FDA Passes on Olorofim Despite Critical Need for Antifungals

Marcia Frellick

June 21, 2023

The US Food and Drug Administration (FDA) is declining to approve the investigational antifungal olorofim and is asking for more data, according to a news release from the manufacturer, F2G Ltd.

Olorofim, (formerly known as F901318) is the first in the orotomide class of antifungals to be evaluated clinically for the treatment of invasive mold infections. Its maker, F2G, is a biotech company based in Manchester, the United Kingdom, that focuses on developing drugs for rare fungal diseases.

The company says it remains optimistic and will address the FDA's requirements and continue to seek approval.

The FDA's denial comes as fungal infections are becoming increasingly common and resistant to treatment. There are only four antifungal classes currently available, and there are few new candidates in the pipeline. No new classes of antifungals have been developed in two decades.

David Andes, MD, chief of the Division of Infectious Diseases at the University of Wisconsin-Madison, told Medscape Medical News he shares the hope that the company can meet the requirements to gain approval.

"Some of the early results were really exciting," he said. "People are enthusiastic about the compound because it has a novel mechanism of action and it is active against a group of fungi that we have limited to no options for."

Early Results "Exciting"

Andes said several physicians have been able to prescribe olorofim under the compassionate use program "and have witnessed success."

Olorofim is the first antifungal agent to be granted breakthrough therapy designation, which the FDA granted in November 2019 for the treatment of invasive mold infections for patients with limited or no treatment options, including patients with refractory aspergillosis or those who are intolerant of currently available therapy. It is also indicated for infections due to Lomentospora prolificans, Scedosporium, and Scopulariopsis species.

Olorofim received a second breakthrough therapy designation in October 2020. The second designation was granted for treatment of central nervous system coccidioidomycosis that is refractory or for cases that cannot be treated with standard-of-care therapy.

It is very difficult for patients to be approved to receive compassionate use medicines, Andes pointed out. "I'd like to have access sooner rather than later," he added.

Andes says the drugs are expensive and are time consuming to produce. And with antifungals, it is difficult to demonstrate safety in comparison with other antimicrobial agents because "it's hard to hurt a fungus without having toxicity with human cells."

Complete Response Letter Issued

F2G received a complete response letter from the FDA regarding its new drug application for olorofim, according to the news release issued by the company. "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, said in the release. "We are assessing the details of the Complete Response Letter, and we plan to meet with the FDA to discuss it further."

Andes says few other antifungals have made it as far as olorofim in clinical trials.

Lance B. Price, PhD, co-director of the Antibiotic Resistance Action Center at George Washington University in Washington, DC, told Medscape Medical News that despite the lack of antifungals in the pipeline, "We can't allow our desperation to override the checkpoints that ensure that antifungals are safe to use in people."

In the meantime, he said, it is important to preserve the utility of current antifungals by avoiding overusing them in medicine and agriculture.

"Sadly," he said, "a drug called ipflufenoquin, which works by a similar mode of action as olorofim, has already been approved by the US Environmental Protection Agency for use in plant agriculture. This could weaken the effectiveness of olorofim for treating things like Aspergillus infections even before the drug has been approved for use in humans."

Plant Drug Undermining Olorofim Efficacy in Humans

"While I'm sure this makes financial sense for the makers of ipflufenoquin, it borders on insanity from a public health perspective," Price said.

Meanwhile, the global threat of fungal infections grows. The World Health Organization (WHO) has launched its first-ever list of health-threatening fungi. Authors of a WHO report that contains the list write, "The invasive forms of these fungal infections often affect severely ill patients and those with significant underlying immune system related conditions."

F2G will continue to expand olorofim's clinical trial program, according to the company's statement. Along with its partner, Shionogi & Co, it is enrolling patients with proven or probable invasive aspergillosis in a global phase 3 trial (OASIS), which will compare outcomes after treatment with olorofim in comparison with amphotericin B liposome (AmBisome) followed by standard of care.

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.