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Baloxavir marboxil - Roche/Shionogi

Drug Profile

Baloxavir marboxil - Roche/Shionogi

Alternative Names: RG 6152; RG 6152-1; S 033188; XOFLUZA; Xofluza

Latest Information Update: 28 May 2021

At a glance

  • Originator Shionogi
  • Developer Roche; Shionogi
  • Class Antivirals; Dibenzothiepins; Esters; Morpholines; Pyridines; Small molecules; Triazines
  • Mechanism of Action Endonuclease inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Influenza A virus infections; Influenza B virus infections; Influenza virus infections
  • No development reported Influenza A virus H5N1 subtype

Most Recent Events

  • 28 May 2021 No recent reports of development identified for preclinical development in Influenza-A-virus-H5N1-subtype in Japan (PO)
  • 28 Apr 2021 Roche plans regulatory filing for Influenza virus infection (direct transmission) in 2023 (Roche pipeline, April 2021)
  • 28 Apr 2021 Roche plans regulatory filing for Influenza virus infection (In Infants) in 2022 (Roche pipeline, April 2021)

Development Overview

Introduction

Baloxavir marboxil is developed by Shionogi and Roche, for the treatment and prevention of influenza virus infections including influenza types A and B infections. It is a cap-dependent endonuclease inhibitor that inhibits mRNA synthesis, thereby blocking influenza virus proliferation by inhibiting the production of proliferation proteins and viral granules. The drug is a one-time, single-dose first-in-class therapy, which the company believes will be potentially more effective than current marketed products. A tablet formulation is available in Japan under the trade name XOFLUZA®, for treatment as well as prophylaxis while an oral granule formulation has been approved for use in pediatric patients in the same country. The product has been launched in the US for treatment of acute, uncomplicated influenza and influenza virus infections with high risk of complications in patients aged 12 years and older. The product is launched in Taiwan for influenza A and influenza B virus infections and approved for influenza virus infections in Japan, Australia, Canada and Switzerland. The drug is approved in the EU, Iceland, Norway and Liechtenstein for treatment of uncomplicated influenza virus infections and post-exposure prophylaxis of influenza influenza virus infections. The product is awaiting approval uncomplicated influenza as well as for post-exposure prophylaxis of influenza infections in peadiatric patients in the US. Clinical development of oral solution for influenza virus infections is underway worldwide. Preclinical development for influenza A virus H5N1 subtype is underway in Japan.

As at May 2021, no recent reports of development had been identified for preclinical development in Influenza-A-virus-H5N1-subtype in Japan (PO).

Company Agreements

In February 2016, Shionogi entered into an license and collaboration agreement with Roche to develop and commercialise baloxavir marboxil (also known as S 033188) worldwide, excluding Taiwan and Japan, where Shionogi has exclusive rights. Shionogi also retains certain co-promotion rights in the US. As per the agreement, Roche disbursed Shionogi an undisclosed upfront payment and is expected to make additional payments on achieving development and commercialisation milestones. [1]

Key Development Milestones

In January 2021, the European Commission (EC) approved baloxavir marboxil for the treatment of uncomplicated influenza in patients aged 12 years and above. In addition, the EC also approved the drug for post-exposure prophylaxis (prevention) of influenza in individuals aged 12 years and above [2] . In November 2020, the Committee for Medicinal Products for Human Use (CHMP) recommended the approval of baloxavir marboxil for the treatment and prevention (post-exposure prophylaxis) of uncomplicated influenza in patients aged 12 years and above. The recommendation was based on the results from the phase III CAPSTONE-1, CAPSTONE-2 and BLOCKSTONE studies (see below) [3] . Prior to December 2019, the European Medicines Agency has received a centralised marketing authorisation application for baloxavir marboxil (Xofluza®) for the treatment of influenza virus infections, that is under evaluation by the Committee for Medicinal Products for Human Use (CHMP) [4] .

In November 2020, Genentech announced that the US FDA approved a supplemental New Drug Application (sNDA) for baloxavir marboxil for prevention of influenza in people 12 years of age and older following contact with someone with influenza (known as post-exposure prophylaxis) and the drug is now available as the first single-dose, post-exposure prevention for influenza [5] .

In November 2020, baloxavir marboxil oral granules (2%) was approved by the Ministry of Health, Labour, and Welfare, for prophylaxis of influenza types A and B infections in paediatric patients, in Japan [6] .

In November 2020, baloxavir marboxil (XOFLUZA®, 20mg tablets) was approved by the Ministry of Health, Labour, and Welfare, for prophylaxis of influenza types A and B infections in Japan. The product was launched subsequently [6] .

In March 2020, Genentech, a member of the Roche Group, announced that the US FDA accepted a New Drug Application (NDA) for Baloxavir marboxil (Xofluza) as one-dose granules for oral suspension (2mg/mL), a convenient option for children who may have difficulty swallowing. The application also seeks approval of Baloxavir marboxil (Xofluza) for the treatment of children who are one to less than 12 years of age, are otherwise healthy but have been symptomatic for no more than 48 hours from acute uncomplicated influenza. The US FDA has also accepted two supplemental NDAs (sNDAs), each for oral suspension and tablet formulation for post-exposure prophylaxis of influenza in people one year age and older. The filings were based on positive results from two phase III studies, miniSTONE-2 and BLOCKSTONE [see below] [7] .

In March 2018, baloxavir marboxil (XOFLUZA®, 10mg/20mg tablets) was launched in Japan, for the treatment of influenza types A and B infections. In February 2018, the product was approved by the Ministry of Health, Labour, and Welfare of Japan, for the treatment of influenza types A and B infections [8] . In October 2017, Shionogi filed a regulatory submission for the drug in adults and children under the priority review system of the Ministry of Health, Labour, and Welfare of Japan (Sakigake fast-track review). The submission was based on data from the phase III CAPSTONE 1 trial [see below] [9] . Baloxavir marboxil was granted fast track designation and priority review by the PMDA, for influenza A or B virus infections, in October 2015 [10] [1] .

In October 2019, the US FDA approved a supplemental New Drug Application (sNDA) for baloxavir marboxil (Xofluza™) for the treatment of acute, uncomplicated influenza, or flu, in people 12 years of age and older who have been symptomatic for no more than 48 hours and who are at high risk of developing flu-related complications [11] . Earlier, in March 2019, the US FDA accepted the supplemental NDA for baloxavir marboxil as a single-oral-dose, for the treatment of acute, complicated influenza in adults patients with 12 years of age or older, and those who have complications such as asthma, chronic lung disease, morbid obesity or heart disease. The FDA assigned PDUFA action date of 4th November 2019. Roche filed the sNDA based on results from the phase III CAPSTONE-2 study [see below] [12] [13] .

In April 2018, baloxavir marboxil oral granules received approval in Japan, for the treatment of influenza virus infections in paediatric patients (Shionogi pipeline, May 2018).

In April 2019, Shinogo reported that the baloxavir marboxil, 20mg and 40mg tablet is available under the brand name Xofluza™ for the treatment of acute, uncomplicated influenza, or flu, in patients aged 12 years and older, who have been symptomatic for not more than 48 hours in the US [12] . In October 2018, the US FDA approved baloxavir marboxil (Xofluza™) for the same indication. The approval was based on clinical and efficacy data from a phase II study and results from the phase III CAPSTONE-1 trial [see below]. Earlier, in June 2018, the US FDA had accepted the NDA and granted the application, priority review. The NDA submission was done in April 2018 [14] [15] [16] .

In February 2020, The Swiss Agency for Therapeutic Products Swissmedic and the Therapeutics Goods Administration (TGA) Australia approved baloxavir marboxil (Xofluza™) for the for the treatment of uncomplicated flu diseases from the age of twelve. The approval was a part of Australia, Canada, Singapore, Switzerland (ACSS) Consortium new active substance (NAS) work sharing initiative. Xofluza was also approved by Health Canada in December 2018 [17] [18] [19] .

In November 2019, Shionogi announced that baloxavir marboxil (Xofluza®, 20mg tablets) launched in Taiwan for the treatment of influenza A or B virus acute infection in patients adults and children 12 years of age and older. Previously, in August 2019, the Taiwan Food and Drug Administration approved baloxavir marboxil [20] [21] . In June 2018, Shionogi filed a NDA to Taiwan FDA, which was supported by the clinical efficacy and safety data from the phase II study in Japan and the phase III CAPSTONE-1 and CAPSTONE-2 trials (see below) [22] .

In July 2019, Hoffmann-La Roche initiated a phase IIIb trial to assess the efficacy of baloxavir marboxil versus placebo to reduce onward transmission of Influenza A or B in household contacts (MV40618; NCT03969212; EudraCT2018-004056-37). The primary endpoint of the trial is to determine a percentage of household contacts (HHCs) who become polymerase chain reaction positive (PCR+) for Influenza by day 5 post IP randomisation from baseline to day 5 (5 days). The randomised, double-blind, placebo-controlled trial intends to recruit approximately 3 160 patients in the US, Argentina, Costa Rica, Greece, Hong Kong, India, Israel, Japan, Mexico, Poland, South Africa, Singapore, Spain, Turkey, the UK, and may expand to China, France and Hungary. The trial was withdrawn in Brazil [23] .

