It’s one dose – but is it worth it?
On Oct. 24, 2018, the FDA approved a new orally administered, single-dose influenza antiviral drug, baloxavir marboxil (XofluzaTM). Baloxavir is a polymerase acidic endonuclease inhibitor, and is effective for the treatment of influenza type A or B strains.
Mechanism of Action
Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein, which is an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription. Thus, baloxavir prevents influenza virus replication.
This mechanism is different than the neuraminidase inhibitors, such as oseltamivir, zanamivir and peramivir, which inhibit the spread of newly formed virus particles within the host cell by blocking the function of neuraminidase, a viral cell surface protein. Neuraminidase is necessary to cleave newly formed progeny viral particles from infected host cells.
The adamantane derivatives, amantadine and rimantadine, inhibit activity of the M2 protein within the influenza A virus. This protein is a transmembrane polypeptide involved in the viral replication process through its actions as an ion channel. Because the genetic sequence of influenza B’s M2 protein is significantly different, adamantane derivatives are effective only for the treatment and prevention of influenza A.
Indications and Usage
Baloxavir is indicated for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours. Dosing is simple – in adults and adolescents over age 12 who weigh between 40 and 80kg, the recommended oral dose is a single 40mg tablet. In those over 80kg, the dose is 80mg.
Unlike oseltamivir, which has been proven to be safe in all age groups and patient types, the safety and efficacy of baloxavir marboxil have not been established in pregnant and lactating patients, patients under age 12 or over age 65, or those weighing < 40 kg.[1,2] Data is also limited on the pharmacokinetics of baloxavir in patients with renal and/or hepatic impairment. Its use should be avoided in those patients until more data become available.
Body weight had a significant effect on the pharmacokinetics of baloxavir (as body weight increases, baloxavir exposure decreases). When dosed with the recommended weight-based dosing, no clinically significant difference in exposure was observed between body weight groups.
When the neuraminidase inhibitors were first developed and used in clinical practice, the emergence of resistant viral isolates was rare. However, continuous changes in gene sequences within the influenza viral genome have led to an increase in the number of drug-resistant viral strains. During the 2007–2008 influenza season, oseltamivir-resistant H1N1 seasonal influenza emerged globally, at rates of up to 68% in some regional populations.[2,6] This led to a resurgence of the adamantane derivatives as the recommended primary agent in some regions of the world. However, the last three seasons of influenza demonstrated relatively low resistance to oseltamivir and the other neuraminidase inhibitors. The CDC has continued to recommend treatment with primarily the neuraminidase inhibitors.[2,7]
Cross-resistance between baloxavir and neuraminidase (NA) inhibitors, or between baloxavir and the M2 proton pump inhibitors (adamantanes), is not expected, because these drugs target different viral proteins.
Two randomized controlled double-blinded clinical trials (sponsored by the manufacturer) were conducted in two different influenza seasons to evaluate efficacy and safety of baloxavir in otherwise healthy subjects with acute uncomplicated influenza.
In Trial 1, a placebo-controlled phase 2 dose-finding trial, a single oral dose of baloxavir was compared with placebo in 400 adult subjects, 20 to 64 years of age, in Japan.
For Trial 2, a phase 3 active- and placebo-controlled trial, baloxavir was studied in 1,436 adult and adolescent subjects 12 to 64 years of age weighing at least 40 kg in the U.S. and Japan. Adults age 20 to 64 years, received baloxavir or placebo as a single oral dose on Day 1 or oseltamivir twice a day for five days. Subjects in the baloxavir and placebo arms received a placebo for the duration of oseltamivir dosing after baloxavir or placebo dosing in that arm. Adolescent subjects 12 to less than 20 years of age received baloxavir or placebo as a single oral dose.
With both trials, eligible subjects had an axillary temperature of at least 38 ̊C, at least one moderate or severe respiratory symptom (cough, nasal congestion or sore throat), and at least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue), and all were treated within 48 hours of symptom onset.
The primary endpoint of both trials, time to alleviation of symptoms, was defined as the time when all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia and fatigue) had been assessed by the subject as none or mild for at least 21.5 hours.
In both trials, baloxavir treatment at the recommended dose resulted in a statistically significant shorter time to alleviation of symptoms compared with placebo in the primary efficacy population (See Tables 1 and 2).
