WO2020194042A1 - Traitement de la grippe au moyen de dérivés de pyridone polycyclique substitués et de promédicaments de ceux-ci chez un sujet ayant une grippe et un état associé à une grippe sévère - Google Patents

Traitement de la grippe au moyen de dérivés de pyridone polycyclique substitués et de promédicaments de ceux-ci chez un sujet ayant une grippe et un état associé à une grippe sévère Download PDF

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Publication number
WO2020194042A1
WO2020194042A1 PCT/IB2019/058102 IB2019058102W WO2020194042A1 WO 2020194042 A1 WO2020194042 A1 WO 2020194042A1 IB 2019058102 W IB2019058102 W IB 2019058102W WO 2020194042 A1 WO2020194042 A1 WO 2020194042A1
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Prior art keywords
compound
virus infection
influenza virus
influenza
subject
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PCT/IB2019/058102
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English (en)
Inventor
Takeki UEHARA
Toru Ishibashi
Takao Shishido
Keita FUKAO
Motoyasu Oonishi
Barry Clinch
Jaspinder Randhawa
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Shionogi & Co., Ltd.
F. Hoffmann-La Roche Ag
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Application filed by Shionogi & Co., Ltd., F. Hoffmann-La Roche Ag filed Critical Shionogi & Co., Ltd.
Priority to US16/825,263 priority Critical patent/US20220008429A2/en
Publication of WO2020194042A1 publication Critical patent/WO2020194042A1/fr
Priority to US17/818,294 priority patent/US20230210860A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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Definitions

  • the present disclosure relates generally to treating an influenza virus infection in a subject having an influenza virus infection and a severe influenza condition, using a substituted polycyclic pyridone derivative having cap-dependent endonuclease inhibitory activity, a prodrug thereof, and a pharmaceutical composition including the same.
  • Influenza is an acute respiratory infectious disease caused by a virus of the
  • orthomyxovirus family Two forms, such as influenza type A and type B, are known to infect humans. These viruses cause an acute febrile infection of a respiratory tract after an incubation period from 1 to 4 days, characterized by a sudden onset of fever, cough, fatigue, headache, and/or myalgia. Annual influenza epidemics are thought to result in between 3 and 5 million cases as severe ill cases, and between 250,000 and 500,000 deaths, every year around the world (WHO 2017).
  • influenza is a disease that can be cured through natural defenses in healthy adults, the disease can be associated with substantial morbidity and occasional mortality in children, elderly, and immunocompromised patients (Non-Patent Document 1).
  • Non-Patent Document 2 Hospitalization due to severe influenza condition may result in high mortality (4% - 8%), intensive care unit (ICU) admission (5% - 17%), and prolonged hospital stays between 5 and 9 days. During a pandemic season, the outcomes may be more serious, such that up to 34% of patients require ICU care and that a mortality rate is as high as 15% (Non-Patent Document 2).
  • anti-influenza virus drugs are currently available for treatment of acute, uncomplicated influenza virus infection in various countries: the M2 ion channel inhibitors (e.g., amantadine and rimantadine), the RNA polymerase inhibitor (e.g., favipiravir), and the neuraminidase (NA) inhibitors (i.e., oseltamivir, zanamivir, and peramivir).
  • the viruses are resistant to amantadine and rimantadine, hence their use in clinical practice is limited.
  • NAI NA inhibitor
  • Non-Patent Document 3 Baloxavir marboxil (BXM) is a small-molecule prodrug of baloxavir, which has an antiviral activity against influenza type A and type B viruses, including those resistant to current antivirals (Non-Patent Document 4). BXM was recently approved in the US, for treatment of uncomplicated influenza virus infection in otherwise healthy individuals > 12 years old. BXM provided more rapid reductions in infectious virus titers than placebo or oseltamivir (Non-Patent Document 5).
  • Non-Patent Document 6 There are no approved drugs for marketing for the treatment of influenza virus infection in hospitalized patients, since there have been no evidence showing such effectiveness in, randomized-controlled clinical trials assessing the effectiveness of NAI treatment against placebo. Despite luck of the evidence, the NAIs have been widely used as the mainstay of treatment for hospitalized patients, and evidence shows a potential reduction in mortality in hospitalized patients treated with NAIs, especially if the treatment is initiated in an early stage, for esample within 48 hours from onset of at lesat one symptom of influenza virus infection (Non-Patent Document 6).
  • Patent Document 1-6 describe BXM and/or compounds having similar structures to substituted polycyclic pyridone derivatives.
  • Patent Document 1 WO2010/147068
  • Patent Document 2 WO2012/039414
  • Patent Document 3 WO2016/175224
  • Patent Document 4 WO2017/104691
  • Patent Document 5 WO2017/221869
  • Patent Document 6 WO2018/030463
  • Non-Patent Document 1 Paules C, Subbarao K. Influenza. Lancet 2017, 390, 697-708.
  • Non-Patent Document 2 Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with influenza. Antivir Ther 2012; 17(1 Pt B): 143-57.
  • Non-Patent Document 3 McKimm-Breschkin JL, Jiang S, Hui DS, Beigel JH, Govorkova EA, Lee N. Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference. Antiviral Res 2018;149: 118-42.
  • Non-Patent Document 4 Uehara T, Shishido T, Ishibashi T, et al. S-033188, a Small Molecule Inhibitor of Cap-dependent Endonuclease of Influenza type A and type B Virus, Leads to Rapid and Profound Viral Load Reduction. Options IXfor the Control of Influenza Chicago, Illinois2016.
  • Non-Patent Document 5 Hayden LG, Sugaya N, Hirotsu N, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med 2018;379:913-23.
  • Non-Patent Document 6 Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A HlNlpdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014, 2, 395-404.
  • a method for treating an influenza virus infection generally involves administering a combination of an effective amount of a compound (A) and an effective amount of a compound (B) to a subject, wherein the subject (1) has an influenza virus infection, (2) has been symptomatic of the influenza virus infection for no more than 96 hours, and (3) further has at least one severe condition of influenza virus infection (severe influenza condition) that is one or more of: (a) being hospitalized due to the influenza virus infection, (b) requiring an extension of hospitalization because of acquiring the influenza virus infection during the hospitalization, (c) having a National Early Warning Score 2 of four or more, (d) being on support for respiration, and (e) having at least one complication attributable to the influenza virus infection that necessitates hospitalization.
