Baloxavir marboxil, sold under the brand name Xofluza, is an antiviral medication for treatment of influenza A and influenza B. It was approved for medical use both in Japan and in the United States in 2018, and is taken as a single dose by mouth. It may reduce the duration of flu symptoms by about a day, but is prone to selection of resistant mutants that render it ineffectual.
Baloxavir marboxil was developed as a prodrug strategy, with its metabolism releasing the active agent, baloxavir acid (BXA). Baloxavir acid then functions as enzyme inhibitor, targeting the influenza virus' cap-dependent endonuclease activity, used in "cap snatching" by the virus' polymerase complex, a process essential to its life-cycle.
The most common side effects of baloxavir marboxil include diarrhea, bronchitis, nausea, sinusitis, and headache.
The US Food and Drug Administration (FDA) considers baloxavir marboxil to be a first-in-class medication.
Medical uses
Baloxavir marboxil is an influenza medication, an antiviral, for individuals who are twelve years of age or older, that have presented symptoms of this infection for no more than 48 hours. The efficacy of baloxavir marboxil administered after 48 hours has not been tested.
In October 2019, the FDA approved an updated indication for the treatment of acute, uncomplicated influenza in people twelve years of age and older at risk of influenza complications.
In November 2020, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people twelve years of age and older after contact with an individual who has the flu.
In August 2022, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people five years of age and older after contact with an individual who has the flu.
In the EU, baloxavir marboxil is indicated for the treatment of uncomplicated influenza and for post-exposure prophylaxis of influenza in individuals aged twelve years of age and older.
Available forms
Baloxavir marboxil is available in tablet form and as granules for mixing in water.
Resistance
In 2.2% of baloxavir recipients in the Phase II trial and in about 10% of baloxavir recipients in the Phase III trial, the infecting influenza strain had acquired resistance to the drug, due to variants of the polymerase protein displaying substitutions of isoleucine-38, specifically, the I38T, I38M, or I38F mutations. There is continuing research into and clinical concern over the resistance appearing in recipients, in response to treatment with this drug.
Contraindications
Baloxavir marboxil should not be co-administered with dairy products, calcium-fortified beverages, or laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminum or zinc.
Side effects
Common side effects following the single dose administration of baloxavir marboxil include diarrhea, bronchitis, common cold, headache, and nausea. Adverse events were reported in 21% of people who received baloxavir, 25% of those receiving placebo, and 25% of oseltamivir.
Mechanism of action
Baloxavir marboxil is an influenza therapeutic agent, specifically, an enzyme inhibitor targeting the influenza virus' cap-dependent endonuclease activity, one of the activities of the virus polymerase complex. In particular, it inhibits a process known as cap snatching, by which the virus derives short, capped primers from host cell RNA transcripts, which it then uses for polymerase-catalyzed synthesis of its needed viral mRNAs. A polymerase subunit binds to the host pre-mRNAs at their 5' caps, then the polymerase's endonuclease activity catalyzes its cleavage "after 10–13 nucleotides". As such, its mechanism is distinct from neuraminidase inhibitors such as oseltamivir and zanamivir.
Chemistry
Baloxavir marboxil is a substituted pyridone derivative of a polycyclic family, whose chemical synthesis has been reported in a number of ways by the company discovering it, Shionogi and Co. of Japan (as well as others); the Shionogi reports have appeared several times in the Japanese patent literature between 2016 and 2019, providing insight into possible industrial synthetic routes that may be in use.