October 28th, 2018

New Flu Drug Offers Convenience, Fast Activity, and a Novel Mechanism — at a Price

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.

3 Responses to “New Flu Drug Offers Convenience, Fast Activity, and a Novel Mechanism — at a Price”

  1. Loretta S says:

    I see I wasn’t the only one who thought Xofluza sounds like a sneeze. I can imagine the manufacturer airing a TV ad with flu victims sneezing, but actually saying, “XoFLUza!”. I even like the generic name of this drug: baloxavir marboxil. It has a nice rhythm to it.

    A single dose sounds good to me. But I can imagine my patients telling the pharmacy no thanks when they see the price tag on a drug their insurance company won’t cover. We’ll see how that plays out. I guess we should be grateful the manufacturer didn’t price it at $1,500 per dose.

  2. Jon Blum says:

    The study cited claiming that baloxavir led to faster recovery in immunocompromised hosts had the following, baffling claim:

    “TTIIS was significantly shorter in BXM than PLC (median 73.2hr vs 102.3hr, p<0.0001) and numerically shorter than Os (81.0 hr, p=0.8347)."

    "Numerically shorter" meant less than 9 hours, but more importantly, look at the P value. How could they say this with a straight face? Hopefully when this goes to press, the journal will not allow them to make a statement like this.

    The reduced viral shedding in the first few days is intriguing, but as you say, whether that will actually impact transmission is not so clear. Is a 10,000X reduction in shedding better than 100X?

    The purpose of coupons is similar to sampling, on the patient side instead of the doctor side. They reduce the patient cost-share to create an incentive to use a more expensive medication. My health system does not accept coupons (and I'm not allowed to sample drugs, either). This is one of many methods the pharmaceutical industry uses to drive up drug costs.

  3. Ken Freedberg says:

    Thanks Paul for the last bullet on cost.

    While we used to always be at the end of conferences and courses (you know that your lecture is especially undervalued when not only is it at the end of the course, but it is after the final exam), this has started to change. Notable was a meeting on NCDs in HIV in low and middle income countries at the Fogarty Center a few years ago when our colleague Emily Hyle was asked to talk about cost-effectiveness right after the overview talk at the beginning of the meeting. In every presentation after that (CVD management, cancer treatment, screening and treatment for renal disease, mental health issues, etc.), towards the end of each presentation, the speaker would turn to Emily for a sort of ‘cost-effectiveness blessing.’

    Now we’ll see if we can get cost-effectiveness to the top of your blog post. Or at least to right after effectiveness…

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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