A antiviral has been FDA-approved, just in time for flu season.
The FDA approved Xofluza (baloxavir marboxil), a first in class polymerase acidic endonuclease inhibitor, just in time for the start of influenza season. Baloxavir marboxil is approved to treat acute, uncomplicated influenza in patients aged 12 years and older.1,2
The antiviral is the first novel mechanism of action introduced to treat the flu in decades and has several characteristics that make baloxavir appealing. Baloxavir marboxil inhibits polymerase acidic endonuclease, an enzyme required for influenza virus replication.3 Its activity and antiviral potency have been seen in vitro against a variety of influenza viruses, including influenza A and B strains known to infect humans, as wells as avian and swine strains. The amino acids forming baloxavir marboxil's target site appear to so far be conserved despite seasonal and pandemic changes to the influenza viruses. As a result, it has shown efficacy in influenza strains resistant to neuraminidase inhibitors.1,2
Like other influenza antivirals, baloxavir marboxil should be initiated within 48 hours of symptom onset. Unike the other currently available agents, baloxavir is a single-dose treatment course.
Baloxavir marboxil appears to be well tolerated.4,5 The most common adverse events during studies were headache, GI upset (diarrhea, nausea, vomiting), bronchitis, nasopharyngitis, sinusitis, and increases in ALT level. No adverse effect was significantly more common with baloxavir marboxil compared to placebo or oseltamivir and only diarrhea and nausea were considered to be medication related. Though not statistically evaluated, baloxavir marboxil appeared to have slightly more diarrhea, but less nausea compared to oseltamivir.4
The medication was mainly approved based on the results of one phase 2 and one phase 3 study.4 In the phase 2 study, baloxavir marboxil showed significantly greater reduction symptoms and influenza virus titers (days 2 and 3) compared to placebo in 389 patients. Most of the patients in the study had influenza A H1N1 and the mean time to symptom alleviation with the 40 mg dose was 28.2 hours shorter than with placebo (P=0.005). Approximately 23% to 29% of the patients (depending on dose) reported adverse events, but there was no significant differences seen compared to placebo.
The CAPSTONE-1 study, the phase 3 trial, compared baloxavir marboxil to both placebo and oseltamivir in 1,366 patients 12-64 years of age with influenza-like illness in the United States and Japan during the 2016/17 influenza season. Patients over the age of 20 received 5 days of active therapy with oseltamivir, 5 days of placebo, or 1 dose of baloxavir marboxil (80 mg for patients 80 kg or more; 40 mg for patients < 80 kg) plus 4 days of placebo. Younger patients (12-19 years) were only randomized to receive a single dose or placebo. Like the phase 2 study, most patients had influenza A; however in this study H3N2 predominated in over 85% of the patients in the United States and over 77% of the Japanese patients. Approximately 9% of patients had Influenza B. Time to symptom alleviation was 26.5 hours shorter with baloxavir vs. placebo (P<0.0001) overall; however symptom alleviation seemed to occur much earlier in adolescents (median symptom alleviation time 38.6 hours vs. placebo; P=0.006).
Patients who initiated therapy with baloxavir marboxil within 24 hours of symptoms also experienced a shorter duration of illness vs. placebo (median difference 32.8 hours; P<.001) while patients who initiated therapy after the first day of illness only say a reduction in symptoms by just over half a day compared to placebo (median difference 13.2 hours;P=.008). Baloxavir use also resulted in shorter times to fever reduction (24.5 hours vs. 42 hours; P<0.001) and median time to return to normal health (129.2 hours vs. 168.8 hours; P=.06 not significant). Infectious viral load declined significantly sooner with baloxavir marboxil compared with both oseltamivir and placebo.
While baloxavir marboxil offers promise, it is not without its limitations. Although patients in the studies were also randomized to receive oseltamivir, statistical analysis of clinical efficacy between the 2 antivirals was presented in either the article or the supplementary appendix. Analyses were conducted on reduction in viral load between the 2; with a significantly shorter time seen with baloxavir marboxil. However, whether this actually translates into superior efficacy cannot and should not be extrapolated from this data alone. Previous studies with oseltamivir indicate a reduction in symptoms by about a day, which is similar to that seen with baloxavir marboxil. It should be noted in both the phase 2 and phase 3 trials, patients requiring hospitalization were excluded and therefore baloxavir's efficacy in severe influenza is not yet known.
CAPSTONE-2, a phase 3 study similar in design to CAPSTONE-1, and evaluating baloxavir in outpatients at high risk for severe pneumonia has been completed, but results have not yet been released. 2,6 According to Clinicaltrials.gov, a study of baloxavir marboxil (up to 3 doses) in combination with standard of care neuraminidase inhibitors in hospitalized patients began on October 17, 2018, and is not projected to be completed until 2021. This medication is also not yet approved for used in pediatric patients. To date, results have only been published for patients over 12 years of age. Two studies are set to begin enrolling infants and children in October and November 2018.7,8 One study will evaluate infants from birth to 1 year and the second will evaluate children aged 1-12 years. Unfortunately, neither study will be completed until 2020.
Baloxamivir has also not been studied in geriatric patients, and it is unknown if any trials are planned in this population specifically. Older adults are at high risk for influenza complications and have age-related pharmacokinetic and pharmacodynamic changes that limit extrapolation of study results seen in younger populations. According to inclusion criteria, patients over 65 years of age were eligible for CAPSTONE-2, but how many were actually enrolled and the effect of the medication in these patients will not be known until the results are published.
Until the results of the pediatric and the inpatient studies are known, baloxavir marboxil should be reserved for outpatients with uncomplicated influenza between the ages of 12-64 years. When the medication will be available, how much it will cost, and other logistical factors have not yet been announced. It does not yet appear to be notably better in efficacy compared to oseltamivir, but its single-dose regimen, amended GI side effect profile, and efficacy against strains resistant to neuraminidase inhibitors may help this novel antiviral find its special niche.
First New Antiviral for Influenza in 2 Decades Approved by FDA