A New Flu Drug is Approved – Should You Start Prescribing It?

The FDA approved baloxavir marboxil (brand name Xofluza) on October 24. It was on the fast track* for approval by the FDA, and they had agreed to deliver their ruling by December 24; they beat that deadline by a good bit. Baloxavir is a completely new type of anti-influenza drug, acting on an earlier stage of influenza virus replication in the host cell than does the more familiar oseltamivir (brand name Tamiflu).

(slide 34 at http://www.shionogi.co.jp/en/ir/pdf/e_p151030.pdf; S-033188 was the name for baloxavir during early stages of research)

Not at all by coincidence, I held a journal club for infectious diseases fellows and faculty at my house last week to discuss the New England Journal article from September 6 (Hayden FG, et al, 379:913) that reported on 2 trials of baloxavir. I imagined the drug being approved by the FDA on Christmas Eve, right before the deadline, followed shortly thereafter by a call from 1 of you readers to our on-call fellow or attending physician asking for advice on use of this new agent. We went through the article, including the supplementary online tables and graphs and the 400-page document detailing all of the study protocol details, with a fine-tooth comb. It really was a well-designed set of studies, but the results may be somewhat more limited than you might hope. Here are a few of the key points we discussed:

1. The studies combined included just under 2000 patients, but most were adults. Bottom line: baloxavir had a modest effect on duration of symptoms compared to placebo, but no real clinical benefit when compared to influenza patients receiving oseltamivir.
2. All of the patients had to be enrolled within 48 hours of illness onset.
3. Only about 200 children (the exact number was hard to determine from the report), none younger than 12 years of age, actually received baloxivir. None of the 12-19 year olds received oseltamivir, the only comparison was to approximately 100 placebo subjects. (Part of this had to do with the fact that oseltamivir is not approved for use in children in Japan, the home of baloxavir's manufacturer and of many of the children in the study.)
4. When looking just at amounts of influenza virus being shed in the respiratory tract, baloxavir decreased the viral quantity much more quickly than did oseltamivir but as stated in #1 above with no substantial clinical benefit.
5. Side effects attributable to baloxavir weren't bad, mostly GI, about 4%.
6. Most of the influenza viruses infecting study subjects were influenza A, so we don't know much about how baloxavir will handle influenza B virus infection.
7. Baloxavir resistance developed in some recipients on therapy, a cautionary note for the future. However, another study published this summer showed that those baloxavir-resistant mutant flu strains did not replicate well in tissue culture, implying they may have lost virulence with this resistance mutation.

So, what would I recommend for now?
- The main down side of baloxivir is that it is new, too early to know about very uncommon or rare side effects as well as how well it will perform in real life where we don't always have the opportunity to start treatment in the first 48 hours of illness. Also note that the number of pediatric age group subjects studied was very small.
- I wouldn't use it all under 12 years of age, we have no data in that age group.
- Baloxir is easier to use than oseltamivir - 1 dose versus 2 daily doses for 5 days with oseltamivir. That could be important for some of your patients and families.
- The part about faster decrease in viral quantity in respiratory secretions in #4 above might be a consideration if your patient is in a household or otherwise in close contact with an immunocompromised/high risk patient. Although not really studied, it's possible that the decrease in viral load might translate to a shorter duration of transmissibility of live virus to others.

Oh, and by the way, baloxivir is being estimated to cost $150 (allegedly with a coupon available in the US to bring it down to $30 for insured individuals), compared to about $135 for oseltamivir, but again oseltamivir coupons are available online and elsewhere. Of course everything varies according to insurance plan, so maybe best to recommend that individuals check with their own plans about both drugs. All other things being equal on the risk/benefit scale, I'd go with whatever is cheaper.

*Actually the correct term is Priority Review, a process set in place by the 1992 Prescription Drug User Fee Act (PDUFA) where pharmaceutical companies pay a user fee to the FDA. Under Priority Review, the FDA reviews an application within 6 months rather than the usual 10 months under Standard Review, partially funded by these fees. A drug manufacturer can request a Priority Review, but the FDA determines if it is appropriate and uses the same criteria for approval that are applied under Standard Review.