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Baloxavir marboxil: A novel oral antiviral treatment for uncomplicated influenza
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Influenza and pneumonia together are the eighth-leading causes of death in the United States. Two major classes of antivirals were once the only options for treatment of influenza: matrix-2 proton pump inhibitors, which are effective against only influenza A viruses, and neuraminidase inhibitors, which have shown growing evidence of resistance from influenza strains.
Oseltamivir phosphate (Tamiflu, Genentech) had been the most recent oral neuraminidase inhibitor to receive FDA approval in 1999, with its twice-daily dosing. As with other anti-infectives, oseltamivir and other neuraminidase inhibitors are not immune to the development of resistance. The need for novel mechanisms to target common influenza strains has been in demand, especially considering the decreased vaccination rate observed during the 2017-2018 influenza season and growing resistance concerns to existing therapies.
Novel influenza antiviral mechanisms had been absent for 19 years since oseltamivir was approved by the FDA. In October 2018, the FDA approved baloxavir marboxil (Xofluza, Genentech) as a one-dose oral treatment for uncomplicated influenza strains A and B.
Pharmacology
Baloxavir is a polymerase acidic, cap-dependent, endonuclease inhibitor that is indicated for the treatment of acute uncomplicated influenza in patients aged 12 years and older who have been symptomatic for no more than 48 hours. It blocks viral proliferation by binding to one of two endonuclease binding sites, inhibiting the initiation of mRNA synthesis for both influenza A and influenza B strains. Because baloxavir exerts its activity earlier in the viral replication process compared with other influenza therapies, it has been shown to reduce the duration of viral shedding. This medication is a prodrug that is hydrolyzed via UGT1A3 and CYP3A4 into its active form, although it is not expected to extensively induce or inhibit CYP450 enzymes. It is administered with or without food as a single oral dose within 48 hours of symptom onset. Dosing is based on body weight, with a recommended single oral dose of 40 mg for 40- to 79-kg patients and 80 mg for patients weighing 80 kg or more. Baloxavir can interact with polyvalent cation-containing products, which can decrease its plasma concentration. It is recommended to avoid coadministration of baloxavir with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids or oral supplements because of the risk for chelation. Cross-resistance between baloxavir and other neuraminidase inhibitors is not expected because the medications target different viral proteins.
Clinical trials
Three multicenter, randomized, double-blind controlled trials conducted during different influenza seasons evaluated the efficacy and safety of baloxavir (see Table). Trial 1 was a dose-finding, phase 2 trial conducted in Japan that enrolled 400 participants aged 20 to 64 years who were randomly assigned to baloxavir or placebo. The CAPSTONE-1 trial was a phase 3 active- and placebo-controlled trial. The trial enrolled 1,436 otherwise healthy adult and adolescent participants aged 12 to 64 years weighing at least 40 kg in the United States and Japan. Adults aged 20 to 64 years were assigned to receive 40 mg or 80 mg of baloxavir as a single dose based on body weight, 75 mg of oseltamivir twice a day for 5 days, or placebo (2:2:1). Participants aged 12 to 19 years were assigned baloxavir as a single dose or placebo (2:1). The CAPSTONE-2 trial was a phase 3 active- and placebo-controlled trial. The trial enrolled 2,184 participants at high risk for influenza-related complications. Participants aged 12 years or older were assigned to receive placebo, a single dose of 40 mg or 80 mg of baloxavir based on body weight, or 75 mg of oseltamivir twice a day for 5 days (1:1:1).