  • severe influenza virus infection severe condition
  • the compound (A) has one of the following formulae:
  • the compound (B) is at least one neuraminidase inhibitor.
  • the neuraminidase inhibitor is one or more of oseltamivir, zanamivir and peramivir, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof In one example, the neuraminidase inhibitor is oseltamivir, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof
  • the onset of the influenza virus infection is the time point when the subject newly has at least one symptom that is at least one systemic symptom and/or at least one respiratory symptom.
  • the at least one systemic symptom includes one or more of headache, feverishness, chills, muscular pain, joint pain, and fatigue.
  • the at least one respiratory symptom includes one or more of coughing, sore throat, and nasal congestion.
  • a condition that necessitates support for respiration is at least one of a ventilator and an inhalation of oxygen from non-atmospheric oxygen supply, and an oxygen concentrator which concentrates the atmospheric oxygen.
  • at least one complication attributable to the influenza virus infection is present.
  • the complication attributable to the influenza virus infection is one or more of inflammation of heart, brain, or muscle tissues, and muti-organ failure.
  • the complication attributable to the influenza virus infection is one or more of pneumonia, central nervous system involvement, myositis, rhabdomyolysis, encephalitis, encephalopathy, severe dehydration myocarditis, pericarditis, otitis media, sinusitis, exacerbation of ischemic heart disease, sepsis, acute lung injury, or acute respiratory distress syndrome, and acute exacerbation of chronic kidney disease or respiratory diseases, for example asthma or chronic obstructive pulmonary disease.
  • the compound (A) is administered in an amount from about 40 mg to about 80 mg. In one example, the compound (A) can be administered as a weight-based dose.
  • about 40 mg is administered to a subject weighing about 40 kg to less than about 80 kg. In one example, about 80 mg is administered to a subject weighing at least 80 kg.
  • the subject is a patient that is younger than 1 year. In this instance:
  • the effective amount is 0.8-1.2 mg/kg body weight, preferably about 1 mg/kg body weight;
  • the effective amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight.
  • the subject is a patient that is 1 year or older but younger than 12 years.
  • the effective amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight;
  • the effective amount is 35- 45 mg, preferably about 40 mg.
  • the compound (A) is administered on the first day of onset of at least one symptom of an influenza virus infection, and again three days after the first day of administration upon onse of at least one symptom of an influenza virus infection. In one example, the compound (A) is administered on the first day of onset of at least one symptom of an influenza virus infection, and again three days and six days after the first day of administration upon onset of at least one symptom of an influenza virus infection. In one example, the compound (A) is administered two times or three times in total.
  • the compound (A) is administered at day 1 or day 4 after the onset of the influenza virus infection.
  • the term“Day 1” indicates the first day of administration.
  • the term “Day 4” indicates the fourth day as counted from the first day of administration.
  • the compound (A) is further administered at day 7, i.e., the seventh day from the first day of administration.
  • the effective amount of the compound (B) is in a range from about 0.1 to about 6000 mg as an active compound. In another example, the effective amount of the compound (B) is in a range from about 0.1 to about 1500 mg as an active compound.
  • the compound (B) is oseltamivir phosphate, and the effective amount administered is about 75 mg twice daily for five days as an active compond.
  • the compound (B) is zanamivir hydrate, and the effective amount administered is 10 mg twice daily for five days as an active compond.
  • the compound (B) is peramivir hydrate.
  • the effective amount administered is 600 mg once daily for five days as an active compond.
  • the effective amount is 10 mg/kg up to a maximum of 600 mg, once daily for five days as an active compond.
  • the compound (B) is administered at one time. In one example, the compound (B) is administed once daily for up to ten days after the onset of the influenza virus infection.
  • the amount of the compound (A) and the amount of the compound (B) administered are effective such that a time to show clinical improvement in the subject is statistically significant as compared to a treated subject with the compound (B).
  • the amount of the compound (A) and the amount of the compound (B) administered are effective such that a time to show clinical improvement in the subject is statistically significant as compared to a non- treated subject.
  • a non-treated subject is a subject that has not been administered with the compound (A) and the compound (B).
  • a p- value indicating the statistical significance of the time to show clinical improvement is less than 0.05, alternately less than 0.005.
  • the time to clinical improvement is a time to hospital discharge or a time until a National Early Warning Score 2 of two or less is maintained for at least 24 hours.
  • each of the compound (A) and the compound (B) is administered through a route individually selected from the group consisting of orally or parenterally.
  • the compound (A) is administered at day 7 after the onset of the influenza virus infection in the case that the subject does not show an improvement in at least one condition selected from the group consisting of (i) continuous use of a ventilator, (ii) continuous fever, (iii) severe immune deficiency, and (iv) any complication attributable to the influenza virus infection.
  • a method for treating an influenza virus infection comprising:
  • (3) further has at least one severe influenza condition selected from the group consisting of:
  • the compound (B) is at least one neuraminidase inhibitor.
  • the at least one neuraminidase inhibitor is at least one compound selected from the group consisting of oseltamivir, zanamivir, peramivir, a
  • the at least one symptom is at least one systemic symptom selected from the group consisting of headache, feverishness, chills, muscular pain, joint pain, and fatigue.
  • the at least one symptom is at least one respiratory symptom selected from the group consisting of coughing, sore throat, and nasal congestion.
  • the severe influenza condition is being on support for respiration, and the support for respiration is selected from the group consisting of a ventilator, inhalation of oxygen from non-atmospheric oxygen supply, and an oxygen concentrator that concentrates atmospheric oxygen.
  • the severe influenza condition is having the at least one complication attributable to the influenza virus infection selected from the group consisting of pneumonia, central nervous system involvement, myositis, rhabdomyolysis, severe dehydration myocarditis, pericarditis, exacerbation of ischemic heart disease, and acute exacerbation of chronic kidney disease, asthma, and chronic obstructive pulmonary disease.
  • a method for treating an influenza virus infection comprising: reading a dosage instruction on a package insert or in a package for a pharmaceutical formulation comprising a compound (A) having one of the following formulae:
  • (3) further has at least one severe influenza condition selected from the group consisting of:
  • (3) further has at least one severe influenza condition selected from the group consisting of:
  • treatment includes administering an effective amount of the compound (A) and an effective amount of the compound (B) to the subject.
