Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents
Frederick G Hayden, Norio Sugaya, Nobuo Hirotsu, Nelson Lee, Menno D de Jong, Aeron C Hurt, Tadashi Ishida, Hisakuni Sekino, Kota Yamada, Simon Portsmouth, Keiko Kawaguchi, Takao Shishido, Masatsugu Arai, Kenji Tsuchiya, Takeki Uehara, Akira Watanabe, Baloxavir Marboxil Investigators Group, Masahisa Arahata, Takahito Doi, Hiromitsu Fujishima, Kensuke Fukuyo, Hiroshi Hachinohe, Hiroshi Harada, Yuji Harada, Sadamune Hatakeyama, Tetsuo Hisadome, Isao Horikawa, Mitsumi Ikeda, Takayuki Ishikawa, Junichi Ito, Norio Iwaki, Hiroyoshi Kanemitsu, Masaharu Kinoshita, Hirokazu Kitada, Takehiko Kokubun, Tomoyuki Komo, Haruo Kuroki, Atsushi Matsunaga, Ikuo Mitani, Hirotaka Miyazono, Shigeaki Morizono, Hisashi Murakawa, Akihiko Nagumo, Seitaro Nakama, Hidehisa Nakazato, Satohiko Nemoto, Yoshimasa Noguchi, Tadahiko Ogasawara, Jun Ogawa, Hiroji Okawa, Haruhiko Okumura, Yasuko Owada, Yasuaki Sadanaga, Ryotaro Sasaki, Hideyuki Sasho, Kazuo Satake, Masahiko Seki, Hiroshi Shudo, Masayuki Sugimoto, Fumihiro Taguchi, Kazunori Takahashi, Jiro Takei, Seishu Tamaki, Hiroaki Tanaka, Koukichi Tanaka, Shinichi Tanaka, Hiroaki Tomori, Akira Uehara, Sigehiro Ueyama, Yoshihiro Umezawa, Toru Umezu, Yutaka Wakasa, Katsumi Yamada, Toshiharu Yamagata, Munemitsu Yamamoto, Kenji Yasuda, Takahiro Yokoyama, Riko Yoshida, Tsuyoshi Yamaguchi, Tsuyoshi Yamato, Tomoaki Ahiko, Katsumaro Aida, Masaki Akahata, Yasushi Amada, Michio Ando, Shunji Asai, Tetsu Chinen, Keisuke Egashira, Toru Fujigaki, Yutaka Fujimaki, Yasushi Fukushima, Akitoshi Funato, Masamichi Gushiken, Yoichiro Haji, Kazuhiro Hashiguchi, Kazuhito Hirose, Kazuyuki Honda, Tadayuki Igarashi, Keiichi Iguchi, Yoshiki Iida, Takashi Iizuka, Minoru Irahara, Takashi Irie, Kiyotaka Ishida, Hajime Ishii, Kazuo Ishikawa, Nobuyuki Kaji, Takashi Kamezawa, Yoichi Karimata, Masaki Kato, Fumihiro Katsura, Toshio Kawada, Kenji Kawamoto, Koki Kikuchi, Hiroshi Kikumori, Shiro Kimura, Heido Kin, Arihiro Kiyosue, Masahiko Kondo, Kunihiko Kooguchi, Jyoji Kurokawa, Katsutoshi Maeda, Kazuhisa Maeda, Yoshihiko Maezawa, Kaneyuki Matsuo, Kazuo Minagawa, Fumiko Minami, Yuko Miyazono, Hisao Mori, Yuko Morita, Ichirou Moriyama, Harumichi Nakamura, Hiroki Nakano, Kiyoshi Niwa, Minoru Nozaki, Akira Numata, Akishige Obata, Ryuta Ono, Yutaka Onoi, Shinichi Osaki, Masahiro Ryuto, Sachiyo Sakaguchi, Susumu Sakayori, Yusuke Sasaki, Shunya Sato, Tatsuyuki Sato, Yasuo Sato, Yuji Sato, Yutaka Segawa, Atsushi Shibasaki, Etsuji Shimamoto, Hiroshi Shimomura, Tatsushi Sugiura, Shin Suzuki, Takayuki Suzuki, Hirotaka Tabuchi, Yoji Takatsuka, Fumihiko Takeda, Kazuo Takeda, Shinichi Tamura, Keiichi Tanaka, Norimitsu Tanaka, Toshihiro Tanaka, Hiroshi Taniguchi, Yuriko Tarukawa, Shuichi Tatera, Akira Toguchi, Muneatsu Toshima, Tomio Tsukazaki, Tetsuya Tsurumachi, Shigehiro Ueyama, Satoko Wada, Manabu Yamamoto, Masayuki