Novel antifungal shows activity in valley fever

An investigational antifungal was associated with clinical improvements in a majority of patients with disseminated coccidioidomycosis (DCM) who failed standard treatments, according to an open-label phase IIb trial.

Among 41 people with DCM and limited or no effective treatment options, complete or partial clinical response to olorofim was observed in 75.6% after 42 days and 73.2% after 84 days of treatment, reported Fariba Donovan, MD, PhD, of the University of Arizona's Valley Fever Center for Excellence in Tucson, and colleagues.

Clinical success rates were greater among those without a central nervous system (CNS) infection, at 80%, dropping to 64.7% among those with CNS infections without implanted CNS devices and 41.7% in those with CNS infections and implanted devices, the researchers detailed in Annals of Internal Medicine.

"Olorofim demonstrated effectiveness in clinical response in 41 patients with intractable DCM and illustrates the potential efficacy of this novel therapeutic option as salvage treatment for patients for whom standard-of-care therapies have failed," Donovan and colleagues wrote. "Overall, although not entirely analogous, our results compare favorably with studies of current azole treatments, especially considering the higher percentage of our study's refractory or progressive cases and CNS cases."

The lung infection coccidioidomycosis, also known as Valley fever, is caused by inhaling spores from the Coccidioides fungus found in soil. Only about 1% of the estimated 206,000 to 360,000 annual cases in the U.S. lead to either chronic pneumonia or DCM; however, DCM is a refractory condition that spreads beyond the lungs and can involve the CNS. Patients require lifelong treatment with amphotericin B or triazole antifungal agents, and complete resolution is rare.

The researchers conducted a subanalysis of DCM within a larger study evaluating olorofim for the treatment of invasive fungal infections in people without suitable alternative treatment options. Patients with DCM ages 16 years or older with resistance to licensed antifungal agents, no clinical improvement despite such antifungal treatment, or significant drug-drug interactions were included.

Patients participated in an 84-day main treatment phase, with the option to continue beyond 90 days in an extended treatment phase. After a first-day oral loading dose of 300 mg, patients received 90 mg twice daily. Among the 41 patients enrolled between May 2019 and August 2022, all had DCM that was poorly controlled with available therapies. Mean time from DCM diagnosis to olorofim treatment was 1,091 days. Nearly three-quarters of patients (73.2%) had CNS infection.

Complete clinical response was defined as resolution of all clinical symptoms and physical findings of DCM. Partial resolution was defined as some symptom and physical finding improvement without new or worsening symptoms.

The investigators didn't pair serological response with clinical response as an endpoint, given the length of time needed to see a serological change with treatment. Serological persistence "may not represent mycologic persistence because even with treatment, serologic markers may decrease but not become negative for years," the authors noted.

Indeed, no DCM patients achieved a successful global response combining clinical, radiologic, and mycologic responses by either day 42 or 84. Among 12 people who had serological data after more than a year of treatment, all remained seropositive.

Among 39 patients who underwent extended olorofim treatment, 61.5% saw clinical success, including six patients who had complete resolution and 18 who saw partial resolution. Most patients received olorofim with a standard-of-care antifungal (82.9%), and their complete or partial response rates at 42 and 84 days (86.7% and 76.7%) were greater than those of patients not on antifungals (45.5% and 54.5%).

Gastrointestinal (39%), hepatobiliary (29.3%), and musculoskeletal (22%) adverse events were seen with olorofim treatment. There were no deaths during the study's main treatment phase, though the all-cause mortality rate at the end of the extended treatment phase was 9.8%. Three patients died of DCM.

Limitations included the study's open-label, single-group design.