#Baloxavir Marboxil for #Prophylaxis against #Influenza in #Household Contacts (N Engl J Med., abstract)

[Source: The New England Journal of Medicine, full page: (LINK). Abstract, edited.]

Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts

Hideyuki Ikematsu, M.D., Frederick G. Hayden, M.D., Keiko Kawaguchi, M.S., Masahiro Kinoshita, M.Pharm., Menno D. de Jong, M.D., Nelson Lee, M.D., Satoru Takashima, M.S., Takeshi Noshi, M.S., Kenji Tsuchiya, M.S., and Takeki Uehara, Ph.D.

 

Abstract

BACKGROUND

Baloxavir marboxil (baloxavir) is a polymerase acidic protein (PA) endonuclease inhibitor with clinical efficacy in the treatment of uncomplicated influenza, including in outpatients at increased risk for complications. The postexposure prophylactic efficacy of baloxavir in the household setting is unclear.

METHODS

We conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the postexposure prophylactic efficacy of baloxavir in household contacts of index patients with confirmed influenza during the 2018–2019 season in Japan. The participants were assigned in a 1:1 ratio to receive either a single dose of baloxavir or placebo. The primary end point was clinical influenza, as confirmed by reverse-transcriptase–polymerase-chain-reaction testing, over a period of 10 days. The occurrence of baloxavir-selected PA substitutions associated with reduced susceptibility was assessed.

RESULTS

A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12 years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was significantly lower in the baloxavir group than in the placebo group (1.9% vs. 13.6%) (adjusted risk ratio, 0.14; 95% confidence interval [CI], 0.06 to 0.30; P<0.001). Baloxavir was effective in high-risk, pediatric, and unvaccinated subgroups of participants. The risk of influenza infection, regardless of symptoms, was lower with baloxavir than with placebo (adjusted risk ratio, 0.43; 95% CI, 0.32 to 0.58). The incidence of adverse events was similar in the two groups (22.2% in the baloxavir group and 20.5% in the placebo group). In the baloxavir group, the viral PA substitutions I38T/M or E23K were detected in 10 (2.7%) and 5 (1.3%) participants, respectively. No transmission of these variants from baloxavir-treated index patients to participants in the placebo group was detected; however, several instances of transmission to participants in the baloxavir group could not be ruled out.

CONCLUSIONS

Single-dose baloxavir showed significant postexposure prophylactic efficacy in preventing influenza in household contacts of patients with influenza. (Funded by Shionogi; Japan Primary Registries Network number, JapicCTI-184180.)

Keywords: Seasonal Influenza; Antivirals; Baloxavir.

——

Successful #Treatment With #Baloxavir Marboxil of a Patient With #Peramivir #Resistant #Influenza A / #H3N2 With a Dual E119D/R292K Substitution After Allogeneic Hematopoietic Cell #Transplantation: A Case Report (BMC Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

BMC Infect Dis. 2020 Jul 6;20(1):478. doi: 10.1186/s12879-020-05205-1.

Successful Treatment With Baloxavir Marboxil of a Patient With Peramivir-Resistant Influenza A/H3N2 With a Dual E119D/R292K Substitution After Allogeneic Hematopoietic Cell Transplantation: A Case Report

Naonori Harada 1, Wataru Shibata 2 3, Hideo Koh 4, Emi Takashita 5, Seiichiro Fujisaki 5, Hiroshi Okamura 1, Satoru Nanno 1, Koichi Yamada 2 3, Hirohisa Nakamae 1, Masayuki Hino 1, Hiroshi Kakeya 2 3

Affiliations: 1 Hematology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. 2 Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan. 3 Research Center for Infectious Disease Sciences (RCIDS), Graduate School of Medicine, Osaka City University, Osaka, Japan. 4 Hematology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. hide_koh@med.osaka-cu.ac.jp. 5 Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.

PMID: 32631240 DOI: 10.1186/s12879-020-05205-1

 

Abstract

Background:

Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir.

Case presentation:

A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/μL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2.

Conclusions:

In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.

