Therapeutic agent for coronavirus infection

Abstract

A coronavirus infection can be treated by administering a pharmaceutical composition containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an active ingredient to a patient suffering from coronavirus infection associated with non-severe pneumonia.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180031625.2 (PCT / JP2021 / 012858) filed on March 26, 2021, entitled “Coronavirus Infection Therapeutic Agent”. TECHNICAL FIELD

[0002] The present application relates to a coronavirus infection therapeutic agent containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (generic name: favipiravir; hereinafter, referred to as Compound A) or a salt thereof as an effective ingredient. BACKGROUND

[0003] New coronavirus (SARS-CoV-2) (non-patent literature 1) is an RNA virus belonging to the order Nidovirales and the family Coronaviridae (non-patent literature 2). In the case of infection with this virus, acute respiratory symptoms such as fever, cough, and dyspnea are accompanied (non-patent literature 1), and if it worsens, it develops into pneumonia. As of March 22, 2020, there were more than 290,000 patients with SARS-CoV-2 infection (COVID-19) and more than 12,000 deaths worldwide, and there were also reports of 1,046 COVID-19 patients in Japan, of which 36 deaths were confirmed (non-patent literature 3).

[0004] Compound A is an antiviral drug developed by Fuji Photo Film Co., Ltd. (former Fuji Photo Film Co., Ltd.), and the efficacy and effect are limited to “new or re-emerging influenza virus infection (however, limited to cases where other anti-influenza virus drugs are ineffective or insufficient)”, and in March 2014, it was approved for manufacture and sale in Japan. Its mechanism of action is to selectively inhibit the RNA polymerase of the virus by converting to triphosphate (T-705 RTP) in vivo, so it is also possible to show effects on RNA viruses other than influenza viruses. In fact, there are reports that it shows effects on Ebola virus, Arenavirinae, or Bunyaviridae RNA viruses in vitro or in vivo (non-patent literatures 4, 5, 6).

[0005] Prior Art Documents

[0006] Non-Patent Literature

[0007] Non-patent literature 1: Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020;395:470-3.

[0008] Non-patent literature 2: Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020 Mar 2. PubMed PMID: 32123347.

[0009] Non-patent literature 3: Coronavirus disease 2019 (COVID-19) situation reports - 62 (22 March 2020) [Internet]. Geneva: World Health Organization. Available from: https: / / www.who.int / docs / default-source / coronaviruse / situation-reports / 20200322-sitrep-62-covid-19.pdf?sfvrsn=f7764c46_2

[0010] Non-patent literature 4: Gowen BB, Wong MH, Jung KH, Sanders AB, Mendenhall M, Bailey KW, et al. In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob Agents Chemother. 2007;51:3168-76.

[0011] Non-patent literature 5: Mendenhall M, Russell A, Smee DF, Hall JO, Skirpstunas R, Furuta Y, et al. Effective oral favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic Fever. PLoS Negl Trop Dis. 2011;5:e1342.

[0012] Non-patent literature 6: Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res. 2014;105:17-21. SUMMARY

[0013] PROBLEMS TO BE SOLVED BY THE INVENTION

[0014] A therapeutic method for coronavirus infectious disease has not been established, and there is a need for early development of a coronavirus infectious disease therapeutic agent. The present invention is to provide a coronavirus infectious disease therapeutic agent, and a method for treating coronavirus infectious disease.

[0015] MEANS FOR SOLVING THE PROBLEMS

[0016] Under such circumstances, the present inventors et al. found that coronavirus infectious disease can be treated by administering Compound A or a salt thereof to a patient with coronavirus infectious disease, and thus completed the present invention.

