University of Liverpool researchers have contributed to positive topline results from the global Phase 3 OASIS study of olorofim, an investigational oral antifungal treatment for invasive aspergillosis, announced by F2G and Shionogi.
The study compared oral olorofim with AmBisome® followed by standard of care in adults with invasive aspergillosis whose infection had not responded to azole antifungal medicines, or who could not take them. Patients were treated either with oral olorofim or with AmBisome® followed by the usual treatment chosen by their doctors. The results showed that olorofim worked similarly to the comparison treatment. By Day 42, all-cause mortality was 23.8% for patients treated with olorofim, compared with 24.3% for patients treated with AmBisome followed by standard care.
Researchers in the University of Liverpool’s Antimicrobial Pharmacodynamics and Therapeutics group played a key role in the earlier development of olorofim, by defining the pharmacological principles and exposure targets needed to select safe and effective regimens for human studies.
Olorofim is the first member of the orotomide class of antifungal agents. It has a novel mechanism of action, inhibiting fungal dihydroorotate dehydrogenase, an enzyme involved in pyrimidine biosynthesis. This mechanism is distinct from currently available antifungal treatments and is designed to target difficult-to-treat mould infections, including Aspergillus species.
The Liverpool team’s preclinical pharmacokinetic-pharmacodynamic research used advanced infection models and mathematical modelling to link drug dose, drug exposure and antifungal effect. Their studies identified the pharmacodynamic index most closely associated with activity, showed that olorofim’s antifungal activity was linked to maintaining adequate drug exposure over time, and provided the evidence base to support regimen selection for Phase 2 and Phase 3 clinical studies.
Professor William Hope OBE, Dame Sally Davies Chair of AMR Research at the University of Liverpool, said:
“Seeing positive Phase 3 topline data for olorofim is an important moment for patients with invasive fungal infections, particularly those with limited treatment options.
“Our contribution was to reduce the uncertainty that can surround early antimicrobial development. By understanding how drug exposure relates to antifungal effect, we were able to help define the pharmacological targets that informed regimen selection for clinical studies.
“This is a strong example of how rigorous pharmacology, infection modelling and close collaboration between academia and industry can help translate a promising discovery into a potential treatment for patients.”
Invasive aspergillosis is a life-threatening fungal infection that primarily affects people with weakened immune systems. Treatment options can be limited by resistance, toxicity, drug interactions and patient suitability for existing therapies. Olorofim is investigational and has not yet been approved by any regulatory authority.
The University of Liverpool’s work forms part of its wider commitment to tackling antimicrobial resistance and developing better treatments for serious bacterial and fungal infections through pharmacology, data science and translational research.
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