Two months to the day before its Dec. 24 PDUFA date, Xofluza (baloxavir marboxil, previously S-033188, RG-6152), gained a nod from the FDA to treat acute uncomplicated influenza in individuals 12 and older who became symptomatic within the previous 48 hours.

The single-dose oral drug, advanced by Roche Holding AG and partner Shionogi & Co. Ltd., was approved in Japan earlier this year and launched in March under the same name. Xofluza is an oral prodrug of the active form of baloxavir, a cap-dependent endonuclease inhibitor that inhibits initiation of mRNA synthesis, and is indicated to treat influenza types A and B.

In nonclinical studies, Xofluza also demonstrated efficacy against Tamiflu (oseltamivir, Roche)-resistant strains and avian strains H7N9 and H5N1.

"This is the first new antiviral flu treatment with a novel mechanism of action approved by the FDA in nearly 20 years," FDA Commissioner Scott Gottlieb said in a statement about the approval, which followed a priority review of the NDA, submitted in April. Xofluza also received the FDA's qualified infectious disease product, or QIDP, designation.

The phase III CAPSTONE-1 study laid the groundwork for approval in acute, uncomplicated influenza. A single dose of Xofluza compared with placebo or oseltamivir 75 mg, twice daily for five days, in otherwise healthy people with the flu reduced the duration of symptoms compared to placebo (median time 54 hours vs. 80 hours; p<0.001), meeting the primary efficacy endpoint. Xofluza showed similar efficacy compared to oseltamivir in relation to duration of symptoms (median time 54 hours vs. 54 hours). The NDA also included data from a placebo-controlled phase II study in otherwise healthy people with the flu.

In CAPSTONE-1, Xofluza was safe and well-tolerated with a side effect profile similar to placebo. The most common adverse events reported were diarrhea (3 percent), bronchitis (2.6 percent), nausea (1.3 percent) and sinusitis (1.1 percent), and all occurred at a lower frequency than placebo.

The study was conducted in the U.S. and Japan by Shionogi, which discovered the compound. Roche holds global rights to Xofluza outside Japan and Taiwan, where Shionogi, of Osaka, Japan, retained rights.

'Potential to replace Tamiflu'

At this month's IDWeek in San Francisco, members of Roche's Genentech unit presented data from CAPSTONE-2, which showed that, in a less healthy group, baloxavir reduced the time to improvement of influenza symptoms by 29.1 hours vs. placebo (median time of 73.2 hours vs. 102.3 hours; p<0.0001).

That trial enrolled people at high risk of serious complications from the flu, including adults 65 and older and those with conditions such as asthma, chronic lung disease, morbid obesity or heart disease. In a subpopulation of participants with influenza type B, the study also showed baloxavir was more effective than Tamiflu in reducing time to improvement of symptoms, cutting that time by a median 27 hours (median time of 74.6 hours vs. 101.6 hours; p<0.05). (See BioWorld, Oct. 5, 2018.)

The 65-and-older group is especially important because, according to the CDC, about 70 percent to 85 percent of seasonal flu-related deaths and 54 percent to 70 percent of seasonal flu-related hospitalizations occur in that group.

"It's very exciting that we're seeing strong results in terms of improvement of influenza symptoms in this high-risk population, because there's no drug currently approved that has this population in the label as an efficacious one," Mark Eisner, Genentech's vice president of product development immunology, infectious disease and ophthalmology, told BioWorld at IDWeek.

Overall, Genentech views Xofluza as "an attractive asset with the potential to replace Tamiflu," Sandra Horning, executive vice president of global development and chief medical officer, said during a recent company meeting.

Although H7N9 has not yet mutated to transmission between humans, it remains a major concern for public health officials. If the virulent bird flu were able to spread widely in the human population, "baloxavir could be a very important treatment for that," Eisner said.

Xofluza will be launched in the U.S. in the coming weeks, according to a spokesperson from Genentech, based in South San Francisco. Pricing was not disclosed, but the company said it will offer a coupon to eligible patients.

Despite mostly seasonal use, Xofluza has a five-year consensus sales forecast of $430.3 million, according to Cortellis Competitive Intelligence.