Table 1. Time to Alleviation of Symptoms after Single Dose in Adult Subjects with Acute Uncomplicated Influenza in Trial 1 (Median Hours)
|XOFLUZA 40 mg (95% CI)
N = 100
|Placebo (95% CI) N = 100|
|Adults (20 to 64 Years of Age)||50 hours (45, 64)||78 hours (68, 89)|
1CI: Confidence interval
2XOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Gehan-Breslow’s generalized Wilcoxon test (p-value: 0.014, adjusted for multiplicity). The primary analysis using the Cox Proportional Hazards Model did not reach statistical significance (p-value: 0.165).
Source: https://www.accessdata.fda. gov/drugsatfda_docs/label/2018/210854s000lbl.pdf
Table 2. Time to Alleviation of Symptoms after Single Dose in Subjects 12 Years of Age and Older with Acute Uncomplicated Influenza in Trial 2 (Median Hours)
|XOFLUZA 40 mg or 80 mg (95% CI)
N = 455
|Placebo (95% CI) N = 230|
|Subjects (≥ 12 Years of Age)||54 hours (50, 59)||80 hours (73, 87)|
1Dosing was based on weight. Subjects weighing < 80 kg received a single 40 mg dose and subjects ≥ 80 kg received a single 80 mg dose.
2CI: Confidence interval
3XOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Peto-Prentice’s generalized Wilcoxon test (p-value: <0.001).
Source: https://www.accessdata.fda. gov/drugsatfda_docs/label/2018/210854s000lbl.pdf
In Trial 2, there was no difference in the time to alleviation of symptoms between subjects who received baloxavir (54 hours) and those who received oseltamivir (54 hours). For adolescent subjects (12 to 17 years of age) in Trial 2, the median time to alleviation of symptoms for subjects who received baloxavir (N=63) was 54 hours (95% CI of 43, 81) compared to 93 hours (95% CI of 64, 118) in the placebo arm (N=27).
In conclusion, they found that single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load one day after initiation of the trial regimen in patients with uncomplicated influenza.[1,3]
Cost & Availability
In an analysis of the popular website, GoodRx.com, which supplies real world drug prices at pharmacies across the U.S., Baloxavir was approximately $158 for a single dose of 80 mg, as compared to $48 for a five-day course of Oseltamivir.[4,5] Although, this is not an astronomical price difference considering the convenience of single dosing, it is unclear if insurers or the uninsured will opt for the higher expense given a cheaper proven alternative.
Availability may also be an issue – at least one pharmacy chain doesn’t appear to be carrying baloxavir yet. And hospitals may not have had time to add baloxavir to their formularies before flu season.
Baloxavir is a promising new addition to the growing family of anti-influenza treatments. Its one-time dosing with similar efficacy to oseltamivir, while targeting a different part of the viral protein, leads to it being an attractive choice for those who can afford the approximately $100 cost difference. More studies are needed to study its safety and efficacy in patients under 12 years and over 65 years, as well as pregnant or lactating patients, and those with severe renal or hepatic impairment.
- S. Food and Drug Administration. Prescribing information for XofluzaTM. Available at: https://www.accessdata.fda. gov/drugsatfda_docs/label/2018/210854s000lbl.pdf. Accessed December 8, 2018.
- Giwa A et al. Influenza: Diagnosis And Management In The Emergency Department. Emergency Medicine Practice. 2018 Dec; 20:3
- Hayden FG et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med 2018; 379:913-923.
- Baloxavir Costs. Available at: https://www.goodrx.com/baloxavir-marboxil/drugPanel. Accessed December 8, 2018.
- Oseltamivir Costs. Available at: https://www.goodrx.com/tamiflu?drug-name=tamiflu. Accessed December 8, 2018.
- Meijer A, Lackenby A, Hungnes O, et al. Oseltamivir- resistant influenza virus A (H1N1), Europe, 2007–08 season. Emerg Infect Dis. 2009;15(4):552-560.
- Centers for Disease Control and Prevention. Influenza antiviral medications: summary for clinicians. Available at: https://www.cdc.gov/flu/professionals/antivirals/sum- mary-clinicians.htm. Accessed December 8, 2018.