In March 2019, Shionogi completed a phase III trial that evaluated the efficacy of a single, oral dose of baloxavir marboxil compared with placebo in the prevention of influenza virus infection in subjects who are household members of influenza-infected patients (P300/2019; 1719T0834; EudraCT2020-000696-20). The randomised, double blind trial was initiated in November 2018, and enrolled 752 patients in Japan [24] .

In March 2020, Roche completed a phase III trial that evaluated the efficacy, safety, and pharmacokinetics of baloxavir marboxil, in combination with a standard-of-care neuraminidase inhibitor (i.e., oseltamivir, zanamivir, or peramivir), compared with a placebo, in combination with a standard-of-care neuraminidase inhibitor (SOC NAI), in hospitalised patients, aged 12 years and older, with influenza (JapicCTI184205; NCT03684044; EudraCT2018-001416-30; CP40617). The randomised, double blind trial was initiated in January 2019, and enrolled 366 patients in Argentina, Australia, Belgium, Bulgaria, Canada, Czech Republic, Estonia, Germany, Hong Kong, Hungary, Israel, Japan, Mexico, New Zealand, Peru, Romania, Serbia, Singapore, South Korea, Spain, Sweden, and the US [25] .

In April 2019, Roche completed a phase III MINISTONE-2 trial that met its primary endpoint and evaluated the safety, pharmacokinetics, and efficacy of baloxavir marboxil, as compared with oseltamivir, in a single influenza episode in otherwise healthy pediatric participants (aged 1-12 years) with influenza-like symptoms (NCT03629184; CP40563; EudraCT2018-002169-21). The randomised, double-blind, placebo-controlled trial was initiated in November 2018, and enrolled 176 patients in the US, Costa Rica, Israel, Mexico, Panama, Poland, Puerto Rico, Russia, Spain. The drug was safe and generally well tolerated in children with flu. Also, baloxavir marboxil was comparable to oseltamivir at reducing the duration of flu symptoms, including fever. In September 2019, company released results from the study. In April 2020, results were presented at 30th European Congress of Clinical Microbiology and Infectious Diseases [26] [27] [28] [29] .

In June 2019, Shionogi announced that the phase III BLOCKSTONE study met its primary endpoint and showed that baloxavir marboxil was effective in preventing influenza infection in people exposed to a household member with influenza (JapicCTI184180). The randomised, placebo-controlled, post-exposure prophylaxis study was initiated in September 2018 and enrolled 750 patients in Japan. The study was completed in January 2019 The study included paediatric populations, post-exposure prophylaxis and severely ill hospitalised people with influenza in Japan. The study evaluated the potential of baloxavir marboxil to reduce transmission in otherwise healthy people [30] [31] [32] . Results from the study were released by the company in June 2019. The company intends to submit the data to global health authorities for approval [33] . In September 2019, positive results from the trial were released by the company [34] . In November 2020, company reported safety results from the trial. In January 2021, updated efficacy results from the trial were released by Roche [2] [5] .

In July 2018, Shionogi announced that the phase III CAPSTONE-2 trial met its primary endpoint of time to improvement of influenza symptoms compared with placebo (NCT02949011; 1602T0832; EudraCT2016-002688-32). The randomised, double-blind study was initiated in December 2016 to evaluate the efficacy of baloxavir marboxil compared with placebo or oseltamivir in patients with influenza. The study enrolled 2 184 patients, aged 12 years and older, in the US, Japan, Australia, Belgium, Bulgaria, Germany, Hungary, South Korea, Latvia, New Zealand, Philippines, Poland, Romania, South Africa, Spain, Taiwan and the UK [35] [36] . Roche released results from the trial in July 2018 [37] . Updated safety and efficacy results from the trial were released by the company in March 2019. Results from subgroup analysis from the study were presented at the 29th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2019) [38] [13] [39] [40] .

In November 2018, Roche initiated the phase III MINISTONE-1 trial to assess the safety, pharmacokinetics and efficacy of baloxavir marboxil in healthy pediatric participants less than one year of age, with influenza like symptoms (NCT03653364; CP40559; EudraCT2018-002154-70). The single arm, open label trial is enrolling approximately 30 patients in the US, Costa Rica, Finland, Israel, Mexico, Panama, Poland, Russia, South Africa, Spain and Thailand [41] .

In December 2017, Shionogi completed a phase III trial that evaluated the safety, efficacy and pharmacokinetics of a single dose baloxavir marboxil, in paediatric patients, aged 6 months to less than 12 years, with influenza virus infection requiring inpatient treatment (JapicCTI163417). The open label trial was initiated in November 2016, and enrolled patients in Japan [42] .

In July 2017,the phase III CAPSTONE-1 trial met its primary endpoint of significant reduction in time to alleviation of symptoms (TTAS), following treatment with baloxavir marboxil, compared with placebo, in patients with influenza infections. Shionogi, in April 2017, completed the trial which investigated the efficacy of a single, oral dose of baloxavir marboxil, compared with placebo or oseltamivir 75mg bid for 5 days, in patients (1601T0831; NCT02954354). The trial was initiated in November 2016, and enrolled 1 436 patients, aged 12 years to 64 years, in the US, Canada and Japan [43] . Data from the trial were released by the company in July 2017 [44] . In April 2019, Shionogi presented efficacy data at the 29th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2019) [45] .

In February 2018, Shionogi completed a phase III trial that evaluated the safety, tolerability, pharmacokinetics, and efficacy of single oral dose of baloxavir marboxil (also known as S-033188) 2% granules, in healthy paediatric patients weighing less than 20 kg for the treatment of influenza types A and B (JapicCTI173811).The open label trial was initiated in December 2017, and enrolled 30 subjects in Japan [46] .

Shionogi initiated a phase II study to assess the safety and efficacy of baloxavir marboxil in adult patients with influenza virus A or B infection (JapicCTI-153090). The randomised, double-blind, placebo-controlled trial enrolled 400 patients in Japan. In August 2016, the company released primary data from the trial along with preclinical results. In December 2016, secondary endpoint results were reported from the study. Additional results from the study were released by the company in April 2017. Updated safety, efficacy and pharmacokinetic data from the trial were presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2017) [47] [48] [49] [36] [1] [50] .

In July 2019, Hoffmann-La Roche in collaboration with Shionogi completed a phase I trial that assessed the pharmacokinetics, safety and tolerability of a single oral dose of baloxavir marboxil in healthy participants (NCT03959332; YP40902). The open-label, two dose level trial was initiated in June 2019 and enrolled 32 healthy volunteers in China [51] .

In June 2019, Roche completed a phase I trial that evaluated the safety and pharmacokinetics of baloxavir marboxil in healthy male volunteers (KCT0003535; ML40799; H-1810-078-979). The open-label trial was initiated in January 2019, and enrolled 30 healthy participants in South Korea [52] .

In April 2018, Shionogi presented results from a phase I study at the 28th European Congress of Clinical Microbiology and Infectious Disease (ECCMID - 2018). The single-center, open-label, randomized, 6-sequence, 3-period, 3-treatment crossover study was conducted in 18 healthy adult male participants in Japan to assess pharmacokinetic (PK) drug-drug interaction between baloxavir marboxil and oseltamivir based on plasma concentration profiles of their active forms, S-033447 and oseltamivir carboxylate, as well as their respective pro-drugs baloxavir marboxil and oseltamivir. Results showed that plasma concentration profiles demonstrated lack of clinically meaningful drug-drug interaction between baloxavir marboxil and oseltamivir in healthy subjects [53] [54] .

In October 2016, Shionogi completed an open-label, phase I study that investigated the absorption, distribution, metabolism, and excretion of [14C] baloxavir marboxil following oral dose administration, in healthy adult male subjects (EudraCT2016-001195-30; ISRCTN74587134, 532T0817). The single-centre, non-randomized, single-dose study intended to enrol 6 volunteers in the UK [55] .

A phase I trial was completed in Japan in 2015, which confirmed the safety and pharmacokinetic profile of the drug [10] [56] . Results from the study were presented at IDWeek 2016 (IDW-2016) [57] .

According to Shionogi pipeline viewed in May 2016, a phase I trial was conducted for influenza virus infections in the US [58] .

In a preclinical study, baloxavir marboxil showed synergistic anti-viral activity in vitro when combined with neuraminidase inhibitors and in a separate study, significant improvement in mortality and body weight in mice infected with a lethal dose of influenza A virus when used in combination with oseltamivir. Nonclinical studies with baloxavir marboxil showed its anti-viral spectrum against seasonal influenza strains as well as oseltamivir-resistant flu strains and avian flu strains (e.g. A/H7N9) [59] . In April 2017, Shionogi presented preclinical results at the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2017) [60] [61] .

