A Critical New Drug Is Coming—Unless Agriculture Gets There First

In the intensive care ward of Radboud University Medical Center, a sprawling hospital in the southeastern Netherlands, Paul Verweij was worried. The physician-scientist was accustomed to dealing with very sick patients; as chair of medical microbiology, his job was to identify dire pathogens so the right treatments could be prescribed.

One group of patients had the kind of grave illnesses that are frequent in an ICU: blood cancers, immune disorders, end-stage lung disease. But layered on top of those, they all were suffering from a fast-growing, life-threatening invasion of an environmental fungus called Aspergillus fumigatus. In the past, a class of drugs called azoles had reliably cured Aspergillus, but these fungal infections were strangely drug-resistant. Five out of every six patients were dying.

Those deaths were tragic, but they were also odd. It’s common for organisms to become resistant to drugs that a patient has taken for a long time. But these patients hadn’t been prescribed azoles; the fungus was already resistant when it infected them. In his lab, Verweij could see an explanation: Their Aspergillus had novel mutations, ones he’d never seen in decades as a microbiologist. With the help of the Dutch public health system, he looked beyond his own hospital—and discovered an identical pattern in deathly ill patients nationwide, an unrecognized outbreak scattered across a dozen ICUs.

Verweij realized that no single hospital could be the source. There had to be something outside the medical system, something present throughout the Netherlands and exerting as much mutational pressure as a prescription drug would. With the help of other investigators, he identified it: a class of agricultural chemicals, functionally identical to azole drugs, that are critical for food and flower growing. Famous for tulips, the Netherlands is the world’s leading producer of flowers. While protecting their plants from diseases, Dutch farmers had unknowingly endangered their neighbors’ health.

“We created a niche,” Verweij says, “where these super-resistant bugs can emerge.”

That realization happened more than a decade ago, an episode well known in a narrow slice of medicine but little reported outside it. Since then, that pattern of resistance has spread to more than 40 countries, including the United States and the United Kingdom; three out of five patients who contract azole-resistant Aspergillus die from it. Disease specialists and plant pathologists hoped that the parallel development of azoles in medicine and agriculture had been a one-time thing. If they kept an eye on each other’s research, they felt, surely this would not happen again.

Except it has. Experts now fear that medicine may be at risk of losing a critically needed new drug because agricultural chemistry has once again deployed a similar compound first. 

The looming conflict arises from the emergence of two compounds, one pharmaceutical and one agricultural, that share a novel mechanism for killing fungi: a drug, olorofim, that is moving through human clinical trials, and a fungicide, ipflufenoquin (trade name Kinoprol), that was registered by the US Environmental Protection Agency last year. Ipflufenoquin, made by Nisso America, is intended to combat diseases of important tree crops, including almonds, apples, and pears. Olorofim, developed by the British firm F2G, is a desperately needed new treatment for Aspergillus and valley fever, which affects up to 150,000 people in the US each year—and occurs most densely in the part of California where most almonds are grown.

Here’s the core of the problem: Medicine and agriculture both need new ways of killing fungi—but as soon as a novel killer is introduced, fungi adapt to protect themselves. Any new compound is in a race against its own obsolescence, and whichever discipline deploys it first will reap the most benefit. At the moment, there’s no federal agency or international body that could assess risks or establish priorities.

Existing agencies haven’t yet officially expressed alarm. But the potential interference of the fungicide with the drug was discussed during a meeting last summer at the National Academies of Sciences, Engineering, and Medicine. Staff members from the US Centers for Disease Control and Prevention, along with European researchers including Verweij, advanced their concerns cautiously in a journal article published just before Christmas that called for global cooperation. “This is not just a US phenomenon,” says Tom Chiller, one of the authors, who is a physician and the CDC’s chief of mycotic diseases. What’s needed but doesn’t exist, he says, is “some sort of standard operating procedure so that when [a company] files an application, that triggers a question: Let’s talk to Public Health.”

Let’s get this out of the way: The Last of Us, the streamer and the game, made human fungal diseases seem terrifying, but also fantastical. However, they definitely exist—and the statistics are terrifying. At least 300 million people contract fungal illnesses every year, and 1.5 million of them die—globally, as many deaths as from malaria or tuberculosis. CDC researchers estimated in 2019 that fungal infections put more than 75,000 Americans in the hospital annually and cost $7.2 billion in health care spending. 

At the end of 2022, the World Health Organization declared its first-ever list of priority fungal pathogens and warned that the incidence and range of fungal infections will grow as the climate warms up. And in March, the CDC revealed that cases of Candida auris, a yeast that behaves like a bacterial superbug, tripled in US hospitals between 2020 and 2021.

