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Antiviral is the first new mechanism of action introduced to treat influenza for decades and has several features that make baloxavir attractive. Baloxavir inhibits the endonuclease acid polymerase, an enzyme necessary for the replication of the influenza virus.3 Its activity and antiviral activity have been observed in vitro against various influenza viruses, including influenza A and B strains known to infect humans, as well as avian and porcine strains. The amino acids forming the target site of baloxamivir seem to be preserved up to now despite seasonal and pandemic influenza virus changes. As a result, it has been shown to be effective in influenza strains resistant to neuraminidase inhibitors.1.2
Like other antiviral medicines, baloxavir should be started within 48 hours of the onset of symptoms. Like other currently available agents, baloxavir is a single dose once completed.
Baloxavir seems to be well tolerated.4.5 The most common adverse events observed in the studies were: headache, gastrointestinal disturbances (diarrhea, nausea, vomiting), bronchitis, nasopharyngitis, sinusitis, and elevated ALT levels. No adverse events were significantly more common with baloxavir compared to placebo or oseltamivir and only diarrhea and nausea were considered to be drug related. Although not statistically evaluated, baloxavir appeared to have slightly more diarrhea but less nausea compared to oseltamivir.4
The drug was primarily approved based on the results of a phase 2 study and a phase 3 study.4 In the phase 2 study, baloxavir showed a significant reduction in reduction symptoms and influenza virus titres (days 2 and 3) compared to placebo in 389 patients. Most patients in the study were infected with H1N1 influenza A and the average symptom relief time with the 40 mg dose was 28.2 hours shorter than with the placebo (p = 0.005) . About 23 to 29% of patients (depending on the dose of baloxavir) reported side effects, but no significant difference was observed compared to placebo.
The CAPSTONE-1 Phase 3 study compared baloxavir with placebo and oseltamivir in 1,366 patients aged 12 to 64 years with influenza-like illness in the United States and Japan during the influenza season 2016- 2017. Patients over 20 years old received 5 days of active treatment with oseltamivir), 5 days of placebo or 1 dose of baloxavir (80 mg for patients of 80 kg or more, 40 mg for patients with less than 80 kg) plus 4 days of placebo. . The youngest patients (12 to 19 years old) were randomized only to receive a single dose of blaoxavir or a placebo. As in the Phase II study, most patients had influenza A; however, in this study, H3N2 predominated in over 85% of patients in the United States and more than 77% of patients in Japanesse. About 9% of patients had influenza B. Baloxavir was reduced by 26.5 hours with placebo (p <0.0001) as a whole; however, symptomatic relief appeared to occur much earlier in adolescents (median symptom relief time of 38.6 hours compared to placebo, p = 0.006).
Patients who started baloxavir treatment within 24 hours of onset of symptoms also had a shorter duration of illness compared to placeob (median difference of 32.8 hours, p <0.001), while that patients who started treatment after the first day of the disease report only more than half a day compared to placebo (median difference 13.2 hours, p = 0.008). The use of baloxavir also reduced fever time (24.5 hours vs. 42 hours, p <0.001) and an average time to normal health (129.2 hours vs. 168.8 hours, p = 0). , 06 not significant). Infectious viral load decreased significantly earlier with baloxavir compared with oseltamivir and placebo.
Although marboxil baloxamivir is promising, it is not without limitations. Although patients participating in the studies were also randomized to receive oseltamivir, no statistical analysis of clinical efficacy between the two antivirals was presented in the article or in the article. additional annex. The viral load reduction analyzes between the two were evaluated with a significantly shorter duration with baloxavir. However, if this really translates into superior efficiency can not and should not be extrapolated from these data alone. Previous studies on oseltamivir indicate a reduction in symptoms of about a day similar to that seen with baloxavir. It should be noted that in phase 2 and phase 3 trials, patients requiring hospitalization were excluded and, therefore, the effectiveness of baloxavir in severe influenza is not yet known.
CAPSTONE-2, a phase 3 study of similar design to CAPSTONE-1, and the evaluation of baloxavir in outpatients at high risk of severe pneumonia have been completed, but the results have not yet been achieved been communicated (2,6). According to Clinicaltrials.gov, a study involving baloxavir (up to 3 doses) in combination with nauraminidase inhibitors at treatment standards in hospitalized patients began on October 17, 2018 and should not be completed until 2021. Baloxamivir is not yet approved. for use in pediatric patients. To date, the results have only been published for patients over 12 years old. Two studies are expected to begin recruiting infants and children in October and November 2018.7.8 One study will evaluate infants from birth to 1 year of age and the second will evaluate children aged 1 to 12 years. Unfortunately, neither study will be completed before 2020.
Baloxamivir has also not been studied in geriatric patients, and it is not known if trials are specifically planned in this population. Older adults are at high risk for influenza-related complications and have age-related pharmacokinetic and pharmacodynamic changes that limit extrapolated study findings in younger populations. According to the inclusion criteria, patients older than 65 years were eligible for CAPSTONE-2, but how many were actually enrolled and the effect of the drug in these patients will not be known until the results are released .
Until the results of pediatric and hospital studies are known, baloxavir should be reserved for ambulatory patients with mild influenza-like illness between 12 and 64 years of age. When the drug becomes available, how much will it cost and other logistical factors have not been announced yet? Its effectiveness does not yet seem much better compared to that of oseltamivir, but its single-dose treatment, its modified side-effect profile of gastrointestinal effects and its efficacy against inhibitor-resistant strains of the neuraminidase could help this new antiviral find its place.
First new antiviral for the flu in 2 decades approved by the FDA
References
- FDA approves new drug to treat flu [news release]. Silver Spring, MD; October 24, 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm. Accessed October 24, 2018.
- Roche Announces FDA Approval of Xofluza (Baloxavir Marboxil) for Influenza [news release]. Basel, Switzerland; October 24, 2018: Roche Media Relations. https://www.roche.com/de/media/releases/med-cor-2018-10-24.htm. Accessed October 24, 2018.
- Noshi T, Kitano M., Taniguchi K, et al. In Vitro Characterization of Baloxavir Acid: The first clonally-dependent endonuclease inhibitor of the PA subunit of the influenza virus polymer. Antiviral research. 2018; doi: https://doi.org/10.1016/j.antiviral.2018.10.008
- Hayden FG, N Sugaya, N Hirotsu, et al. Baloxavir marboxil in the treatment of uncomplicated influenza in adults and adolescents. N Engl J Med. 2018; 379: 913-923
- Koshimichi H, Ishibashi T, Kawaguchi N, et al. Safety, tolerability and pharmacokinetics of the new anti-influenza agent, baloxavir marboxil in healthy adults: results of the Phase I study. Clinical investigation of a drug. 2018; https://doi.org/10.1007/s40261-018-0710-9
- Study of S-033188 (Baloxavir Marboxil) compared to placebo or Oseltamivir in patients at high risk for influenza complications (CAPSTONE 2). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02949011?cond=baloxavir&rank=5. Updated 24 July 2018. Accessed 24 October 2018.
- Study to evaluate the safety, pharmacokinetics and efficacy of Baloxavir Marboxil in healthy children participating in the study, from birth to less than one year and with symptoms similar to those of influenza. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03653364?cond=baloxavir&rank=3. Updated August 31, 2018. Accessed October 24, 2018.
- A study to evaluate the safety, pharmacokinetics, and efficacy of Baloxavir Marboxil in healthy children with flu-like symptoms. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03629184?cond=baloxavir&rank=2. Updated 14 August 2018. Accessed 24 October 2018.
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