The primary endpoint of each trial was the time to alleviation of symptoms, including cough, sore throat, nasal congestion, headache, fever, myalgia and fatigue. Participants were required to self-assess their symptoms as “none,” “mild,” “moderate” or “severe” twice a day. “None” or “mild” were enough to constitute the alleviation of a symptom. For trial 1 and CAPSTONE-1, eligible participants had an axillary temperature of at least 38°C (100.4°F), at least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom (headache, fever or chills, muscle or joint pain, or fatigue). All participants must have experienced influenza symptoms for up to 48 hours in duration. For CAPSTONE-2, eligible participants required the same inclusion criteria but also required the presence of a least one high-risk factor for influenza complications adapted from the CDC. Risk factors included asthma or chronic lung disease, diabetes, HIV/AIDS, age 65 years or older, heart disease and stroke. A virologic endpoint of CAPSTONE-1 and CAPSTONE-2 was the median duration of infectious virus detection.
A summary of the primary outcomes is presented in the Table. In CAPSTONE-1, the median duration of infectious virus shedding was shorter in the baloxavir group (24 hours) compared with the oseltamivir group (72 hours, P < 0.001) and the placebo group (96 hours, P < 0.001). In CAPSTONE-2, the median duration of infectious virus shedding was significantly lower in the baloxavir group (48 hours) compared with 96 hours in both the placebo and oseltamivir groups. The phase II trial and CAPSTONE-1 trial also evaluated the emergence of amino acid changes associated with reduced susceptibility to baloxavir. The authors found reduced susceptibility to baloxavir in 2.2% of recipients in the phase II trial and 9.7% of recipients in the CAPSTONE-1 trial.
The number of participants in trial 1 and CAPSTONE-1 who were infected with influenza B was a limiting factor in the overall outcomes. Most of the participants in trial 1 were infected with influenza A/H1N1 (63%), followed by influenza B (25%) and influenza A/H3N2 (12%). Most participants in the CAPSTONE-1 were infected with influenza A/H3N2 (90%), followed by in-fluenza B (9%) and influenza A/H1N1 (2%). In CAPSTONE-2, most participants were infected with influenza A/H3N2 (47.9%), followed by influenza B (41.6%) and influenza A/H1N1 (6.9%).
Safety and tolerability
Baloxavir appears to be well-tolerated, with the most commonly reported side effects being diarrhea, bronchitis, nausea, nasopharyngitis and headache. It has not been evaluated in human pregnancy or lactation; therefore, no data are available to inform on drug-associated risk. No adverse developmental effects were observed in rats or rabbits at five to seven times the recommended human dosage, although baloxavir and its metabolites have been shown to be present in the milk of lactating rats. Inherent risks to the mother and fetus associated with influenza virus infection in pregnancy exist and should be evaluated when determining treatment.
Conclusion
Vaccination remains imperative to prevent influenza. For cases in which vaccination was ineffective or was not received, there is a new treatment option available. Baloxavir marboxil is the first cap dependent endonuclease inhibitor approved by the FDA for treatment of uncomplicated influenza. Baloxavir is administered as a one-time dose based on body weight and may be an attractive treatment choice because of medication adherence. Although studies incorporating special populations such as hospitalized patients have not been conducted, baloxavir has demonstrated safety and efficacy for the treatment of acute uncomplicated influenza A and B infections for patients aged 12 years and older.
- References:
- CDC. Leading causes of death available. https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm. Accessed November 28, 2018.
- CDC. Estimates of influenza vaccination coverage among adults—United States, 2017–18 flu season. https://www.cdc.gov/flu/fluvaxview/coverage-1718estimates.htm. Accessed November 28, 2018.
- Hayden F, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1716197.
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- Shinogi. Shionogi enters into a license and collaboration agreement with Roche for its anti-flu drug, S-033188. http://www.shionogi.eu/media/381353/e160229-roche-188.pdf. Accessed November 28, 2018.
- Xofluza (baloxavir marboxil) [package insert]. South San Francisco, CA: Genentech USA Inc.; 2018.
- For more information:
- Adrian C. Schenk, PharmD, is a post-graduate year 1 (PGY-1) pharmacy practice resident at Denver Health Medical Center. Schenk can be reached at adrian.schenk@dhha.org.
- Kati Shihadeh, PharmD, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.
Disclosures: Schenk and Shihadeh report no relevant financial disclosures.