  • composition useful for treating a subject that:
  • (3) further has at least one severe influenza condition selected from the group consisting of:
  • composition comprises the compound (A) and the compound
  • the treatment comprises administering an effective amount of a compound (A) and an effective amount of a compound (B) to the subject, and
  • the compound (B) is at least one neuraminidase inhibitor.
  • a package comprising a pharmaceutical formulation comprising a compound (A) having one of the following formulae:
  • (3) further has at least one severe influenza condition selected from the group consisting of:
  • Fig. 1 is a graph showing the experimental results of measuring the plasma concentration of Compound (III) (baloxavir or“BXA”), after oral administration of prodrug Compound (P-6) (baloxavir marboxyl or“BXM”), to rats under non-fasting conditions.
  • Compound (III) baloxavir or“BXA”
  • prodrug Compound (P-6) baloxavir marboxyl or“BXM”
  • Fig. 2 is a table showing the experimental results of measuring the plasma concentration of Compound (II-6) (BXM), after oral administration, to rats under non-fasting conditions.
  • Fig. 3A and 3B are graphs of experimental results showing the therapeutic efficacy of 2- day delayed administration of Compound (III) (BXA) against lethal co-infection with influenza type A virus (inoculation: day 0) and Streptococcus pneumoniae (inoculation: day 2) in mice. Mice were monitored daily for survival and body weight through 15 days post infection.
  • Fig. 4A and 4B are graphs of experimental results showing the therapeutic efficacy of 3- day delayed administration of Compound (III) against lethal co-infection with influenza type A virus (inoculation: day 0) and Streptococcus pneumoniae (inoculation: day 2) in mice. Mice were monitored daily for survival and body weight through 15 days post infection. When the treatment was delayed until 3 days post virus infection, a significant difference in survival time was observed in groups treated with BXA + OSP in comparison with the vehicle treated group ( * , P ⁇ 0.05).
  • Fig. 5A and 5B are graphs of experimental results showing the therapeutic efficacy of 4- day delayed administration of Compound (III) against lethal co-infection with influenza type A virus (inoculation: day 0) and Streptococcus pneumoniae (inoculation: day 2) in mice. Mice were monitored daily for survival and body weight through 15 days post infection.
  • Figure 6 is a table showing a summary of the National Early Warning Score 2 (NEWS).
  • NEWS National Early Warning Score 2
  • Figure 7 is an overview of the design of the clinical trial from Test Example 3.
  • a method for treating an influenza virus infection generally involves administering a combination of an effective amount of a compound (A) and an effective amount of a compound (B) to a subject, wherein the subject (1) has an influenza virus infection, (2) is at 96 hours or less since the onset of the influenza virus infection when the combination is initially administered, and (3) further has at least one severe influenza condition.
  • P is a group to form a prodrug selected from the group consisting of:
  • L is straight or branched lower alkylene
  • P R0 is alkyl
  • P R2 is alkyl
  • P R3 is each independently hydrogen
  • P R4 is alkyl
  • the compound (A) that can be used in the disclosed method has a formula:
  • P R is a group to form a prodrug, or its pharmaceutically acceptable salt.
  • P R is selected from the group consisting of:
  • L is straight or branched lower alkylene
  • P R0 is alkyl
  • P R2 is alkyl
  • P R3 is each independently hydrogen
  • P R4 is alkyl
  • P R is a group to form a prodrug
  • Parenter compound in the present description means a compound to be a source before synthesizing the "prodrug” and/or a compound released from the "prodrug” by the reaction by enzymes, a gastric acid, and the like under physiological conditions in vivo, and specifically means a compound shown by the formula (III), or pharmaceutically acceptable salt thereof or a solvate thereof.
  • Examples of one embodiment of compounds that can be used for the compound (A) in the present description include compounds that are described in the PCT/JP2016/063139 application published as WO 2016/175224A1.
  • alkyl includes a C1 to C15, alternatively a C1 to C1O, alternatively a C1 to C6, alternatively a C1 to C4, linear or branched hydrocarbon group.
  • Examples of“alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like.
  • “alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl or n-pentyl.
  • Another embodiment of“alkyl” is methyl, ethyl, n-propyl, isopropyl or tert-butyl.
  • alkylene includes a C1 to C15, alternately a C1 to C1O, alternately a C1 to C6 and alternately a C1 to C4 linear or branched bivalent hydrocarbon group. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • One or more hydrogen, carbon and/or other atoms in the compounds used in the present invention may be replaced with isotopes of hydrogen, carbon and/or other atoms respectively.
  • isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2 H 3 H 11 C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 123 I and 36 C1 respectively.
  • the compounds used in the present invention include compounds replaced with these isotopes.
  • the compounds replaced with the above isotopes are useful as medicines and include radiolabeled compounds of the compound used in the present invention.
  • A“method of radiolabeling” in the manufacture of the“radiolabeled compounds” is encompassed by the present invention, and the“radiolabeled compounds” are useful for studies on metabolized drug pharmacokinetics, studies on binding assay and/or diagnostic tools.
  • a radiolabeled compound used in the present invention can be prepared using well- known methods in the field of this invention.
  • a tritium-labeled compound used in the present invention can be prepared by introducing a tritium to a certain compound used in the present invention, through a catalytic dehalogenation reaction using a tritium. This method comprises reacting with an appropriately-halogenated precursor of the compound used in the present invention with tritium gas in the presence of an appropriate catalyst, such as Pd/C, and in the presence or absent of a base.
  • an appropriate catalyst such as Pd/C
  • the other appropriate methods of preparing a tritium-labeled compound can be found in“Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”.
  • a 14 C-labeled compound can be prepared by using a raw material having 14 C.
  • the pharmaceutically acceptable salts of the compounds used in the present invention include, for example, salts with alkaline metal (e.g., lithium, sodium, potassium or the like), alkaline earth metal (e.g., calcium, barium or the like), magnesium, transition metal (e.g., zinc, iron or the like), ammonia, organic bases (e.g., trimethylamine, triethylamine,
  • salts with inorganic acids e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid or the like
  • organic acids e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like).
  • salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are included.
