Nature Comms: Efficacy of Baloxavir Marboxil Against Bovine H5N1 Virus in Mice

 

Credit NIAID

#18,764

Influenza antivirals have been around for nearly 50 years (Amantadine was approved in the US in 1976), while oseltamivir (aka Tamiflu) was approved in 1999, and Baloxavir in 2018.  

By early 2006, influenza resistance to Amantadine and Rimantadine had grown so great that the CDC no longer recommended their use. 

Although more expensive, our fallback - an NAI inhibitor called oseltamivir - was thought unlikely to be felled by similar resistance. While occasional instances of oseltamivir resistance had been recorded, in nearly every case, it developed after a person was placed on the drug (`spontaneous mutations’).

But what was thought to be unlikely in 2006, happened with unsettling rapidity less than 2 years later. 

By the end of 2008 nearly all of the seasonal H1N1 samples tested in the United States were resistant to oseltamivir and the CDC was forced to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).

An influenza antiviral crisis seemed unavoidable, but in an unlikely Deus Ex Machina moment a new swine-origin H1N1 virus - one that happened to retain its sensitivity to Tamiflu - swooped in as a pandemic strain in the spring of 2009, supplanting the older resistant H1N1 virus. 

Since then we've monitored seasonal flu for any signs of increasing resistance (see EID Journal: Multicountry Spread of Influenza A(H1N1)pdm09 Viruses with Reduced Oseltamivir Inhibition, May 2023–February 2024).

In 2018, a new generation antiviral (Baloxavir) was introduced, but it is far more expensive, and less readily available in the United States, than oseltamivir.  And as we've seen (see here, here, here, and here), Baloxavir has been flirting with sporadic seasonal flu resistance issues of its own.

 Last November the CDC reported finding: 

. . .  a different change in the polymerase acidic (PA) protein of a virus collected from a recently confirmed human case of H5N1 bird flu in California (A/California/150/2024). This change, PA-I38M, is associated with decreased susceptibility to the influenza antiviral medication baloxavir marboxil and has been sporadically detected in a small number of avian influenza viruses.

So far, H5N1 continues to be broadly susceptible to oseltamivir, although we've see a few cracks emerge (see Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms).

 In a recent EID Journal: Antiviral Susceptibility of Influenza A(H5N1) Clade 2.3.2.1c and 2.3.4.4b Viruses from Humans, 2023–2024, the authors advised:

". . . higher antiviral dosing and combination antiviral treatment (e.g., oseltamivir and baloxavir) should be considered, in particular for patients with H5N1 who are hospitalized or immunocompromised." 

While some recent (animal) studies have suggested that Baloxavir might be a better treatment option (see Baloxavir improves disease outcomes in mice after intranasal or ocular infection with Influenza A virus H5N1-contaminated cow’s milk), there is a dearth of clinical data on its use against H5N1 in humans.

While neither drug can claim to `cure' severe influenza, both - if given early enough - can help moderate the symptoms and shorten the duration of illness.  And in a severe flu infection, that could be lifesaving. 

Assuming, of course, the influenza virus hasn't acquired resistance.

All of which brings us to a new study, which once again finds that Baloxavir may be superior to oseltamivir (at least, against bovine H5N1 in infected mice) - if it is administered early enough - but warns that delayed administration could significantly increase the chances of developing resistance. 

I've only posted the abstract, and some excerpts, so follow the link to read it in its entirety.  

When you return I'll have a postscript about the frequently ignored elephant in the room.

Efficacy of baloxavir marboxil against bovine H5N1 virus in mice

Maki Kiso, Ryuta Uraki, Seiya Yamayoshi & Yoshihiro Kawaoka
Nature Communications volume 16, Article number: 5356 (2025)
Published: 20 June 2025

Abstract

Since the first detection of highly pathogenic avian influenza (HPAI) H5N1 (clade 2.3.4.4b) in U.S. dairy cattle in early 2024, the virus has spread rapidly, posing a major public health concern as the number of human cases continues to rise.

Although human-to-human transmission has not been confirmed, experimental data suggest that the bovine H5N1 virus can transmit via respiratory droplets in ferrets, highlighting its pandemic potential. With no vaccines currently available, antiviral drugs remain the only treatment option.

Here, we investigate the efficacy of the polymerase inhibitor baloxavir marboxil (BXM) against this virus in mice. We find that early treatment post-infection is effective, but delayed treatment significantly reduces BXM efficacy and increases the risk of BXM resistance, underscoring the importance of timely BXM administration for effective treatment.

        (SNIP)

With no vaccines against bovine H5N1 virus ready to be deployed, antiviral drugs have been crucial to treat infected individuals. We previously examined the susceptibility of bovine H5N1 viruses to several of the antiviral drugs that are available to treat humans infected with influenza virus in mice5.

Although oral oseltamivir phosphate or intranasal zanamivir, both of which are neuraminidase (NA) inhibitors, reduced viral replication in the nasal turbinate, lungs, and brain compared to control treatment, they were unable to prevent the lethality of bovine H5N1 virus infection in mice.

In contrast, the polymerase inhibitors favipiravir and baloxavir marboxil (BXM) were effective against bovine H5N1 virus when treatment was initiated 1 h post-infection. BXM is more widely used globally than favipiravir as a treatment for influenza.

In this study, we conduct a detailed assessment of the therapeutic efficacy of BXM in mice infected with the bovine H5N1 virus. We show that early BXM treatment significantly suppresses viral replication and improves survival in mice, whereas delayed administration reduces efficacy and facilitates the emergence of resistance, highlighting the importance of timely antiviral intervention.

        (Continue . . . )
 

The aforementioned elephant is a combination of limited supplies and logistics.   

While exact numbers have not been disclosed, our National Strategic Stockpile reportedly has somewhere around 50-60 million courses of oseltamivir on hand; sufficient to treat less than 20% of the nation during a severe flu pandemic (assuming a single, standard dose).

Stockpiles of Baloxavir are similarly unknown, but according to a media report last year (see The U.S. strategic drug stockpile is inadequate for a bird flu outbreak) likely numbers only in the hundreds of thousands of doses.  

Even during moderately severe seasonal flu epidemics we've seen spot antiviral shortages and difficulties in rapidly dispensing oseltamivir (see 2022's CDC HAN #0482: Prioritizing Antiviral Treatment of Influenza in the Setting of Reduced Availability of Oseltamivir).

That Baloxavir may be superior to oseltamivir in the treatment of H5N1 is obviously important information, but its value is greatly diminished if we don't have an adequate stockpile, or the ability to dispense it rapidly during a pandemic. 

While I'm hopeful our antiviral armamentarium can help `take the edge off' the opening months of the next pandemic, it is by no means assured. Meanwhile, vaccines may be a year or more away (see SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1).

Our first line of defense will - once again - likely rely heavily on NPIs (non-pharmaceutical interventions), like face masks, hand washing, ventilation, staying home while sick, and avoiding crowds.

Which is why I'm recommending that people consider now (see A Personal Pre-Pandemic Plan) what they will do if another pandemic flu should embark on a new world tour.