconazole compared to voriconazole alone in patients with invasive pulmonary aspergillosis) and the MARIO trial (echinocandin followed by either ibrexafungerp or voriconazole in patients with invasive candidiasis) will be completed.
Olorofim is a member of a novel class of antifungal drugs named ortomides and inhibits an enzyme involved in fungal pyrimidine synthesis. Olorofim has activity against several clinically important groups of fungi, including Histoplasma spp, Aspergillus spp, and Scedosporium spp. No clinical trial testing the efficacy of olorofim has been yet completed, but preliminary data presented at ECCMID 2023 from the single arm FORMULA-OLS trial testing the drug in patients with invasive fungal infections lacking suitable alternative treatment options showed that among five patients with proven invasive Scopulariopsis spp infections, three had achieved complete therapeutic success and two partial therapeutic success at day 84. It is early days to judge the performance of olorofim but despite not being a broad-spectrum antifungal drug, it is expected that it can have a place in treating fungal infections.
Fosmanogepix is a novel drug with a broad-spectrum activity that targets an enzyme in the glycosylphosphatidylinositol anchor biosynthesis pathway. In a small Phase 2 trial in nine patients with invasive candidaemia caused by Candida auris, the day 30 survival was 89%. Fosmanogepix is now being tested in a Phase 3 trial in which it will be compared with caspofungin plus fluconazole in patients with candidemia and/or invasive candidiasis.
Overall, these new antifungal drugs raise hope that replenishing the arsenal of therapeutic options for invasive fungal infections might be possible. If combined with investments to develop better diagnostic tools and improve surveillance, the availability of new antifungal drugs could open a new page in the fight against pathogenic fungi.
© 2023 Getty Images - BSIP