Drug Properties & Chemical Synopsis

  • Route of administration PO
  • Formulation Granules, Suspension, Tablet, unspecified
  • Class Antivirals, Dibenzothiepins, Esters, Morpholines, Pyridines, Small molecules, Triazines
  • Target Endonuclease
  • Mechanism of Action Endonuclease inhibitors
  • WHO ATC code

    J05 (Antivirals for Systemic Use)

  • EPhMRA code

    J5 (Antivirals for Systemic Use)

  • Chemical name Carbonic acid, (((12aR)-12-((11S)-7,8-difluoro-6,11-dihydrodibenzo(b,E)thiepin-11-yl)-3,4,6,8,12,12a-hexahydro-6,8-dioxo-1H-(1,4)oxazino(3,4-C)pyrido(2,1-F)(1,2,4)triazin-7-yl)oxy)methyl methyl ester
  • Molecular formula C27 H23 F2 N3 O7 S
  • SMILES C(OCOC1C(C=CN2N(C3N(C(C2=1)=O)CCOC3)C1C2C(SCC3C1=CC=C(C=3F)F)=CC=CC=2)=O)(=O)OC
  • Chemical Structure
  • CAS Registry Number 1985606-14-1

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Influenza A virus H5N1 subtype - - No development reported (Preclinical) Japan PO / unspecified Shionogi 28 May 2021
Influenza A virus infections - In adolescents, In adults, In children Marketed Japan PO / Tablet Shionogi 01 Mar 2018
Influenza A virus infections aged 12 years and above In adolescents, In adults, In the elderly Marketed Taiwan PO / Tablet Shionogi 25 Nov 2019
Influenza A virus infections - Prevention Marketed Japan PO / Tablet Shionogi 28 Nov 2020
Influenza A virus infections - In children, In infants, Prevention Registered Japan PO / Granules Shionogi 27 Nov 2020
Influenza B virus infections aged 12 years and above In adolescents, In adults, In the elderly Marketed Taiwan PO / Tablet Shionogi 25 Nov 2019
Influenza B virus infections - Prevention Marketed Japan PO / Tablet Shionogi 28 Nov 2020
Influenza B virus infections - In adolescents, In adults, In children Marketed Japan PO / Tablet Shionogi 01 Mar 2018
Influenza B virus infections - In children, In infants, Prevention Registered Japan PO / Granules Shionogi 27 Nov 2020
Influenza B virus infections post-exposure prophylaxis in patients aged one year and older In children, In infants, Prevention Preregistration USA PO / Tablet Roche 27 Mar 2020
Influenza virus infections 12 years of age and older In adolescents, In adults, In children, In the elderly, Prevention Marketed USA PO / Tablet Shionogi 23 Nov 2020
Influenza virus infections 12 years of age and older In adolescents, In adults, In children, In the elderly Marketed USA PO / Tablet Roche, Shionogi 18 Oct 2019
Influenza virus infections In patients with uncomplicated influenza aged 12 years and above In adolescents, In adults Marketed USA PO / Tablet Roche, Shionogi 04 Apr 2019
Influenza virus infections - In children, In infants Registered Japan PO / Granules Shionogi 01 Apr 2018
Influenza virus infections - In adolescents, In adults, In children, In the elderly, Prevention Registered European Union, Iceland, Liechtenstein, Norway PO / Tablet Roche 11 Jan 2021
Influenza virus infections - In adolescents, In adults, In children, In the elderly Registered European Union, Iceland, Liechtenstein, Norway PO / Tablet Roche 11 Jan 2021
Influenza virus infections uncomplicated influenza in patients aged 12 years and older In adolescents, In adults, In the elderly Registered Australia, Canada, Switzerland PO / Tablet Roche, Shionogi 28 Feb 2020
Influenza virus infections acute uncomplicated influenza in otherwise healthy children aged 1-12 years In children, In infants Preregistration USA PO / Suspension Roche 27 Mar 2020
Influenza virus infections post-exposure prophylaxis in patients aged one year and older In children, In infants, Prevention Preregistration USA PO / Suspension Roche 27 Mar 2020
Influenza virus infections aged 1-12 years In children, In infants Phase III Costa Rica, Israel, Mexico, Panama, Poland, Puerto Rico, Russia, Spain PO / Suspension Roche 20 Nov 2018
Influenza virus infections - In adolescents, In adults, In children Phase III Costa Rica, Greece, Hong Kong, India, Poland, Turkey, United Kingdom PO / Suspension Roche 10 Oct 2019
Influenza virus infections - In infants, In neonates Phase III Costa Rica, Finland, Israel, Mexico, Panama, Poland, Russia, South Africa, Spain, Thailand PO / unspecified Roche 23 Jan 2019
Influenza virus infections less than 1 year of age In infants, In neonates Phase III USA PO / Suspension Roche 28 Nov 2018
Influenza virus infections In hospitalised partients with severe Influenza Combination therapy, In adolescents, In adults, In children, In the elderly Phase III Argentina, Australia, Belgium, Bulgaria, Canada, Czech Republic, Estonia, Germany, Hungary, Israel, Japan, Mexico, New Zealand, Peru, Romania, Serbia, Singapore, South Korea, Spain, Sweden, USA PO / unspecified Roche 08 Jan 2019
Influenza virus infections - In adolescents, In adults, In the elderly Phase III New Zealand, Philippines, South Africa, South Korea, United Kingdom PO / Tablet Roche, Shionogi 01 Dec 2016
Influenza virus infections - In volunteers Phase I China PO / unspecified Roche, Shionogi 04 Jun 2019

Commercial Information

Involved Organisations

Organisation Involvement Countries
Shionogi Originator Japan
Shionogi Owner Japan
Roche Licensee World

Brand Names

Brand Name Organisations Indications Countries
XOFLUZA Shionogi, Roche Influenza A virus infections, Influenza B virus infections, Influenza virus infections Japan, Taiwan, USA
Xofluza Roche Influenza virus infections European Union, Iceland, Liechtenstein, Norway

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
Influenza ex US, ex Japan Roche, Shionogi III 2019 85 - - 01 Feb 2021
Influenza Japan Roche, Shionogi Marketed 2018 100 - 01 Jan 2035 01 Feb 2021
Influenza US Roche, Shionogi Marketed 2018 100 - - 01 Feb 2021

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
Influenza ex US, ex Japan 0 0 0 2 50 100 150 200 200 250 01 Feb 2021
Influenza Japan 0 21 244 4 185 185 230 230 230 230 01 Feb 2021
Influenza US 0 0 13 8 50 200 400 550 600 750 01 Feb 2021
Total 0 21 257 14 285 485 780 980 1030 1230

Scientific Summary

Pharmacokinetics

In phase III miniSTONE-2 trial baloxavir exposure, administered as a weight-based single oral dose, was similar to those in adult populations receiving a single dose of 40mg. Also, when stratified according to body weight, plasma concentrations were similar across body weight groups. In the intensive PK cohort (n = 19), baloxavir reached Cmax about four hours after administration. The observed Cmax (mean [min–max] = 73.1 [18.10–137.00] ng/mL) was in a similar range to that observed in the non-Asian adult population treated with a 40mg dose (mean [min–max] = 63.9 [11.1–133] and 60.6 [12.2–158] ng/mL in otherwise-healthy (OwH) and HR patients, respectively). In the sparse sampling cohort (n = 107), concentration at 24 hours (C24) was 57.1 (min–max: 0.00–217) ng/mL. The central tendency and overall range of exposure data was similar to that observed in OwH (37.2 ng/mL [7.35–81.4]) and HR non-Asian patients (35.9 ng/mL [5.77–90.2]) treated with a single 40mg dose. Mean C24 in non-Asian adults (OwH) was 57.9 ng/mL [21.4–155], also in close agreement with C24 values observed in this study. In this study patients were randomised 2:1 to receive either a single oral dose of baloxavir marboxil (2 mg/kg for patients weighing <20 kg or 40mg for patients = 20 kg) or oseltamivir [29] [28] .

Treatment with baloxavir marboxil was associated with rapid and profound decline in viral titer within 24 hours (change from baseline to Day 2 in log 10 TCID 50 /ml: -3.83 in 10 mg, - 3.53 in 20 mg, -4.54 in 40 mg groups vs -1.32 in placebo group; Figure 1). The geometric mean plasma concentration of active drug S-033447 at 24 hours post-dose (C 24 ) was 14.3, 29.1, and 58.2 ng/ml in 10 mg, 20 mg and 40 mg groups, respectively, increasing in a nearly dose-proportional manner. C 24 was positively correlated with reduction in viral titer at Day 2 and Day 3, and weakly correlated with time to resolution of fever. There was no clear relationship between C 24 and time to alleviation of other symptoms. The data were presented from 400 patients with influenza enrolled in a phase II trial [47] [48] [50] .

In a phase I study, treatment with baloxavir marboxil indicated low quantification limit (< 0.100 ng/mL) of plasma concentrations of baloxavir marboxil in almost all PK samples in healthy volunteers. S 033447 exposure (Cmax and AUC) increased in dose-proportional manner in the dose range from 6 – 80 mg. The geometric mean t1/2,z of S 033447 ranged from 48.9 to 90.9 hours across dose groups and the geometric mean plasma S 033447 concentration at 24 hours post dose was 6.92 ng/mL after administration of a 6 mg dose of baloxavir marboxil . The geometric means of Feu0–72 of S 033447 ranged from 1.7% to 2.3%. The results were reported from 40 patients enrolled in an randomised study [57] [56] .