  • the compounds used in the present invention or its pharmaceutically acceptable salts may form solvates (e.g., hydrates or the like) and/or crystal polymorphs.
  • the present invention encompasses those various solvates and crystal polymorphs.
  • “Solvates” may be those wherein any numbers of solvent molecules (e.g., water molecules or the like) are coordinated with the compounds used in the present invention.
  • Recrystallization of the compounds used in the present invention or its pharmaceutically acceptable salts may produce crystal polymorphs.
  • the group to form a prodrug is converted into OH group by action of drug-metabolizing enzymes, hydrolases, gastric acids, and/or enterobacteria, after in vivo administration (for example, oral administration).
  • a prodrug shows improved bioavailability and/or AUC (area under the blood concentration curve) in in vivo administration compared to that of the Compound (III).
  • a prodrug is efficiently absorbed into the body, e.g. from a stomach and/or intestines, after in vivo administration (for example, by oral administration), and then is converted into the Compound (III).
  • the prodrug shows an effect of treating and/or preventing influenza virus infection higher than the Compound (III).
  • Examples of an embodiment of a particularly preferable substituent of the group to form a prodrug include following groups.
  • a general method for producing the compound (A) used in the present invention will be exemplified below.
  • extraction and purification a treatment performed in a normal experiment of organic chemistry may be conducted.
  • Synthesis of the compound (A) used in the present invention can be carried out referring to the procedures known in the art.
  • a salt of the compound (A) used in the present invention in the case where the compound (A) used in the present invention is obtained in a form of a salt, it may be purified as it is and, in the case where the compound (A) used in the present invention is obtained in a free form, a salt may be formed by a normal method by dissolving or suspending the compound (A) in a suitable organic solvent, and adding an acid or a base.
  • P R is a group to form a prodrug as set forth above.
  • Compound (II) can be obtained by a method including converting a hydroxyl group of Compound (III) into an ester group or ether group.
  • the active agent (Compound (III)) can be used to prepare its prodrugs (i.e., compounds having the formula of Compound (II)).
  • the compounds of formula III (Compound (III)) used in the present invention have a cap- dependent endonuclease inhibitory activity.
  • Compound (III) and its prodrugs i.e., Compound (II) are useful as a therapeutic or preventive agent for influenza virus infection, particularly the compound of formula II-6 (Compound (P-6)) described below.
  • the compounds used in the present invention may be administered orally as a powder, a granule, tablets, capsules, pills, a liquid and the like or parenterally as an injection, suppositories, a percutaneous drug, an inhalant and the like.
  • the effective doses of the present compounds may be mixed with excipients suitable for the dosage form, such as fillers, binders, humectants, disintegrators, and lubricants, as appropriate, to form pharmaceutical preparations.
  • sterilization is performed with a suitable carrier.
  • compositions of the prodrugs (Compound (II)) and Compund (III) used in the present invention can be administered either orally or parenterally.
  • commonly used dosage forms such as tablets, granule, powder, and capsules, may be prepared according to conventional methods.
  • any commonly used dosage form such as an injection, may be suitably used.
  • the compounds according to the present invention can be suitably used as oral preparations because of their high oral absorbability.
  • the dose of the prodrugs (Compound (II)) and Compund (III) depends on the condition of the disease, administration route, or age or weight of the patient.
  • the usual oral dose for adults is in a range from 0.1 to 100 mg/kg per day, alternately in a range from 1 to 20 mg/kg per day.
  • patients weighing from 40 kg to less than 80 kg each receive a dose in a range from 80 mg to 120 mg.
  • patients weighing from 40 kg to less than 80 kg each receive a single dose of 40 mg.
  • patients weighing at least 80 kg receive a dose in a range from 160 to 240 mg.
  • patients weighing at least 80 kg receive a single dose of 80 mg.
  • the dose can be 0.8-1.2 mg/kg, alternately about 1.8-2.2 mg/kg, alternately 1 mg/kg, alternately 2 mg/kg.
  • the compound can be administered orally, dermally, subcutaneously, intravenously, intraarterially, intramuscularly, intraperitoneally, transmucosally, via inhalation, transnasally, ophthalmically, via an inner ear and/or vaginally.
  • the compound (B) that can be used in the method of the present invention is at least one neuraminidase inhibitor.
  • One neuraminidase inhibitor includes a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable solvate thereof.
  • the neuraminidase inhibitor can include one or more of oseltamivir, zanamivir, peramivir, laninamivir octanoate, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof.
  • the neuraminidase inhibitor is one or more of oseltamivir, zanamivir, peramivir, a pharmaceutically acceptable salt thereof, and a
  • oseltamivir, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is oseltamivir phosphate.
  • zanamivir, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is zanamivir hydrate.
  • peramivir, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof is peramivir hydrate.
  • pharmaceutically acceptable solvate thereof is laninamivir octanoate hydrate.
  • the compound (A) and the compound (B) used in the present invention can be used in combination with other drugs or the like (hereinafter referred to as combination drugs) to increase the activity of the compound, reduce the dose of the compound, or the like.
  • combination drugs drugs or the like
  • the compound (A) and the compound (B) can be combined with or in a coupled formulation with RNA-dependent RNA polymerase inhibitor (e.g.,
  • a compound used in the present invention and the combination drug are also possible.
  • the timing of administration for a compound used in the present invention and the combination drug is not limited. They can be administered to the subjects to be treated, at the same time or at different times.
  • a compound used in the present invention and the combination drug can be administered as two or more formulations independently comprising each active ingredient or a single formulation comprising two or more active ingredients.
  • the dose for combination drugs may be appropriately selected in reference to the clinical dose.
  • the compounding ratio of the compounds used in the present invention and co- administered drugs may be appropriately selected depending on the subject to be treated, administration route, disease to be treated, symptoms, combination of the drugs and the like.
  • 1 part by weight of the compounds used in the present invention may be used in combination with 0.01 to 100 parts by weight of co-administered drugs.
  • RT represents a retention time at LC/MS: liquid chromatography/mass spectrometry, and was measured under the following conditions.
  • UV detection wavelength 254nm
  • the neuraminidase inhibitor is one or more of oseltamivir, zanamivir and peramivir. In one example, the neuraminidase inhibitor is oseltamivir.
