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october 4, 2018 shionogi & co., ltd, osaka, japan, announced the latest results of the global phase iii study evaluating the anti-influenza drug baloxavir in high-risk individuals with influenza-related complications (capstone-2) at idweek, held october 3-7, 2018, in san francisco, ca.

the main results of caston-2 are presented as follows:

        baloxavir significantly improved the primary endpoint, time to improvement of influenza symptoms (ttiis, median time 73.2 h vs 102.3 h, p < 0.0001), compared with placebo and met the primary objective of the study. in the analysis of influenza virus subtypes, baloxavir significantly shortened ttiis compared to placebo for influenza a/h3n2 and b viruses (median time 75.4 h vs 100.4 h, p < 0.05; 74.6 h vs 100.6 h, p < 0.05, respectively).

        baloxavir showed significant advantages over placebo in important secondary endpoints:

        significant reduction in sustained viral release time in vivo (viral release time, median time 48 h vs. 96 h, p < 0.0001)

        significant reduction in antibiotic use secondary to influenza infection (3.4% vs. 7.5%; p = 0.01).

        significant reduction in the incidence of influenza-related complications (2.8% vs. 10.4%; p < 0.05)

        baloxavir effectively improved key endpoints over oseltamivir:

        ttiis was decreased (median time 73.2 h vs 81 h; p = 0.8347). in the analysis of influenza virus subtypes, ttiis values were significantly reduced for influenza b viruses (median time 74.6 h vs 101.6 h; p < 0.05).

        significant reduction in sustained viral release time in vivo (viral release time, median time 48 h vs. 96 h; p < 0.0001).

        reduced incidence of influenza-related complications (2.8% vs 4.6%)

        baloxavir was well tolerated, with no new safety signals identified and a low overall rate of adverse events reported (25.1%) with placebo (29.7%) and oseltamivir (28%). the most common adverse events reported after treatment with baloxavir were bronchitis (2.9%), diarrhea (2.7%), nausea (2.7%), and sinusitis (1.9%), with an overall lower frequency than placebo.

        data from castston-2 suggest that baloxavir was of significant benefit and clinical relevance to patients susceptible to influenza-related complications. there are no clinical studies showing significant benefit from the use of other drugs in high-risk populations. it should be noted that baloxavir has an advantage over oseltamivir in reducing the time to virus release and relieving symptoms of influenza b virus infection. based on these results, shionogi believes that baloxavir will be a promising treatment option for influenza a and b, not only for general patients, but also for people with risk factors for complications from influenza.

        shionogi regards infectious diseases one of its research and development priorities and takes “protecting people from the threat of infectious diseases” as its core social mission. shionogi has continuously introduced innovative drugs for the treatment of infectious diseases to safeguard the health of the population.

about baloxavir

        baloxavir was discovered and developed by shionogi. its novel drug mechanism of action lies in the inhibition of cap-dependent nucleic acid endonuclease, a key enzyme for viral replication. baloxavir is an oral single-dose antiviral drug for treatment of uncomplicated influenza, different from all current antiviral treatments. in non-clinical studies, baloxavir showed good antiviral efficacy against most influenza viruses including oseltamivir-resistant strains as well as avian strains (h7n9, h5n1) [1,2,3]. baloxavir has been commercially available in japan under the trade name xofluza® for the treatment of influenza a and b in adults and children. shionogi submitted an nda for baloxavir in the u.s. on april 24, 2018, in cooperation with roche, for the treatment of patients aged 12 years and older with acute uncomplicated influenza. based on a phase ii clinical study in japan and a global phase iii study in patients with uncomplicated influenza (capstone-1) [4], the us fda has accepted its submission for nda and granted it priority to review. the deadline for pdufadate review comments submitted by fda was december 24, 2018 [5]. an nda for baloxavir was submitted to taiwan by shionogi on june 29, 2018 for the treatment of patients aged 12 years and older with influenza [6].

        shionogi and roche, including roche’s subsidiary genentech usa, signed an agreement to further co-develop and commercialize baloxavir globally, under the terms of which roche has global development rights for territories other than japan and taiwan.

        roche will further advance baloxavir to include pediatric and severe hospitalized influenza patients in global phase iii clinical studies. shionogi will conduct a phase iii clinical study for post-exposure prophylaxis of influenza virus in japan for the 2018/2019 influenza season.