Keywords: Allogeneic hematopoietic cell transplantation; Baloxavir marboxil; Dual E119D/R292K substitution; Immunocompromised host; Influenza A/H3N2; Neuraminidase mutation; Peramivir resistance.

Keywords: Seasonal Influenza; Antivirals; Drugs Resistance; Hematology; H3N2; Cancer; Immunosuppression; Peramivir; Baloxavir.

—–

#Influenza #H1N1pdm09 virus exhibiting reduced #susceptibility to #baloxavir due to a PA E23K #substitution detected from a #child without baloxavir #treatment (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 20 June 2020, 104828 | In Press, Journal Pre-proof | Short Communication

Influenza A(H1N1)pdm09 virus exhibiting reduced susceptibility to baloxavir due to a PA E23K substitution detected from a child without baloxavir treatment

Emi Takashita 1, Takashi Abe 2, Hiroko Morita 1, Shiho Nagata 1, Seiichiro Fujisaki 1, Hideka Miura 1, Masayuki Shirakura 1, Noriko Kishida 1, Kazuya Nakamura 1, Tomoko Kuwahara 1, KeikoMitamura 3, Masataka Ichikawa 4, Masahiko Yamazaki 5, Shinji Watanabe 1, Hideki Hasegawa 1, The Influenza Virus Surveillance Group of Japan,  Rika Komagome 6, Asami Ohnishi 7, Rika Tsutsui 8, Masaki Takahashi 9, MieSasaki 10, Shiho Tamura 11, Chihiro Shibata 12, Kenichi Komabayashi 13, Nozomi Saito 14, Aoi Saito 15, Fuminori Mizukoshi 16, Akira Wakatsuki 17, Hiroyuki Tsukagoshi 18, Noriko Suzuki 19, Yuka Uno 20, Noriko Oitate 21, Wakako Nishikawa  22, Mami Nagashima 23, Sumi Watanabe 24, Chiharu Kawakami 25, Hideaki Shimizu 26, Hazime Amano 27, Satoko Kanazawa 28, Kaori Watanabe 29, Kazunari Yamamoto 30, Tetsuya Yoneda 31, Sachiko Nakamura 32, Kaori Sato 33, Masayuki Oonuma 34, Michiko Takeuchi 35, ErinaTanaka 36, Masahiro Nishioka 37, Yusuke Sato 38, Yukiko Sakai 39, Takaharu Maehata 40, Toshihiko Furuta 41, Yoshihiro Yasui 42, Takuya Yano 43, Asa Tanino 44, Sachi Hirata 45, Akiko Nagasao 46, Satoshi Hiroi 47, Hideyuki Kubo 47, Fumika Okayama 48, Tomohiro Oshibe 49, Ai Mori 50, Ryutaro Murayama 51, Shoko Chiba 52, Yuki Matsui 53, Yuko Kiguchi 54, Koji Takeuchi 55, Tetsuo Mita 56, Kayoko Nomiya 57, Yukie Shimazu 58, Yoshiki Fujii 59, Shoichi Toda 60, Yumiko Kawakami 61, Yukari Terajima 62, Mayumi Yamashita 63, Tomiyo Takahashi 64, Yuki Ashizuka 65, Chinami Wasano 66, Takashi Kimura 67, Sanae Moroishi 68, Miho Urakawa 69, Takashi Sakai 70, Kaori Nishizawa 71, Toru Hayashi 72, Yu Matsuura 73, Yuka Hamada 74, Yumani Kuba 75