  • At least one systemic symptom is present and includes one or more of headache, feverishness, chills, muscular pain, joint pain, and fatigue.
  • At least one respiratory symptom is present and includes one or more of coughing, sore throat, and nasal congestion.
  • the severe influenza condition can include one or more of (a) being hospitalized due to the influenza virus infection, (b) requiring an extension of hospitalization because of acquiring the influenza virus infection during the hospitalization, (c) having a
  • the severe influenza condition is a National Early Warning Score 2 (NEWS2) of four or more.
  • NEWS2 National Early Warning Score 2
  • NewS2 is a similar but updated score to incorporate an additional oxygen scale for patients at risk of hypercapnic respiratory failure (target oxygen saturation of 88%- 92%, rather than the standard target of ⁇ 96 %).
  • NEWS National early warning score
  • a weighting score of 2 is added for patients requiring supplemental oxygen to maintain their prescribed oxygen saturation range.
  • NEWS2 was developed for patients aged 2-16 years; however, children aged 12-16 years have very similar physiological parameter ranges as adults.
  • NEWS2 is not used as an early warning system to identify patients who may need escalating levels of care; rather, it is used to standardize vital sign collection which will facilitate setting severity levels for inclusion and demonstrating response to treatment. Most pediatric early warning scores are complex and designed to detect critical illness in younger children.
  • a patient achieving a NEWS2 of greater than or equal to 2 represents a degree of clinical improvement (i.e., clinically stable and potentially eligible for discharge).
  • the time to clinical improvement is defined as the time to hospital discharge or time to NEWS2 of 2 and maintained for 24 hours, whichever comes first.
  • the method of statistical analysis and the selection of a clinically meaningful difference between treatment groups are possible for an endpoint of this design.
  • the NEWS2 should be calculated based upon vital sign values recorded during the patient assessment.
  • the oxygen saturation should be scored according to either the SpO 2 Scale 1 or 2 presented in the table.
  • the SpO 2 Scale 2 is for patients with a target oxygen saturation requirement of 88%- 92% (e.g., in patients with hypercapnic respiratory failure related to advanced lung diseases, such as chronic obstructive pulmonary disease (COPD]). This should only be used in patients confirmed to have hypercapnic respiratory failure by blood gas analysis on either a prior or their current hospital admission.
  • COPD chronic obstructive pulmonary disease
  • the decision to use the SpO 2 Scale 2 should be made by the treating physician and should be recorded in the eCRF. In all other circumstances, the SpO 2 Scale 1 should be used.
  • the consciousness level should be recorded according to the best clinical condition of the patient during the assessment. Patients who are assessed as “Alert” (A) should be assigned a score of 0. Patients assessed as “New Confusion” (C), “Responsive to Voice” (V), “Responsive to Pain” (P), or "Unconscious” should be assigned a score of 3.
  • Scores should be assigned for respiratory rate, systolic blood pressure, pulse, and temperature according to the table in Figure 6.
  • the NEWS2 should be recorded in the eCRF at the screening visit to ensure patients meet the eligibility criteria.
  • the individual components of the score should also be recorded in the eCRF. Additional NEWS2 values will be calculated electronically throughout the study by the sponsor based upon entry of vital sign parameters by the investigator in the appropriate eCRF.
  • the severe influenza condition is the need for support for respiration.
  • the support for respiration is at least one of a ventilator and an inhalation of oxygen from non-atmospheric oxygen supply, and an oxygen concentrator which concentrates the atmospheric oxygen.
  • the complication attributable to the influenza virus infection is one or more of inflammation of heart, brain, or muscle tissues, and muti-organ failure.
  • the complication attributable to the influenza virus infection is one or more of pneumonia, central nervous system involvement, myositis, rhabdomyolysis, encephalitis, encephalopathy, severe dehydration myocarditis, pericarditis, otitis media, sinusitis, exacerbation of ischemic heart disease, sepsis, acute lung injury, or acute respiratory distress syndrome, and acute exacerbation of chronic kidney disease or respiratory diseases, for example asthma or chronic obstructive pulmonary disease.
  • the effective amount of the compound (A) is in a range from about 0.1 mg to about 240 mg. In another example, the effective amount of the compound (A) is in a range from about 3 mg to about 80 mg per dose.
  • the effective amount of the compound (A) is admistered two times or three times in total.
  • the compound (A) can be administered as a weight-based dose. In one example, at or about 40 mg is administered to a subject weighing about 40 kg to less than about 80 kg. In one example, about 80 mg is administered to a subject weighing at least about 80 kg.
  • the compound (A) is administered on the first day of administration upon onset of at least one symptom of an influenza virus infection and again three days later.
  • the compound (A) is further administered six days after the first day of administration upon onset of at least one symptom of an influenza virus infection. In one example, the compound (A) is administered at six days after the first day of administration upon onset of at least one symptom of an influenza virus infection in the case that the subject does not show an improvement in at least one condition selected from the group consisting of (i) continuous use of a ventilator, (ii) continuous fever, (iii) severe immune deficiency, and (iv) any complication attributable to the influenza virus infection, as compared to the respective conditions of a subject that has been administered with none of anti-influenza drug including the compound (A) and the compound (B).
  • the subject is a patient that is younger than 1 year. In this instance:
  • the effective amount is 0.8-1.2 mg/kg body weight, preferably about 1 mg/kg body weight;
  • the effective amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight;
  • the subject is a patient that is 1 year or older but younger than 12 years.
  • the effective amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight; or
  • the effective amount is 35- 45 mg, preferably about 40 mg.
  • the compound (A) is administered at or before about 120 hours after the onset of the disease in the subject. In one example, the compound is administered at or before about 72 hours, alternately at or before about 84 hours, alternately at or before about 96 hours, alternately at or before about 120 hours, alternately at or before about 144 hours, alternately at or before about 168 hours, after the onset of the disease in the subject. In one example, the compound is administered at or before about 96 hours after the onset of the disease in the subject. In another example, the compound is administered at or before about 84 hours after the onset of the disease in the subject.
  • the amount of the compound administered is effective such that a reduction in a time to show clinical improvement in the subject is statistically significant as compared to that of a non-treated subject.
  • a non-treated subject is a subject that has not been treated with the compound (A) and the compound (B).
