The unique characteristics of fungi were thrust into pop culture awareness with the recent premiere of the post-apocalyptic television show “The Last of Us.” In this fictional world, the Cordyceps fungus—which invades insects, arthropods and other fungi while evading their immune systems—has adapted to humans (Front Pharmacol 2021 Feb 8. doi:10.3389/fphar.2020.602364).
Although “The Last of Us” is science fiction, the ability of fungi to adapt to human hosts is not. After the recent focus on viruses, fungi are ready to get more attention, and experts say it’s about time.
In October 2022, the World Health Organization (WHO) released a report listing “priority pathogens,” a group of 19 fungi that it identified as being the greatest threat to public health (https://www.who.int/publications/ i/ item/ 9789240060241). In the report, the WHO explained that evidence indicates a growing incidence of fungal diseases worldwide, with “the reported incidence of invasive fungal infections increased significantly among hospitalized patients” during the COVID-19 pandemic.
“There are indications that [fungal] infections are increasing, and there are multiple factors involved in that,” said Tom M. Chiller, MD, MPHTM, the deputy branch chief of the CDC’s Mycotic Diseases Branch. “One of those factors is that there has been some movement toward identifying them in a better way, but there are also more susceptible hosts.”
Most fungal infections are in compromised hosts, according to Dr. Chiller, often those on immunosuppressive drugs. Medical improvements in transplants and cancer treatments have increased the number of people living on immunosuppressive therapy.
“[Fungi] hide within our own machinery and are hard to kill selectively,” Dr. Chiller said. “You need an immune response to get rid of them, and if you have no immunity or immune response, then even with the best of drugs they are still hard to beat down.”
They are affected by and adapt to their environments.
“As the environment changes, as the climate changes, that affects fungi,” Dr. Chiller said. “Fungi have been around for millions of years. They are very hardy. They know how to survive, and that has contributed to their rise and the challenge in treatment and getting rid of them.”
Fungi are also more similar to humans than viruses or bacteria are, because fungi are eukaryotes.
According to the WHO report, there are a limited number of antifungal medicines used in clinical practice, and only a few more in development. Fungal infections receive less than 1.5% of all infectious disease research funding.
“We have a limited armamentarium,” Dr. Chiller said. “We need new targets and new classes.”
Available Options
Polyenes were one of the first classes of antifungal drugs developed. Within this class, IV amphotericin B, a broad-spectrum antifungal, is used to treat systemic infections by binding to ergosterol, a component in the fungal cellular membrane.
“IV amphotericin comes with a lot of toxicities and is difficult to tolerate,” said Todd McCarty, MD, an associate professor of medicine at the University of Alabama at Birmingham.
For many common fungal infections, clinicians may turn to better tolerated drugs from the azoles or echinocandin classes.
Commonly used azoles, which also impair synthesis of ergosterol, include fluconazole, posaconazole and voriconazole, Dr. McCarty said.
“The biggest issue with these are that all three come with a lot of drug–drug interactions, and patients with invasive mold infections tend to be on a lot of medications,” Dr. McCarty said.
The most recently approved class of antifungal drugs is the echinocandins, such as caspofungin. Approved in 2003, it has been almost 20 years since a new antifungal class was approved for invasive fungal infections. This class is widely used against Candida, and can be used to treat Aspergillus. However, echinocandins are available in IV formulation only.
“There are several drugs within each of these classes, and they all work very well in many patients,” Dr. Chiller said. “They have been game changers and lifesavers.”
The problem comes when an organism becomes resistant.
“If they are resistant to one class, that eliminates one-third of available treatments; if they are resistant to two classes, that eliminates two-thirds. Sometimes you are left with an infection resistant to all three classes,” Dr. Chiller said. “We need new targets, and some new drugs in the pipeline have completely new targets or mechanisms of action.”
Down the Pipeline
Dr. McCarty discussed four promising antifungal therapeutics that may join the future treatment armamentarium.
Rezafungin, a once-weekly echinocandin, is likely the farthest along in development, he said. In January, the FDA Antimicrobial Drugs Advisory Committee recommended approval of rezafungin (Cidara Therapeutics) for the treatment of candidemia and invasive candidiasis and the FDA approved Rezzayo in March 2023.
The phase 3 ReSTORE trial showed noninferiority of rezafungin to caspofungin in patients with candidemia and invasive candidiasis (Lancet 2023;401[10370]:49-59). The multicenter trial randomly assigned 199 patients 1:1 to receive IV rezafungin once weekly or IV caspofungin for no more than four weeks. The 30-day all-cause mortality was 24% for rezafungin compared with 21% for caspofungin (difference, 2.4%; 95% CI, 9.7%-14.4%).
