F2G Ltd announced positive interim results from its ongoing Phase 2b study of olorofim, demonstrating promising efficacy in patients with invasive fungal infections who have limited or no treatment options. The data, presented at IDWeek 2022, showed a 44% complete or partial response rate at day 42 among the first 100 patients analyzed.
Study Population and Design
The multicenter, open-label Phase 2b study (Study 32, NCT03583164) enrolled patients aged 18 years and older with proven invasive fungal infection or probable pulmonary invasive aspergillosis. Causative organisms included Aspergillus spp., Lomentospora prolificans, Scedosporium spp., Scopulariopsis spp., Coccidioides spp., and other olorofim-susceptible fungi.
Approximately 75% of patients had moderate to high levels of immunosuppression, with about half suffering from fungal infections due to Aspergillus. Patients had limited alternative treatment options due to failure of available therapy, resistance of infecting isolate to all licensed agents, intolerance to available therapy, inability to manage drug-drug interactions, and/or inability to produce therapeutic drug levels.
Efficacy Results
The primary endpoint analysis revealed a 44% response rate defined as complete or partial response at day 42. When stable response was included, the overall response rate reached 69%. All-cause mortality rates were 15% at day 42 and 20% at day 84.
"We are encouraged by these results because they demonstrate a positive risk-benefit profile for olorofim as an oral therapeutic option for the treatment of serious or life-threatening invasive fungal infections in patients who have limited or no treatment options," said John H. Rex, MD, chief medical officer of F2G.
Safety Profile
Olorofim was generally well tolerated across the study population. The median dosing duration in the main phase was 84 days, while patients who entered the extension phase received treatment for a median of 308 days.
The only significant serious adverse event was drug-induced liver injury (DILI), which was thought to be possibly related to olorofim in 8% of study patients. Only 2% of patients required discontinuation due to DILI. Other non-serious adverse events included diarrhea, nausea, and vomiting.
Novel Mechanism of Action
Olorofim represents the first antifungal from the orotomide class, working through a novel mechanism of action different from existing antifungal classes. The drug exerts fungicidal activity through inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) in the pyrimidine synthesis pathway.
This unique mechanism provides activity against a broad range of fungi, including Aspergillus spp. (including azole-resistant and cryptic species), rare molds such as Lomentospora prolificans and Scopulariopsis, and dimorphic fungi including Coccidioides spp.
Regulatory Recognition
Olorofim is the only antifungal medication to receive Breakthrough Therapy Designation from the US Food and Drug Administration (FDA). The drug has received orphan drug status from both the European Medicines Agency and FDA for multiple indications, including invasive aspergillosis, invasive scedosporiosis, and coccidioidomycosis.
The FDA has also granted Qualified Infectious Disease Product (QIDP) designation for invasive aspergillosis, invasive scedosporiosis, invasive lomentosporiosis, coccidioidomycosis, invasive disease due to Scopulariopsis species, and invasive fusariosis.
Treatment Protocol
Enrolled patients receive an initial loading dose of 150 mg twice daily of oral olorofim on day one, followed by 90 mg twice daily for up to 90 days. Patients are monitored for four weeks after treatment completion, with some receiving extended therapy as clinically indicated.
Future Development
F2G has initiated a global Phase 3 trial called "OASIS" (NCT05101187) to compare olorofim versus AmBisome followed by standard of care in patients with lower respiratory tract invasive fungal disease caused by proven or probable Aspergillus species infection.
"Mortality remains unacceptably high in patients with severe and life-threatening fungal infections being treated with currently available therapies," noted Johan Maertens, MD, PhD, Professor of Hematology at University Hospitals Leuven and primary author for Study 32. "These data provide evidence that we are on the path to meeting this need in patients currently with limited or no treatment options."