  • the time to clinical improvement is a time until hospital discharge or a time until a National Early Warning Score 2 of two or less is maintained for at least 24 hours.
  • a reduction in the time to show clinical improvement in a subject is statistically significant relative to that of a non-treated subject, where a p- value indicating the statistical significance is less than 0.05, alternately 0.03 or less, alternately 0.02 or less, alternately 0.003 or less, alternately 0.001 or less, alternately 0.001 or less.
  • the amount of the compound administered is effective such that a reduction in a time to show clinical improvement in the subject is statistically significant as compared to that of a subject treated with the compound (B).
  • a p-value indicating the statistical significance of the reduction in a time to show clinical improvement relative to that of a subject treated with the compound (B) is less than 0.05, alternately 0.03 or less, alternately 0.02 or less, alternately 0.003 or less, alternately 0.001 or less, alternately 0.001 or less.
  • the compound (B) is administered only once. In one example, the compound (B) is administered daily for up to five days after the onset of the influenza virus infection. In one example, the compound (B) is administed once daily for up to ten days after the onset of the influenza virus infection.
  • the effective amount of the compound (B) is in a range from about 0.1 to about 6000 mg as an active compound. In another example, the effective amount of the compound (B) is in a range from about 0.1 to about 1500 mg as an active compound.
  • the compound (B) is oseltamivir phosphate, and the effective amount administered is about 75 mg twice daily for five days as an active compound. In another example, the compound (B) is oseltamivir phosphate, and the effective amount administered is about 75 mg twice daily for ten days as an active compound.
  • the compound (B) is zanamivir hydrate, and the effective amount administered is 10 mg twice daily for five days as an active compound. In another example, the compound (B) is zanamivir hydrate, and the effective amount administered is 10 mg twice daily for ten days as an active compound.
  • the compound (B) is peramivir hydrate.
  • the effective amount administered is 600 mg once daily for five days as an active compound.
  • the effective amount is 10 mg/kg up to a maximum of 600 mg, once daily for five days as an active compound.
  • the compound (B) is peramivir hydrate.
  • the effective amount administered is 600 mg once daily for ten days as an active compound.
  • the effective amount is 10 mg/kg up to a maximum of 600 mg, once daily for ten days as an active compound.
  • the compound (A) and the compound (B) are administered orally. In another example, the compound (A) and the compound (B) are administered parenterally.
  • the compound (A) and the compound (B) are administered through at least one route selected from the group consisting of orally, dermally, subcutaneously, intravenously, intraarterially, intramuscularly, intraperitoneally, transmucosally, via inhalation, transnasally, ophthalmically, via an inner ear and vaginally.
  • the compound (A) and the compound (B) can be administered with any material in any amounts that are suitable for use with the compound.
  • the compound (A) and the compound (B) are administered in combination with at least one material selected from the group consisting of an RNA-dependent RNA polymerase inhibitor, an M2 protein inhibitor, a PB2 Cap binding inhibitor, a HA maturation inhibitor, a recombinant siabdase, a re-assemble inhibitor, RNA interference compound, a receptor of hemagglutinin binding inhibitor, a membrane of HA fusion inhibitor, a NP nuclear translocation inhibitor, a CXCR inhibitor, a CRM1 inhibitor, an anti-HA antibody and an immunological agent.
  • the compound (A) and the compound (B) are administered in one example.
  • MHAA4549A (as described in McBride et al., Antimicrobial Agents and Chemistry, Vol. 61, Issue 11, (2017)), TCN-032 (as described in Ramos et al., JID 2015: 11 (2015)), VIS-410 (as described in Tharakaraman et al., PNAS, vol. 112, no. 35, 10890-10895 (2015)), CR-8020 (as described in Ekiert et al., Science, 333(6044), 843-850 (2011)), CR-6261 ( as described in Ekiert et al., Science, 324(5924), 246-251 (2009)), CT-P27 (as described in Celltrion, Press Release, Oct. 12, 2016) and MEDI-8852 (as described in Cell, 166(3), 596-608 (2016)).
  • the compound (A) and the compound (B) are administered in at least one form selected from the group consisting of a tablet, powder, a granule, a capsule, a pill, a film, a suspension, an emulsion, an elixir, a syrup, lemonade, spirit, aromatic water, extract, decoction and tincture.
  • the compound (A) and the compound (B) are administered in at least one form selected from the group consisting of a sugar-coated tablet, a film-coated tablet, an enteric- coated tablet, a sustained-release tablet, a troche tablet, a sublingual tablet, a buccal tablet, a chewable tablet, an orally disintegrated tablet, a dry syrup, a soft capsule, a micro capsule or a sustained-release capsule.
  • the compound (A) and the compound (B) are administered in at least one form selected from the group consisting of an injection, an infusion, an eye drop, a nose drop, an ear drop, an aerosol, an inhalation, a lotion, an impregnation, a liniment, a mouthwash, an enema, an ointment, a plaster, a jelly, a cream, a patch, a cataplasm, an external powder or a suppository.
  • Test Example 1 BA test
  • mice or SD rats were fasted and were allowed free access to sterilized tap water.
  • Oral administration was performed mandatory into the stomach by oral sonde.
  • Intravenous administration was performed from caudal vein by syringes with needle.
  • Figures 1 and 2 show a result of measuring the plasma concentration of Compound (III) and Compound (II-6), respectively, after oral administration of prodrug Compound (II-6) to rats under non-fasting conditions.
  • the concentration of Compound (II-6) in all plasma samples was below the limit of quantification ( ⁇ 0.500 ng/mL) for all time points tested (0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h) and for all doses tested (0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg). Therefore, prodrug Compound (II-6) was found to have metabolized promptly to Compound (III) in vivo after administration.
  • the prodrug compounds (Compound (II)) were absorbed into the body after oral administration, and rapidly converted into Compund (III) in the blood.
  • the prodrug compounds used in the present example also showed excellent oral absorbability. Therefore, the prodrug compounds used in the present example, including Compound (II-6), can be useful agents for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.
