A New Antifungal Class Shows Promise Against Deadly Fungi

Fungal infections impose a significant and often underrecognized global health burden, and treating them presents unique challenges. Because fungi are eukaryotic organisms like humans, identifying drug targets that harm fungal cells without damaging human tissues is difficult, and only a few antifungal drug classes are currently available. Scientists at F2G addressed this challenge by discovering the orotomides, a new antifungal compound class that inhibits fungal dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis.

In this Innovation Spotlight, John Rex, the chief medical officer of F2G, discusses the need for better antifungal therapeutics and highlights the promise of F2G’s lead candidate olorofim.

What is the global health burden of fungal infections?

There are many kinds of fungal infections: annoying topical infections such as athlete’s foot, infections of the eye surface that can cause blindness, and deeply invasive infections that can be lethal, especially during cancer treatment. The global burden of fungal disease is thus substantial. An estimate from Global Action for Fungal Infections (GAFFI) says that “each year, more than 80 million people are at a high risk of either succumbing to a fungal disease or experiencing vision loss. Approximately 6.55 million patients develop life-threatening fungal infections annually, of which 3.75 million unfortunately do not survive.”

Why are these infections so difficult to treat?

Two issues make fungal infections difficult to treat. First, the number of available therapies is constrained by the shared eukaryotic nature of fungi and humans. This biological similarity makes it difficult to identify drug targets that do not also harm human cells. Second, fungal infections often involve body sites that are intrinsically more difficult to treat. Infections of the nail, for example, require therapy to be continued during the many months required to grow a new nail. Invasive fungal infections often involve hard-to-treat body sites such as the brain or bone.

What are the current standards of treatment for fungal infections, and where do they fall short?

For invasive infections, there are only a few standard classes of systemic therapies: the polyenes (IV only), the azoles (IV or oral), the echinocandins (IV only), and flucytosine (oral and useful for only one fungal infection). A few additional compounds are available for topical use. Overall, there are gaps in the spectrum: there are fungi for which no current therapy is effective; resistance has developed to these agents, especially to the azole antifungals; and both side effects and drug-drug interactions limit the utility of these agents.

What are orotomides, and how did F2G scientists discover this novel compound class?

The orotomides were discovered by F2G scientists in 2004 by screening a small molecule library versus Aspergillus fumigatus. Initial hits were developed via classical structure-activity relationship work, leading ultimately to the synthesis of olorofim in 2011, the first orotomide to reach clinical development. Based on data from a combination of microbiological, genetic, and biochemical analyses, olorofim was shown to act via inhibition of the enzyme dihydroorotate dehydrogenase (DHODH), a key enzyme in pyrimidine biosynthesis.¹

What preclinical insights led you to think orotomides would have promise as antifungal agents?

Three exciting features were soon apparent for the orotomides. First, the inhibition of DHODH by the early orotomides was shown to be specific for fungal DHODH.¹ Although the enzymatic activity of DHODH is used by nearly all living organisms, the structure of the enzyme differs substantially. Importantly, human DHODH and fungal DHODH are very different, and thus it is possible to selectively inhibit fungal DHODH. Second, the orotomides were found to have consistent activity versus Aspergillus and a large, related group of filamentous fungi called the Pezizomycotina. These fungi are key causes of lethal fungal diseases and include genera for which no current agent is active, such as Lomentospora. Finally, the orotomides were very active against these fungi both in vitro and in animal models of human infection. Excitingly, the observed activity included demonstrations that the orotomides were fungicidal.

Why are orotomides more promising than current treatments?

First, the orotomides are exciting as new therapies due to their spectrum of activity: olorofim has very predictable activity versus a range of fungi for which no current therapies are active. Second, olorofim is reliably dosed by mouth and thus is easy to use for the extended periods of therapy often needed for invasive fungal infections. Third, olorofim has a limited number of easily managed drug-drug interactions, making it compatible with advanced medical treatments needed to support organ transplantation or treatment of malignancy, especially hematological malignancy. Finally, olorofim is well tolerated for months to years. Its only significant adverse event is that it can cause drug-induced liver injury (DILI); like the azole antifungals, monitoring for DILI is required during therapy and is managed by dose adjustment.

What does your lead candidate treat, and what results did you see in the recent clinical trial?

F2G has completed an open-label, single-arm Phase 2 study of olorofim in which 202 patients with limited or no treatment options for proven invasive fungal disease or probable invasive pulmonary aspergillosis received olorofim orally for 84 days during the main treatment phase with extended therapy as needed.² Successful global response with stable disease included as success was 75.2 percent and 63.4 percent at days 42 and 84, successful clinical response was 59.9 percent and 54.0 percent, and all-cause mortality was 11.9 percent and 16.3 percent, respectively. The mean dosing duration was 73 days during the main treatment phase, with dosing up to 988 days in extended treatment.

Are there any concerns with antimicrobial resistance or negative host cell effects?

Emergence of antimicrobial resistance is a concern for all antimicrobial agents. Encouragingly, olorofim generally shows unimodal susceptibility distributions in susceptible genera— that is, isolates tested in current surveys of key genera are generally found to be susceptible.^3,4 Further, the rate of emergence of resistance in the laboratory is low, and resistance has not been noted to emerge during therapy of infections in the completed Phase 2 trial.

What comes next for your lead candidate, and where do you see this drug fitting into the antifungal treatment landscape?

Next up is a Phase 3 study in invasive aspergillosis in which olorofim will be compared with a standard of care second-line therapy—AmBisome-based therapy—in patients who cannot be treated with an azole, which is the preferred first-line therapy. The results of this study will be available this year. Studies of olorofim as therapy for infections due to Coccidioides spp., such as coccidioidomycosis or Valley fever, are also planned. Based on these studies, we anticipate usage of olorofim in patients with invasive fungal infections for whom azoles, the only oral class and the generally preferred therapy, cannot be used due to limitations such as resistance, intolerance, or drug-drug interactions.