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Sixty seconds on . . . baloxavir

BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4531 (Published 26 October 2018) Cite this as: BMJ 2018;363:k4531

Rapid Response:

Baloxavir: Roche’s new oseltamivir?

Is baloxavir really an “advance” in influenza therapy? What does the evidence say?

First, the US approval was based on two randomized trials which compared baloxavir to oseltamivir (Tamiflu) and placebo. According to the FDA, baloxavir beat placebo but not oseltamivir (on time to alleviation of symptoms).[1]

But according to Japanese regulators who approved the drug in February, baloxavir did not beat placebo in the subgroup of US adults >20 years old, likely the primary population that will be offered this drug in the US, even though time to alleviation of symptoms in the placebo group was similar in both Japanese and US adults.[2]

Second, the drug was granted “priority review,” a pathway for speeding drugs to market that FDA deems “if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.”[1] But the drug was only studied in patients with uncomplicated influenza-like illness. While the authors claim that future studies in more seriously ill patients are planned, the current trials specifically excluded high-risk patients.[3] And the label carries a warning: “XOFLUZA [baloxavir] has not been shown to prevent such complications [serious bacterial infections following influenza].” Oseltamivir’s label has carried that same warning since 2000 given the lack of evidence from randomized trials, yet governments still stockpiled billions worth of the drug.

Third, despite the FDA touting the importance of new drugs because of the threat of “resistance” to antivirals,[1] the trials with baloxavir do not state that that the drug was studied in patients with resistance to oseltamivir, so we have no evidence of what the drug does in that situation. Effects in patients with “resistance” may be affected by patient factors and in vitro activity alone is not a direct measure of patient benefit. Effects in patients with resistance to other drugs remains hypothetical. And, if resistance is common, shouldn’t it be easy to study? Since most patients recover spontaneously on placebo it is ethical to test this hypothesis. Furthermore, the drug has not been studied to evaluate a potential effect on decreasing influenza transmission so its effects for this important outcome remain unknown.

Fourth, despite baloxavir’s novel mechanism of action, there remains no evidence this translates into any added benefit for patients. Indeed the authors state that baloxavir has “greater antiviral activity”[3] than older drugs like oseltamivir yet in these studies that in vitro activity did not translate to patient benefits. The sole benefit of baloxavir seems to be ease of dosing administration with a single dose.

Lastly the symptom measures used in the baloxavir trials represent a subset of the symptoms experienced by patients with influenza, and the effects of the drug on the entire range of symptoms of influenza remain unknown. More comprehensive measures of patient symptoms in influenza have been developed.[4]

We’re having déjà vu. It took us four years to access the full data on oseltamivir, and when we did, it turned out more ineffective and less safe than manufacturer-funded and authored journal publications had suggested. How long will it take for an independent analysis of baloxavir? Is Roche prepared to provide the data?

Taken over the arc of 50 years the registration trials of baloxavir provide evidence of the same benefit of a whole host of registered and never registered antivirals: shortening of illness duration on a specific subset of patient symptoms, mostly related to patient fever (body temperature), which could be addressed by antipyretics. Use of acetaminophen was allowed but not reported in the results of the current studies.[3] All other concomitant therapies were not allowed. The claimed new mechanism of action is at odds with evidence of baloxavir providing symptomatic relief that is not superior to oseltamivir in patients as seen in practice, especially since resistance testing is not routinely done in real-world settings. The potential effects in patients who test negative for influenza could point to inaccurate diagnosis or an alternative mode of action such as direct action on the central nervous system. This may be the way adamantanes and neuraminidase inhibitors reduce fever and duration of symptoms.[5][6] This is a constant concern with each new generation of antivirals.

The current evidence shows baloxacvir is a “new option” that may be effective in shortening the duration of a subset of symptoms of influenza, whose effects in US adults remains unclear, that is easier to administer, but whose other benefits are hypothetical at this point and require further testing.

Roche markets both oseltamivir and the new baloxavir. Following FDA’s approval of generic oseltamivir,[7] could baloxavir be Roche’s new oseltamivir?

Peter Doshi
Tom Jefferson
Mark Jones
John H. Powers III

References

[1] FDA. FDA approves new drug to treat influenza. Oct 24, 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm
[2] Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau. Xofluza 10 mg and 20 mg_Shionogi & Co., Ltd._Review Report. Feb 8, 2018. http://www.pmda.go.jp/files/000225380.pdf
[3] Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018 Sep 6;379(10):913–23. https://doi.org/10.1056/NEJMoa1716197
[4] Powers JH 3rd, Bacci ED, Guerrero ML, Leidy NK, Stringer S, Kim K, et al. Reliability, Validity, and Responsiveness of InFLUenza Patient-Reported Outcome (FLU-PRO©) Scores in Influenza-Positive Patients. Value Health. 2018 Feb;21(2):210–8.
[5] Jefferson T, Demicheli V, Di Pietrantonj C, Rivetti D. Amantadine and rimantadine for influenza A in adults. Cochrane Database of Systematic Reviews 2006 , Issue 2 . Art. No.: CD001169. DOI: 10.1002/14651858.CD001169.pub3
[6] Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr 10;(4):CD008965.
[7] FDA. The FDA approves first generic version of widely used influenza drug, Tamiflu. Aug 4, 2016. https://web.archive.org/web/20160808151428/http://www.fda.gov/Drugs/Drug...

Competing interests: PD has received travel funds from the European Respiratory Society (2012, for a talk on oseltamivir) and Uppsala Monitoring Center (2018); grants from the Laura and John Arnold Foundation (2017-20), American Association of Colleges of Pharmacy (2015), Patient-Centered Outcomes Research Institute (2014-16), Cochrane Methods Innovations Fund (2016-18), and UK National Institute for Health Research (2011-14, for a Cochrane review of neuraminidase inhibitors for influenza); and is an editor at The BMJ and unpaid member of the Reagan-Udall Foundation for the FDA. MJ was a co-investigator on a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for influenza; was a co-recipient of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews; and is a paid consultant on a John and Laura Arnold Foundation grant for development of a RIAT Support Center (2017-2020). TJ was a recipient of a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for influenza. In 2011-13, TJ acted as an expert witness in litigation related to the antiviral oseltamivir. He has acted as a consultant for Roche (1997-99). In 2014 he was retained as a scientific adviser to a legal team acting on oseltamivir. TJ has a potential financial conflict of interest in the drug oseltamivir. JHP reports personal fees from Abbvie, Cardeas, Cempra, Contrafect, Gilead, Johnson & Johnson, MedImmune, Novartis, Otsuka, Pfizer, Roche, Romark and Trius outside the submitted work.

29 October 2018
Peter Doshi
Assistant professor
Tom Jefferson, Mark Jones, John H. Powers III
University of Maryland School of Pharmacy
Baltimore, MD, USA