  • Test Example 2 Bacterial co-infection mouse model for delayed treatment with BXA
  • BXA the active form of BXM, was synthesized at Shionogi & Co., Ltd. (Osaka, Japan)
  • Oseltamivir phosphate (“OSP”) was purchased from AK Scientific, Inc. (Union City, CA, USA). Suspension of BXA and solution of OSP were prepared with 0.5% methylcellulose 400 solution (MC, FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan). Administration dose was 0.2 mL per mouse. Doses of BXA and OSP were selected based on human doses in clinics. In this study, suspension of BXA was subcutaneously administered in mice to maintain the plasma concentration of BXA as seen in humans. (1.2) Virus and bacteria
  • A/Osaka/129/2009 strain of influenza virus and Streptococcus pneumoniae SRI 326 strain of bacteria were clinically isolated in Japan individually and adapted to mice in Shionogi.
  • mice were used in the study. Body weights and survival were monitored once daily. The mice were immediately euthanized and regarded to be dead in the analysis for survival time when they lost more than 30% of their body weight compared to their weight pre-infection of virus according to humane endpoints. Upon virus or bacteria inoculation, mice were anesthetized by intramuscular administration at 100 pL of anesthetic solution containing 0.03 mg/mL
  • medetomidine hydrochloride 0.4 mg/mL midazolam, 0.5 mg/mL butorphanol tartrate in saline. All mouse studies were conducted under applicable laws and guidelines and with the approval of the Shionogi Animal Care and Use Committee (Approval number: S18060D-0002).
  • mice were treated with both BXA subcutaneously at a dose of 10 mg/kg (single dose) and OSP orally at a dose of 10 mg/kg (bid for 5 days).
  • Control mice were treated subcutaneously with 0.5% MC (single dose). Mice were examined once daily for survival and body weight through 15 days post virus infection.
  • mice were treated with both BXA subcutaneously at a dose of 10 mg/kg (single dose) and OSP orally at a dose of 10 mg/kg (bid for 5 days).
  • Control mice were treated subcutaneously with 0.5% MC (single dose). Mice were examined once daily for survival and body weight through 15 days post virus infection.
  • mice administered subcutaneously with BXA were subcutaneously administered in mice to maintain the plasma concentration of BXA as seen in humans.
  • the dose of OSP was calculated based on human pharmacokinetic data: in mice, 5 mg/kg twice daily is equivalent to the human clinical dose, and for the treatment of critically ill patients double the high dose is recommended. Therefore, in this study, mice were treated with 10 mg/kg twice daily for 5 days (double the high dose) of OSP as the reference drug treatment (Ward et al, J. Antimicrob Chemother., Feb: 55 Suppl 1 : i5-i21 (2005)).
  • mice were inoculated with Streptococcus pneumoniae at 2 days after virus infection.
  • a sign of co-infection appears initially as the loss of body weight at day 3 after virus infection. Therefore, we evaluated the effect of delayed treatment up to 4 days after virus infection, considering that antiviral therapy may be started after onset of influenza symptoms in clinic.
  • BXA was more effective for the prevention of mortality than administration of vehicle or OSP in mice infected with influenza type A virus followed by Streptococcus pneumoniae.
  • a randomized , double-blind, placebo-controlled, multicenter study was conduected to assess the efficacy, safety, and pharmacokinetics of baloxavir marboxil in combination with a standard of care neuraminidase inhibitor (“SOC NAI”) (i.e., oseltamivir, zanamivir, or peramivir), compared with a matching placebo in combination with a SOC NAI in approximately 240 hospitalized adults and adolescent patients (aged 3 12 years) with influenza virus infection.
  • SOC NAI neuraminidase inhibitor
  • Baloxavir marboxil was administered as a weight-based dose (40 mg for patients weighing 40 to ⁇ 80 kg, 80 mg for patients weighing 3 80 kg) on Days 1 and 4, and also on Day 7 if clinical improvement had not occurred at Day 5.
  • Clinical improvement is evaluated based on (i) continuous use of a ventilator, (ii) continuous fever, (iii) severe immune deficiency and/or (iv) any complication attributable to the influenza virus infection.
  • Specific criteria for extended dosing to Day 7 include ongoing mechanical ventilation, persistence of fever, severely
  • the repeat-dose regimen was to ensure that plasma baloxavir concentrations remain above a target-threshold concentration for a longer duration in severely ill patients owing to the greater potential of a protracted influenza illness.
  • AUC tau concentration-time curve for a dosing interval
  • SOC NAI i.e., oseltamivir, zanamivir, or peramivir
  • the SOC NAI treatment was extended to Day 10 or beyond at the discretion of the investigator and in accordance with local clinical practice.
  • the study consisted of two periods: a 10-day treatment period and a 25-day follow-up period. Therefore, the maximum study duration for each patient was 35 days.
  • the primary efficacy objective for this study was to evaluate the efficacy of baloxavir marboxil plus a SOC NAI, compared with matching placebo plus SOC NAI on the basis of the following endpoint:
  • TTCI time to clinical improvement, defined as time to hospital discharge or time to NEWS2 of ⁇ 2 and maintained for 24 hours, whichever comes first
  • the median TTCI was compared between the baloxavir marboxil plus SOC NAI and matching placebo plus SOC NAI arms using the stratified log-rank test within three regions (i.e., North America; Europe, Middle East, and Africa (EMEA); rest of the world ROW), NEWS2 (£
  • the log-rank test requires the assumption of proportional hazards to be met.
  • the proportional hazards assumption was tested graphically using the log cumulative hazard plot by treatment group. The plots for each treatment group are parallel if the proportional hazard assumption holds. In the event the proportional hazards assumption was violated the Gehan- Wilcoxon test was used to analyze the data.
  • the estimand is the median change in TTCI. This absolute measure was assessed over the duration of the study (35 days). Intercurrent events are those that occur after treatment initiation and either preclude observation of the variable or affect its interpretation. Intercurrent events were accounted for through censoring rules. Patients who withdrew, who were lost to follow-up, who did not have a clinical response event, or who died were censored at their last contact date or date of death, whichever was applicable. No dose reductions or treatment cross-overs were anticipated.
  • the primary endpoint was the time to clinical improvement (TTCI), defined as time to hospital discharge or time to National Early Warning Score 2 (NEWS2) of 2 maintained for 24 hours, whichever occurs first.
  • TTCI time to clinical improvement
  • NEWS2 National Early Warning Score 2
  • the key secondary endpoint was the proportion of patients per category in the 6-point ordinal scale at Day 7.
