Baloxavir marboxil
Clinical data
Trade namesXofluza
Other namesBXM (S-033188), BXA (S-033447)
AHFS/Drugs.comMonograph
MedlinePlusa618062
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • ({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]triazin-7-yl}oxy)methyl methyl carbonate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC27H23F2N3O7S
Molar mass571.55 g·mol−1
3D model (JSmol)
  • O=C(OCOC(C(C=C1)=O)=C(N1N([C@@H]2C3=CC=CC=C3SCC4=C(F)C(F)=CC=C24)[C@@]5([H])N6CCOC5)C6=O)OC
  • InChI=1S/C27H23F2N3O7S/c1-36-27(35)39-14-38-25-19(33)8-9-31-24(25)26(34)30-10-11-37-12-21(30)32(31)23-15-6-7-18(28)22(29)17(15)13-40-20-5-3-2-4-16(20)23/h2-9,21,23H,10-14H2,1H3/t21-,23+/m1/s1
  • Key:RZVPBGBYGMDSBG-GGAORHGYSA-N

Baloxavir marboxil, sold under the brand name Xofluza, is an antiviral medication for treatment of influenza A and influenza B.[4] It was approved for medical use both in Japan and in the United States in 2018,[7][8][9] and is taken as a single dose by mouth.[4] It may reduce the duration of flu symptoms by about a day, but is prone to selection of resistant mutants that render it ineffectual.[10]

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.[11]

The most common side effects of baloxavir marboxil include diarrhea, bronchitis, nausea, sinusitis, and headache.[12]

The US Food and Drug Administration (FDA) considers baloxavir marboxil to be a first-in-class medication.[13]

Medical uses

Baloxavir marboxil is an influenza medication, an antiviral,[14][4] for individuals who are twelve years of age or older,[5][14] that have presented symptoms of this infection for no more than 48 hours.[5][14][15] The efficacy of baloxavir marboxil administered after 48 hours has not been tested.[14]

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.[4][9]

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.[4][12]

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.[4][16]

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.[5]

Available forms

Baloxavir marboxil is available in tablet form and as granules for mixing in water.[12]

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.[17] There is continuing research into and clinical concern over the resistance appearing in recipients, in response to treatment with this drug.[18][19][20]

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.[12]

Side effects

Common side effects following the single dose administration of baloxavir marboxil include diarrhea, bronchitis, common cold, headache, and nausea.[4][15][7] Adverse events were reported in 21% of people who received baloxavir, 25% of those receiving placebo, and 25% of oseltamivir.[17]

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.[21] 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.[22] 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.[22]

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.[23][24][25][26][27]

Baloxavir acid (BXA) or simply baloxavir, the active moiety[28]

Baloxavir marboxil (BXM) is a prodrug whose active agent, baloxavir acid (BXA) is released rapidly in vivo, as the hydrolysis of baloxavir marboxil is catalyzed by arylacetamide deacetylases in cells of the blood, liver, and lumen of the small intestine.[29][30][31] The compound numbers for baloxavir marboxil and baloxavir acid used in publications by Shionogi and others during discovery and development (prior to assignment of a United States Adopted Name (USAN)) were, respectively, S-033188 and S-033447.[32] As reported in a review of the patent literature, the carbonic acid ester (carbonate) 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.[29][33]

History

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 participants by about one day compared with a placebo treatment group, and comparable with what was seen for an oseltamivir treatment group.[15] On the first day after baloxavir was started in its treatment group of participants, viral loads decreased more than in participants 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.[17]

Baloxavir marboxil was developed for the market by Shionogi Co., a Japanese pharmaceutical company, and Switzerland-based Roche AG.[34] The names under which baloxavir marboxil and baloxavir acid appear in Shionogi research reporting are S-033188 and S-033447, respectively.

Society and culture

Japan's Ministry of Health, Labour and Welfare (JMHLW) and the US Food and Drug Administration (FDA) approved baloxavir marboxil based on evidence of its benefits and side effects from two clinical trials in adult and pediatric participants with uncomplicated influenza (Trial 1, 1518T0821 and Trial 2, NCT02954354[35]),[4] involving 1119 participants.[15][36] Both trials included clinical sites and participants in Japan, with Trial 2 adding clinical locations in the United States.[4][15]

Baloxavir marboxil was approved for sale in Japan in February 2018.[37] In October 2018, the FDA approved it for the treatment of acute uncomplicated influenza in people twelve years of age and older who have been symptomatic for no more than 48 hours.[7][8] 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 2018.[7][8] Specifically, the FDA approved the use of baloxavir marboxil for people at high risk of developing influenza-related complications.[38] 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.[9] 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.[12]

Baloxavir marboxil was approved for medical use in Australia in February 2020.[1]