Yamauchi, Takato Yokoyama, Ryota Yoshimura, Ryuji Yoshimura, Nobuo Yurino, Hessam Aazami, Haider Afzal, Bassil Aish, Sady Alpizar, Dario Altamirano, Madhavi Ampajwala, Saadat Ansari, Niaz Ausaf, Steven Bauer, Richard Beasley, Jennifer Bellucci-Jackson, Larry Berman, Richard Bernstein, Salvatore Bianco, Michael Winnie, Haresh Boghara, Tasha Boone, Jose M Carpio, Stephen Coleman, Gilda De La Calle, Patrick Dennis, Michael DeSantis, Oscar DeValle, Michael Dever, Chrisette Dharma, Rennee Dhillon, Larry Doehring, Bernard Garcia, Hiram Garcia, Ramon Garcia-Septien, Shaila Gogate, Marcy Goisse, Glenn Michael Gould, David Grant, Mario Guillen, Sabine Hazan-Steinberg, Barry Heller, Laura Helman, Melanie Hoppers, Jeffrey Jenkins, Audrey Jones, Adam Kaplan, Zeid Kayali, Richard Kelly, Flory Kreutter, Gustavo Ledo-Sanchez, Holly Lim, Jesus Lorites, Aslam Loya, Edwin Mangune, Barry McLean, George Melikian, Mahfouz Michael, John Murphy IV, Salil Nadkarni, Yamini Naygandhi, Stephen Ong, Yogesh Paliwal, Dena Petersen, James Peterson, David Pham, Tiffany Pluto, Joe Pouzar Jr, Marina Raikhel, Robert Rosen, Mercedes Samson, Jorge Santander, Martin Schear, Neal Secrist, Karl Sitz, Brian Siu, Alex Slandzicki, Joel Solis, Weily Soong, Roberto Sotolongo, Roy Springer, Jeffrey Stewart, James Sullivan, Edward Tavel Jr, Gustavo Torres, Barry Troyan, Pilar Trueba, William VanNess III, Michael Vaughn, Francisco Velazquez, Debra Weinstein, Frederick G Hayden, Norio Sugaya, Nobuo Hirotsu, Nelson Lee, Menno D de Jong, Aeron C Hurt, Tadashi Ishida, Hisakuni Sekino, Kota Yamada, Simon Portsmouth, Keiko Kawaguchi, Takao Shishido, Masatsugu Arai, Kenji Tsuchiya, Takeki Uehara, Akira Watanabe, Baloxavir Marboxil Investigators Group, Masahisa Arahata, Takahito Doi, Hiromitsu Fujishima, Kensuke Fukuyo, Hiroshi Hachinohe, Hiroshi Harada, Yuji Harada, Sadamune Hatakeyama, Tetsuo Hisadome, Isao Horikawa, Mitsumi Ikeda, Takayuki Ishikawa, Junichi Ito, Norio Iwaki, Hiroyoshi Kanemitsu, Masaharu Kinoshita, Hirokazu Kitada, Takehiko Kokubun, Tomoyuki Komo, Haruo Kuroki, Atsushi Matsunaga, Ikuo Mitani, Hirotaka Miyazono, Shigeaki Morizono, Hisashi Murakawa, Akihiko Nagumo, Seitaro Nakama, Hidehisa Nakazato, Satohiko Nemoto, Yoshimasa Noguchi, Tadahiko Ogasawara, Jun Ogawa, Hiroji Okawa, Haruhiko Okumura, Yasuko Owada, Yasuaki Sadanaga, Ryotaro Sasaki, Hideyuki Sasho, Kazuo Satake, Masahiko Seki, Hiroshi Shudo, Masayuki Sugimoto, Fumihiro Taguchi, Kazunori Takahashi, Jiro Takei, Seishu Tamaki, Hiroaki Tanaka, Koukichi Tanaka, Shinichi Tanaka, Hiroaki Tomori, Akira Uehara, Sigehiro Ueyama, Yoshihiro Umezawa, Toru Umezu, Yutaka Wakasa, Katsumi Yamada, Toshiharu Yamagata, Munemitsu Yamamoto, Kenji Yasuda, Takahiro Yokoyama, Riko Yoshida, Tsuyoshi Yamaguchi, Tsuyoshi Yamato, Tomoaki Ahiko, Katsumaro Aida, Masaki Akahata, Yasushi Amada, Michio Ando, Shunji Asai, Tetsu Chinen, Keisuke Egashira, Toru