Virus World

The U.S. Food and Drug Administration (FDA) expanded the approved indication for Xofluza (baloxavir marboxil) to include post-exposure prevention of influenza (flu) for patients 12 years of age and older after contact with a person who has the flu, according to press releases Xofluza, previously available only in tablet form, is also now available as granules for mixing in water. Xofluza was originally approved in 2018 for treating uncomplicated flu in patients 12 years of age and older who have been symptomatic for no more than 48 hours. “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,” said Debra Birnkrant, MD, Director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Americans will have to be more vigilant than ever as these viruses spread concurrently.”

In addition, Roche, the developer of the product, said it is determining a path forward with the FDA for a potential indication for Xofluza as a treatment for acute uncomplicated influenza in otherwise healthy children from one to 12 years of age and for the prevention of influenza in the same age group who have been exposed to influenza. Xofluza is currently not approved for use in this population, Roche said. Xofluza’s safety and efficacy for post-flu exposure prevention is supported by one randomized, double-blind, controlled trial in which 607 subjects, 12 years of age and older who were exposed to a person with influenza in their household, received either a single dose of Xofluza or a single dose of a placebo. Of these 607 subjects, 303 received Xofluza and 304 received the placebo. The trial’s primary endpoint was the proportion of subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom from day one to day 10. Of those who received Xofluza, 1 percent of subjects met these criteria, compared to 13 percent of subjects who received a placebo for the clinical trial.

FDA Press Release (Nov, 23, 2020):

https://www.fda.gov/news-events/press-announcements/fda-expands-approval-influenza-treatment-post-exposure-prevention

On January 31, 2019, an 11-year old boy in Japan went to a medical clinic with a fever. The providers there diagnosed him with influenza, a strain called H3N2, and sent him home with a new medication called baloxavir. For a few days, he felt better, but on February 5, despite taking the medication, his fever returned. Two days later, his 3-year-old sister also came down with a fever. She, too, was diagnosed with H3N2 influenza on February 8.

An analysis of flu samples collected from her and her brother show she was sickened by a strain of H3N2 harboring a new kind of mutation—one that Yoshihiro Kawaoka, University of Wisconsin-Madison professor of pathobiological sciences, says is resistant to baloxavir, is just as capable of making people sick as the non-mutated version, and is capable of passing from person to person. He and colleagues describe this in a study published today in Nature Microbiology that examined the effects of baloxavir treatment on influenza virus samples collected from patients before and after treatment. "We sequenced the entire viral genome of the 11-year-old boy with drug sensitive influenza virus (before treatment) and the sample from the girl that is drug resistant," says Kawaoka. "Out of 13,133 nucleotides, there was only one nucleotide difference between the two." 

In other words, what distinguished the virus collected from the brother before treatment and the virus collected from the sister later was a single mutation, a single change in just one letter among the more than 13,000 found in the genetic code of the virus. "It tells you the virus acquired resistance during treatment and transmitted from brother to sister," Kawaoka explains. Baloxavir is part of a new class of antiviral drugs that targets the machinery flu viruses use to copy their genetic material inside their human or animal hosts. It was first licensed in Japan, the United States, and in Hong Kong in 2018 and 2019. In fact, baloxavir represented 40 percent of the market share of influenza drugs in Japan during the 2018-2019 flu season. It will soon be licensed in 20 more countries, Kawaoka says. However, as he and his co-authors note in the paper, clinical trial data on the drug revealed that some patients infected with either H3N2 or H1N1 influenza who took baloxavir developed a mutation at position 38 of the polymerase acidic protein, part of the virus's machinery that is targeted by the drug. A previous study by another group showed that the particular mutation had not been described among 17,000 H3N2 virus samples catalogued prior to December 2018. "The new drug is safe, it went through phase three and was approved safety-wise, but even during clinical trials, the emergence of drug resistance was identified," Kawaoka explains. In fact, a previous study in pediatric patients showed the mutation appeared in the samples collected from nearly 1 in 4 of the 77 children enrolled who were also treated with baloxavir.

"Baloxavir-resistant viruses emerge with a relatively high rate in kids" says Kawaoka, also a professor of virology at the University of Tokyo.....For H1N1 influenza, the researchers tested 74 samples from patients before treatment (10 adults and 64 children), and 22 samples from patients both before and after treatment (7 adults and 15 children). There were no instances of mutation in any of the samples before treatment, but there were mutations in one adult and four children after, or in about 23 percent of patients. For H3N2, the team tested 141 patient samples before treatment (40 adults and 101 children), and two of those from children possessed the mutation. They also studied 16 patient samples before and after treatment (4 adults and 12 children), in which they found no mutations in adult samples but four of the child samples had the mutation.

Published in  Nature Microbiology (November 25, 2019):

https://doi.org/10.1038/s41564-019-0609-0