A patient with leukemia undergoes a bone marrow transplant to treat her disease. The procedure goes well. But before her immune system has time to recover, another problem takes hold — a fungal infection caused by Candida, a type of yeast that lives on the skin or inside the body, commonly in the gut. It bypassed her hobbled immune system, making its way into her bloodstream, infecting her spleen and other internal organs, triggering sepsis. Her doctors are now in a race to keep her from becoming one of the estimated 19% to 24% affected patients who succumb to this type of invasive Candida infection.
“Candida is extraordinarily aggressive and there are very few treatment options. And if you don’t make the diagnosis on time or you give the wrong therapy, because the Candida is resistant to that therapy, you don’t have many opportunities to correct the course,” said Dr. David Angulo, CEO and president of New Jersey-based Scynexis, a biotechnology company developing antifungal treatments.
While fungal infections don’t grab as much attention as super bugs, they’re a threat that’s looming large. Behind this increasing threat are factors such as drug resistance, a greater number of high-risk patients and more environmental exposure, said Dr. Neil Clancy, professor of medicine at the University of Pittsburgh and chief of the Infectious Diseases Section at VA Pittsburgh Health Care System.
“(Fungal infections are) a lesser problem than bacterial infections — but it's a major problem,” he said.
A rising threat
Although there are millions of species of fungi, only a few hundred affect human health. Most often they cause non-life-threatening nuisance infections like athlete’s foot. The fungi that make people sick often come from inside their bodies, but these organisms can also be encountered in the environment. Inhaling microscopic spores from the desert-dwelling fungus, Coccidioides, for example, causes coccidioidomycosis, commonly known as Valley fever. Severe and life-threatening systemic fungal infections are less common, and primarily affect people in certain high-risk groups such as cancer patients, organ transplant recipients and those being treated in the ICU.
And as people live longer with serious and complex diseases, they are more are at risk for these virulent infections, Clancy said. Some fungi, such as Candida auris, have developed resistance to one or more of the limited antifungal drugs available, complicating treatment.
“There's probably broader changes that are going on and these might be things like climate change, or environmental change with various habitats being destroyed or altered and, people moving into places that previously were less inhabited or uninhabited,” Clancy said. “So, it's probably multifactorial, but all these things are coming together and we're seeing more fungal infections and we're seeing infections by more types of fungi.” It's not just human infections, but animal infections, both in nature and on farms, he said.
"In the past 20 years there was very limited innovation in the antifungal space."
Dr. David Angulo
CEO, president, Scynexis
There’s also emerging research that hints fungi may play a broader role in human health. According to the American Association for Cancer Research, fungal infections could not only be more likely to occur in cancer patients, but also involved in the formation and spread of certain types of cancer, including pancreatic cancer.
“I think we'll learn a lot more (in) the years ahead, but you know, Candida, in particular in the gut, may be linked to a wide variety of diseases as well as just general health,” Clancy explained.
Insufficient treatment options
Antifungal treatments aren’t keeping pace with the growth of fungal infections. Currently, there are three broad classes of systemic antifungal drugs — azoles, polyenes, and beta-glucan synthesis inhibitors (echinocandins), Clancy said. And in each category, the options are limited. The complexity of drug development is often the barrier to getting more drugs on the market.
“Unlike bacteria, fungi are eukaryotes. So, at least genetically, they’re more closely related to humans than they are to bacteria or viruses, or most of the things that infect humans,” Clancy said. “So, coming up with drugs that target the fungus, but don't target human cells is very tricky. It's much more difficult than coming up with an antibiotic or an antiviral drug.”
Scynexis is one of the companies that has taken on the challenge. Its compound, ibrexafungerp, is the first in a novel class of structurally distinct glucan synthase inhibitors, triterpenoids, launched in the past 20 years, Angulo said.
The company’s drug Brexafemme has already been approved in the U.S. for vulvovaginal Candidiasis. The compound is also currently in phase 3 for Invasive Candidiasis (IC) and a bloodstream infection caused by the fungus called Candidemia. If all goes well, it may be on track to gain approval by the end of 2024, Angulo said.
Ibrexafungerp, meanwhile, has the potential to combat numerous types of fungal infections — including drug-resistant strains — and could also be given as an oral treatment, which would be an advantage over the many systemic antifungals that have to be given intravenously, Angulo said.
A number of other companies also have antifungals in the pipeline, including Pfizer, which is in phase 2 with the broad spectrum antifungal, Fosmanogepix it acquired along with Amplyx Pharmaceuticals in 2021. Cidara Therapeutics also has a phase 3 antifungal called Rezafungin in development, which was designed to prevent invasive fungal disease in bone marrow transplant patients.
If these treatments make it to market, they may give doctors a broader toolkit to fight serious fungal infections.
“In the past 20 years there was very limited innovation in the antifungal space. Fortunately, now we're seeing multiple products that are in clinical stages of development, addressing many of the antifungal needs,” Angulo said. “That is actually a fantastic thing that is happening right now.”
Even so, it’s likely not enough to meet the growing need, he said.
A call to action
The World Health Organization recently sounded the alarm, releasing a list of “priority pathogens,” a list of 19 fungi that present a threat to public health, while urging action to tackle this growing issue. The CDC has also drawn attention to the threat.
“The CDC has advocated for the past two, three years for products (that work) against particular pathogens like Candida auris,” Angulo said.
The Biomedical Advanced Research and Development Authority (BARDA) is also partnering with companies that are developing treatments for multi-drug-resistant fungal infections and spur further interest in the market.
And of course, there’s “The Last of Us,” the HBO television series about a global pandemic sparked by a fungus, which may have also inadvertently given the field a small boost. And don’t worry: While the fungi that causes the fictional outbreak on the show is a real one that infects insects, the rest of the storyline is more appropriately assigned to the realm of science fiction, Angulo said. It’s not realistic for this type of fungi to infect humans and control their complex brains. However, while the plot may not be grounded in reality, it has focused some needed attention on the need for antifungal treatments, Angulo said.
But even with this newfound interest, it’s likely a long road ahead for the field.
“It is still far from optimal . . . because really, the need is so great and there is so much of a gap to fill in terms of many, many years with no innovation,” he said.