Adverse Events

Phase III

Baloxavir marboxil was well tolerated with a numerically lower overall incidence of adverse events (20.7%) compared with placebo (24.6%) or oseltamivir (24.8%) in patients with influenza infections in the phase III CAPSTONE-1 trial. No new safety signals were identified. The incidence of treatment-related adverse events were comparable to that of placebo arm. Baloxavir marboxil showed a statistically significant decrease in the incidence of treatment-related adverse events compared to oseltamivir (p = 0.0088). The most common adverse events reported were diarrhea (3.0%), bronchitis (2.6%), nausea (1.3%) and sinusitis (1.1%), and all of these adverse events occurred at a lower frequency than placebo. The incidence of nausea was less frequent in patients treated with S 033188, compared to oseltamivir. The results were reported from 1 436 patients enrolled in the study [16] [59] [44] [43] .

Baloxavir marboxil was well tolerated in the phase III CAPSTONE-2 trial. Safety signals were not observed. Baloxavir marboxil also reduced the use of antibiotics and incidence of influenza-related complications (3.4% and 2.8% respectively) compared to placebo (7.5% and 10.4%; p = 0.01 and p < 0.05). Baloxavir marboxil had a numerically lower overall incidence of reported adverse events (25.1%) compared with placebo (29.7%) or oseltamivir (28%) [40] [63] [35] . Updated results showed that baloxavir had a numerically lower overall incidence of reported adverse events (25.1%) compared with placebo (29.7%) or oseltamivir (28.0%). The most common adverse events reported in the baloxavir group were bronchitis (3%), diarrhoea (3%), nausea (2%), headache (1%) and sinusitis (2%) [39] . Results from subgroup analysis indicated the percentage of baloxavir recipients with complications (3.0% vs 4.7%. p = 0.559) or required antibacterial therapy (3.6% vs 4.7%, p = 0.778) did not differ significantly from oseltamivir recipients. The treatment-emergent I38 variant was observed in 0.6% baloxavir recipient. Baloxavir significantly reduced percentage of patients with pre-specified complications compared with placebo (3.0% vs 11.3%, p = 0.005) and numerically reduced percentage of patients requiring antibacterial therapy (3.6% vs 7.7%, p = 0.155). Results were reported from 484 patients enrolled in the randomised study [38] .

Phase II

In a phase II proof of concept clinical trial a single oral dose of baloxavir marboxil (10 mg, 20 mg or 40 mg) was well tolerated in all dose groups in patients with influenza A and B virus infection. Treatment related adverse events were reported in 27.0%, 23.0%, 26.0% and 29.0% of patients in the 10, 20, 40 mg and placebo groups, respectively; most were mild and resolved without treatment. The data were presented from 400 patients with influenza enrolled in a phase II trial [47] [49] [36] [50] .

Results from a phase I study showed that treatment with single oral doses of baloxavir marboxil at the doses of 6 – 80 mg were generally safe and well tolerable in healthy volunteers. One subject experienced a treatment emergent adverse event of headache, which was mild in severity and resolved without any treatments. The results were reported from 40 patients enrolled in an randomised study [57] [56] .

In the phase III BLOCKSTONE study, baloxavir marboxil was well tolerated in the study and no new safety signals were identified. The most frequently reported adverse events included diarrhea (3%), bronchitis (3%), nausea (2%), sinusitis (2%), and headache (1%). Baloxavir marboxil exhibited a comparable safety profile to placebo. The overall incidence of adverse events was 22.2% and 20.5% in baloxavir and placebo respectively. No serious adverse events were reported for baloxavir [5] [34] [33] [32] .

In the phase III MINISTONE-2 study baloxavir marboxil demonstrated a similar safety profile to oseltamivir. 46.1% patients treated with baloxavir marboxil experienced at least one treatment emergent AE compared to 53.4% in the oseltamivir arm. The safety profile was consistent with that reported in the previous studies in adults and adolescents [26] [28] .

Pharmacodynamics

Summary

Preclinical study

Result from preclinical study demonstrated profound antiviral activity against influenza A and B viruses including oseltamivir-resistant virus (NA/H274Y). Single day dosing of baloxavir marboxil in a mouse lethal infection model prevented mortality which was superior than multiple day dosing of oseltamivir [36] .

Baloxavir marboxil demonstrated more potent in vivo and in vitro activity against pathogenic H5N1 avian influenza virus, as compared with oseltamivir. Superior efficacy in mice infected with influenza B virus was also displayed by a one day oral dosing of S 033188 (5 or 50mg/kg bid), as compared with a proportionate dose of oseltamivir [48] .

Results from a preclinical study showed that baloxavir marboxil (5 or 50 mg/kg, BID for 1 day) completely eliminated mortality in mice infected with influenza B virus, whereas in mice treated with clinically equivalent dose of oseltamivir phosphate (5 mg/kg, bid for 5 days) only 20% of animals survived. Baloxavir marboxil treatment also significantly reduced viral titer and prevented body weight loss, consistent with the prolonged survival [61] .

In preclinical studies, baloxavir marboxil and S 033447 exhibited potent in vitro and in vivo activity against A/Hong Kong/483/97 (H5N1) strain compared to oseltamivir. S 033447 demonstrated more potent antiviral activity against A/Hong Kong/483/97 strain than oseltamivir acid in virus yield reduction assay. In mice infected with A/Hong Kong/483/97 strain, baloxavir marboxil (5 or 50mg/kg, bid for 1 day) completely eliminated mortality and exhibited significant survival time compared to vehicle or oseltamivir (5 mg/kg, bid for 5 days). Baloxavir marboxil treatment also led to significant reduction of viral titer and prevention of body weight loss compared to vehicle or oseltamivir treatment [60] .

Drug Interactions

Results from a phase I trial showed that no affect in the PK of S 033447 (baloxavir marboxil's active form ) with the geometric mean ratios (90% confidence interval: CI) of 1.03 (0.92-1.15) for Cmax and 1.01 (0.96-1.06) for AUC was observed on co-administration of baloxavir marboxil and oseltamivir. Co-administration of baloxavir marboxil and oseltamivir did not affect the PK of oseltamivir carboxylate with the geometric mean ratios (90% CI) of 0.96 (0.91-1.01) for Cmax and 0.96 (0.92-1.00) for AUC. Slight increase in the AUC ( not clinically meaningful) of oseltamivir was observed on co-administration with baloxavir marboxil with the geometric mean ratio (90% CI) of 1.23 (1.14-1.33) whereas Cmax of oseltamivir was not affected. The single-center, open-label, randomized, 6-sequence, 3-period, 3-treatment crossover study assesed pharmacokinetic (PK) drug-drug interaction between baloxavir marboxil and oseltamivir based on plasma concentration profiles of their active forms, S-033447 and oseltamivir carboxylate, as well as their respective pro-drugs baloxavir marboxil and oseltamivir in 18 healthy adult male participants [53] [54] .

Immunogenicity

Summary

Therapeutic Trials

Phase III

Updated data from the phase III CAPSTONE-1 trial, demonstrated emergence of PAI38X variants as early as 3 days after treatment with baloxavir in 9.7% (36/370) of patients. The median time to alleviation of symptom (TTAS) was reported to be longer in baloxavir recipients shedding PA/I38X virus (63.1 hours) versus those without (51.0 hours) but shorter than in placebo recipients (80.2 hours). The time to sustained cessation of infectious virus detection was longer in those with I38X substitutions, of whom % showed transient increases in viral titers, compared to those without and to placebo (median, 192 versus 48 versus 96 hours). The proportion with symptom rebound was similar across these subgroups (11.5, 8.0, and 13.0 percentage, respectively). NGS in 7 selected patients revealed that PA/I38X virus was first detected 3 to 5 days after baloxavir treatment. The susceptibility to baloxavir was reported to be reduced by 65 to 155-fold versus wild-type virus (0.31 - 0.69 ng/mL vs 36 - 63 ng/mL), in five pairs of clinical isolates with PA/I38 variants [45] . Earlier results reported significant reduction in time to alleviation of symptoms (TTAS) (p < 0.001) in otherwise healthy patients with influenza infections in the phase III CAPSTONE-1 trial. The median TTAS was 53.7 hours (p < 0.001) in baloxavir marboxil group, compared with 53.8 hours (p = 0.7560) in oseltamivir group and 80.2 hours in placebo group, respectively. TTAS was similar between baloxavir marboxil and oseltamivir groups [64] . Significant improvement compared with placebo or oseltamivir for important virological endpoints was seen. The percentage of patients determined to be positive for influenza virus titer was significantly lower in the baloxavir marboxil group in comparison with the oseltamivir group at one, two and four days from the start of treatment. Additionally, the time to cessation of viral shedding was significantly decreased to 24 hours (p < 0.0001) in the baloxavir marboxil as compared with the 72 hours (p < 0.0001) in oseltamivir group and 96 hours in placebo group. Significant reduced fever by 24 hours (p < 0.0001) compared with 42 hours in placebo. The results were reported from 1 436 patients enrolled in the study [16] [59] [44] [43] .