The safety and efficacy of baloxavir marboxil, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 subjects where participants were assigned to receive either baloxavir marboxil, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms.[7] In both trials, subjects treated with baloxavir marboxil had a shorter time to alleviation of symptoms compared with subjects who took the placebo.[7] In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received baloxavir marboxil and those who received the other flu treatment.[7]

The safety and efficacy of baloxavir marboxil for post-flu exposure prevention is supported by one randomized, double-blind, controlled trial in which 607 subjects, twelve years of age and older who were exposed to a person with influenza in their household, received either a single dose of baloxavir marboxil or a single dose of a placebo.[12] Of these 607 subjects, 303 received baloxavir marboxil and 304 received the placebo.[12] The trial's primary endpoint was the proportion of subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom from day 1 to day 10.[12] Of those who received baloxavir marboxil, 1% of subjects met these criteria, compared to 13% of subjects who received a placebo for the clinical trial.[12]

Baloxavir marboxil was approved for medical use in the European Union in January 2021.[5]

References

  1. 1 2 3 "Xofluza Australian prescription medicine decision summary". Therapeutic Goods Administration (TGA). 2 March 2020. Archived from the original on 13 March 2020. Retrieved 16 August 2020.
  2. ↑ "Xofluza Product information". Health Canada. 25 April 2012. Archived from the original on 12 August 2022. Retrieved 29 May 2022.
  3. ↑ "Summary Basis of Decision (SBD) for Xofluza". Health Canada. 23 October 2014. Archived from the original on 31 May 2022. Retrieved 29 May 2022.
  4. 1 2 3 4 5 6 7 8 9 10 "Xofluza- baloxavir marboxil tablet, film coated". DailyMed. 28 October 2019. Archived from the original on 28 October 2020. Retrieved 9 January 2020.
  5. 1 2 3 4 5 "Xofluza EPAR". European Medicines Agency (EMA). 9 November 2020. Archived from the original on 30 January 2021. Retrieved 25 January 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ↑ "Xofluza Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  7. 1 2 3 4 5 6 7 "FDA approves new drug to treat influenza" (Press release). U.S. Food and Drug Administration (FDA). 24 October 2018. Archived from the original on 24 October 2019. Retrieved 23 October 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  8. 1 2 3 "Drug Approval Package: Xofluza Film-Coated Tablets (Baloxavir marboxil)". U.S. Food and Drug Administration (FDA). 7 December 2018. Archived from the original on 26 July 2020. Retrieved 10 May 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  9. 1 2 3 "FDA Approval Package for 210854Orig1s001" (PDF). U.S. Food and Drug Administration (FDA). 16 October 2019. Archived (PDF) from the original on 9 April 2021. Retrieved 30 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  10. ↑ "Baloxavir Marboxil for Uncomplicated Influenza: Mechanism of Action & Side Effects". Huateng Pharma. Archived from the original on 24 February 2021. Retrieved 29 May 2020.
  11. ↑ Noshi T, Kitano M, Taniguchi K, Yamamoto A, Omoto S, Baba K, et al. (December 2018). "In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit". Antiviral Res. 160: 109–117. doi:10.1016/j.antiviral.2018.10.008. PMID 30316915.
  12. 1 2 3 4 5 6 7 8 9 "FDA Expands Approval of Influenza Treatment to Post-Exposure Prevention" (Press release). U.S. Food and Drug Administration (FDA). 23 November 2020. Archived from the original on 23 November 2020. Retrieved 23 November 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  13. ↑ New Drug Therapy Approvals 2018 (PDF) (Report). U.S. Food and Drug Administration (FDA). January 2019. Archived from the original on 17 September 2020. Retrieved 16 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  14. 1 2 3 4 "Baloxavir Marboxil Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. 19 August 2019. Archived from the original on 7 October 2019. Retrieved 9 January 2020.
  15. 1 2 3 4 5 Food and Drug Administration (23 July 2019). "Drug Trial Snapshot: Xofluza". U.S. Food and Drug Administration (FDA). Archived from the original on 12 December 2019. Retrieved 7 January 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  16. ↑ "Genentech Announces FDA Approval of Xofluza to Treat Influenza in Children Aged Five and Older" (Press release). Genentech. 11 August 2022. Archived from the original on 12 August 2022. Retrieved 11 August 2022 – via Business Wire.
  17. 1 2 3 Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, et al. (September 2018). "Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents". N. Engl. J. Med. 379 (10): 913–923. doi:10.1056/NEJMoa1716197. PMID 30184455. S2CID 52173453.
