Antiviral compound (H84T is a protein,) offers hope against deadly flu

What keeps most infectious disease researchers up at night aren't infamous viruses like Ebola. Instead, influenza, commonly known as the flu, continues to be a clear and present danger to humanity.

"Influenza is a huge problem, as the virus sickens or kills millions of people each year," says David Markovitz, M.D., professor of internal medicine in the division of infectious diseases at Michigan Medicine. "A new pandemic along the lines of the 1918 Spanish flu has the potential to kill millions here and abroad."

To that end, he and an extensive team of collaborators have worked for years on broad-spectrum antiviral drugs developed from, of all things, banana plants.

In a new paper published in the Proceedings of the National Academy of Sciences, Markovitz, first author Evelyn Coves-Datson, a M.D., Ph.D. student, Akira Ono, Ph.D., professor of microbiology and immunology and their team have shown that an engineered compound based on a banana lectin, a protein called H84T, has real potential for clinical use against influenza.

In their experiments, more than 80% of mice exposed to a form of influenza that is typically fatal were able to survive the disease after receiving an injection of the protein, even up to 72 hours after exposure.

The team also provides early evidence that the compound is safe. A downside of naturally occurring banana lectin—which can cause inflammation by inappropriately activating the immune system—wasn't present in mice given H84T. Furthermore, because H84T is a protein, there was concern that the body would recognize it as foreign and develop antibodies against it, thereby neutralizing it or causing harm. The team found that while mice did develop antibodies against H84T, they didn't appear to be adversely affected by them.

The compound works because it targets a sugar called high mannose, which is present on the outside of certain viruses but not on most healthy cells. "We were able to show that H84T blocks the ability of the influenza virus to fuse with structures termed endosomes in the human cell, a key step in infection," he explains. Doing so disabled their ability to replicate and wreak havoc.

Amazingly, this mechanism of action, binding of high mannose sugars on the surface of viruses, means that H84T is effective not only against influenza, but also against Ebola, HIV, measles, MERS, a new deadly viral illness that was first reported in Saudi Arabia in 2012, SARS and all other coronaviruses tested.

Even more promising is that the compound works where Tamiflu (oseltamivir), the current standard therapy for severe flu, has failed. "We've also shown that there may be a synergistic effect between H84T and Tamiflu," says Markovitz.

His team hopes to do more research with the compound in humans in the hopes of getting it to market. "We envision the government potentially stockpiling it in the event of a pandemic." However, he says, "there are many difficulties to commercialization. Pharmaceutical economics do not seem to favor the development of antivirals or antibacterials for one-time usage, which is a huge problem."

https://www.pnas.org/content/early/2020/01/09/1915152117#sec-11

FDA Approval of Xofluza (baloxavir marboxil) for High Risk of Developing Influenza-Related Complications

 Genentech, a member of the Roche Group,  announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Xofluza™ (baloxavir marboxil) for the treatment of acute, uncomplicated influenza, or flu, in people 12 years of age and older who have been symptomatic for no more than 48 hours and who are at high risk of developing flu-related complications. Xofluza is a first-in-class, one-dose oral medicine with a novel proposed mechanism of action that inhibits polymerase acidic endonuclease, an enzyme essential for viral replication.

"With the flu season rapidly approaching, we can now offer Xofluza as the first and only FDA-approved treatment option indicated specifically for those at high risk of flu complications," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “People with chronic conditions such as asthma, heart disease and diabetes are at higher risk of developing serious complications from the flu, so it is critical that these patients speak with their healthcare providers about possible treatment at the first signs and symptoms of the disease.”

The flu has the potential to cause a variety of complications, ranging from sinus or ear infections to more serious complications such as pneumonia. This expanded indication for Xofluza was approved based on results from the Phase III CAPSTONE-2 study of a single dose of 40 mg or 80 mg of Xofluza compared to oseltamivir (75 mg twice daily for five days), or placebo in people 12 years of age or older who met CDC criteria for being at high risk of complications from the flu. Xofluza significantly reduced the time to improvement of flu symptoms compared to placebo, including in people infected with the flu type B virus. Adverse events reported in at least 1% of adult and adolescent subjects treated with Xofluza included diarrhea (3%), bronchitis (3%), nausea (2%), sinusitis (2%) and headache (1%).

Xofluza is currently approved in several countries for the treatment of flu types A and B. In October 2018, Xofluza was first approved by the FDA for the treatment of acute, uncomplicated flu in otherwise healthy people 12 years of age and older who have been symptomatic for no more than 48 hours, representing the first new antiviral to treat the flu in the U.S. in 20 years.

