HIV and ID Observations

National Library of Medicine

Last week, the FDA approved a new drug for treatment of influenza, baloxavir marboxil (Xofluza).

The drug is indicated for treatment of symptomatic influenza in patients 12 years of age or older. As with existing treatments, it should be started within 48 hours of symptom onset.

In a comparative clinical trial in otherwise healthy outpatients, baloxavir and oseltamivir (commonly known as Tamiflu) comparably reduced the duration of flu symptoms — both on average by about 36 hours. Each treatment was more effective if started within 24 hours of symptom onset.

Baloxavir differs from oseltamivir in several ways, some of them potentially important:

• Treatment is a single dose. Patients receive 40 mg if their weight is between 40 and 80 kg, and 80 mg (two pills) if 80 kg or more. As every primary care clinician knows, oseltamivir is 75 mg twice daily for 5 days.
• Side effects ascribed to the treatment occurred less frequently in those randomized to baloxavir vs oseltamivir — specifically, 3.9% and 8.4% for baloxavir and oseltamivir, respectively (p=0.009). The side effects table from the study indicate that GI-related side effects (especially nausea) were numerically more common with oseltamivir. In clinical practice, this is the most commonly encountered problem with the drug, which can be diminished (but not eliminated) when oseltamivir is taken with food. The incidence of severe adverse events did not differ between arms.
• Baloxavir lowered influenza viral loads in respiratory secretions faster than oseltamivir. The clinical significance of this faster antiviral action is unclear. Might this make patients less contagious more quickly? Or could this translate to a clinical benefit in very immunocompromised hosts, or in the most severe cases? A study in “high risk” adults demonstrated a faster recovery time compared to oseltamivir if the infecting virus was influenza B; outcomes in influenza A were similar. A different clinical trial of the drug in hospitalized patients is about to start.
• The mechanism of action is different. Unlike the neuraminidase inhibitors (oseltamivir, et al), baloxavir blocks influenza replication through inhibition of viral endonuclease (see the fine video below). It’s the first flu drug with this mechanism of action. The good news is that baloxavir should retain activity against neuraminidase-resistant strains, which periodically emerge and could be a substantial global threat.
• Baloxavir treatment selects for resistance. This excellent accompanying editorial to the above-cited phase 3 trial describes the resistance concerns in more detail. Will this resistance limit the usefulness of the drug? Or will the impaired replication capacity of resistance variants make them less transmissible?
• Oseltamivir is generic, and cheap. A 5-day course costs around $50. Payers have undoubtedly negotiated a much lower price. (That stuff is kept secret from us patients and clinicians, remember.) Baloxavir will cost $150, regardless of the dose, with coupons available to lower the price.

My colleague Ken Freedberg, whose research focus is cost-effectiveness, often jokes that he’s frequently the last to speak at a conference since the topic of cost is so often considered secondary to the “scientific” parts of the program.

Please note, Ken, that I meant no offense by putting cost last in the bulleted list above.

Especially since with baloxavir, it’s probably this very point — cost — that will limit use of the drug, at least initially. Insurance plans are not eager (an understatement) to add new treatments to their formularies that cost more than existing options unless they are clearly more effective, or safer, or preferably both.

With baloxavir, while it seems to have some advantages over osteltamivir in these metrics, we’re not quite there yet.

In the meantime, we can make fun of the brand name —Xofluza! — which, if you say it loudly and quickly, kind of sounds like someone sneezing.