Xofluza Approved for Postexposure Prevention of Flu

In continuation of my update on Baloxavir marboxil (BXM)

The approved indication for Xofluza (baloxavir marboxil) has been expanded to include postexposure prevention of influenza for those who may have come in contact with someone who has the flu, the U.S. Food and Drug Administration announced Monday.

Xofluza was approved in 2018 to treat uncomplicated flu in patients 12 years and older who are symptomatic for no more than two days. The drug was previously only available in a tablet form but is now available in granule form for mixing in water.

The expanded approval decision was based on data from the Phase III BLOCKSTONE study, a randomized, double-blind, controlled trial of 607 individuals ages 12 years and older who were exposed to a household member with the flu. Individuals were randomly assigned to receive either a single dose of Xofluza (303 individuals) or placebo (304 individuals). One percent of those who received Xofluza compared with 13 percent who received placebo were infected with influenza and presented with fever and at least one respiratory symptom over 10 days. These data were published in the New England Journal of Medicine in July.

The most commonly reported side effects of Xofluza include diarrhea, bronchitis, nausea, sinusitis, and headache.

"This expanded indication for Xofluza will provide an important option to help prevent influenza just in time for a flu season that is anticipated to be unlike any other because it will coincide with the coronavirus pandemic," Debra Birnkrant, M.D., director of the Division of Antiviral Products in the FDA Center for Drug Evaluation and Research, said in an agency news release. "Americans will have to be more vigilant than ever as these viruses spread concurrently."

https://en.wikipedia.org/wiki/Baloxavir_marboxil

FDA Approval of Xofluza (baloxavir marboxil) for High Risk of Developing Influenza-Related Complications

 Genentech, a member of the Roche Group,  announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Xofluza™ (baloxavir marboxil) for the treatment of acute, uncomplicated influenza, or flu, in people 12 years of age and older who have been symptomatic for no more than 48 hours and who are at high risk of developing flu-related complications. Xofluza is a first-in-class, one-dose oral medicine with a novel proposed mechanism of action that inhibits polymerase acidic endonuclease, an enzyme essential for viral replication.

"With the flu season rapidly approaching, we can now offer Xofluza as the first and only FDA-approved treatment option indicated specifically for those at high risk of flu complications," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “People with chronic conditions such as asthma, heart disease and diabetes are at higher risk of developing serious complications from the flu, so it is critical that these patients speak with their healthcare providers about possible treatment at the first signs and symptoms of the disease.”

The flu has the potential to cause a variety of complications, ranging from sinus or ear infections to more serious complications such as pneumonia. This expanded indication for Xofluza was approved based on results from the Phase III CAPSTONE-2 study of a single dose of 40 mg or 80 mg of Xofluza compared to oseltamivir (75 mg twice daily for five days), or placebo in people 12 years of age or older who met CDC criteria for being at high risk of complications from the flu. Xofluza significantly reduced the time to improvement of flu symptoms compared to placebo, including in people infected with the flu type B virus. Adverse events reported in at least 1% of adult and adolescent subjects treated with Xofluza included diarrhea (3%), bronchitis (3%), nausea (2%), sinusitis (2%) and headache (1%).

Xofluza is currently approved in several countries for the treatment of flu types A and B. In October 2018, Xofluza was first approved by the FDA for the treatment of acute, uncomplicated flu in otherwise healthy people 12 years of age and older who have been symptomatic for no more than 48 hours, representing the first new antiviral to treat the flu in the U.S. in 20 years.

About CAPSTONE-2

CAPSTONE-2 is a Phase III, multicenter, randomized, double-blind study that evaluated a single dose of Xofluza compared with placebo and oseltamivir in people 12 years of age or older who are at a high risk of complications from the flu. The Centers for Disease Control and Prevention (CDC) defines people at high risk of serious flu complications as those who have conditions such as asthma, chronic lung disease, diabetes, heart disease, morbid obesity or adults 65 years of age or older. The study was conducted globally by Shionogi & Co., Ltd.