About CAPSTONE-2

CAPSTONE-2 is a Phase III, multicenter, randomized, double-blind study that evaluated a single dose of Xofluza compared with placebo and oseltamivir in people 12 years of age or older who are at a high risk of complications from the flu. The Centers for Disease Control and Prevention (CDC) defines people at high risk of serious flu complications as those who have conditions such as asthma, chronic lung disease, diabetes, heart disease, morbid obesity or adults 65 years of age or older. The study was conducted globally by Shionogi & Co., Ltd.

Participants enrolled in the study were randomly assigned to receive a single dose of 40 mg or 80 mg of Xofluza, placebo or 75 mg of oseltamivir twice a day for five days. The primary objective of the study was to evaluate the efficacy of a single dose of Xofluza compared with placebo by measuring the time to improvement of flu symptoms. Key findings from the study found that:

Xofluza significantly reduced the time to improvement of flu symptoms versus placebo in people at high risk of complications from the flu (median time 73 hours versus 102 hours; p<0.001). Similar efficacy results were seen between Xofluza and oseltamivir in relation to duration of symptoms (median time 73 hours versus 81hours). In subjects infected with type B virus, the median time to improvement of flu symptoms was shorter in the Xofluza group compared to the placebo group (75 hours versus 101 hours respectively). Adverse events reported in at least 1% of adult and adolescent subjects treated with Xofluza included diarrhea (3%), bronchitis (3%), nausea (2%), sinusitis (2%) and headache (1%). Xofluza was well-tolerated and no new safety signals were identified.

About Xofluza ™ (baloxavir marboxil)

Xofluza is a first-in-class, one-dose oral medicine with a novel proposed mechanism of action that has demonstrated efficacy in a wide range of influenza viruses, including in vitro activity against oseltamivir-resistant strains and avian strains (H7N9, H5N1) in non-clinical studies. Unlike other currently available antiviral treatments, Xofluza is the first in a new class of antivirals designed to inhibit the cap-dependent endonuclease protein, which is essential for viral replication.

New One-Dose Flu Drug Shows Promise

An experimental single-dose flu drug shows promise as a new way to alleviate the misery of influenza, researchers say. 

The drug  called baloxavir (structre)  worked better than no treatment in one phase of a new study. The study also found it as effective as the current standard drug, oseltamivir (Tamiflu), at controlling symptoms such as coughing, sore throat, headache, fever, muscle and joint pain, and fatigue.

Moreover, in light of concerns about flu-drug resistance, most patients treated with baloxavir responded as expected, the study authors said.

"There are few approved influenza antivirals, and current treatments have limitations," said study lead author Dr. Frederick Hayden, of the University of Virginia School of Medicine.

"For example, currently circulating influenza viruses are resistant to the older class of antivirals," he said. These include the drugs amantadine (brand name Symmetrel) and rimantadine (Flumadine).

Resistance is also growing to the class of drugs including widely used Tamiflu and Relenza (zanamivir), Hayden said. "Consequently, there are medical needs for new anti-influenza agents with different mechanisms of action and greater potency," he added.

Hayden, professor emeritus of clinical virology and medicine, said the new study indicates that baloxavir resolves flu symptoms as quickly, effectively and safely as current options, without yet raising concerns about resistance. It also demonstrated "significantly greater antiviral effects," he added.

Also, while Tamiflu must be taken twice a day for five days, baloxavir requires just one dose.

The investigation was funded by the drug company Shionogi, Inc., which developed and manufactures baloxavir.

Baloxavir is approved for use in Japan. In the United States, it remains an "investigational drug," with the U.S. Food and Drug Administration expected to decide on approval by the end of this year.

The new study, which was published Sept. 6 in the New England Journal of Medicine, unfolded in two trials, both involving otherwise healthy flu patients at low risk for influenza complications.

One trial was conducted during the 2015-2016 flu season. About 400 patients, aged 20 to 64, received one of three doses of baloxavir (ranging from 10 to 40 milligrams) or a placebo. Flu symptoms eased notably faster among all three baloxavir groups, compared with placebo (untreated) patients, the findings showed.

The following flu season, nearly 1,100 patients, aged 12 to 64, were treated with baloxavir or Tamiflu. The drugs relieved symptoms in roughly the same time period, with similar side-effect risk.

However, about 10 percent of the baloxavir patients had a less than robust response to the drug. Hayden acknowledged that "the clinical and public health implications of reduced susceptibility to baloxavir are not fully understood."

Dr. Timothy Uyeki, author of an accompanying journal editorial, heads the influenza division at the U.S. Centers for Disease Control and Prevention's National Center for Immunization and Respiratory Diseases.

"There is a need for antiviral drugs with new mechanisms of action," he agreed.Uyeki highlighted the benefit of baloxavir's single-dose regimen. Besides its convenience, it "avoids concerns about compliance with a five-day treatment course of oseltamivir," he said.

But he also stressed the need for further testing.

