Pharmacology Consult

Pediatric implications of Xofluza — a new antiviral drug for influenza

Four FDA-approved antiviral drugs are recommended by the CDC for the treatment of influenza during the 2018-2019 season. The latest drug to be included, approved by the FDA in October 2018, is Xofluza (baloxavir marboxil, Genetech). It is a prodrug that is hepatically metabolized to its active metabolite, baloxavir. Baloxavir marboxil is unique because it functions by a different mechanism of action than oseltamivir — including Tamiflu (Genentech) and generic versions — Relenza (zanamivir, GlaxoSmithKline) and Rapivab (peramivir, Seqirus). These last three drugs are all neuraminidase inhibitors (NIs) — preventing virus replication by inhibiting the influenza viral enzyme neuraminidase. Xofluza functions to inhibit influenza viral replication as well, via a different mechanism. It is a cap-dependent endonuclease inhibitor, inhibiting viral replication by disrupting viral RNA transcription. Because these four antiviral drugs inhibit viral replication, they are most effective when given early in the influenza disease course.

Baloxavir marboxil is indicated for use in patients aged 12 to 64 years and thus has limited use in the pediatric population. It is important to consider that baloxavir marboxil has limited clinical trial experience in the adolescent age group as well, described later.

Edward A. Bell

Clinical studies supporting baloxavir marboxil

The FDA’s approval of baloxavir marboxil was based in part on a phase 3 clinical trial published in 2018 (Hayden and colleagues). This randomized, placebo-controlled trial was conducted during the 2016-2017 influenza season and included participants — mostly from Japan but some from the United States — aged 12 to 64 years (n = 1,064) who had laboratory-confirmed, uncomplicated influenza. Participants aged 20 to 64 years were additionally randomly assigned to oseltamivir, whereas participants aged 12 to 19 years were given only baloxavir marboxil or placebo. Participants given baloxavir marboxil received a single, weight-based dose of 40 mg or 80 mg in a tablet. The primary endpoint was time to alleviation of influenza symptoms. Participants were enrolled and treated within 48 hours of the onset of influenza symptoms. Most participants (84.8% to 88.1%) were infected with influenza A(H3N2) virus. Overall, those who received baloxavir marboxil demonstrated a shorter time to symptom alleviation (53.7 hours) compared with those who received placebo (80.2 hours) — a 26.5-hour difference (P < .001). Adolescents who received baloxavir marboxil (n = 63) also demonstrated a shorter time to symptom alleviation — a difference of 38.6 hours compared with placebo (P < .006). However, the difference in time to alleviation of symptoms was not statistically significant between baloxavir marboxil and oseltamivir in participants aged 20 to 64 years (53.5 hours vs. 53.8 hours after receipt of baloxavir marboxil vs. placebo, respectively). Baloxavir marboxil was superior to placebo and oseltamivir in reducing influenza viral load 1 day after initiation of treatment. The median duration of infectious virus detection was shorter in participants who received baloxavir marboxil (24 hours) vs. placebo (96 hours; P < .001) or oseltamivir (72 hours; P < .001). This may have clinical implications for reduced virus transmission. Nearly 10% of participants who received baloxavir marboxil yielded influenza virus with reduced susceptibility (protein variants with I38T/M amino acid substitutions). More participants who received oseltamivir experienced treatment-related adverse effects (8.4%) vs. patients who received baloxavir marboxil (4.4%; P = .009) or placebo (3.9%).

A study presented at IDWeek 2018 by Ison and colleagues evaluated baloxavir marboxil in participants at higher risk for influenza complications. The analysis was similar to the phase 3 trial by Hayden and colleagues — a randomized, double-blind study comparing baloxavir marboxil to placebo and oseltamivir in participants aged 12 years and older (n = 1,163). Nearly 48% of participants were infected with influenza A(H3N2) virus, whereas 41.6% were infected with influenza B and 6.9% were infected with influenza A(H1N1). The most common risk factors for influenza-related complications in the study were age older than 65 years (27.4%) and the presence of chronic lung disease or asthma (39.2%). The time to symptom improvement — the primary endpoint — was significantly shorter for participants who received baloxavir marboxil (73.2 hours) vs. placebo (102.3 hours), but not vs. oseltamivir (81 hours). Participants who received baloxavir marboxil had significantly fewer influenza complications (P < .0001) and less systemic antibiotic use (P = .0112) than participants receiving placebo but not oseltamivir.