CAPSTONE-2 phase III trial met its primary endpoint of time to improvement of influenza symptoms compared with placebo (median time of 73.2 hours versus 102.3 hours; p < 0.0001), as defined by Centers for Disease Control and Prevention (CDC). Baloxavir marboxil demonstrated superior efficacy (reduced time to improvement of influenza symptoms) versus placebo and oseltamivir in influenza type B (median time of 74.6 hours versus 100.6 hours and 101.6 hours, respectively (p = 0.0138, p = 0.0251). Significant reduction in time to resolution of fever (median time of 30.8 hours versus 50.7 hours; p < 0.0001), the incidence of influenza-related complications (2.8% versus 10.4% ; p < 0.05), the use of systemic antibiotics (3.4% versus 7.5%; p = 0.01) and the length of time the virus continued to be released from the body (viral shedding; median time of 48 hours versus 96 hours; p < 0.0001) were observed. A significant difference was observed in the time to cessation of viral shedding that favored baloxavir marboxil. No significant reduction in the time to resolution of fever (median time of 30.8 hours for baloxavir marboxil versus 34.3 hours for oseltamivir; p < 0.2425), the incidence of influenza-related complications (2.8% for XOFLUZA versus 4.6% for oseltamivir; p = 0.2558) and the use of systemic antibiotics (3.4%% for baloxavir marboxil versus 3.9% for oseltamivir; p = 0.8478). Significantly reduced the length of time the virus continued to be released from the body (viral shedding; median time of 48 hours versus 96 hours; p < 0.0001). Results were reported from 2184 patients [39] . Overall patient population of the study showed numerically shorter time to improvement of influenza symptoms of baloxavir marboxil versus oseltamivir with a median time to improvement of symptoms of 73.2 hours for baloxavir marboxil compared with 81.0 hours for oseltamivir (p = 0.8347). In the subpopulation of people with influenza type B, a subgroup where some antiviral treatments have shown only limited efficacy or inconclusive data, baloxavir marboxil was significantly more efficacious than oseltamivir in reducing the time to improvement of symptoms (median time of 74.6 hours versus 101.6 hours; p < 0.05) [40] [37] [63] [35] .

Updated results from the phase III BLOCKSTONE study showed that the trial met its primary endpoint. Baloxavir marboxil showed a statistically significant prophylactic effect on influenza after a single oral dose, by reducing the risk of patients from developing influenza after exposure to an infected household member, by 90% compared with placebo. The proportion of household members aged 12 years and above who developed laboratory-confirmed clinical influenza was 1.3% in the baloxavir marboxil group versus 13.2% in the placebo-treated group. Earlier data showed that proportion of household members who became symptomatically ill following infection with flu was significantly lower in those treated preventively with baloxavir compared with those treated with placebo (proportion of subjects with influenza virus infection, fever and other influenza symptoms in the 10-day observation period: 1.9% of baloxavir marboxil treated household members had the flu compared versus 13.6% in the placebo-treated group p < 0.0001). Treatment with baloxavir marboxil also remained statistically significant regardless of influenza A subtype (H1N1: 1.1% versus 10.6%, p=0.0023; H3: 2.8% versus 17.5% p<0.0001) as compared to placebo. A statistically significant benefit was also reported in household contacts who are at high risk of flu-associated complications (2.2% versus 15.4%, p=0.0435), and children under 12 years of age (4.2% versus 15.5% p=0.0339), who are more vulnerable to developing the flu. Treatment with baloxavir marboxil also demonstrated a significant 76% reduction in the risk of household members developing the flu (5.3% versus 22.4%respectively, p<0.0001) when compered to placebo [2] [34] [33] [32] .

Phase II

Result from a phase II proof of concept study demonstrated that all the three doses (10mg, 20mg or 40mg) of baloxavir marboxil in patients with influenza A and B virus infection led to a significant reductions in time to alleviation of symptoms using wilcoxon test (p<0.05); however, statistically no difference was observed using cox proportional hazard model when compared with placebo and a reduction in viral load was observed. Median time to alleviation of seven influenza symptoms (TTAS) was 54.2 hours (95% CI 47.7, 66.8) in the 10 mg group, 51.0 hours (95% CI 44.5, 62.4) in the 20 mg group, 49.5 hours (95% CI 44.5, 64.4) in the 40 mg group and 77.7 hours (95% CI 67.6, 88.7) in the placebo group (2-sided p = 0.0085, 0.0182 and 0.0046 for 10, 20 and 40 mg vs placebo, respectively, stratified generalized Wilcoxon test). Secondary endpoint data showed that 40 mg dose of baloxavir marboxil was associated with shorter time to alleviation of systemic symptoms compared with placebo, such as feverishness / chills (median 23.0 hours versus 28.8 hours, p = 0.0216), headache (37.9 hours versus 43.7 hours, p = 0.0304), fatigue (31.1 hours versus 42.7 hours, p = 0.0463), aches and pains (25.4 hours versus 41.9 hours, p = 0.0145), rapid resolution of fever (28.9 hours versus 45.3 hours, p<0.0001) and nasal congestion (21.9 hours versus 42.8 hours, p = 0.0081). However, sore throat and cough tended to persist despite rapid viral clearance in patients treated with baloxavir marboxil. The trial was conducted in 400 patients with influenza infections [49] [47] [36] [50] .

In the phase III MINISTONE-2 study time to alleviation of influenza signs and symptoms of baloxavir marboxil arm was comparable to oseltamivir (median time of 138.1 hours (95% CI: 117, 163) vs 150.0 hours (95% CI: 115, 166), respectively). Baloxavir marboxil reduced the length of time that the influenza virus continued to be released from the body by more than two days compared with oseltamivir (viral shedding; median time of 24.2 hours vs 75.8 hours, respectively) [26] [28] .

Future Events

Expected Date Event Type Description Updated
31 Dec 2023 Regulatory Status Roche plans regulatory filing for Influenza virus infection (direct transmission) in 2023 (Roche pipeline, April 2021) 28 Apr 2021
31 Dec 2022 Regulatory Status Roche plans regulatory filing for Influenza virus infection (In Infants) in 2022 (Roche pipeline, April 2021) 28 Apr 2021
23 Nov 2020 Regulatory Status The US FDA is expected to make a decision on sNDA for one-dose granules for oral suspension and tablet formulation for the post-exposure prophylaxis of influenza in people one year of age and older, in November 2020 [7] 02 Apr 2020
23 Nov 2020 Regulatory Status The US FDA is expected to make a decision on NDA for one-dose granules for oral suspension, for the treatment of acute uncomplicated influenza in otherwise healthy children aged one to less than 12 years of age who have been symptomatic for no more than 48 hours, in November 2020 [7] 02 Apr 2020
01 Jun 2020 Trial Update Shionogi plans a phase III trial for Influenza virus infection (In Infants, In Children, In adults, In elderly, Prevention) in Japan (PO) (EudraCT2020-000696-20) 08 Dec 2020
04 Nov 2019 Regulatory Status US FDA assigns PDUFA action date of 04/11/2019 for Baloxavir marboxil for Influenza virus infections (In adolescents, In adults, In elderly) with high risk of complications [12] 23 Oct 2019
04 Jun 2019 Trial Update Roche plans a phase I trial in Healthy Chinese volunteers in June 2019 (700307675), (NCT03959332) 11 Jun 2019
31 Mar 2019 Trial Update Shionogi plans a post exposure phase III prophylaxis study for Influenza infections in Japan [62] 12 Nov 2018
21 Dec 2018 Regulatory Status US FDA assigns PDUFA action date of 24/12/2018 for Baloxavir marboxil for Influenza virus infections (In adolescents, In adults) [16] 26 Oct 2018
13 Dec 2018 Trial Update Roche plans a phase III trial for Influenza virus infectionsin USA, Israel and Puerto Rico (700298852), (NCT03629184) 10 Dec 2018
13 Dec 2018 Trial Update Roche plans a phase III trial for Influenza infections in USA, Israel and South Africa (NCT03653364) 10 Dec 2018
30 Nov 2018 Trial Update Roche plans a phase III trial for Influenza infections (Combination therapy) in USA, Australia, Belgium, Brazil, Bulgaria, Canada, Czech republic, Estonia, Finland, France, Germany, Hong Kong, Hungary, Israel, Japan, South Korea, Mexico, Netherlands, New Zealand, Peru, Romania, Serbia, Singapore, Spain, Sweden, Turkey, Ukraine (700300072), (NCT03684044) 13 Dec 2018
30 Nov 2018 Regulatory Status Genentech plans to launch baloxavir marboxil (XOFLUZA™) for Influenza infections in USA in the coming weeks [62] 11 Apr 2019