It remains unclear what benefits might accrue from combining baloxavir with Tamiflu, Uyeki noted.

Also, he cautioned, the current research only included otherwise healthy people aged 12 to 64 who were not at high risk for flu complications. Whether baloxavir will benefit high-risk groups -- young children, the elderly, pregnant women and others with underlying chronic medical conditions -- remains unknown, Uyeki said.

"A lot more studies are needed of the clinical benefit of baloxavir treatment of influenza in high-risk outpatients," he added.

FDA Approves First Generic Version of Widely Used Influenza Drug Tamiflu

In continuation of my update on tamiflu oseltamivir phosphate

U.S. Food and Drug Administration approved the first generic version of Tamiflu (oseltamivir phosphate), a widely used medication for the treatment of the flu (influenza A and B) in patients two weeks of age and older who have had flu symptoms for no more than 48 hours; and prevention of the flu in patients one year of age and older. Tamiflu was approved in 1999.

The FDA is committed to improving patient access to safe and effective generic drugs. Generic drugs approved by the FDA have the same high-quality and strength as brand-name drugs. The generic manufacturing and packaging sites must pass the same quality standards as those of brand-name drugs.

The most common side effects reported by people using oseltamivir phosphate in clinical trials included nausea and vomiting.

Patients must use oseltamivir phosphate as directed by their health care provider. Oseltamivir phosphate does not take the place of receiving a flu vaccination. Talk to your health care provider about when you should receive an annual flu vaccination.

Oseltamivir phosphate does not treat or prevent illness caused by infections other than the influenza virus, and oseltamivir phosphate does not prevent bacterial infections that may happen with the flu. The FDA does not know if oseltamivir phosphate is effective in people who start treatment after two days of developing symptoms, or have weakened immune systems.

Patients and health care providers may find more information on oseltamivir phosphate in the drug label.

Novel compound found effective against avian influenza virus (H5N1)....

Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed.

Now  researchers from Japan,  lead by Yoshihiro Kawaoka,  have come up with a new neuraminidase inhibitor, R-125489, and its prodrug, CS-8958.  CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal influenza strains following a single intranasal dose.

As per the claim by the researchers, R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single dose of CS-8958 (1,500 µg/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of oseltamivir (50 mg/kg twice daily).

Researchers conclude that, CS-8958 is a promising candidate for a new neuraminidase inhibitor to prevent and treat influenza patients infected with H5N1 and other subtype viruses... 

Ref : Yoshihiro Kawaoka et. al., PLoS Pathogens Feb., 2010

Triple-combo Drug for Antiviral-resistant H1N1 ?

In laboratory testing, the triple combination of oseltamivir (Tamiflu), amantadine (Symmetrel) and ribavirin showed a significant capacity to stop flu-virus growth, says Mark Prichard....

More...http://www.sciencedaily.com/releases/2009/10/091027132426.htm

A best way to deal with flu pandemic......

We are aware most of the virus and baterii are getting resistance to most of the drugs. I have mentioned in my earlier blog how the virus change their structure (mutation) and become resistant to the drugs being used to treat. Scientists are scared, because many countries have started using Oseltamivir (Tamiflu) for global influenza pandemic. As per a report Tamiflu (oseltamivir) has been stockpiled by many countries anxious to be prepared should a flu pandemic strike, but the problem according to an international team of researchers, is that influenza viruses can become resistant to antiviral drugs, and the widespread use of a single drug is likely to increase the risk that a resistant strain will emerge.

The concern is that if such a strain were to spread widely, the effectiveness of antiviral drugs such as Tamiflu in treating infected patients, as well as their ability to slow the spread of a pandemic, would be greatly reduced. A research group lead by Joseph Wu (University of Hong Kong), claims that they have developed a mathematical model to arrive at a conclusion. The team found that treating just the first 1% of the population in a local epidemic with a secondary drug, rather than with oseltamivir, could substantially delay the development of resistance to oseltamivir and this reduction in resistance was predicted to benefit not only local populations, but also those in distant parts of the world where the pandemic would subsequently spread through air travel and more interesting out come of the research is "in the current emerging swine flu situation, the secondary drug could be Relenza (zanamivir), the only other approved drug to which the new H1N1 strain has been found to be susceptible". This strategy say the researchers could be as effective because it delays use of the primary stockpiled drug until a certain proportion of the local population (about 1.5% according to the model) has been infected with virus that remains susceptible to the primary drug - with drug-sensitive virus in the majority as people recover from infection and develop immunity, only a minority of further infections are likely to be resistant to the primary drug.

The researchers say technically, such a delay could be achieved by postponing the launch of any antiviral intervention, but because even a short delay would mean denying antiviral drugs to people who would benefit from them, the researchers instead propose the deployment of a small stockpile of a secondary antiviral during the early phase of the local epidemic. More.....