Two additional studies of baloxavir marboxil are currently recruiting pediatric participants with influenza-like symptoms. Another study is recruiting hospitalized patients aged 12 years or older to evaluate the combination of baloxavir marboxil with a standard-of-care NI for the treatment of severe influenza.

Professional society recommendations

Recommendations by the AAP for the treatment of influenza during the 2018-2019 season were published before the availability of baloxavir marboxil. Guidelines published in 2018 by the Infectious Diseases Society of America briefly describe the studies mentioned earlier, but they do not make a formal recommendation. Current recommendations from the CDC include the use of oseltamivir, zanamivir, peramivir or baloxavir marboxil for the treatment of influenza in patients with uncomplicated disease. In children with severe or complicated influenza, oral oseltamivir is the antiviral drug recommended by the CDC. Influenza A and B viruses’ susceptibility to oseltamivir remains high in the U.S. — greater than 99% — as of the week ending Feb. 9.

Conclusions

Baloxavir marboxil has a very limited role in the current treatment of influenza in children aged 12 years and older. It does offer potential advantages that have yet to be demonstrated and evaluated. Its greatest potential advantage relates to its long elimination half-life (approximately 80 hours), which allows it to be given as a one-time dose within 48 hours of symptom onset. Although this pharmacokinetic characteristic may be beneficial for children and families with the potential for poor medication adherence, this property may also be “abused” by some (“Can you prescribe the new flu drug that I only have to give to my child once?”). More important considerations include the lack of significant clinical experience with baloxavir marboxil in the pediatric population. The NI agents, especially oseltamivir, have much greater demonstrated clinical experience and benefit in the pediatric population. The cost of baloxavir marboxil is approximately $160, compared with $50 to $100 for generic oseltamivir. Baloxavir marboxil may offer additional benefits of reduced viral transmission, its use in the treatment of NI-resistant influenza, and additive or synergistic therapy when combined with an NI. These benefits, however, are theoretical and require additional demonstration and evaluation. Clinical trials are currently recruiting participants to assess these benefits, and the results are eagerly awaited.

Disclosure: Bell reports no relevant financial disclosures.

Four FDA-approved antiviral drugs are recommended by the CDC for the treatment of influenza during the 2018-2019 season. The latest drug to be included, approved by the FDA in October 2018, is Xofluza (baloxavir marboxil, Genetech). It is a prodrug that is hepatically metabolized to its active metabolite, baloxavir. Baloxavir marboxil is unique because it functions by a different mechanism of action than oseltamivir — including Tamiflu (Genentech) and generic versions — Relenza (zanamivir, GlaxoSmithKline) and Rapivab (peramivir, Seqirus). These last three drugs are all neuraminidase inhibitors (NIs) — preventing virus replication by inhibiting the influenza viral enzyme neuraminidase. Xofluza functions to inhibit influenza viral replication as well, via a different mechanism. It is a cap-dependent endonuclease inhibitor, inhibiting viral replication by disrupting viral RNA transcription. Because these four antiviral drugs inhibit viral replication, they are most effective when given early in the influenza disease course.

Baloxavir marboxil is indicated for use in patients aged 12 to 64 years and thus has limited use in the pediatric population. It is important to consider that baloxavir marboxil has limited clinical trial experience in the adolescent age group as well, described later.

