Roche's Xofluza may give rise to resistant strains, raising fears of a 'worst case scenario'
In 2018, Shionogi rolled out Xofluza in Japan as a one-dose kill for influenza, with Roche following suit in the US. Soon, though, Japanese regulators noticed the drug was leading to resistant flu strains, and now a new study in Nature confirms the drug leads to specific mutations that may hamper its promise to neutralize the virus in a single dose.
“In a worst case scenario, these mutations could render the drug entirely useless,” Andrew Pekosz, a molecular biologist at Johns Hopkins who was not involved in the study, told Endpoints News. “They haven’t yet, and it’s not clear why that’s been the case.”
Notably, Pekosz said, the mutant viruses have not spread extensively in humans. Rather, researchers at the University of Wisconsin and the University of Tokyo took strains from patients in Japan who had received Xofluza and found some contained mutations to a structure the virus uses to replicate itself, called the polymerase complex.
Xofluza, or baloxavir acid, targets this complex to kill the virus. When researchers tested the mutant strains in animal and cell lines, they found it was resistant to the drug and capable of spreading. Of 77 sampled children, 18 (23%) had mutant strains.
“This is not the first study, maybe one of the most extensive ones, that show a single mutation can cause resistance,” Pekosz said. “And those resistant viruses still seem to have the ability to replicate and spread just like the wild virus.”
Roche billed Xofluza as the first flu treatment approved in 20 years and touted the compliance advantages over its predecessor Tamiflu; One dose on one day as opposed to 10 doses over 5 days. But resistance has been a continual problem with such drugs. Most notably, the once-common flu drug amantadine is no longer prescribed as virtually all strains have become resistant.
As Xofluza neared approval, researchers warned it may cause resistance. A New England Journal of Medicine editorial published a month before the drug’s US approval found treatment led to “the emergence of viral escape mutants with reduced susceptibility.”
“The issue for public health is whether these influenza viruses with reduced susceptibility to baloxavir are transmissible,” wrote Timothy M. Uyeki.
That question remains inconclusive, although the authors of the Nature study noted that one child who had not received Xofluza nevertheless tested positive for a resistant strain, “suggesting the possibility of person-to-person transmission of the variant.”
For Pekosz, the questions underscore the need for flu drug cocktails that attack the virus from multiple angles, like how doctors treat the HIV; If a virus needs two precise mutations to survive and evolve, it’s much more less likely to.
“We’re making it too easy for the virus to escape,” he said.