6 Hokkaido Institute of Public Health; 7 Sapporo City Institute of Public Health; 8 Aomori Prefectural Public Health and Environment Center; 9 Iwate Prefectural Research Institute for Environmental Sciences and Public Health; 10 Miyagi Prefectural Institute of Public Health and Environment; 11 Sendai City Institute of Public Health; 12 Akita Prefectural Research Center for Public Health and Environment; 13 Yamagata Prefectural Institute of Public Health; 14 Fukushima Prefectural Institute of Public Health; 15 Ibaraki Prefectural Institute of Public Health; 16 Tochigi Prefectural Institute of Public Health and Environmental Sciences; 17 Utsunomiya City Institute of Public Health and Environment Science; 18 Gunma Prefectural Institute of Public Health and Environmental Sciences; 19 Saitama Institute of Public Health; 20 Saitama City Institute of Health Science and Research;  21 Chiba Prefectural Institute of Public Health; 22 Chiba City Institute of Health and Environment; 23 Tokyo Metropolitan Institute of Public Health; 24 Kanagawa Prefectural Institute of Public Health; 25 Yokohama City Institute of Public Health; 26 Kawasaki City Institute of Public Health; 27 Yokosuka Institute of Public Health; 28 Sagamihara City Institute of Public Health; 29 Niigata Prefectural Institute of Public Health and Environmental Sciences; 30 Niigata City Institute of Public Health and Environment; 31 Toyama Institute of Health; 32 Ishikawa Prefectural Institute of Public Health and Environmental Science; 33 Fukui Prefectural Institute of Public Health and Environmental Science; 34 Yamanashi Institute for Public Health; 35 Nagano Environmental Conservation Research Institute; 36 Nagano City Health Center; 37
Gifu Prefectural Research Institute for Health and Environmental Sciences; 38 Gifu Municipal Institute of Public Health; 39 Shizuoka Institute of Environment and Hygiene; 40 Shizuoka City Institute of Environmental Sciences and Public Health; 41 Hamamatsu City Health Environment Research Center; 42 Aichi Prefectural Institute of Public Health; 43 Mie Prefecture Health and Environment Research Institute; 44 Shiga Prefectural Institute of Public Health; 45 Kyoto Prefectural Institute of Public Health and Environment; 46 Kyoto City Institute of Health and Environmental Sciences; 47 Osaka Institute of Public Health; 48 Sakai City Institute of Public Health; 49 Hyogo Prefectural Institute of Public Health Science; 50 Kobe Institute of Health; 51 Amagasaki City Institute of Public Health; 52 Nara Prefecture Institute of Health; 53 Wakayama Prefectural Research Center of Environment and Public Health; 54 Wakayama City Institute of Public Health; 55 Tottori Prefectural Institute of Public Health and Environmental Science; 56 Shimane Prefectural Institute of Public Health and Environmental Science; 57 Okayama Prefectural Institute for Environmental Science and Public Health; 58 Hiroshima Prefectural Technology Research Institute; 59 Hiroshima City Institute of Public Health; 60 Yamaguchi Prefectural Institute of Public Health and Environment; 61 Tokushima Prefectural Public Health, Pharmaceutical and Environmental Sciences Center; 62 Kagawa Prefectural Research Institute for Environmental Sciences and Public Health; 63 Ehime Prefecture Institute of Public Health and Environmental Science; 64 Kochi Public Health and Environmental Science Research Institute; 65 Fukuoka Institute of Health and Environmental Sciences; 66 Fukuoka City Institute of Health and Environment; 67 Kitakyushu City Institute of Health and Environmental Sciences; 68 Saga Prefectural Institute of Public Health and Pharmaceutical Research; 69 Nagasaki Prefectural Institute for Environment Research and Public Health; 70 Kumamoto Prefectural Institute of Public-Health and Environmental Science; 71 Kumamoto City Environmental Research Center; 72 Oita Prefectural Institute of Health and Environment; 73 Miyazaki Prefectural Institute for Public Health and Environment; 74 Kagoshima Prefectural Institute for Environmental Research and Public Health; 75 Okinawa Prefectural Institute of Health and Environment; 1 Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan; 2 Abe Children’s Clinic, Minowa 2-15-22, Kohoku, Yokohama, Kanagawa, 223-0051, Japan; 3 Eiju General Hospital, Higashi Ueno 2-23-16, Taito, Tokyo, 110-8645, Japan; 4 Ichikawa Children’s Clinic, Higashi Odake 1544-3, Isehara, Kanagawa, 259-1133, Japan; 5 Zama Children’s Clinic, Tatsuno Dai 2-20-24, Zama, Kanagawa, 252-0023, Japan

Received 18 February 2020, Revised 14 May 2020, Accepted 28 May 2020, Available online 20 June 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104828

 

Highlights

  • Influenza A(H1N1)pdm09 virus carrying a PA E23K substitution was detected.
  • The PA E23K mutant virus showed reduced baloxavir susceptibility.
  • The PA E23K mutant virus was isolated from a child without baloxavir treatment.
  • Possible transmission of the PA E23K mutant virus among humans is suggested.
  • Baloxavir susceptibility monitoring of influenza viruses is essential.