Against that disease burden, medicine has surprisingly little power. Dozens of antibiotics and antivirals exist, but there are only a handful of drugs for fungi. The US Food and Drug Administration hasn’t approved a new drug to treat invasive fungal infections since 2002.

That’s largely because developing antifungal drugs is hard. On a cellular level, fungi are more like humans than not, so deriving drugs that can kill them and not us is a triumph of chemistry. Because of that similarity, fungal drugs can be toxic even in low doses. One of the oldest in use, amphotericin B, is known among specialists as “shake and bake” for the tremors and fevers it sets off.

Doctors need solutions. “There are patients who, for whatever reason, are refractory—we give them a drug that should work and it doesn’t,” says George Thompson, a physician and professor at the University of California Davis, School of Medicine who specializes in invasive fungal infections. “There are patients whom we give the correct drug, but they just can’t tolerate it. And then there are also fungal pathogens that we don’t really have any good options for right now. Some of those patients fail everything we do.”

Physicians have been eagerly anticipating olorofim, which represents a new class of fungal drug, technically termed a DHODH inhibitor. “New class” is important: It indicates a new molecular mechanism, one that fungi would not have experienced before. Olorofim has been in development for more than a decade and is currently in phase 2 trials; the FDA has given it a “breakthrough therapy” designation to fast-track it because it fills a critical unmet need. 

But last summer, in email chatter leading up to that National Academies meeting, olorofim’s sponsors learned their drug was not the first DHODH inhibitor on track to be rolled out in the US. Ipflufenoquin, which works on the same molecular pathway, had just gained approval after making its way through a similar regulatory channel at the EPA. That sparked worry among the drug’s developers: If the agricultural version deployed first, olorofim’s effectiveness might be threatened before it could even debut. “Fungi have so many intracellular targets that are the same as in human cells that to find one that is druggable and doesn’t induce significant human toxicity is a real challenge,” says Emma Harvey, F2G’s global head of medical affairs. “We think we’ve done that. So now to find that agricultural fungicides are targeting the same enzyme—that’s a real concern for us.”

As much as humans need antifungal compounds, plants need them too. In fact, going purely by the numbers of organisms affected, plants might need them more. Eighty percent of all plant diseases are caused by fungi. The Irish potato famine of the 19th century, the American chestnut blight and Dutch elm disease epidemics of the 20th century, the worldwide switch from Gros Michel bananas to the modern Cavendish, the fact that the world’s coffee industry resides in South America though it began in South Asia—all of those were the result of fungal pandemics. And between pandemic waves, growers of all varieties of plants—wheat, cacao, pears, grapes, tomatoes—are engaged in a persistent low-level battle against fungal diseases.

“It’s been estimated that there would be 20 percent yield losses in crops all over the world without fungicides because of how damaging fungi are to plants,” says Marin Talbot Brewer, a plant pathologist and professor of mycology at the University of Georgia. “And it’s not just that they affect the amount of food that we have, but they can affect the quality of food as well because some produce mycotoxins.”

Viewed through that lens, the development of a new plant fungicide ought to be welcome. Ipflufenoquin’s manufacturer Nisso said in paperwork submitted to the EPA that the compound offered a “novel, undefined” method of killing, and thus might slow down plant fungi for a while. 

Representatives of the manufacturer, a subsidiary of the Japanese firm Nippon Soda Co., declined an interview. “It is our corporate policy not to discuss our technology,” Shane Barney, Nisso America’s head of agrochemicals, told WIRED by email. 

For more information on the compound, he pointed WIRED to the docket that the company submitted to the EPA when it filed for registration (the agency’s equivalent of approval) in 2020. Those public documents define how the fungicide should be applied, set the amounts of residues that can be left behind after application, and confirm the fungicide passed toxicity tests for other plants, pollinators, and birds. For human health, the documents confirm that the compound passed toxicity evaluations for work and home exposures and exposure via food and drinking water. The EPA assessed all this as adequate and registered ipflufenoquin in March 2022. California registered the compound at the same time. (WIRED was not able to ascertain whether growers are applying it yet.) 

What the evaluations submitted to the EPA did not do is assess whether the fungicide could pose an indirect risk, rather than a direct one. That is, they asked whether exposure to ipflufenoquin could harm people, but not whether exposure would affect any other organism that could then threaten human health. This represents a gap in what regulators requested, rather than what the company provided. It’s also exactly what happened with the azole fungicides and Aspergillus, and is why public health experts fear that history could repeat itself.

