F2G's pioneering antifungal candidate olorofim has encountered a regulatory hurdle after the FDA issued a complete response letter requiring additional data, even as new Phase 2b results published in The Lancet Infectious Diseases reinforce the drug's potential to address critical unmet needs in invasive fungal infections.
The UK-based biopharmaceutical company received the FDA's complete response letter indicating that additional data and analyses would be required, preventing the agency from completing its review within the scheduled timeframe ending June 17th. However, the FDA encouraged F2G to collaborate on strengthening the data package for resubmission.
Breakthrough Therapy Addresses Treatment-Resistant Infections
Olorofim represents the first in a new class of orotomide antifungal agents, offering a novel mechanism of action distinct from current therapies including azoles, echinocandins, and polyene-based medicines. The drug selectively targets a key enzyme in the pyrimidine biosynthesis pathway, providing fungicidal activity against a broad range of rare and resistant fungal infections.
"Olorofim, the first in a new class of antifungals, has a novel mechanism of action and shows potential in addressing rare fungal infections in well-defined and high need populations," said Dr. John H. Rex, Chief Medical Officer of F2G. "We are committed to developing olorofim for patients who have exhausted treatment options and are in need of a new effective therapy."
Phase 2b Study Demonstrates Clinical Efficacy
The comprehensive Phase 2b study (Study 32) enrolled 202 patients with proven or probable invasive fungal diseases between June 2018 and September 2022. The multicenter, open-label trial evaluated oral olorofim in patients with limited or no treatment options, including infections caused by Aspergillus species (101 patients, including 22 cases with azole-resistant strains), Lomentospora prolificans (26), Scedosporium species (22), Coccidioides species (41), and other rare fungi (12).
The primary endpoint showed a global response rate of 28.7% at day 42, as determined by an independent Data Review Committee applying MSG/EORTC criteria. When stable disease was included as a successful outcome, the response rate increased to 75.2% at day 42 and 63.4% at day 84. Clinical response rates were 59.9% and 54.0% at days 42 and 84, respectively.
"The data published in The Lancet ID show successful global and clinical responses in patients with both brief and lengthy periods from diagnosis to initiation of olorofim treatment, with infections due to highly resistant organisms and those in difficult-to-treat sites such as brain and bone," noted Dr. Johan Maertens, Professor of Hematology at University Hospitals Leuven and the study's Principal Investigator.
Safety Profile and Treatment Duration
The study demonstrated that olorofim was generally well-tolerated, even with extended dosing exceeding two years in some patients. The mean dosing duration was 73 days during the main treatment phase, with 114 subjects receiving extended treatment averaging 361 days. During the main treatment phase, 61.9% of patients received olorofim as monotherapy, and 70.8% received seven days or fewer of concomitant antifungal therapy.
All-cause mortality rates were 11.9% at day 42 and 16.3% at day 84. Liver biochemistry changes deemed possibly related to olorofim occurred in 9.9% of patients overall, with all events successfully managed through dose modifications. Only 3% of patients required permanent discontinuation due to liver-related issues, while 9.9% experienced generally self-limiting gastrointestinal intolerance.
Regulatory Recognition and Partnership
The FDA granted olorofim breakthrough designation in 2019, recognizing the critical need for new antifungal therapies. The drug has also received orphan drug status from both the FDA and European Medicines Agency for multiple indications, including invasive aspergillosis, invasive scedosporiosis, and coccidioidomycosis.
Japanese pharmaceutical company Shionogi joined the development program in 2023, paying $100 million upfront to license European and Asian rights while F2G retained North American rights. The partnership reflects growing recognition of resistant fungal infections as azole resistance increases, partly due to agricultural use of these compounds.
Ongoing Development Program
F2G and Shionogi are currently conducting the Phase 3 OASIS trial (NCT05101187), comparing olorofim to AmBisome (liposomal amphotericin B) in patients with invasive aspergillosis. Results from this pivotal study are expected next year and will be crucial for the drug's regulatory pathway.
"There is a critical unmet need for novel antifungal therapies as lifesaving interventions," Dr. Maertens emphasized. "Cancer treatments and organ transplants, combined with an aging population, have led to a rise in individuals at risk of invasive fungal infections—many of which are increasingly difficult to treat."
The completed Study 32 data will support F2G's revised regulatory submission, though the company has not specified a timeline for resubmission to the FDA.
