U.S. health regulators have approved the first new type of flu drug in two decades

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Fig. 1 | Novel mode of action of Xofluza (baloxavir marboxil). Xofluza is hydrolyzed in vivo to the active form that selectively inhibits cap-dependent endonuclease, a key enzyme involved in the initiation of influenza virus mRNA synthesis. Thus, proteins needed for the construction of new influenza virions cannot be synthesized in the presence of the drug.

U.S. health regulators have approved the first new type of flu drug in two decades.

Wednesday’s approval of Xofluza for people age 12 and older comes ahead of the brunt of this winter’s flu season.

Xofluza is a pill that can reduce severity and shorten duration of flu symptoms after one just dose.

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Baloxavir marboxil (trade name Xofluza) is a medication being developed by Shionogi Co., a Japanese pharmaceutical company, for treatment of influenza A and influenza B.

The drug was in late-stage trials in Japan and the United States as of early 2018, with collaboration from Roche AG.

The medication is given as a single dose and may reduce the duration of flu symptoms by about a day.

Baloxavir marboxil.svg

Shionogi’s infectious disease portfolio of antibac­terials and antivirals is emblematic of that success.

In antibacterials, the company has demonstrated notable progress in particular in the rapid discovery of unique chemical structures for antibiotics against carbapenem-resistant Gram-negative bacterial strains. Several of these dangerous bugs feature on both the World Health Organization and the US Centers for Disease Control and Prevention global priority lists as critical threats, and the development of drugs to combat these pathogens is among the most serious challenges in modern medicine.

Most recently, Shionogi announced a pact with CARB-X, the public–private partnership devoted to antibacterial R&D. CARB-X and Shionogi will develop an antibiotic to treat infections caused by carbape­nem-resistant Enterobacteriaceae (CRE); Shionogi received an initial award of up to $4.7 million and is eligible for $2.9 million more in potential milestone payments. In the US, up to half of all bloodstream infections caused by CRE result in death.

Leader in antibacterials

Antibiotic discovery has long been key to Shionogi’s success, and antibiotics have featured heavily in the company’s portfolio over the years. The company has launched more than a dozen antibacterials, includ­ing five drugs discovered by Shionogi. These include two oxacephem-class antibiotics that were launched in the 1980s. Even today, these drugs remain on the market without generic competition thanks to a difficult chemical synthesis mastered by Shionogi and the drugs’ continued utility in the treatment of certain Gram-negative bacterial infections.

Shionogi’s latest antibiotic advance is cefiderocol, a novel siderophore cephalosporin antibacterial with a unique mechanism of cell entry. The drug candidate has been granted the coveted Qualified Infectious Disease Product status by the US Food and Drug Administration (FDA) and has shown potent efficacy against a variety of priority Gram-negative patho­gens, including carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeru­ginosa, and CRE. Global phase 3 studies are ongoing in subjects with hospital- and ventilator-acquired pneumonia and with carbapenem-resistant Gram-negative bacterial infections. Ultimately, successful development of cefiderocol would bring success to Shionogi where several large pharmaceutical compa­nies have failed with siderophore compounds over the past decades. Yamano said that Shionogi plans to file its regulatory submission with the US FDA in 2018 and then move on to global submission, including in European countries and Japan. Though the company believes it can market the drug itself in some markets, Shionogi will look for a partner for rest-of-world territories, he said.

Success in antivirals

Shionogi’s antiviral platform has also enjoyed con­siderable success. The best-in-class HIV integrase inhibitor Tivicay (dolutegravir) was launched in 2013 and reached nearly $2 billion in global sales in 2017 (dolutegravir is also part of the triple-combination HIV therapy Triumeq). Tivicay provides a higher genetic barrier to resistance than competing molecules; a follow-on compound, cabotegravir, is in phase 3 trials for use as a long-acting injectable formulation. Tivicay’s high affinity for the HIV inte­grase arises from its unique binding mode, in which chelation via two metal ions is responsible for the binding of the compound.

That same two-metal binding concept was applied to the rational design of Shionogi’s promising new flu drug Xofluza (baloxavir marboxil), which was approved in Japan in February 2018 and continues to be developed elsewhere (Fig. 1). The drug is a cap-dependent endonuclease inhibitor that pre­vents mRNA synthesis, the first and necessary step in the life cycle of a flu virus once it enters a cell. This first-in-class drug prevents the expression of proteins required for flu to proliferate, and sharply reduces viral load. Xofluza has shown potent activity against both type A and type B seasonal influenza, as well as avian flu virus strains including H5N1 and H7N9.

“We believe we can apply our accumulated know-how in designing two-metal chelating compounds in the future for the discovery of new antiviral com­pounds,” said Yamano.

Contact:

Yoshinori Yamano,
CSO for Infectious Diseases
Pharmaceutical Research Division
Shionogi Pharmaceutical Research Center
Osaka, Japan
Tel: +81 6 6331 6293
Email: yoshinori.yamano@shionogi.co.jp
Website: www.shionogi.co.jp/en

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It was developed by the Roche Group and Shionogi & Co.

It works about as well as Tamiflu, Roche’s older flu treatment, which is also available in cheaper generic versions. Tamiflu is taken twice daily for five days.

Health officials have said an estimated 80,000 Americans died of flu and its complications last winter, the disease’s highest death toll in at least four decades. The severe flu season increased demand for Tamiflu and led to spot shortages.

Roche’s Genentech unit plans to launch Xofluza within a few weeks. It will cost $150 without insurance.

The need for only one dose is an advantage since patients don’t always take all their medicine, said Dr. Mark Eisner, Genentech’s head of development of infectious disease medicines.

Each year, flu typically kills about 12,000 to 56,000 Americans and up to 650,000 people worldwide.

“With thousands of people getting the flu every year, and many people becoming seriously ill, having safe and effective treatment alternatives is critical.

This novel drug provides an important, additional treatment option,” said U.S. Food and Drug Administration Commissioner Dr. Scott Gottlieb said in a statement.

In company testing on 1,064 people, Xofluza ended coughing, sneezing and fever, or greatly reduced symptoms, in just over two days on average.

A comparison group given Tamiflu fared similarly.

While Xofluza didn’t work faster than Tamiflu, it did reduce the level of the virus in patients’ nose and throat quicker.

Further testing is planned to determine whether Xofluza is better than Tamiflu for preventing spread of the flu to others and for treating patients at high risk for hospitalization and pneumonia, such as people with diabetes or lung disease, pregnant women, young children and the elderly.

“We think this can be important for patients, important for public health,” Eisner said.

Xofluza side effects were mild—diarrhea, nausea, headaches and bronchitis—and occurred at about the same rate as study participants given Tamiflu or placebo pills.

Flu treatments generally work best if taken within 48 hours of symptoms beginning, and health officials encourage vaccination, preferably by the end of October.

Relenza inhalers and Rapivab injections also are available for treating flu.

Xofluza, also known as baloxavir marboxil, worked against both Type A and B flu strains.

The pill was initially developed by Shionogi of Japan, where it’s already approved.

Roche has the rights to market Xofluza everywhere but Japan and Taiwan.

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