 

Abstract

Human-to-human transmission of PA I38 mutant influenza A(H3N2) viruses with reduced baloxavir susceptibility has been reported in Japan. In December 2019, we detected a PA E23K mutant A(H1N1)pdm09 virus from a child without baloxavir treatment. The PA E23K mutant virus exhibited reduced baloxavir susceptibility but remained susceptible to neuraminidase inhibitors. Epidemiological data suggest possible transmission of this PA E23K mutant virus among humans, although its growth capability relative to that of the wild-type virus was reduced. Therefore, baloxavir susceptibility monitoring of influenza viruses is essential.

Keywords: Influenza A; Antivirals; Drugs Resistance; Baloxavir; Oseltamivir; Pediatrics; Japan.

——

The #Antiviral Effects of #Baloxavir Marboxil Against #Influenza A Virus Infection in #Ferrets (Influenza Other Respir Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Influenza Other Respir Viruses. 2020 Jun 13. doi: 10.1111/irv.12760. Online ahead of print.

The Antiviral Effects of Baloxavir Marboxil Against Influenza A Virus Infection in Ferrets

Mitsutaka Kitano 1, Takanobu Matsuzaki 1, Ryoko Oka 1, Kaoru Baba 2, Takahiro Noda 2, Yuki Yoshida 1, Kenji Sato 1, Kohei Kiyota 1, Tohru Mizutare 1, Ryu Yoshida 1, Akihiko Sato 1, Hiroshi Kamimori 1, Takao Shishido 1, Akira Naito 1

Affiliations: 1 Shionogi & Co., Ltd., Toyonaka, Japan. 2 Shionogi TechnoAdvance Research, Co., Ltd., Toyonaka, Japan.

PMID: 32533654 DOI: 10.1111/irv.12760

 

Abstract

Background:

Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients.

Objectives:

To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets.

Methods:

Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM.

Results:

The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half-life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post-infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4.

Conclusions:

The results highlight the rapid antiviral action of BXM with post-exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission.

Keywords: baloxavir marboxil; ferrets; influenza A virus; pharmacodynamics; pharmacokinetics.

© 2020 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.

Keywords: Influenza A; Antivirals; Baloxavir; Oseltamivir; Animal models.

—–

#Baloxavir Marboxil Single-dose #Treatment in #Influenza-infected #Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2) (Pediatr Infect Dis J., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Pediatr Infect Dis J. 2020 Jun 5. doi: 10.1097/INF.0000000000002747. Online ahead of print.

Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2)

Jeffrey Baker 1, Stanley L Block 2, Balpreet Matharu 3, Laura Burleigh  Macutkiewicz 3, Steffen Wildum 4, Sophie Dimonaco 3, Neil Collinson 3, Barry Clinch 3, Pedro A Piedra 5

Affiliations: 1 From the Clinical Research Prime, Idaho Falls, Idaho. 2 Kentucky Pediatric and Adult Research Inc., Bardstown, Kentucky. 3 F. Hoffmann-La Roche Ltd, Welwyn Garden City, Hertfordshire, United Kingdom. 4 F. Hoffmann-La Roche Ltd, Basel, Switzerland. 5 Baylor College of Medicine, Houston, Texas.

PMID: 32516282 DOI: 10.1097/INF.0000000000002747

 

Abstract

Background:

Baloxavir marboxil (baloxavir) is a novel, cap-dependent endonuclease inhibitor that has previously demonstrated efficacy in the treatment of influenza in adults and adolescents. We assessed the safety and efficacy of baloxavir in otherwise healthy children with acute influenza.