Participants enrolled in the study were randomly assigned to receive a single dose of 40 mg or 80 mg of Xofluza, placebo or 75 mg of oseltamivir twice a day for five days. The primary objective of the study was to evaluate the efficacy of a single dose of Xofluza compared with placebo by measuring the time to improvement of flu symptoms. Key findings from the study found that:

Xofluza significantly reduced the time to improvement of flu symptoms versus placebo in people at high risk of complications from the flu (median time 73 hours versus 102 hours; p<0.001). Similar efficacy results were seen between Xofluza and oseltamivir in relation to duration of symptoms (median time 73 hours versus 81hours). In subjects infected with type B virus, the median time to improvement of flu symptoms was shorter in the Xofluza group compared to the placebo group (75 hours versus 101 hours respectively). Adverse events reported in at least 1% of adult and adolescent subjects treated with Xofluza included diarrhea (3%), bronchitis (3%), nausea (2%), sinusitis (2%) and headache (1%). Xofluza was well-tolerated and no new safety signals were identified.

About Xofluza ™ (baloxavir marboxil)

Xofluza is a first-in-class, one-dose oral medicine with a novel proposed mechanism of action that has demonstrated efficacy in a wide range of influenza viruses, including in vitro activity against oseltamivir-resistant strains and avian strains (H7N9, H5N1) in non-clinical studies. Unlike other currently available antiviral treatments, Xofluza is the first in a new class of antivirals designed to inhibit the cap-dependent endonuclease protein, which is essential for viral replication.

New One-Dose Flu Drug Shows Promise

An experimental single-dose flu drug shows promise as a new way to alleviate the misery of influenza, researchers say. 

The drug  called baloxavir (structre)  worked better than no treatment in one phase of a new study. The study also found it as effective as the current standard drug, oseltamivir (Tamiflu), at controlling symptoms such as coughing, sore throat, headache, fever, muscle and joint pain, and fatigue.

Moreover, in light of concerns about flu-drug resistance, most patients treated with baloxavir responded as expected, the study authors said.

"There are few approved influenza antivirals, and current treatments have limitations," said study lead author Dr. Frederick Hayden, of the University of Virginia School of Medicine.

"For example, currently circulating influenza viruses are resistant to the older class of antivirals," he said. These include the drugs amantadine (brand name Symmetrel) and rimantadine (Flumadine).

Resistance is also growing to the class of drugs including widely used Tamiflu and Relenza (zanamivir), Hayden said. "Consequently, there are medical needs for new anti-influenza agents with different mechanisms of action and greater potency," he added.

Hayden, professor emeritus of clinical virology and medicine, said the new study indicates that baloxavir resolves flu symptoms as quickly, effectively and safely as current options, without yet raising concerns about resistance. It also demonstrated "significantly greater antiviral effects," he added.

Also, while Tamiflu must be taken twice a day for five days, baloxavir requires just one dose.

The investigation was funded by the drug company Shionogi, Inc., which developed and manufactures baloxavir.

Baloxavir is approved for use in Japan. In the United States, it remains an "investigational drug," with the U.S. Food and Drug Administration expected to decide on approval by the end of this year.

The new study, which was published Sept. 6 in the New England Journal of Medicine, unfolded in two trials, both involving otherwise healthy flu patients at low risk for influenza complications.

One trial was conducted during the 2015-2016 flu season. About 400 patients, aged 20 to 64, received one of three doses of baloxavir (ranging from 10 to 40 milligrams) or a placebo. Flu symptoms eased notably faster among all three baloxavir groups, compared with placebo (untreated) patients, the findings showed.

The following flu season, nearly 1,100 patients, aged 12 to 64, were treated with baloxavir or Tamiflu. The drugs relieved symptoms in roughly the same time period, with similar side-effect risk.

However, about 10 percent of the baloxavir patients had a less than robust response to the drug. Hayden acknowledged that "the clinical and public health implications of reduced susceptibility to baloxavir are not fully understood."

Dr. Timothy Uyeki, author of an accompanying journal editorial, heads the influenza division at the U.S. Centers for Disease Control and Prevention's National Center for Immunization and Respiratory Diseases.

"There is a need for antiviral drugs with new mechanisms of action," he agreed.Uyeki highlighted the benefit of baloxavir's single-dose regimen. Besides its convenience, it "avoids concerns about compliance with a five-day treatment course of oseltamivir," he said.

But he also stressed the need for further testing.

It remains unclear what benefits might accrue from combining baloxavir with Tamiflu, Uyeki noted.

Also, he cautioned, the current research only included otherwise healthy people aged 12 to 64 who were not at high risk for flu complications. Whether baloxavir will benefit high-risk groups -- young children, the elderly, pregnant women and others with underlying chronic medical conditions -- remains unknown, Uyeki said.

"A lot more studies are needed of the clinical benefit of baloxavir treatment of influenza in high-risk outpatients," he added.