FDA Issues Complete Response for Drug for Rare Fungal Infections


The FDA is requesting additional data and analysis for olorofim. F2G plans to resubmit revised NDA with complete data set from phase 2 study.

The FDA has issued a complete response letter (CRL) for F2G’s new drug application (NDA) for olorofim to treat patients with invasive fungal infections. The agency is requesting additional data and analyses.

Olorofim is being developed for difficult-to-treat invasive, rare fungal mold infections such as azole-resistant aspergillosis, scedosporiosis and lomentosporiosis. Invasive fungal infections can cause morbidity and mortality, particularly among immunosuppressed patients. Effective therapies are limited, and even when therapies exist, some patients may become resistant.

Olorofim works through a novel mechanism of action, different from existing classes of antifungals, by inhibiting the enzyme dihydroorotate dehydrogenase (DHODH) in the pyrimidine synthesis pathway, a pathway for DNA synthesis.

Francesco Maria Lavino

Francesco Maria Lavino

“While F2G is disappointed with this outcome, we remain optimistic about olorofim’s potential to address an unmet need for patients with invasive fungal infections who have exhausted their treatment alternatives,” Francesco Maria Lavino, chief executive officer of F2G, said in a press release “We are assessing the details of the CRL and we plan to meet with the FDA to discuss it further, but we are confident that we can identify a regulatory path forward in the United States.”

The initial NDA included data from the first 100 patients enrolled in the then-ongoing phase 2b study. At day 42, 44% of patients had a complete or partial response to treatment. Olorofim was generally well tolerated. The only significant serious adverse event was drug-induced liver injury, which was thought to be possibly related to olorofim in eight study patients; only two patients required discontinuation of olorofim because of liver injury. Non-serious adverse events included diarrhea, nausea and vomiting.

The study has now completed enrollment with a total of 203 patients, and the company indicated that the full data set will be submitted as part of the revised NDA package.

F2G continues to expand olorofim’s clinical development program, and along with its partner Shionogi, is enrolling patients with invasive aspergillosis in a global phase 3 trial to compare treatment with olorofim versus Gilead Science’s antifungal AmBisome (amphotericin B) followed by standard of care.

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