Development History

Event Date Update Type Comment
28 May 2021 Phase Change - No development reported No recent reports of development identified for preclinical development in Influenza-A-virus-H5N1-subtype in Japan (PO) Updated 28 May 2021
28 Apr 2021 Regulatory Status Roche plans regulatory filing for Influenza virus infection (direct transmission) in 2023 (Roche pipeline, April 2021) Updated 30 Apr 2021
28 Apr 2021 Regulatory Status Roche plans regulatory filing for Influenza virus infection (In Infants) in 2022 (Roche pipeline, April 2021) Updated 30 Apr 2021
01 Feb 2021 Financial Update Credit Suisse financial data update Updated 14 Mar 2021
11 Jan 2021 Phase Change - Registered Registered for Influenza virus infections (In adolescents, In children, In the elderly, In adults) in Iceland, Norway, Liechtenstein and the European Union (PO) [2] Updated 12 Jan 2021
11 Jan 2021 Phase Change - Registered Registered for Influenza virus infections (In adolescents, In children, In the elderly, Prevention, In adults) in Iceland, Norway, Liechtenstein and European Union (PO) [2] Updated 12 Jan 2021
11 Jan 2021 Scientific Update Updated efficacy data from the phase III BLOCKSTONE trial in Influenza virus infection released by Roche [2] Updated 12 Jan 2021
28 Nov 2020 Phase Change - Marketed Launched for Influenza A virus infections (Prevention) in Japan (PO) [6] Updated 09 Apr 2021
28 Nov 2020 Phase Change - Marketed Launched for Influenza B virus infections (Prevention) in Japan (PO) [6] Updated 09 Apr 2021
27 Nov 2020 Phase Change - Preregistration Preregistration for Influenza A virus infections (Prevention) in Japan (PO) before November 2020 [6] Updated 09 Apr 2021
27 Nov 2020 Phase Change - Preregistration Preregistration for Influenza B virus infections (Prevention) in Japan (PO) before May 2020 [6] Updated 09 Apr 2021
27 Nov 2020 Phase Change - Registered Registered for Influenza A virus infections (In children, In infants, Prevention) in Japan (PO) [6] Updated 09 Apr 2021
27 Nov 2020 Phase Change - Registered Registered for Influenza A virus infections (Prevention) in Japan (PO) [6] Updated 09 Apr 2021
27 Nov 2020 Phase Change - Registered Registered for Influenza B virus infections (In children, In infants, Prevention) in Japan (PO) [6] Updated 09 Apr 2021
27 Nov 2020 Phase Change - Registered Registered for Influenza B virus infections (Prevention) in Japan (PO) [6] Updated 09 Apr 2021
23 Nov 2020 Phase Change - Marketed Launched for Influenza virus infections (In adolescents, In children, In the elderly, Prevention, In adults) in USA (PO, Tablet) [5] Updated 25 Nov 2020
23 Nov 2020 Phase Change - Registered Registered for Influenza virus infections (In children, In adolescents, In adults, In the elderly, Prevention) in USA (PO, Tablet) before November 2020 [5] Updated 25 Nov 2020
23 Nov 2020 Scientific Update Adverse events data from a phase III BLOCKSTONE trial in Influenza virus infections released by Genentech [5] Updated 25 Nov 2020
13 Nov 2020 Regulatory Status The Committee for Medicinal Products for Human Use (CHMP) recommends approval of baloxavir marboxil for Influenza virus infection (In children, In adolescents, In adults, In the elderly) [3] Updated 24 Nov 2020
18 Apr 2020 Scientific Update Pharmacokinetics data from a phase III miniSTONE-2 trial in Influenza virus infections presented at the 30th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2020) [29] Updated 07 Jul 2020
06 Apr 2020 Trial Update Shionogi plans a phase III trial for Influenza virus infection (In Infants, In Children, In adults, In elderly, Prevention) in Japan (PO) (EudraCT2020-000696-20) Updated 08 Dec 2020
27 Mar 2020 Phase Change - Preregistration Preregistration for Influenza B virus infections (In infants, In children, Prevention) in USA (PO, Suspension) before March 2020 [7] Updated 09 Feb 2021
27 Mar 2020 Phase Change - Preregistration Preregistration for Influenza virus infections (In children, In infants) in USA (PO, Suspension) before March 2020 [7] Updated 09 Feb 2021
27 Mar 2020 Phase Change - Preregistration Preregistration for Influenza virus infections (In infants, In children, Prevention) in USA (PO, Tablet) before March 2020 [7] Updated 09 Feb 2021
27 Mar 2020 Regulatory Status The US FDA accepts sNDA for oral suspension and tablet formulation of baloxavir marboxil for post-exposure prophylaxis of Influenza for review [7] Updated 02 Apr 2020
27 Mar 2020 Regulatory Status The US FDA is expected to make a decision on NDA for one-dose granules for oral suspension, for the treatment of acute uncomplicated influenza in otherwise healthy children aged one to less than 12 years of age who have been symptomatic for no more than 48 hours, in November 2020 [7] Updated 02 Apr 2020
27 Mar 2020 Regulatory Status The US FDA is expected to make a decision on sNDA for one-dose granules for oral suspension and tablet formulation for the post-exposure prophylaxis of influenza in people one year of age and older, in November 2020 [7] Updated 02 Apr 2020
27 Mar 2020 Regulatory Status The US FDA accepts NDA for oral suspension of baloxavir marboxil for Acute uncomplicated influenza for review [7] Updated 02 Apr 2020
16 Mar 2020 Trial Update Hoffmann-La Roche completes a phase III trial in Influenza virus infections (In children, In adolescents, In adults, In the elderly, Combination therapy) in Argentina, Australia, Belgium, Bulgaria, Canada, Czech Republic, Estonia, Germany, Hong Kong, Hungary, Israel, Japan, Mexico, New Zealand, Peru, Romania, Serbia, Singapore, South Korea, Spain, Sweden, and the USA (PO) (NCT03684044) Updated 18 Jun 2020
28 Feb 2020 Phase Change - Registered Registered for Influenza virus infections (In adolescents, In adults, In the elderly) in Switzerland (PO) [17] Updated 28 Feb 2020
25 Feb 2020 Phase Change - Preregistration Preregistration for Influenza virus infections (In adolescents, In adults, In the elderly) in Switzerland (PO) before February 2020 [17] Updated 28 Feb 2020
21 Feb 2020 Phase Change - Preregistration Preregistration for Influenza virus infections (In adolescents, In the elderly, In adults) in Australia (PO) before February 2020 [19] [17] Updated 28 Feb 2020
21 Feb 2020 Phase Change - Registered Registered for Influenza virus infections (In adolescents, In the elderly, In adults) in Australia (PO) [19] [17] Updated 28 Feb 2020
04 Dec 2019 Phase Change - Preregistration Preregistration for Influenza virus infections (In adolescents, In the elderly, In adults) in European Union (PO) prior to December 2019 [4] Updated 09 Dec 2019
25 Nov 2019 Phase Change - Marketed Launched for Influenza A virus infections (In adolescents, In the elderly, In adults) in Taiwan (PO) [20] Updated 05 Dec 2019
25 Nov 2019 Phase Change - Marketed Launched for Influenza B virus infections (In adolescents, In the elderly, In adults) in Taiwan (PO) [20] Updated 05 Dec 2019
17 Oct 2019 Phase Change - Marketed Launched for Influenza virus infections (In adolescents, In children, In the elderly, In adults) in USA (PO) [11] Updated 23 Oct 2019
17 Oct 2019 Phase Change - Registered Registered for Influenza virus infections (In adolescents, In adults, In children, In the elderly) in USA (PO) [11] Updated 23 Oct 2019
10 Oct 2019 Phase Change - III Phase-III clinical trials in Influenza virus infections (In children, In adolescents, In adults) in United Kingdom, Turkey, Poland, India, Hong Kong, Greece and Costa Rica (PO) after October 2019 (NCT03969212) (EudraCT2018-004056-37) Updated 29 Dec 2020
10 Oct 2019 Trial Update Roche initiates a phase IIIb trial for Influenza virus infections (In children, In adolescents, In adults) in Argentina, Israel, Japan, Mexico, South Africa, Singapore and Spain (PO) (NCT03969212) (EudraCT2018-004056-37) Updated 29 Dec 2020
10 Oct 2019 Trial Update Roche initiates a phase IIIb trial for Influenza virus infections (In adolescents, In adults, In children) in USA, Japan, United Kingdom (PO) (NCT03969212) Updated 12 Nov 2019
02 Sep 2019 Scientific Update Safety and efficacy data from the phase III MINISTONE-2 trial in Influenza virus released by Shionogi [26] Updated 05 Sep 2019
02 Sep 2019 Scientific Update Updated efficacy and adverse events data from the phase III BLOCKSTONE trial in Influenza virus infections released by Genentech [34] Updated 05 Sep 2019
28 Aug 2019 Phase Change - Registered Registered for Influenza A virus infections (In adolescents, In the elderly, In adults) in Taiwan (PO) [21] Updated 03 Sep 2019
