Baloxavir marboxil, sold under the brand name Xofluza, is an antiviral medication for treatment of influenza A and influenza B flu. It was approved for medical use 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 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. BXM was developed for the market by Shionogi Co., a Japanese pharmaceutical company, and Switzerland-based Roche AG. The names under which BXM and BXA appear in Shionogi research reporting are S-033188 and S-033447, respectively.
Medical use
Baloxavir marboxil is an influenza medication, an antiviral, that is taken as a single dose tablet, by mouth, by individuals that are 12 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.
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 patients, in response to treatment with this drug.
Side effects
Common side effects following the single dose administration of baloxavir were 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 ; 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. Baloxavir marboxil is a prodrug whose active agent, baloxavir acid is released rapidly in vivo, as the hydrolysis of BXM is catalysed by arylacetamide deacetylases in cells of the blood, liver, and lumen of the small intestine. The compound numbers for BXM and BXA used in publications by Shionogi and others during discovery and development were, respectively, S-033188 and S-033447. As reported in a review of the patent literature, the carbonic acid ester moiety of the prodrug—shown in the lower left-hand corner of the image above—was prepared during discovery and development research from a late stage 2-hydroxy-4-pyridone precursor by treatment with chloromethyl methyl carbonate.
Approval
Japan's Ministry of Health, Labour and Welfare and the U.S. Food and Drug Administration approved baloxavir marboxil based on evidence of its benefits and side effects from two clinical trials in adult and pediatric patients with uncomplicated influenza, involving 1119 patients. Both trials included clincal sites and patients in Japan, with Trial 2 adding clinical locations in the United States. As of September 2018, in the only report of a Phase III randomized, controlled trial, baloxavir reduced the duration of influenza symptoms of otherwise healthy outpatients by about one day compared with a placebo treatment group, and comparable with what was seen for an oseltamivir treatment group. On the first day after baloxavir was started in its treatment group of patients, viral loads decreased more than in patients in either the oseltamivir or placebo groups; however, after five days, the effect on viral load of the single dose of baloxavir was indistinguishable from the effect observed following the complete, 5-day regimen of oseltamivir in its treatment group. Baloxavir marboxil was approved for sale in Japan in February 2018. On 24 October 2018, the FDA approved it for the treatment of acute uncomplicated influenza in people 12 years of age and older who have been symptomatic for no more than 48 hours. The FDA application of baloxavir marboxil was granted priority review in the United States, and approval of Xofluza was granted to Shionogi & Co., Ltd. in October 2019. Specifically, the FDA approved the use of baloxavir marboxil for people at high risk of developing influenza-related complications.
Research
While it is being studied in COVID-19, no published evidence supports its use as of 8 April 2020.