  18. ↑ "Roche's flu med Xofluza drives drug resistance and may be a bad choice for kids, study says". FiercePharma. 26 November 2019. Archived from the original on 25 November 2020. Retrieved 8 January 2020.
  19. ↑ "New flu drug drives drug resistance in influenza viruses". EurekAlert (Press release). Archived from the original on 16 January 2021. Retrieved 8 January 2020.
  20. ↑ Imai M, Yamashita M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Kiso M, Murakami J, et al. (January 2020). "Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets". Nature Microbiology. 5 (1): 27–33. doi:10.1038/s41564-019-0609-0. PMID 31768027. S2CID 208279215.
  21. ↑ Eisfeld AJ, Neumann G, Kawaoka Y (January 2015). "At the centre: influenza A virus ribonucleoproteins". Nature Reviews. Microbiology. 13 (1): 28–41. doi:10.1038/nrmicro3367. PMC 5619696. PMID 25417656.
  22. 1 2 O'Hanlon R, Shaw ML (April 2019). "Baloxavir marboxil: the new influenza drug on the market". Current Opinion in Virology. 35: 14–18. doi:10.1016/j.coviro.2019.01.006. PMID 30852344. S2CID 73726080.
  23. ↑ WO 2019070059, Okamoto K, Ueno T, Hato Y, Hakogi T, Majima S, "Method for stereoselective preparation of substituted polycyclic pyridone derivative.", published 2019, assigned to Shionogi & Co., Ltd., Japan.
  24. ↑ JPWO 2018030463, Kawai M, Tomita K, Akiyama T, Okano A, Miyagawa M, "Pharmaceutical composition containing polycyclic pyridone derivatives as cap-dependent endonuclease (CEN) inhibitors.", published 2017, assigned to Shionogi and Co., Ltd., Japan.
  25. ↑ JPWO 2017221869, Shibahara S, Fukui N, Maki T, "Polycyclic pyridone derivative, crystal and preparation method thereof.", published 2017, assigned to Shionogi and Co., Ltd., Japan.
  26. ↑ JPWO 2016175224, Kawai M, Tomita K, Akiyama T, Okano A, Miyagawa M, "Preparation of polycyclic pyridone derivatives as cap-dependent endonuclease (CEN) inhibitors and prodrugs thereof.", published 2016, assigned to Shionogi and Co., Ltd., Japan
  27. ↑ CN 108440564, Zhu X, Jiang W, "Process for preparation of substituted polycyclic carbamoylpyridone derivative and its prodrug.", published 2018
  28. ↑ "Baloxavir". PubChem. U.S. National Library of Medicine. CID 124081876. Retrieved 28 July 2021.
  29. 1 2 Hughes DL (June 2019). "Review of the Patent Literature: Synthesis and Final Forms of Antiviral Drugs Tecovirimat and Baloxavir Marboxil". Organic Process Research & Development. 23 (7): 1298–1307. doi:10.1021/acs.oprd.9b00144. S2CID 197172102.
  30. ↑ Yoshino R, Yasuo N, Sekijima M (November 2019). "Molecular Dynamics Simulation reveals the mechanism by which the Influenza Cap-dependent Endonuclease acquires resistance against Baloxavir marboxil". Scientific Reports. 9 (1): 17464. Bibcode:2019NatSR...917464Y. doi:10.1038/s41598-019-53945-1. PMC 6877583. PMID 31767949.
  31. ↑ Kawaguchi N, Koshimichi H, Ishibashi T, Wajima T (November 2018). "Evaluation of Drug-Drug Interaction Potential between Baloxavir Marboxil and Oseltamivir in Healthy Subjects". Clinical Drug Investigation. 38 (11): 1053–1060. doi:10.1007/s40261-018-0697-2. PMID 30203386.
  32. ↑ Yang J, Huang Y, Liu S (May 2019). "Investigational antiviral therapies for the treatment of influenza". Expert Opinion on Investigational Drugs. 28 (5): 481–488. doi:10.1080/13543784.2019.1606210. PMID 31018720. S2CID 131775842.
  33. ↑ "Baloxavir Marboxil". Pharmaceutical Substances. Archived from the original on 26 July 2020. Retrieved 8 January 2020.
  34. ↑ Branswell H (27 June 2018). "A flu drug — shown to reduce the duration of symptoms — could upend treatment in U.S.". Stat. Archived from the original on 20 October 2020. Retrieved 28 June 2018.
  35. ↑ "A Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Otherwise Healthy Patients With Influenza". ClinicalTrials.gov. 3 November 2016. Archived from the original on 21 January 2022. Retrieved 11 August 2022.
  36. ↑ Otake T (24 February 2018). "One-dose flu drug Xofluza gets nod from health ministry". Japan Times Online. Archived from the original on 2 November 2021. Retrieved 8 January 2020.
  37. ↑ "Xofluza (Baloxavir Marboxil) Tablets 10mg/20mg Approved For The Treatment Of Influenza Types A And B In Japan" (Press release). Shionogi & Co., Ltd. 23 February 2018. Archived from the original on 20 January 2021. Retrieved 23 February 2018 – via publicnow.com.
  38. ↑ "Genentech Announces FDA Approval of Xofluza (Baloxavir Marboxil) for People at High Risk of Developing Influenza-Related Complications" (Press release). Genentech. 17 October 2019. Archived from the original on 24 October 2019. Retrieved 23 October 2019 – via Business Wire.

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