A few days after an 11-year-old boy in Japan was diagnosed with the H3N2 strain of the flu and prescribed Xofluza, he stopped responding to the drug. Then his sister came down with the virus. Genetic testing showed she had a mutated form of H3N2 that would make her resistant to Xofluza, which was developed by Roche’s Genentech and is marketed in Japan by Shionogi.
The two children were part of a study led by the University of Wisconsin-Madison with a bottom-line conclusion that could be at odds with Roche’s plans for developing Xofluza: The drug may not be the best choice for children, the researchers suggested in the journal Nature Microbiology.
The FDA speedily approved Xofluza, the highly touted follow-up to Roche’s blockbuster flu med Tamiflu, last fall for use in patients over 12, and the company has pursued an aggressive marketing and development plan for the product. It continues to study the drug in children under 12 and has already nabbed that designation in other countries, including Japan.
But data from Roche’s trials showing the emergence of drug-resistance mutations concerned Yoshihiro Kawaoka, a professor of pathobiological sciences at the University of Wisconsin. So he designed a study to collect flu samples from patients with either H1N1 or H3N2 and to sequence their genes before and/or after treatment with Xofluza.
They tested 40 H3N2 samples from adults and 101 from children before treatment and found two with the resistance mutation—both from children. They also tested four adults and 12 children both before and after treatment. Four of the youngsters had developed resistance mutations. No such mutations were found in the adults.
In the H1N1 group, there were no mutations seen before treatment, but 23% of patients whose samples were tested after treatment did develop mutations—most of them children.
Barry Clinch, Ph.D., group clinical science director and global head of influenza and infectious disease product development at Genentech, told FiercePharma the company would collaborate with Shionogi and the Japanese National Institute of Infectious Diseases to better understand the new findings.
Clinch said the emergence of viral variants such as the one described in the study “is a normal property of antivirals.” Similar mutations have emerged with older antivirals like Roche’s Tamiflu, he added, and they have also been seen more commonly in children than adults.
“Genentech, Roche and Shionogi are actively seeking to understand the occurrence and potential clinical impact of viral variants with reduced susceptibility to Xofluza-resistant strains in a global phase 3 transmission study and analysis of surveillance data,” Clinch said.
The University of Wisconsin researchers wanted to understand more about how the resistance mutation works, so they took the mutant H1N1 and H3N2 viruses and tested them in hamsters and ferrets. They discovered that the mutation continues to replicate and that ferrets with the mutated form of the flu could transmit it to healthy animals.
Genentech, Roche and Shionogi have also studied the transmission of resistant variants in ferrets, in collaboration with academic partners in Australia and the U.K., Clinch said. The company has submitted the data for publication and will present them at medical meetings next year.
Meanwhile, Roche has an ongoing phase 3 development program for Xofluza that includes children. Positive results from one global study in children under age 12 will be submitted to the FDA in early 2020, Clinch said. An ongoing study is designed to assess Xofluza’s ability to lessen the transmission of the flu to healthy people. There are also ongoing studies that include infants as well as hospitalized patients, he added.
Xofluza has scored some recent wins in follow-up studies. In September, Roche released results from a study showing that the drug lowered the chance of healthy people contracting the flu from infected family members. About 2% of study participants who received Xofluza got the flu after exposure, as compared with 14% of people given a placebo.
Clinch told FiercePharma at the time that the data could be critical for establishing Xofluza as a preventive treatment—and for persuading payers to cover it. The company won FDA approval last month to extend the marketing of the product to people facing a high risk of complications from the flu. Roche is also hoping to expand the product’s label to include patients younger than one year old.
Fact is, Roche needs Xofluza to be a success. In the first half of this year, sales of Tamiflu plummeted 29% to $277 million as generics took over the market. But Xofluza brought in just $6 million in sales.
The University of Wisconsin researchers were careful to say that the mutation they tracked would be unlikely to lead to widespread resistance to Xofluza. But Kawaoka worries that drug-resistance mutations could become problematic in hospitals and nursing homes, as well as in large families with people living in close proximity. His recommendation for prescribing Xofluza? “It’s a good drug for adults,” he said in a statement.