about the capstone-2 study

        the capstone-2 study was a phase iii, multicenter, randomized, double-blind trial to evaluate the efficacy of single-dose oral baloxavir versus placebo and oseltamivir therapy in the treatment of patients aged 12 years or older with acute uncomplicated influenza. this study was conducted globally by shionogi, on a total of 2,184 influenza patients recruited. patients in the trial were randomly assigned to receive a single dose of 40 or 80 mg of baloxavir, placebo, or 75 mg of oseltamivir twice daily for 5 days, depending on body weight, and 1163 (53%) of them had rt-pcr-confirmed influenza virus infection (influenza virus subtypes: 47.9% for a/h3n2, 6.9% for a/h1n1, and 41.6% for influenza b). the most common risk factors were asthma or chronic lung disease (39.2%), age over 65 years (27.4%), endocrine disorders (32.8%), metabolic disorders (13.5%), heart disease (12.7%), and morbid obesity (10.6%). the primary endpoint of the study was improvement in the duration of flu symptoms. important secondary endpoints were time to fever resolution, time to cessation of viral release, viral levels in the body by time point, and incidence of influenza-related complications. 

about influenza

        seasonal pandemic influenza outbreaks remain an important public health issue, and the availability of drugs that offer significant improvements over existing therapies is also eagerly anticipated. novel influenza outbreaks cause 3-5 million cases of severe disease production, millions of hospitalizations, and even 650,000 deaths per year worldwide [7,8,9,10,11]. the centers for disease control and prevention (cdc) classifies children under 2 years of age, adults 65 years and older, pregnant women, and people of any age with asthma and chronic lung disease, heart disease, blood disorders, endocrine disorders, metabolic diseases, and extremely obese people with weakened immune systems as being at high risk for influenza [12].

reference:

1. t. noshi et al. s-033447/s-033188, a novel small molecule inhibitor ofcap-dependent endonuclease of influenza a and b virus: in vitro antiviralactivity against laboratory strains of influenza a and b virus in madin-darbycanine kidney cells. poster presentation at options ix, august 2016.

2. k.taniguchi et al. inhibitory effect of s-033188, a novel inhibitor ofinfluenza virus cap-dependent endonuclease, against avian influenza a/h7n9virus in vitro and in vivo. poster presentation at eswi, september 2017.

3. k.taniguchi et al. inhibitory effect of s-033188/s-033447, a novelinhibitor of influenza virus cap-dependent endonuclease, against highlypathogenic avian influenza virus a/h5n1. poster presentation at eccmid, april2017.

4. frederick g. hayden et al. baloxavir marboxil for uncomplicatedinfluenza in adults and adolescents. n engl j med 2018 sep 6; 379:913-923.https://www.nejm.org/doi/full/10.1056/nejmoa1716197?query=featured_home

5. press release on june 26, 2018 fda accepts baloxavir marboxil new drugapplication and grants priority review for the treatment of influenza

6. press release on july 2, 2018 shionogi filed for the new drugapplication of baloxavir marboxil in taiwan for the treatment of influenza

7. http://www.who.int/mediacentre/news/releases/2017/seasonal-flu/en/ worldhealth organization website, up to 650 000 people die of respiratory diseaseslinked to seasonal flu each year, accessed december 14, 2017.

8. http://www.who.int/mediacentre/factsheets/fs211/en  world health  organization  website, influenza (seasonal), accessedjanuary 31, 2018. 

9. baxter  d.  evaluating the  case  for trivalent  or  quadrivalent influenza  vaccines.  hum accin immunother. 2016; 12(10):2712-2717. 

10. https://www.cdc.gov/flu/about/disease/2015-16.htm  cdc website,  estimated  influenza illnesses, edical  visits, hospitalizations,  and deaths  averted  by vaccination  in  the united state. accessed april 19, 2017. 

11. nair  h,  et al.  global  burden of  respiratory  infections due  to  seasonal influenza  in young children: asystematic review and meta-analysis. lancet. 2011 dec 3;378(9807):1917-30.

12. https://www.cdc.gov/flu/about/disease/high_risk.htm  cdc website,  people  at high  risk  of  developing flu–related complications,accessed january 23, 2018.