1. N Engl J Med. 2018 Sep 6;379(10):913-923. doi: 10.1056/NEJMoa1716197.

Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents.

Hayden FG(1), Sugaya N(1), Hirotsu N(1), Lee N(1), de Jong MD(1), Hurt AC(1),
Ishida T(1), Sekino H(1), Yamada K(1), Portsmouth S(1), Kawaguchi K(1), Shishido 
T(1), Arai M(1), Tsuchiya K(1), Uehara T(1), Watanabe A(1); Baloxavir Marboxil
Investigators Group.

Collaborators: Arahata M, Doi T, Fujishima H, Fukuyo K, Hachinohe H, Harada H,
Harada Y, Hatakeyama S, Hisadome T, Horikawa I, Ikeda M, Ishikawa T, Ito J, Iwaki
N, Kanemitsu H, Kinoshita M, Kitada H, Kokubun T, Komo T, Kuroki H, Matsunaga A, 
Mitani I, Miyazono H, Morizono S, Murakawa H, Nagumo A, Nakama S, Nakazato H,
Nemoto S, Noguchi Y, Ogasawara T, Ogawa J, Okawa H, Okumura H, Owada Y, Sadanaga 
Y, Sasaki R, Sasho H, Satake K, Seki M, Shudo H, Sugimoto M, Taguchi F, Takahashi
K, Takei J, Tamaki S, Tanaka H, Tanaka K, Tanaka S, Tomori H, Uehara A, Ueyama S,
Umezawa Y, Umezu T, Wakasa Y, Yamada K, Yamagata T, Yamamoto M, Yasuda K,
Yokoyama T, Yoshida R, Yamaguchi T, Yamato T, Ahiko T, Aida K, Akahata M, Amada
Y, Ando M, Asai S, Chinen T, Egashira K, Fujigaki T, Fujimaki Y, Fukushima Y,
Funato A, Gushiken M, Haji Y, Hashiguchi K, Hirose K, Honda K, Igarashi T, Iguchi
K, Iida Y, Iizuka T, Irahara M, Irie T, Ishida K, Ishii H, Ishikawa K, Kaji N,
Kamezawa T, Karimata Y, Kato M, Katsura F, Kawada T, Kawamoto K, Kikuchi K,
Kikumori H, Kimura S, Kin H, Kiyosue A, Kondo M, Kooguchi K, Kurokawa J, Maeda K,
Maeda K, Maezawa Y, Matsuo K, Minagawa K, Minami F, Miyazono Y, Mori H, Morita Y,
Moriyama I, Nakamura H, Nakano H, Niwa K, Nozaki M, Numata A, Obata A, Ono R,
Onoi Y, Osaki S, Ryuto M, Sakaguchi S, Sakayori S, Sasaki Y, Sato S, Sato T, Sato
Y, Sato Y, Segawa Y, Shibasaki A, Shimamoto E, Shimomura H, Sugiura T, Suzuki S, 
Suzuki T, Tabuchi H, Takatsuka Y, Takeda F, Takeda K, Tamura S, Tanaka K, Tanaka 
N, Tanaka T, Taniguchi H, Tarukawa Y, Tatera S, Toguchi A, Toshima M, Tsukazaki
T, Tsurumachi T, Ueyama S, Wada S, Yamamoto M, Yamauchi M, Yokoyama T, Yoshimura 
R, Yoshimura R, Yurino N, Aazami H, Afzal H, Aish B, Alpizar S, Altamirano D,
Ampajwala M, Ansari S, Ausaf N, Bauer S, Beasley R, Bellucci-Jackson J, Berman L,
Bernstein R, Bianco S, Winnie M, Boghara H, Boone T, Carpio JM, Coleman S, De La 
Calle G, Dennis P, DeSantis M, DeValle O, Dever M, Dharma C, Dhillon R, Doehring 
L, Garcia B, Garcia H, Garcia-Septien R, Gogate S, Goisse M, Gould GM, Grant D,
Guillen M, Hazan-Steinberg S, Heller B, Helman L, Hoppers M, Jenkins J, Jones A, 
Kaplan A, Kayali Z, Kelly R, Kreutter F, Ledo-Sanchez G, Lim H, Lorites J, Loya
A, Mangune E, McLean B, Melikian G, Michael M, Murphy J IV, Nadkarni S, Naygandhi
Y, Ong S, Paliwal Y, Petersen D, Peterson J, Pham D, Pluto T, Pouzar J Jr,
Raikhel M, Rosen R, Samson M, Santander J, Schear M, Secrist N, Sitz K, Siu B,
Slandzicki A, Solis J, Soong W, Sotolongo R, Springer R, Stewart J, Sullivan J,
Tavel E Jr, Torres G, Troyan B, Trueba P, VanNess W III, Vaughn M, Velazquez F,
Weinstein D.

Author information: 
(1)From the Department of Medicine, University of Virginia School of Medicine,
Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama 
(N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, 
Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.),
Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A.,
K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, 
Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) -
all in Japan; the Division of Infectious Diseases, Department of Medicine,
University of Alberta, Edmonton, Canada (N.L.); the Department of Medical
Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam
(M.D.J.); the Department of Microbiology and Immunology, University of Melbourne,
at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC,
Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).

Comment in
    N Engl J Med. 2018 Sep 6;379(10):975-977.

BACKGROUND: Baloxavir marboxil is a selective inhibitor of influenza
cap-dependent endonuclease. It has shown therapeutic activity in preclinical
models of influenza A and B virus infections, including strains resistant to
current antiviral agents.
METHODS: We conducted two randomized, double-blind, controlled trials involving
otherwise healthy outpatients with acute uncomplicated influenza. After a
dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and 
oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80
mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of
oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was 
the time to alleviation of influenza symptoms in the intention-to-treat infected 
population.
RESULTS: In the phase 2 trial, the median time to alleviation of influenza
symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the
placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected
population included 1064 patients; 84.8 to 88.1% of patients in each group had
influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 
hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared
with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to
alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was
associated with greater reductions in viral load 1 day after initiation of the
regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of
baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir
recipients. The emergence of polymerase acidic protein variants with I38T/M/F
substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and
9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial,
respectively.
CONCLUSIONS: Single-dose baloxavir was without evident safety concerns, was
superior to placebo in alleviating influenza symptoms, and was superior to both
oseltamivir and placebo in reducing the viral load 1 day after initiation of the 
trial regimen in patients with uncomplicated influenza. Evidence for the
development of decreased susceptibility to baloxavir after treatment was also
observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1
ClinicalTrials.gov number, NCT02954354 .).

DOI: 10.1056/NEJMoa1716197 
PMID: 30184455  [Indexed for MEDLINE]