Novel antifungal shows promise for patients with refractory disseminated coccidioidomycosis

1. In this single-group, open-label trial, olorofim was associated with a complete or partial clinical response in over 75% of patients with disseminated coccidioidomycosis (DCM) and limited or no treatment options.

2. Clinical success rates were highest among patients without central nervous system (CNS) infection.

Evidence Rating Level: 2 (Good)

Study Rundown: Every year, thousands of patients with symptomatic coccidioidomycosis in the United States develop chronic pneumonia or disseminated coccidioidomycosis (DCM), which can cause extrathoracic disease, substantial morbidity, and death. With limited therapeutic options, complete resolution is uncommon among patients with DCM. This study evaluated the safety, tolerability, and efficacy of olorofim, an antifungal agent active against Coccidioides species, in patients with DCM who had failed previous antifungal therapy. Although no patients had complete disease clearance after the initial treatment period, most demonstrated a complete or partial clinical response. Among those who received extended treatment, over two-thirds achieved a successful clinical response after six months. At the final study visit, conducted after a median follow-up of more than one year, over half of patients had a successful clinical response, including some with complete disease resolution. Outcomes were more favourable among patients without central nervous system (CNS) infection and those with CNS infection without implanted devices, while patients with CNS infection and implanted CNS devices had lower response rates. No deaths were reported during the initial treatment period; however, some patients died during extended treatment for reasons unrelated to olorofim. Gastrointestinal adverse events were most common, while hepatic biochemical abnormalities were also reported, though relatively few patients discontinued treatment because of them. The study’s generalizability is limited by its single-group, open-label design. Nevertheless, these findings suggest that olorofim may offer a promising treatment option for patients with refractory DCM.

Click to read this study in AIM

Relevant Reading: F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase

In-Depth [prospective cohort]: This single-group, open-label trial assessed the safety, tolerability, and efficacy of olorofim in patients with disseminated coccidioidomycosis (DCM) with limited or no treatment options. Patients aged ≥16 years were enrolled at 10 US sites from May 2019 to August 2022 if their disease was predicted to be resistant to licensed antifungals, had not improved with prior therapy, involved significant drug-drug interactions, or caused treatment intolerance. The primary and secondary outcomes were treatment effectiveness at 42 and 84 days, respectively, according to Mycoses Study Group-European Organization for Research and Treatment of Cancer response criteria. Among 41 patients, 80.5% were male, 56.1% were White, and the median age was 45 years (range, 21-72). CNS infection was present in 73.2% of patients, including 43.3% of those with CNS infection who had implanted devices. Patients had used a mean of 3.5 prior antifungals (range, 2-6), and 82.9% had previously received amphotericin B. Olorofim was administered for a median of 409 days (interquartile range [IQR], 182-523). Although no patients achieved a successful global response at day 42 or 84, 75.6% had a complete or partial clinical response at day 42 and 73.2% at day 84. At day 180, 68.4% of patients receiving extended treatment had a successful clinical response. At the final study visit, 61.5% had a successful clinical response, including 15.4% with complete and 46.2% with partial resolution. Success rates were 80.0% among patients without CNS infection, 64.7% among those with CNS infection without implanted devices, and 41.7% among those with implanted devices. No deaths occurred during the main treatment phase; by the end of extended treatment, all-cause mortality was 9.8%, with 3 deaths attributed to DCM. Gastrointestinal adverse events occurred in 51.2% of patients, while olorofim-related hepatic biochemical elevations occurred in 22.0%; only 1 patient discontinued treatment because of these abnormalities. Overall, olorofim appears promising for patients with refractory DCM, particularly those without CNS infection.

Image: PD

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