28 Aug 2019 Phase Change - Registered Registered for Influenza B virus infections (In adolescents, In the elderly, In adults) in Taiwan (PO) [21] Updated 03 Sep 2019
28 Aug 2019 Regulatory Status Shionogi intends to launch baloxavir marboxil for Influenza A and B virus infections in Taiwan [21] Updated 03 Sep 2019
23 Jul 2019 Trial Update Roche initiates a phase IIIb trial for Influenza virus infections (In adolescents, In adults, In children) in South Africa (PO) (NCT03969212) Updated 29 Jul 2019
11 Jul 2019 Trial Update Roche completes a phase I trial in Influenza virus infections (In volunteers) in China (PO) (NCT03959332) Updated 29 Aug 2019
04 Jun 2019 Trial Update Roche completes a phase-I trial in Influenza virus infections (In volunteers) in South Korea (PO) (KCT0003535) Updated 03 Jul 2019
04 Jun 2019 Phase Change - I Phase-I clinical trials in Influenza virus infections (In volunteers) in China (PO) (NCT03959332) Updated 11 Jun 2019
04 Jun 2019 Trial Update Roche plans a phase IIIb trial for Influenza virus infections (In adolescents, In adults, In the elderly) in USA, Brazil, Costa Rica, Greece, Hong Kong, India, Israel, Mexico, Singapore, South Africa, and Spain (PO) (NCT03969212) (EudraCT2018-004056-37) Updated 04 Jun 2019
03 Jun 2019 Scientific Update Efficacy and adverse events data from the phase III Blackstone trial in Influenza virus infections released by Genentech [33] Updated 07 Jun 2019
27 May 2019 Trial Update Roche plans a phase I trial in Healthy Chinese volunteers in June 2019 , (NCT03959332) Updated 11 Jun 2019
13 Apr 2019 Scientific Update Efficacy data from the phase III CAPSTONE-1 trial in Influenza virus infections presented at the 29th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2019) [45] Updated 29 May 2019
13 Apr 2019 Scientific Update Subgroup adverse events data from the CAPSTONE-2 phase III trial in Influenza virus infections presented at the 29th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2019) [38] Updated 29 May 2019
04 Apr 2019 Regulatory Status US FDA assigns PDUFA action date of 04/11/2019 for Baloxavir marboxil for Influenza virus infections (In adolescents, In adults, In elderly) with high risk of complications [12] Updated 23 Oct 2019
04 Apr 2019 Phase Change - Marketed Launched for Influenza virus infections (In adolescents, In adults) in USA (PO) [12] before April 2019 Updated 11 Apr 2019
04 Apr 2019 Phase Change - Preregistration Preregistration for Influenza virus infections (In adolescents, In adults, In children, In the elderly) with high-risk complication in USA (PO) [12] before April 2019 Updated 11 Apr 2019
04 Apr 2019 Regulatory Status The US FDA accepts sNDA for Baloxavir marboxil for Influenza virus infections (In adolescents, In adults) with high-risk complication (PO) [12] before April 2019 Updated 11 Apr 2019
04 Apr 2019 Trial Update Roche plans a clinical trial for Influenza virus infection (In volunteers, Prevention) to reduce transmission [12] Updated 11 Apr 2019
02 Apr 2019 Trial Update Roche completes a phase III trial in Influenza virus infections (In children, In infants) in Spain, Russia, Puerto Rico, Poland, Panama, Mexico, Israel, Costa Rica, USA (PO) (NCT03629184) Updated 17 May 2019
25 Mar 2019 Trial Update Shionogi completes a phase III trial for Influenza virus infection (In Infants, In Children, In adults, In elderly, Prevention) in Japan (PO) (EudraCT2020-000696-20) Updated 08 Dec 2020
12 Mar 2019 Trial Update Roche completes enrollment in a phase-I trial in Influenza virus infections (In volunteers) in South Korea (PO) (KCT0003535) Updated 03 Apr 2019
06 Mar 2019 Regulatory Status The US FDA accepts sNDA for baloxavir marboxil for Influenza virus infections for review [13] Updated 11 Mar 2019
05 Mar 2019 Scientific Update Updated efficacy and adverse events data from the CAPSTONE 2 phase III trial in Influenza virus infections released by Roche and Genentech [13] [39] Updated 11 Mar 2019
31 Jan 2019 Trial Update Shionogi completes the phase III BLOCKSTONE trial in Influenza virus infection (Prevention) in Japan (PO) prior to January 2019 (JapicCTI184180) Updated 16 Sep 2019
23 Jan 2019 Phase Change - III Phase-III clinical trials in Influenza virus infections (In neonates, In infants) in Thailand, Spain, South Africa, Russia, Poland, Panama, Mexico, Israel, Finland, and Costa Rica (PO) after January 2019 (NCT03653364) (EudraCT2018-002154-70) Updated 29 Dec 2020
08 Jan 2019 Phase Change - III Phase-III clinical trials in Influenza virus infections (In children, In adolescents, In adults, In the elderly, Combination therapy) in Sweden, Spain, Singapore, Serbia, Romania, Peru, New Zealand, Mexico, South Korea, Japan, Israel, Hungary, USA, Argentina, Australia, Belgium, Bulgaria, Canada, Estonia, Germany, and Czech Republic (PO) (NCT03684044) Updated 05 Jul 2019
02 Jan 2019 Trial Update Roche initiates a phase-I trial in Influenza virus infections (In volunteers) in South Korea (PO) (KCT0003535) Updated 19 Mar 2019
31 Dec 2018 Phase Change - Preregistration Preregistration for Influenza virus infections (In adolescents, In adults, In the elderly) in Canada (PO) before December 2018 [19] [17] Updated 28 Feb 2020
31 Dec 2018 Phase Change - Registered Registered for Influenza virus infections (In adolescents, In the elderly, In adults) in Canada (PO) [19] [17] Updated 28 Feb 2020
28 Nov 2018 Phase Change - III Phase-III clinical trials in Influenza virus infections (In infants, In children) in USA (PO, Suspension) (NCT03629184) Updated 10 Dec 2018
28 Nov 2018 Phase Change - III Phase-III clinical trials in Influenza virus infections (In neonates, In infants) in USA (PO, Suspension) (NCT03653364) Updated 10 Dec 2018
20 Nov 2018 Phase Change - III Phase-III clinical trials in Influenza virus infections (In children, In infants) in Spain, Russia, Puerto Rico, Poland, Panama, Mexico, Israel, Costa Rica (PO) (NCT03629184) (EudraCT2018-002169-21) Updated 17 May 2019
09 Nov 2018 Trial Update Shionogi initiated enrolment in a phase III trial for Influenza virus infection (In Infants, In Children, In adults, In elderly, Prevention) in Japan (PO) (EudraCT2020-000696-20) Updated 08 Dec 2020
25 Oct 2018 Regulatory Status Genentech plans to launch baloxavir marboxil (XOFLUZA™) for Influenza infections in USA in the coming weeks [62] Updated 11 Apr 2019
25 Oct 2018 Trial Update Shionogi plans a post exposure phase III prophylaxis study for Influenza infections in Japan [62] Updated 12 Nov 2018
24 Oct 2018 Phase Change - Registered Registered for uncomplicated Influenza virus infections (In adolescents, In adults) in USA (PO) [15] Updated 26 Oct 2018
03 Oct 2018 Scientific Update Adverse events and efficacy data from the phase III CAPSTONE-2 trial in Influenza virus infections released by Genentech [40] Updated 10 Oct 2018
30 Sep 2018 Phase Change - III Phase-III clinical trials in Influenza virus infections (Prevention) in Japan (PO) [30] Updated 12 Nov 2018
25 Sep 2018 Trial Update Roche plans a phase III trial for Influenza infections (Combination therapy) in USA, Australia, Belgium, Brazil, Bulgaria, Canada, Czech republic, Estonia, Finland, France, Germany, Hong Kong, Hungary, Israel, Japan, South Korea, Mexico, Netherlands, New Zealand, Peru, Romania, Serbia, Singapore, Spain, Sweden, Turkey, Ukraine , (NCT03684044) Updated 13 Dec 2018
31 Aug 2018 Trial Update Roche plans a phase III trial for Influenza infections in USA, Israel and South Africa (NCT03653364) Updated 10 Dec 2018
14 Aug 2018 Trial Update Roche plans a phase III trial for Influenza virus infectionsin USA, Israel and Puerto Rico , (NCT03629184) Updated 10 Dec 2018
17 Jul 2018 Scientific Update Initial efficacy and adverse events data from the phase III CAPSTONE-2 trial in Influenza virus infections released by Shinonogi [63] Updated 19 Jul 2018
16 Jul 2018 Scientific Update Updated efficacy data from the phase III CAPSTONE-2 trial in Influenza virus infections released by Roche [37] Updated 20 Jul 2018
16 Jul 2018 Trial Update Roche plans a phase III trial for Influenza virus infection in pediatric and severely ill hospitalised populations [37] Updated 20 Jul 2018
29 Jun 2018 Phase Change - Preregistration Preregistration for Influenza B virus infections (In adolescents, In the elderly, In adults) in Taiwan (PO) [22] Updated 03 Sep 2019
29 Jun 2018 Phase Change - Preregistration Preregistration for Influenza A virus infections (In adolescents, In elderly, In adults) in Taiwan (PO) [22] Updated 04 Jul 2018