Methods:

MiniSTONE-2 (Clinicaltrials.gov: NCT03629184) was a double-blind, randomized, active controlled trial enrolling children 1-<12 years old with a clinical diagnosis of influenza. Children were randomized 2:1 to receive either a single dose of oral baloxavir or oral oseltamivir twice daily for 5 days. The primary endpoint was incidence, severity and timing of adverse events (AEs); efficacy was a secondary endpoint.

Results:

In total, 173 children were randomized and dosed, 115 to the baloxavir group and 58 to the oseltamivir group. Characteristics of participants were similar between treatment groups. Overall, 122 AEs were reported in 84 (48.6%) children. Incidence of AEs was similar between baloxavir and oseltamivir groups (46.1% vs. 53.4%, respectively). The most common AEs were gastrointestinal (vomiting/diarrhea) in both groups [baloxavir: 12 children (10.4%); oseltamivir: 10 children (17.2%)]. No deaths, serious AEs or hospitalizations were reported. Median time (95% confidence interval) to alleviation of signs and symptoms of influenza was similar between groups: 138.1 (116.6-163.2) hours with baloxavir versus 150.0 (115.0-165.7) hours with oseltamivir.

Conclusions:

Oral baloxavir is well tolerated and effective at alleviating symptoms in otherwise healthy children with acute influenza. Baloxavir provides a new therapeutic option with a simple oral dosing regimen.

Keywords: Seasonal Influenza; Antivirals; Baloxavir; Pediatrics.

——

Early #treatment with #baloxavir marboxil in high-risk #adolescent and #adult outpatients with uncomplicated #influenza (#CAPSTONE2)… (Lancet Infect Dis., abstract)

[Source: Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial

Prof Michael G Ison, MD,  Simon Portsmouth, MD, Yuki Yoshida, MS, Takao Shishido, PhD, Melissa Mitchener, PharmD, Kenji Tsuchiya, MS, Takeki Uehara, PhD, Frederick G Hayden

Published: June 08, 2020 | DOI: https://doi.org/10.1016/S1473-3099(20)30004-9

 

Summary

Background

Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.

Methods

We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.

Findings

2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (−7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.

Interpretation

Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications.

Funding

Shionogi.

Keywords: Seasonal Influenza; Antivirals; Baloxavir.

——

#Modeling #mitigation of #influenza #epidemics by #baloxavir (Nat Commun., abstract)

[Source: Nature Communications, full page: (LINK). Abstract, edited.]

Modeling mitigation of influenza epidemics by baloxavir

Zhanwei Du, Ciara Nugent, Alison P. Galvani, Robert M. Krug & Lauren Ancel Meyers

Nature Communications volume 11, Article number: 2750 (2020)

 

Abstract

Influenza viruses annually kill 290,000–650,000 people worldwide. Antivirals can reduce death tolls. Baloxavir, the recently approved influenza antiviral, inhibits initiation of viral mRNA synthesis, whereas oseltamivir, an older drug, inhibits release of virus progeny. Baloxavir blocks virus replication more rapidly and completely than oseltamivir, reducing the duration of infectiousness. Hence, early baloxavir treatment may indirectly prevent transmission. Here, we estimate impacts of ramping up and accelerating baloxavir treatment on population-level incidence using a new model that links viral load dynamics from clinical trial data to between-host transmission. We estimate that ~22 million infections and >6,000 deaths would have been averted in the 2017–2018 epidemic season by administering baloxavir to 30% of infected cases within 48 h after symptom onset. Treatment within 24 h would almost double the impact. Consequently, scaling up early baloxavir treatment would substantially reduce influenza morbidity and mortality every year. The development of antivirals against the SARS-CoV2 virus that function like baloxavir might similarly curtail transmission and save lives.

Keywords: Seasonal Influenza; Antivirals; Baloxavir.