EPA staff acknowledged this to WIRED by email. “EPA uses well-established risk assessment procedures to evaluate risks to human health and the environment from fungicides and other pesticides to determine whether they present unreasonable adverse effects to humans or the environment,” an agency spokesperson wrote. “EPA did not ask the company to verify whether ipflufenoquin shared a mode of action with any drugs in development and currently used in humans.”

The spokesperson added that the agency only became aware of the conflict after the drug was registered. In March 2022, a volunteer group created by the fungicide industry, called the Fungicide Resistance Action Committee (FRAC), evaluated ipflufenoquin as it routinely does for new compounds. (The group does this out of enlightened self-interest; the longer resistance can be held off, the longer commercial life the industry’s products will have.) FRAC ranked ipflufenoquin as a DHODH inhibitor, meaning it had the same mode of action as olorofim. It also judged the fungicide to have a “moderate to high” risk of provoking resistance in plant pathogens.

Asked whether agency officials were aware of the similarity, the EPA spokesperson said no. “EPA did not become aware of this until several months after the pesticide registration was issued,” they wrote. “To EPA’s knowledge, the applicant did not misrepresent ipflufenoquin’s mode of action during the registration process. The applicant provided EPA with the knowledge they had at the time.”

It’s not clear what will happen next. In part that’s because researchers will have to wait to see whether resistance emerges in fungi once ipflufenoquin is applied to fields, and then assess whether that creates cross-resistance to olorofim. To researchers’ knowledge, no resistance exists yet. “We have been very fortunate that we have seen no preexisting resistance to olorofim in fungi,” says John Rex, a physician and longtime drug developer who is F2G’s chief medical officer. “We have a database of 1,000 isolates and have not identified preexisting resistance.” 

But work done by F2G’s scientists and presented in part to the Clinical Laboratory Standards Institute in January, shows that exposing Aspergillus to ipflufenoquin does appear to begin the development of resistance. “Experimentally, there has been the induction of a change in a gene that suggests resistance in vitro,” Harvey says. “What we don’t know is whether that would translate into resistance clinically.” (That work has not yet been peer-reviewed.)

The issue of how to set priorities between medicine and agriculture over a mechanism they both want to use is urgent because other conflicts are coming. F2G scientists believe that a new herbicide that is close to market—tetflupyrolimet, made by FMC for use against weeds in rice paddies—uses a molecular mechanism similar to ipflufenoquin. (The company didn’t respond to a request for comment.) And a forthcoming fungicide, aminopyrifen from Agro-Kanesho, and a still-in-trials human drug, fosmanogepix from Pfizer, share a different new molecular mechanism, inhibition of an enzyme dubbed GWT1. Meanwhile, ipflufenoquin has been approved in Canada and is seeking registration in Australia and Europe.

The world has already experienced how difficult it can be to control enthusiasm for an agricultural compound once it comes to market. Azole fungicides were so effective that they didn’t stay confined to agriculture. They are now formulated into paints, building materials, plastics—a staggering array of consumer goods, and a possible explanation for why azole resistance has spread so rapidly. Just in the US, the CDC estimates that azole use increased more than 400 percent between 2013 and 2016, and continues to rise.

Beneath all these concerns lies a crucial question: How broad and deep must a risk assessment be? Though they reside in the environment, in decaying plant matter and dirt. Aspergillus and the valley fever fungus Coccidioides aren’t plant pathogens. And olorofim is not on the market; though it has been described in journal articles and conference presentations, it has not been approved by the FDA. Using the registration process to ask about either would have been beyond the EPA’s scope.

But elsewhere in the government, a model now exists for interrogating the unintended consequences of pharmaceuticals. A new rule at the FDA, known as Guidance 152, could expand the agency’s power to evaluate new animal antibiotics. Previously, the FDA could evaluate only whether new drugs would be safe and effective for animals. The new guidance, currently in draft form and open to public comment, allows it to also examine whether those new animal drugs would create resistant bacteria that threaten human health.

In written comments, that EPA spokesperson confirmed that the agency is exploring how it might examine the potential conflict posed by ipflufenoquin and olorofim. “EPA, CDC, FDA and the US Department of Agriculture are developing a mechanism for sharing information about not-yet approved products with each other,” the staff member told WIRED by email. “If, for example, there is a medically important antifungal drug that shares properties with an antifungal pesticide, this may affect EPA’s analysis of the benefits of the pesticide and thus whether the registration of the pesticide meets the [legal] standard of ‘no unreasonable adverse effects.’” 

For researchers, such collaboration can’t come too soon. “My goal here is not to stop fungicides from being approved,” says the CDC’s Chiller. “My goal here is just to take a pause and say: Let’s know what we're going into, transparently and openly. So we clinical folks can anticipate the consequences, and we’re not just caught off guard.”