Nav: Home

Flu's response to new drug explored

June 26, 2018

The new influenza drug Xofluza, developed by the Japanese pharmaceutical company Shionogi, was approved for clinical use in Japan in February 2018. Scientists from EMBL Grenoble have now investigated the drug's mode of action in detail, and uncovered possible mechanisms by which viral resistance to it could emerge. Scientific Reports published the results of this collaboration between EMBL and Shionogi scientists 25 June.

Every year, 290,000 to 650,000 deaths and 3 to 5 million cases of severe illness worldwide are associated with flu, an infectious disease caused by influenza viruses A and B. Vaccines and anti-viral drugs are available for flu, but viral strains with resistance to these drugs are emerging. The need for an effective drug with a novel mechanism of action is high.

First flu drug with a novel mode of action since the 1990s

Xofluza (baloxavir marboxil) is the first entirely new anti-influenza drug approved for clinical use since the 1990s. The body metabolizes Xofluza into baloxavir acid, which inhibits a key viral enzyme known as influenza polymerase. With this enzyme inactivated, the virus is unable to replicate and an infection cannot proceed. Clinical trials on healthy patients by Shionogi have shown that one oral dose of Xofluza is effective in reducing viral production and relieving symptoms.

In the current paper, researchers at EMBL's site in Grenoble and Shionogi delved into the mode of action of the drug and possible mechanisms by which viral resistance to it could emerge. During two clinical trials, Shionogi scientists took nose/throat swabs of patients before and after treatment with Xofluza, and sequenced the viral RNA. They showed that in a minority of treated patients, a specific mutation occurs in the virus's polymerase enzyme. "This mutation makes the virus around 30 to 50 times less susceptible to the drug. However, this mutation also caused impairment of viral replication, and did not seem to have a negative effect on the treatment outcome so far," says Shinya Omoto, co-corresponding author of the paper and a member of the Shionogi team.

Small change, big effect

Stephen Cusack's group at EMBL Grenoble determined crystal structures of the drug bound to the typical polymerase of the virus as well as the mutant polymerase. The mutation only leads to a very small structural change: one amino acid is mutated into another, smaller by just a single methyl group. Cusack: "Still, this apparently minor change leads to reduced contact between the polymerase and the drug, weakening the drug's effect. However the virus pays a price for escaping the drug, since we found that the same mutation also lowers the activity of the polymerase, meaning that the mutant virus is less effective at replicating itself. It is therefore uncertain whether this Xofluza-resistant virus would ever spread."

The knowledge from this paper can be already be used to try to tweak and improve the drug further. But before making definite claims about the possibility of resistance developing, Xofluza will need to be used by many people around the world. "Only that way can we find out if resistance spreads and becomes a problem," Cusack explains. "Finding out could take several years, but at least we know what mutations to monitor. In the meantime, in our lab at EMBL Grenoble, we will keep working on influenza polymerase with the aim of supporting the development the next generation of influenza drugs."
-end-


European Molecular Biology Laboratory

Related Clinical Trials Articles:

COVID-19 clinical trials lack diversity
Despite disproportionately higher rates of COVID-19 infection, hospitalization and death among people of color, minority groups are significantly underrepresented in COVID-19 clinical trials.
Why we should trust registered clinical trials
In a time when we have to rely on clinical trials for COVID-19 drugs and vaccines, a new study brings good news about the credibility of registered clinical trials.
Inclusion of children in clinical trials of treatments for COVID-19
This Viewpoint discusses the exclusion of children from coronavirus disease 2019 (COVID-19) clinical trials and why that could harm treatment options for children.
Review evaluates how AI could boost the success of clinical trials
In a review publishing July 17, 2019 in the journal Trends in Pharmacological Sciences, researchers examined how artificial intelligence (AI) could affect drug development in the coming decade.
Kidney patients are neglected in clinical trials
The exclusion of patients with kidney diseases from clinical trials remains an unsolved problem that hinders optimal care of these patients.
Clinical trials beginning for possible preeclampsia treatment
For over 20 years, a team of researchers at Lund University has worked on developing a drug against preeclampsia -- a serious disorder which annually affects around 9 million pregnant women worldwide and is one of the main causes of death in both mothers and unborn babies.
Underenrollment in clinical trials: Patients not the problem
The authors of the study published this month in the Journal of Clinical Oncology investigated why many cancer clinical trials fail to enroll enough patients.
When designing clinical trials for huntington's disease, first ask the experts
Progress in understanding the genetic mutation responsible for Huntington's disease (HD) and at least some molecular underpinnings of the disease has resulted in a new era of clinical testing of potential treatments.
New ALS therapy in clinical trials
New research led by Washington University School of Medicine in St.
Telemedicine helps improve participation in clinical trials
Videos and creative uses of other visuals provide a novel way to obtain informed consent during clinical trials to improve participants' understanding and retention of trial information, according to a study by Nemours Children's Health System presented at the American Thoracic Society (ATS) Annual Conference.
More Clinical Trials News and Clinical Trials Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Warped Reality
False information on the internet makes it harder and harder to know what's true, and the consequences have been devastating. This hour, TED speakers explore ideas around technology and deception. Guests include law professor Danielle Citron, journalist Andrew Marantz, and computer scientist Joy Buolamwini.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

How to Win Friends and Influence Baboons
Baboon troops. We all know they're hierarchical. There's the big brutish alpha male who rules with a hairy iron fist, and then there's everybody else. Which is what Meg Crofoot thought too, before she used GPS collars to track the movements of a troop of baboons for a whole month. What she and her team learned from this data gave them a whole new understanding of baboon troop dynamics, and, moment to moment, who really has the power.  This episode was reported and produced by Annie McEwen. Support Radiolab by becoming a member today at Radiolab.org/donate.