25 Jun 2018 Regulatory Status US FDA assigns PDUFA action date of 24/12/2018 for Baloxavir marboxil for Influenza virus infections (In adolescents, In adults) [16] Updated 26 Oct 2018
25 Jun 2018 Phase Change - Preregistration Preregistration for Influenza virus infections (In adolescents, In adults) in USA (PO) [16] before June 2018 Updated 28 Jun 2018
25 Jun 2018 Regulatory Status Baloxavir marboxil receives priority review status for uncomplicated Influenza in the US [16] Updated 28 Jun 2018
25 Jun 2018 Regulatory Status US FDA accepts NDA for Baloxavir marboxil for uncomplicated Influenza for review [16] Updated 28 Jun 2018
25 Jun 2018 Scientific Update Updated efficacy and adverse events data from the phase III CAPSTONE-1 trial in Influenza virus infections released by Roche [16] Updated 28 Jun 2018
24 Apr 2018 Regulatory Status Shinonogi files an NDA application with the US FDA for Influenza virus infections (In adolescents, In adults) [63] Updated 19 Jul 2018
21 Apr 2018 Scientific Update Drug interactions data from a phase I trial in Influenza virus infections presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2017) [53] Updated 08 May 2018
21 Apr 2018 Trial Update Shionogi initiates enrolment in a phase I trial for Influenza virus infections (Before April 2018) Updated 08 May 2018
20 Apr 2018 Trial Update Shionogi completes the phase III CAPSTONE 2 trial in Influenza virus infections (In adolescents, In the elderly, In adults) in USA, Japan, United Kingdom, Taiwan, Spain, South Africa, Romania, Poland, Philippines, New Zealand, Latvia, South Korea, Hungary, Germany, Bulgaria, Belgium, Australia (PO) (NCT02949011) Updated 17 May 2018
01 Apr 2018 Phase Change - Registered Registered for Influenza virus infections (In children, In infants) in Japan (PO, Granules) Updated 15 May 2018
01 Mar 2018 Phase Change - Marketed Launched for Influenza-A virus infections (In adolescents, In children, In adults) in Japan, Japan (PO) Updated 08 Mar 2018
01 Mar 2018 Phase Change - Marketed Launched for Influenza-B virus infections (In adolescents, In children, In adults) in Japan, Japan (PO) Updated 08 Mar 2018
26 Feb 2018 Phase Change - Preregistration Preregistration for Influenza-B virus infections in Japan (PO, 20mg/10mg) [9] Updated 26 Feb 2018
23 Feb 2018 Trial Update Shionogi completes a phase III trial in Influenza virus infections (In infants, In children) in Japan (PO) (JapicCTI-173811) Updated 16 Sep 2019
23 Feb 2018 Phase Change - Registered Registered for Influenza-A virus infections (In adolescents, In children, In adults) in Japan (PO, 20mg/10mg) - First global approval [8] Updated 26 Feb 2018
23 Feb 2018 Phase Change - Registered Registered for Influenza-B virus infections (In adolescents, In children, In adults) in Japan (PO, 20mg/10mg) - First global approval [8] Updated 26 Feb 2018
18 Dec 2017 Trial Update Shionogi completes a phase III trial in Influenza virus infections (In infants, In children) in Japan (PO) (JapicCTI163417) Updated 04 Jan 2018
15 Dec 2017 Phase Change - III Phase-III clinical trials in Influenza virus infections (In infants, In children) in Japan (PO) (JapicCTI-173811) Updated 15 May 2018
07 Dec 2017 Other Chemical structure information added Updated 07 Dec 2017
25 Oct 2017 Phase Change - Preregistration Preregistration for Influenza-A virus infections in Japan (PO, 20mg/10mg) [9] Updated 26 Feb 2018
05 Oct 2017 Scientific Update Updated efficacy and adverse events data from the phase III CAPSTONE-1 trial in Influenza virus infections released by Shionogi [59] Updated 09 Oct 2017
13 Sep 2017 Regulatory Status Shionogi announces intention to submit NDA to US FDA for Influenza virus infections [64] Updated 15 Sep 2017
13 Sep 2017 Scientific Update Efficacy data from the phase III CAPSTONE-1 trial in Influenza virus infections released by Shionogi [64] Updated 15 Sep 2017
24 Jul 2017 Scientific Update Efficacy and adverse events data from a phase III trial in Influenza virus infection released by Shionogi [44] Updated 31 Jul 2017
29 Apr 2017 Scientific Update Pharmacodynamics data from a preclinical study in Influenza virus infections presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2017) [61] Updated 01 Jul 2017
25 Apr 2017 Scientific Update Updated safety, efficacy and pharmacokinetics data from a phase II trial in Influenza infections presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2017) [47] Updated 03 Jul 2017
25 Apr 2017 Scientific Update Pharmacodynamics data from a preclinical study in Influenza virus infections presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID-2017) [60] Updated 01 Jul 2017
24 Apr 2017 Scientific Update Pharmacodynamics data from a preclinical trial in Influenza-A virus H5N1 subtype released by Shionogi [48] Updated 15 May 2017
24 Apr 2017 Phase Change - Preclinical Preclinical trials in Influenza-A virus H5N1 subtype in Japan (PO) before April 2017 [48] Updated 28 Apr 2017
24 Apr 2017 Scientific Update Pharmacokinetics data from a phase II trial in Influenza virus infections released by Shionogi [48] Updated 28 Apr 2017
22 Apr 2017 Trial Update Shionogi completes a phase III trial in Influenza virus infection (In adolescents, In adults) in Canada, Japan and USA (NCT02954354) Updated 19 May 2017
01 Dec 2016 Phase Change - III Phase-III clinical trials in Influenza virus infections with high risk of complications (In adolescents, In the elderly, In adults) in United Kingdom, Taiwan, Spain, South Africa, Romania, Poland, Philippines, New Zealand, Latvia, South Korea, Hungary, Germany, Bulgaria, Belgium, Australia (PO) (NCT02949011) Updated 26 Feb 2018
01 Dec 2016 Phase Change - III Phase-III clinical trials in Influenza virus infections with high risk of complications (In adolescents, In adults, In the elderly) in Japan, USA (PO) (NCT02949011) Updated 08 Mar 2017
14 Nov 2016 Trial Update Shionogi plans a phase III trial for Influenza virus infections (In adolescents, In adults) in USA (NCT02954354) Updated 14 Nov 2016
02 Nov 2016 Phase Change - III Phase-III clinical trials in Influenza virus infections (In infants, In children) in Japan (PO) (JapicCTI163417) Updated 14 Nov 2016
01 Nov 2016 Phase Change - III Phase-III clinical trials in Influenza virus infections (In adolescents, In adults) in Canada (PO) (NCT02954354) Updated 19 May 2017
01 Nov 2016 Phase Change - III Phase-III clinical trials in Influenza virus infections (In adolescents, In adults) in USA, Japan (PO) (NCT02954354) Updated 08 Mar 2017
26 Oct 2016 Scientific Update Adverse events and pharmacokinetics data from a phase I trial in Healthy volunteers presented at the IDWeek 2016 (IDW-2016) [57] Updated 30 Dec 2016
02 Oct 2016 Trial Update Shionogi completes the phase I trial in Healthy volunteers in United Kingdom (ISRCTN74587134) Updated 07 Oct 2016
28 Aug 2016 Scientific Update Pharmacodynamics data from a preclinical study in influenza A and B virus infection released by Shionogi [36] Updated 06 Sep 2016
28 Aug 2016 Scientific Update Efficacy, adverse events and immunogenicity data from a phase II clinical trial in Influenza A and B virus infection released by Shionogi [36] Updated 31 Aug 2016
28 Aug 2016 Trial Update Shionogi plans a phase III trials for Influenza virus infections (In adolescents, In adults, In the elderly) [36] (NCT02949011) Updated 31 Aug 2016
06 Mar 2016 Phase Change - Preregistration Preregistration for Influenza virus infections with high risk of complications (In the elderly) in USA (PO) [13] Updated 11 Mar 2019
29 Feb 2016 Phase Change - I Phase-I clinical trials in Influenza virus infections in USA (PO) Updated 29 Jul 2016
29 Feb 2016 Licensing Status S 033188 licensed to Roche worldwide, excluding Taiwan and Japan [1] Updated 09 Jun 2016
15 Feb 2016 Trial Update Shionogi initiates a phase-I trial in Influenza virus infections (In volunteers) in United Kingdom (PO) (ISRCTN74587134) Updated 08 Oct 2016
03 Dec 2015 Phase Change - II Phase-II clinical trials in Influenza virus infections in Japan before December 2015 (JapicCTI-153090) (PO) Updated 02 Feb 2016
27 Oct 2015 Regulatory Status Japanese PMDA grants S 033188 priority review [10] Updated 09 Jun 2016
01 Oct 2015 Regulatory Status S 033188 receives Fast track status from the PMDA for for influenza A or B virus infections [1] Updated 07 Oct 2016
01 Oct 2015 Phase Change - I Phase-I clinical trials in Influenza virus infections in Japan (PO) [10] Updated 09 Jun 2016
01 Oct 2015 Regulatory Status Shionogi plans NDA fling for Influenza virus infections in Japan in 2017 [10] Updated 09 Jun 2016

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