——

Characterization of contemporary #influenza B #recombinant viruses harboring #mutations of reduced susceptibility to #baloxavir marboxil, in vitro and in mice (Antiviral Res., abstract9

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 25 April 2020, 104807 | In Press, Journal Pre-proof | Research paper

Characterization of contemporary influenza B recombinant viruses harboring mutations of reduced susceptibility to baloxavir marboxil, in vitro and in mice

Yacine Abed 1, Clément Fage 1, Liva Checkmahomed 1, Marie- Christine Venable, Guy Boivin, CHUQ-CHUL and Laval University, Québec City, Québec, Canada

Received 21 January 2020, Revised 16 April 2020, Accepted 18 April 2020, Available online 25 April 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104807

 

Highlights

  • Clinical trials showed that I38T/M/F PA substitutions rapidly emergedin influenza A viruses causing baloxavir resistance.
  • We rescued B/Phuket/3073/2013 viruses with I38T/M and E23KPA mutationsfor in vitro and mouse characterizations.
  • The I38T, I38M and E23K substitutions increased baloxavir IC50s by 12.6-, 5.5-, and 2.6-fold, respectively, vs the WT.•
  • The I38T/M mutants showed similar viral fitness vs the WT both in vitro and in mouse experiments.
  • The potential for baloxavir-resistance in influenza A and B viruses reinforces the need of novel antiviral strategies.

 

Abstract

Baloxavir marboxil (BXM) is a potent inhibitor of the polymerase acidic (PA) protein of influenza viruses. However, clinical trials predominantly involving influenza A(H1N1) and A(H3N2) infections showed that BXM exhibited a low barrier of resistance. Contrasting with influenza A viruses, BXM-resistant influenza B variants remain poorly documented. We evaluated the impact of I38T/M and E23K PA substitutions, previously reported in influenza A viruses, on in vitro properties and virulence of contemporary influenza B recombinant viruses. Influenza B/Phuket/3073/2013 recombinant wild-type (WT) virus and the I38T, I38M and E23K PA mutants were assessed for their susceptibility to baloxavir acid (BXA), the active metabolite of BXM, by plaque reduction assays in ST6GalI-cells. Luciferase-based minigenome tests were performed to determine polymerase activity. Replication kinetics and genetic stability were evaluated in ST6GalI-cells. Virulence was evaluated in BALB/c mice. The I38T, I38M and E23K substitutions increased BXA IC50s values by 12.6-, 5.5-, and 2.6-fold, respectively, compared to the WT. Minigenome assays revealed a 46% loss of polymerase activity for the E23K substitution vs the WT while the I38T and I38M PA variants retained ≈ 80% of activity. Peak viral titers were comparable for the WT, I38T and I38M recombinants (7.95±0.5, 7.45±0.25 and 8.11±0.28 logTCID50/mL), respectively, whereas it was significantly lower for the E23K mutant (6.28±0.28 logTCID50/mL; P<0.05 vs the WT). In mice, the WT, I38T and I38M recombinants induced mortality rates of 60%, 40% and 100%, respectively and similar lung viral titers were obtained for the three groups at days 3 and 6 p.i.. In conclusion, the fitness of BXA-resistant I38T and I38M PA mutants appears unaltered in contemporary influenza B viruses warranting surveillance for their emergence.

1 Equally contributed.

© 2020 Published by Elsevier B.V.

Keywords: Seasonal Influenza; Influenza B; Antivirals; Drugs Resistance; Baloxavir.

—–

#Population #Pharmacokinetics and Exposure-Response Relationships of #Baloxavir Marboxil in Patients Infected with #Influenza at High #Risk of Influenza #Complications (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Population Pharmacokinetics and Exposure-Response Relationships of Baloxavir Marboxil in Patients Infected with Influenza at High Risk of Influenza Complications

Hiroki Koshimichi, Sylvie Retout, Valerie Cosson, Vincent Duval, Stefan De Buck, Yoshiyuki Tsuda, Toru Ishibashi, Toshihiro Wajima

DOI: 10.1128/AAC.00119-20

 

ABSTRACT

Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor, baloxavir acid, reduces the time to improvement of influenza symptoms in patients infected with type A or B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic model for baloxavir acid was developed using 11846 plasma concentration data items from 1827 subjects including 2341 plasma concentration data items from 664 patients at high risk of influenza complications. A three-compartment model with first-order elimination and first-order absorption with lag time well described the plasma concentration data. Body weight and race were found to be the most important factors influencing clearance and volume of distribution. The exposures in high-risk patients were similar to those in otherwise healthy patients, and no pharmacokinetic difference was identified regarding any risk factors for influenza complications.