Edward A. Bell

Clinical studies supporting baloxavir marboxil

The FDA’s approval of baloxavir marboxil was based in part on a phase 3 clinical trial published in 2018 (Hayden and colleagues). This randomized, placebo-controlled trial was conducted during the 2016-2017 influenza season and included participants — mostly from Japan but some from the United States — aged 12 to 64 years (n = 1,064) who had laboratory-confirmed, uncomplicated influenza. Participants aged 20 to 64 years were additionally randomly assigned to oseltamivir, whereas participants aged 12 to 19 years were given only baloxavir marboxil or placebo. Participants given baloxavir marboxil received a single, weight-based dose of 40 mg or 80 mg in a tablet. The primary endpoint was time to alleviation of influenza symptoms. Participants were enrolled and treated within 48 hours of the onset of influenza symptoms. Most participants (84.8% to 88.1%) were infected with influenza A(H3N2) virus. Overall, those who received baloxavir marboxil demonstrated a shorter time to symptom alleviation (53.7 hours) compared with those who received placebo (80.2 hours) — a 26.5-hour difference (P < .001). Adolescents who received baloxavir marboxil (n = 63) also demonstrated a shorter time to symptom alleviation — a difference of 38.6 hours compared with placebo (P < .006). However, the difference in time to alleviation of symptoms was not statistically significant between baloxavir marboxil and oseltamivir in participants aged 20 to 64 years (53.5 hours vs. 53.8 hours after receipt of baloxavir marboxil vs. placebo, respectively). Baloxavir marboxil was superior to placebo and oseltamivir in reducing influenza viral load 1 day after initiation of treatment. The median duration of infectious virus detection was shorter in participants who received baloxavir marboxil (24 hours) vs. placebo (96 hours; P < .001) or oseltamivir (72 hours; P < .001). This may have clinical implications for reduced virus transmission. Nearly 10% of participants who received baloxavir marboxil yielded influenza virus with reduced susceptibility (protein variants with I38T/M amino acid substitutions). More participants who received oseltamivir experienced treatment-related adverse effects (8.4%) vs. patients who received baloxavir marboxil (4.4%; P = .009) or placebo (3.9%).

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A study presented at IDWeek 2018 by Ison and colleagues evaluated baloxavir marboxil in participants at higher risk for influenza complications. The analysis was similar to the phase 3 trial by Hayden and colleagues — a randomized, double-blind study comparing baloxavir marboxil to placebo and oseltamivir in participants aged 12 years and older (n = 1,163). Nearly 48% of participants were infected with influenza A(H3N2) virus, whereas 41.6% were infected with influenza B and 6.9% were infected with influenza A(H1N1). The most common risk factors for influenza-related complications in the study were age older than 65 years (27.4%) and the presence of chronic lung disease or asthma (39.2%). The time to symptom improvement — the primary endpoint — was significantly shorter for participants who received baloxavir marboxil (73.2 hours) vs. placebo (102.3 hours), but not vs. oseltamivir (81 hours). Participants who received baloxavir marboxil had significantly fewer influenza complications (P < .0001) and less systemic antibiotic use (P = .0112) than participants receiving placebo but not oseltamivir.

Two additional studies of baloxavir marboxil are currently recruiting pediatric participants with influenza-like symptoms. Another study is recruiting hospitalized patients aged 12 years or older to evaluate the combination of baloxavir marboxil with a standard-of-care NI for the treatment of severe influenza.

Professional society recommendations

Recommendations by the AAP for the treatment of influenza during the 2018-2019 season were published before the availability of baloxavir marboxil. Guidelines published in 2018 by the Infectious Diseases Society of America briefly describe the studies mentioned earlier, but they do not make a formal recommendation. Current recommendations from the CDC include the use of oseltamivir, zanamivir, peramivir or baloxavir marboxil for the treatment of influenza in patients with uncomplicated disease. In children with severe or complicated influenza, oral oseltamivir is the antiviral drug recommended by the CDC. Influenza A and B viruses’ susceptibility to oseltamivir remains high in the U.S. — greater than 99% — as of the week ending Feb. 9.

Conclusions

Baloxavir marboxil has a very limited role in the current treatment of influenza in children aged 12 years and older. It does offer potential advantages that have yet to be demonstrated and evaluated. Its greatest potential advantage relates to its long elimination half-life (approximately 80 hours), which allows it to be given as a one-time dose within 48 hours of symptom onset. Although this pharmacokinetic characteristic may be beneficial for children and families with the potential for poor medication adherence, this property may also be “abused” by some (“Can you prescribe the new flu drug that I only have to give to my child once?”). More important considerations include the lack of significant clinical experience with baloxavir marboxil in the pediatric population. The NI agents, especially oseltamivir, have much greater demonstrated clinical experience and benefit in the pediatric population. The cost of baloxavir marboxil is approximately $160, compared with $50 to $100 for generic oseltamivir. Baloxavir marboxil may offer additional benefits of reduced viral transmission, its use in the treatment of NI-resistant influenza, and additive or synergistic therapy when combined with an NI. These benefits, however, are theoretical and require additional demonstration and evaluation. Clinical trials are currently recruiting participants to assess these benefits, and the results are eagerly awaited.

Disclosure: Bell reports no relevant financial disclosures.