  • the categories within this scale reflect the clinical status of patients during their hospital stay.
  • the clinical status was assessed to reflect the most accurate condition of the patient from a medical perspective, to minimize the effects of administrative or non- medical factors (e.g., the hospital bed availability may lead to patients not being cared for in the ward most suitable for their condition).
  • the 6-point ordinal scale was used in this study to investigate the change in clinical state of patients as the key secondary endpoint.
  • Non-ICU hospital ward (or "ready for hospital ward") not requiring supplemental oxygen /non-invasive ventilation
  • Non-ICU hospital ward (or “ready for hospital ward ”) requiring supplemental oxygen/non-invasive ventilation
  • Adolescent patients not able to legally consent written informed consent for study participation is obtained from patient's parents or legal guardian, with assent as appropriate by the patient, depending on the patient's level of understanding and capability to provide assent • Age 3 12 years at the time of signing the Informed Consent Form/Assent Form
  • RIDT Rapid Influenza Diagnostic Test
  • RT-PCR reverse transcriptase-po lymerase chain reaction
  • a patient with a negative RIDT may be enrolled if influenza virus infection is suspected based on local surveillance data or if the patient reports contact with a known case of influenza virus infection within the prior 7 days and all other inclusion criteria are met
  • the time interval between the onset of symptoms and randomization is within 96 hours
  • the onset of symptoms is defined as the time when the patient experiences at least one new general symptom (e.g., headache, feverishness or chills, muscle or joint pain, fatigue), respiratory symptom (e.g., cough, sore throat, nasal congestion), or fever.
  • at least one new general symptom e.g., headache, feverishness or chills, muscle or joint pain, fatigue
  • respiratory symptom e.g., cough, sore throat, nasal congestion
  • fever e.g., cough, sore throat, nasal congestion
  • hospitalization e.g., pneumonia, CNS involvement, myositis, rhabdomyolysis, acute
  • COPD severe dehydration
  • myocarditis myocarditis
  • pericarditis exacerbation of ischemic heart disease
  • a woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
  • Examples of contraceptive methods with a failure rate of ⁇ 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone- releasing intrauterine devices, and copper intrauterine devices.
  • the reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
  • the compounds used in the present invention, lactose, and calcium stearate were mixed uniformly to obtain powder medicines in the form of powders or fine granules.
  • the powder medicines were filled into capsule containers to give capsules.
  • lactose and calcium stearate are mixed uniformly and the mixture is compressed and molded. Then, it is crushed, granulated and sieved to give suitable sizes of granules.
  • Formulation Example 4 Orally disintegrated tablets The compounds used in the present invention and crystalline cellulose are mixed, granulated and tablets are made to give orally disintegrated tablets.
  • the compounds used in the present invention and lactose are mixed, crushed, granulated and sieved to give suitable sizes of dry syrups.
  • the compounds used in the present invention and phosphate buffer are mixed to give injection.
  • the compounds used in the present invention and phosphate buffer are mixed to give injection.
  • the compound used in the present invention and lactose are mixed and crushed finely to give inhalations.
  • the compounds used in the present invention and base such as adhesive plaster or the like are mixed to give patches.

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Abstract

L'invention concerne un procédé de traitement d'une infection par le virus de la grippe. Le procédé selon l'invention consiste, d'une manière générale, à administrer une quantité efficace d'un composé (A), par exemple le baloxavir marboxil, et un composé (B), par exemple un inhibiteur de la neuraminidase, à un sujet qui (1) présente une infection par le virus de la grippe, (2) a été symptomatique de l'infection par le virus de la grippe pendant un maximum de 96 heures, et (3) présente en outre au moins un état associé à une grippe sévère choisi parmi les éléments suivants : (a) hospitalisation en raison d'une infection sévère par le virus de la grippe, (b) nécessité d'une prolongation de l'hospitalisation en raison de l'infection par le virus de la grippe pendant l'hospitalisation, (c) score d'alerte précoce national 2 de quatre ou plus, (d) utilisation de la respiration artificielle et (e) présence d'au moins une complication attribuable à l'infection par le virus de la grippe qui nécessite une hospitalisation.
PCT/IB2019/058102 2019-03-22 2019-09-24 Traitement de la grippe au moyen de dérivés de pyridone polycyclique substitués et de promédicaments de ceux-ci chez un sujet ayant une grippe et un état associé à une grippe sévère WO2020194042A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/825,263 US20220008429A2 (en) 2019-03-22 2020-03-20 Treating influenza using substituted polycyclic pyridone derivatives and prodrugs thereof in a subject having influenza and a severe influenza condition
US17/818,294 US20230210860A1 (en) 2019-03-22 2022-08-08 Treating influenza using substituted polycyclic pyridone derivatives and prodrugs thereof in a subject having influenza and a severe influenza condition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/IB2019/052349 WO2020194024A1 (fr) 2019-03-22 2019-03-22 Traitement de la grippe utilisant des dérivés de pyridone polycycliques substitués et des promédicaments associés chez un sujet ayant une grippe et un état grippal sévère
IBPCT/IB2019/052349 2019-03-22

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PCT/IB2019/058102 WO2020194042A1 (fr) 2019-03-22 2019-09-24 Traitement de la grippe au moyen de dérivés de pyridone polycyclique substitués et de promédicaments de ceux-ci chez un sujet ayant une grippe et un état associé à une grippe sévère

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CN112903838A (zh) * 2021-01-15 2021-06-04 浙江海正药业股份有限公司 法维拉韦中有关物质的测定方法

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US20180118760A1 (en) * 2015-04-28 2018-05-03 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
EP3391888A1 (fr) * 2015-12-15 2018-10-24 Shionogi & Co., Ltd. Médicament pour traiter la grippe caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'endonucléase coiffe-dépendante avec un médicament antigrippal

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US20180118760A1 (en) * 2015-04-28 2018-05-03 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
EP3391888A1 (fr) * 2015-12-15 2018-10-24 Shionogi & Co., Ltd. Médicament pour traiter la grippe caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'endonucléase coiffe-dépendante avec un médicament antigrippal

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112903838A (zh) * 2021-01-15 2021-06-04 浙江海正药业股份有限公司 法维拉韦中有关物质的测定方法

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