Exposure-response analyses were performed regarding the time to improvement of symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses suggested that body weight-based dosage, 40 mg for patients weighing < 80 kg and 80 mg for patients weighing ≥ 80 kg, can shorten the time to improvement of influenza symptoms and reduce virus titer for both type A and B influenza virus regardless of the exposure levels of the high-risk patients as well as for the otherwise healthy influenza patients.

The results of our population pharmacokinetic and exposure-response analyses in patients with risk factors of influenza complications should provide useful information on the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for the optimization of dose regimens.

Copyright © 2020 Koshimichi et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Influenza A; Seasonal Influenza; Antivirals; Baloxavir.

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#Baloxavir #treatment of ferrets infected with #influenza A #H1N1pdm09 virus reduces onward #transmission (PLOS Pathogens, abstract)

[Source: PLOS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS |  PEER-REVIEWED | RESEARCH ARTICLE

Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission

Leo Yi Yang Lee , Jie Zhou , Rebecca Frise, Daniel H. Goldhill, Paulina Koszalka, Edin J. Mifsud, Kaoru Baba, Takahiro Noda, Yoshinori Ando, Kenji Sato, Aoe-Ishikawa Yuki, Takao Shishido, Takeki Uehara,  [ … ], Wendy S. Barclay

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Published: April 15, 2020 | DOI: https://doi.org/10.1371/journal.ppat.1008395

 

Abstract

Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels. Our results support the concept that antivirals which decrease viral shedding could also reduce influenza transmission in the community.

 

Author summary

During seasonal influenza outbreaks and global pandemics, influenza can cause significant morbidity and mortality and spread rapidly. Influenza viruses constantly change, and the effectiveness of vaccination can be low if the match between the vaccine and circulating viruses is poor. However, antiviral drugs target conserved parts of the virus and therefore typically remain effective against new seasonal or pandemic strains of influenza. The new antiviral baloxavir is more effective than existing drugs, such as oseltamivir, in reducing the amount of virus particles produced by infected people, suggesting it might reduce the onward spread of influenza viruses to others. To test this, we developed an effective way to deliver baloxavir to ferrets, the best available animal model of influenza virus transmission. We then treated influenza-infected ferrets with baloxavir to determine if they were less likely to pass their virus onto healthy ferrets housed in the same cage, or in the adjacent cage. In both cases, we found that compared to oseltamivir or placebo treatment, infected ferrets treated with baloxavir produced fewer virus particles and were less likely to transmit virus to healthy ferrets. Our results suggest baloxavir can contribute to the early control of influenza outbreaks by limiting community-based viral spread.

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Citation: Lee LYY, Zhou J, Frise R, Goldhill DH, Koszalka P, Mifsud EJ, et al. (2020) Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission. PLoS Pathog 16(4): e1008395. https://doi.org/10.1371/journal.ppat.1008395

Editor: Anice C. Lowen, Emory University School of Medicine, UNITED STATES

Received: December 3, 2019; Accepted: February 10, 2020; Published: April 15, 2020

Copyright: © 2020 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. This work was funded by F. Hoffmann-La Roche (https://www.roche.com/) and Shionogi & Co. Ltd (https://www.shionogi.com/) who both played a role in the study design, data collection and analysis, decision to publish and preparation of the manuscript.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Leo Yi Yang Lee, Jie Zhou, Rebecca Frise, Daniel H. Goldhill, Paulina Koszalka and Edin J. Mifsud have nothing to declare. Kaoru Baba, Takahiro Noda, Yoshinori Ando, Kenji Sato, Aoe-Ishikawa Yuki, Takao Shishido and Takeki Uehara are employees of Shionogi & Co. Ltd. Steffen Wildum, Elke Zwanziger, Neil Collinson, Klaus Kuhlbusch, Barry Clinch and Aeron C. Hurt are employees of F. Hoffmann La Roche Ltd. Wendy S. Barclay has received honoraria from Roche, Sanofi Pasteur and Seqirus.

Keywords: Seasonal Influenza; H1N1pdm09; Antivirals; Baloxavir; Animal models.

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