Fujigaki, Yutaka Fujimaki, Yasushi Fukushima, Akitoshi Funato, Masamichi Gushiken, Yoichiro Haji, Kazuhiro Hashiguchi, Kazuhito Hirose, Kazuyuki Honda, Tadayuki Igarashi, Keiichi Iguchi, Yoshiki Iida, Takashi Iizuka, Minoru Irahara, Takashi Irie, Kiyotaka Ishida, Hajime Ishii, Kazuo Ishikawa, Nobuyuki Kaji, Takashi Kamezawa, Yoichi Karimata, Masaki Kato, Fumihiro Katsura, Toshio Kawada, Kenji Kawamoto, Koki Kikuchi, Hiroshi Kikumori, Shiro Kimura, Heido Kin, Arihiro Kiyosue, Masahiko Kondo, Kunihiko Kooguchi, Jyoji Kurokawa, Katsutoshi Maeda, Kazuhisa Maeda, Yoshihiko Maezawa, Kaneyuki Matsuo, Kazuo Minagawa, Fumiko Minami, Yuko Miyazono, Hisao Mori, Yuko Morita, Ichirou Moriyama, Harumichi Nakamura, Hiroki Nakano, Kiyoshi Niwa, Minoru Nozaki, Akira Numata, Akishige Obata, Ryuta Ono, Yutaka Onoi, Shinichi Osaki, Masahiro Ryuto, Sachiyo Sakaguchi, Susumu Sakayori, Yusuke Sasaki, Shunya Sato, Tatsuyuki Sato, Yasuo Sato, Yuji Sato, Yutaka Segawa, Atsushi Shibasaki, Etsuji Shimamoto, Hiroshi Shimomura, Tatsushi Sugiura, Shin Suzuki, Takayuki Suzuki, Hirotaka Tabuchi, Yoji Takatsuka, Fumihiko Takeda, Kazuo Takeda, Shinichi Tamura, Keiichi Tanaka, Norimitsu Tanaka, Toshihiro Tanaka, Hiroshi Taniguchi, Yuriko Tarukawa, Shuichi Tatera, Akira Toguchi, Muneatsu Toshima, Tomio Tsukazaki, Tetsuya Tsurumachi, Shigehiro Ueyama, Satoko Wada, Manabu Yamamoto, Masayuki Yamauchi, Takato Yokoyama, Ryota Yoshimura, Ryuji Yoshimura, Nobuo Yurino, Hessam Aazami, Haider Afzal, Bassil Aish, Sady Alpizar, Dario Altamirano, Madhavi Ampajwala, Saadat Ansari, Niaz Ausaf, Steven Bauer, Richard Beasley, Jennifer Bellucci-Jackson, Larry Berman, Richard Bernstein, Salvatore Bianco, Michael Winnie, Haresh Boghara, Tasha Boone, Jose M Carpio, Stephen Coleman, Gilda De La Calle, Patrick Dennis, Michael DeSantis, Oscar DeValle, Michael Dever, Chrisette Dharma, Rennee Dhillon, Larry Doehring, Bernard Garcia, Hiram Garcia, Ramon Garcia-Septien, Shaila Gogate, Marcy Goisse, Glenn Michael Gould, David Grant, Mario Guillen, Sabine Hazan-Steinberg, Barry Heller, Laura Helman, Melanie Hoppers, Jeffrey Jenkins, Audrey Jones, Adam Kaplan, Zeid Kayali, Richard Kelly, Flory Kreutter, Gustavo Ledo-Sanchez, Holly Lim, Jesus Lorites, Aslam Loya, Edwin Mangune, Barry McLean, George Melikian, Mahfouz Michael, John Murphy IV, Salil Nadkarni, Yamini Naygandhi, Stephen Ong, Yogesh Paliwal, Dena Petersen, James Peterson, David Pham, Tiffany Pluto, Joe Pouzar Jr, Marina Raikhel, Robert Rosen, Mercedes Samson, Jorge Santander, Martin Schear, Neal Secrist, Karl Sitz, Brian Siu, Alex Slandzicki, Joel Solis, Weily Soong, Roberto Sotolongo, Roy Springer, Jeffrey Stewart, James Sullivan, Edward Tavel Jr, Gustavo Torres, Barry Troyan, Pilar Trueba, William VanNess III, Michael Vaughn, Francisco Velazquez, Debra Weinstein
Abstract
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 .).
Source: PubMed