Friday, October 26, 2018

FDA Approval Of Xofluza : A New Class Of Influenza Antiviral


Credit NIAID










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Widely used antiviral medications - much like antibiotics - have a limited useful life, as viruses are often able to develop resistance over time. Our oldest class of flu antivirals - M2 ion channel blockers (e.g. Amantadine, Rimantadine) - were developed in the 1950s.

But by late 2005 Amantadine began to lose its effectiveness against the H3N2 seasonal flu virus and some strains of the H5N1 bird flu. In January of 2006 the CDC issued a warning  to doctors not to rely on Amantadine or Rimantadine to treat influenza.
Tamiflu (Oseltamivir) which had been approved in 1999, while far more expensive, became the new treatment standard.  
Within a couple of years seasonal H1N1 began to show growing resistance to Tamiflu as well (although H3N2 remained sensitive).  This resistance was due to a mutation, known as H274Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 274.

By the winter of 2008 - in the space of just about a year – seasonal H1N1 had gone from almost 100% sensitive to the drug to nearly 100% resistant (see CIDRAP On the CDC Change Of Advice On Tamiflu).
It seemed as if antiviral crisis was unavoidable, when in a Deus Ex Machina moment - a new swine-origin H1N1 virus - one that happened to be sensitive to Tamiflu, emerged as a pandemic strain the following spring.
In a matter of months pdmH1N1 supplanted the old H1N1 virus.
Since then, resistance to Tamiflu has been low (roughly 2%), but a few small cracks in its veneer have appeared.
Russia's Late Season Flu Surge Continues - More Resistant H1N1pdm In Moscow
Eurosurveilance: A(H1N1)pdm09 Virus With Cross-Resistance To Oseltamivir & Peramivir - Japan, March 2016

Eurosurveillance: Community Cluster Of Antiviral Resistant pH1N1 in Japan 


NEJM: Oseltamivir Resistant H1N1 in Australia
We've seen antiviral resistance develop quickly, and spread globally in a matter of months. Since it can take many years to develop and get approval for a replacement drug - the approval of a new class of antiviral this week is welcomed news. 
Xofluza is a single dose flu treatment - which inhibits the replication of the virus - and must be given within 48 hours of onset of symptoms in order to be effective. It is approved for acute, uncomplicated flu in those 12 years of age or older.  
Restrictions which means that - for now, at least - Tamiflu will remain an important part of the influenza antiviral armamentarium.

FDA approves new drug to treat influenza

For Immediate Release

October 24, 2018

Today, the U.S. Food and Drug Administration approved Xofluza (baloxavir marboxil) for the treatment of acute uncomplicated influenza (flu) in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

“This is the first new antiviral flu treatment with a novel mechanism of action approved by the FDA in nearly 20 years. 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 FDA Commissioner Scott Gottlieb, M.D. “While there are several FDA-approved antiviral drugs to treat flu, they’re not a substitute for yearly vaccination. Flu season is already well underway, and the U.S. Centers for Disease Control and Prevention recommends getting vaccinated by the end of October, as seasonal flu vaccine is one of the most effective and safest ways to protect yourself, your family and your community from the flu and serious flu-related complications, which can result in hospitalizations. Yearly vaccination is the primary means of preventing and controlling flu outbreaks.”

Flu is a contagious respiratory illness caused by influenza viruses. When patients with the flu are treated within 48 hours of becoming sick, antiviral drugs can reduce symptoms and duration of the illness.

“When treatment is started within 48 hours of becoming sick with flu symptoms, antiviral drugs can lessen symptoms and shorten the time patients feel sick,” said Debra Birnkrant, M.D., director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Having more treatment options that work in different ways to attack the virus is important because flu viruses can become resistant to antiviral drugs.”

The safety and efficacy of Xofluza, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 patients where participants were assigned to receive either Xofluza, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms. In both trials, patients treated with Xofluza had a shorter time to alleviation of symptoms compared with patients who took the placebo. In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received Xofluza and those who received the other flu treatment.

The most common adverse reactions in patients taking Xofluza included diarrhea and bronchitis.

Xofluza was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted approval of Xofluza to Shionogi & Co., Ltd.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency is also responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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