“The biggest difference [with rezafungin] is that it allows a once-a-week IV infusion instead of a daily one,” Dr. McCarty said. “This would allow patients to have one dose upon discharge from the hospital, and if further doses are needed, they can come to an infusion center rather than having to stay in the hospital or having to take a daily dose of an IV echinocandin at home.”
Another phase 3 trial called ReSPECT is studying rezafungin for prophylaxis against invasive fungal infections including Pneumocystis (ClinicalTrials.gov Identifier: NCT04368559).
Ibrexafungerp (Brexafemme, Scynexis) is an oral, non-azole medication that is approved for vulvovaginal candidiasis (VVC) and to reduce incidence of recurrent VVC, but is not yet approved for any systemic or invasive candidemia and candidiasis, Dr. McCarty said. Ibrexafungerp represents a new class of oral glucan synthase inhibitors that are structurally similar to echinocandins with a mechanism of action through inhibition of beta-1,3-glucan synthase, but with a new binding site (Front Cell Infect Microbiol 2021 Sep 6. doi:10.3389/fcimb.2021.732223).
An oral formulation of ibrexafungerp is in human trials.
There are several ongoing phase 3 trials of ibrexafungerp. The FURI study is evaluating efficacy and safety in patients with severe fungal infection who are refractory or resistant to standard antifungals (ClinicalTrials.gov Identifier: NCT03059992). Positive interim data released in late 2022 showed 82.3% positive clinical outcomes in patients treated with ibrexafungerp, with 94.6% survival at 30 days after therapy.
The CARES study is evaluating efficacy and safety in patients with Candida auris. Interim data presented in September 2022 showed a complete or partial response rate of 78% in patients with C. auris.
The MARIO trial is a phase 3, double-blind study of patients with invasive candidiasis treated with IV echinocandin followed by either oral ibrexafungerp or oral fluconazole (ClinicalTrials.gov Identifier: NCT05178862).
“This could fill a niche if it can work when there is azole resistance, and it could provide an opportunity for oral step-down,” Dr. McCarty said.
Fosmanogepix is an antifungal in a new class with a new mechanism of action compared with any available antifungal, Dr. McCarty said. It will be available as both an IV and oral formulation, which provides an opportunity to continue with the same drug throughout the course of treatment.
“[Fosmanogepix] completed a small phase 2 study but has not started phase 3,” Dr. McCarty said. “The company developing it was bought by Pfizer and nothing has happened since. Hopefully the trial will be coming along soon.”
Olorofim (F2G) is an oral drug in a new class of antifungals called orotomides, and has a new, unique mechanism of action, according to Dr. Chiller. Olorofim inhibits dihydroorotate dehydrogenase enzyme.
“This is a really exciting drug,” Dr. Chiller said. “It isn’t pan-fungal. It doesn’t kill everything, but it is exciting for fungal genera like Coccidioides and Aspergillus, which is probably the No. 1 cause of mold infections.”
Oloform is being studied for invasive fungal infections in patients with limited or no treatment options. The FDA application is supported by data from the first 100 patients in a phase 2 study that showed a 44% response rate, and all-cause mortality at days 42 and 84 of 15% and 20%, respectively. The FDA is expected to make a decision by June 17.
Although the potential regulatory approval of these new antifungals demonstrates great progress in the field, Dr. McCarty said further development of additional classes will be necessary.
“We need drugs that are better tolerated and safer,” he said.
That need is clear when fungal infections are seen from a 30,000-foot view.
“There are an estimated 4 or 5 million fungal species, and we have identified about 120,000,” Dr. Chiller said. “Think about that potential. We are seeing new emerging species causing human disease every year.”
These new fungal mysteries present real challenges to researchers that dwarf the fictional zombie fungi in “The Last of Us,” because they present real life-and-death scenarios.
An example is the often multidrug-resistant C. auris, Dr. Chiller said. First reported in 2009 in Japan, outbreaks have since been reported around the globe.
“It was highly invasive, and something people hadn’t seen before,” Dr. Chiller explained. The emergence of C. auris left researchers with a lot of questions. C. auris represents the kinds of challenges the field will face, and supports the need for new and more effective therapeutics.
Dr. McCarty has research contracts with Cidara, F2G (olorofim) and Scynexis, and a prior research contract with Amplyx. Dr. Chiller reported no relevant financial disclosures.
This article is from the March 2023 print issue.