[0017] According to the present invention, the following invention can be provided: [1]

[0019] A coronavirus infectious disease therapeutic agent, which is administered to a patient with non-severe pneumonia, and contains 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an effective ingredient. [2]

[0021] The coronavirus infectious disease therapeutic agent described in [1], wherein the patient is a patient with novel coronavirus infectious disease. [3]

[0023] The coronavirus infectious disease therapeutic agent as claimed in [1] or [2], wherein the patient is a patient who satisfies the following (1) to (3) completely:

[0024] (1) Coronavirus positive

[0025] (2) Lung lesion found from chest image

[0026] (3) Fever of 37.5°C or higher found. [4]

[0028] The coronavirus infectious disease therapeutic agent as claimed in any one of [1] to [3], wherein 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is administered at 1000 to 2400 mg twice a day (on day 1); 400 to 1200 mg twice a day (on day 2 and thereafter) as a 6-fluoro-3-hydroxy-2-pyrazinecarboxamide. [5]

[0030] The coronavirus infectious disease therapeutic agent as claimed in any one of [1] to [3], wherein 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is administered at 1800 mg twice a day (on day 1); 800 mg twice a day (on day 2 and thereafter) as a 6-fluoro-3-hydroxy-2-pyrazinecarboxamide. [6]

[0032] The coronavirus infectious disease therapeutic agent as claimed in any one of [1] to [5], wherein 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof is administered for 14 days.

[0033] In addition, according to the present application, the following inventions are also provided.

[0034] (a) A pharmaceutical composition for treating coronavirus infectious disease, which is a pharmaceutical composition containing Compound A or a salt thereof, which is administered to a patient with non-severe pneumonia.

[0035] (b) Compound A or a salt thereof for treating coronavirus infectious disease, which is Compound A or a salt thereof, which is administered to a patient with non-severe pneumonia.

[0036] (c) A method for treating coronavirus infectious disease, which is a method for treating coronavirus infectious disease by administering Compound A or a salt thereof, which is administered to a patient with non-severe pneumonia.

[0037] (d) Use of Compound A or a salt thereof for manufacturing a coronavirus infectious disease therapeutic agent, which is administered to a patient with non-severe pneumonia.

[0038] Effects of the Invention

[0039] Coronavirus infectious disease can be treated by administering Compound A or a salt thereof to a patient with coronavirus infectious disease with non-severe pneumonia. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 time to COVID-19 reduction in the mITT population DETAILED DESCRIPTION

[0041] Hereinafter, the present application will be described in detail.

[0042] In the present specification, unless otherwise specifically stated, each term has the following meaning.

[0043] In the present specification, the numerical range indicated by "~" means a range including the numerical values recited before and after "~" as the minimum value and the maximum value, respectively.

[0044] Compound A means 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.

[0045] As the salt of Compound A, a salt of a basic group such as an amino group, or an acidic group such as a hydroxy group or a carboxyl group, which is generally known, can be mentioned.

[0046] As the salt of the basic group, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; a salt with an organic carboxylic acid such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and a salt with a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, can be mentioned.

[0047] As the salt of the acidic group, a salt with an alkali metal such as sodium and potassium; a salt with an alkaline earth metal such as calcium and magnesium; an ammonium salt; and a salt with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine and meglumine, and the like, can be mentioned.

[0048] Among the above salts, as the preferable salt, a pharmacologically acceptable salt can be mentioned, and as the more preferable salt, a salt with sodium or meglumine can be mentioned.

[0049] In Compound A or its salt, in the case where isomers (for example, optical isomers, geometric isomers and tautomers, and the like) exist, the present application includes all of the isomers, and includes hydrates, solvates and all crystal forms.

[0050] The term "coronavirus" used in the present specification is an RNA virus belonging to the order Nidovirales and the family Coronaviridae. The infection caused by the coronavirus is coronavirus infection. The "novel coronavirus" is a newly identified and reported novel coronavirus within the coronavirus, and for example, SARS-CoV-2 can be mentioned. The infection caused by SARS-CoV-2 is also referred to as COVID-19. In the "novel coronavirus", a variant or strain of the known coronavirus is also included.

[0051] The term "treatment" means alleviation or improvement of one or more symptoms derived from a specific disease suffered by a subject, and delay of the progress of the disease. In the embodiments of the present application, for example, it means alleviation or improvement of symptoms such as fever, cough, pneumonia, and the like in a patient with coronavirus infection, and it means alleviation of body temperature, transcutaneous arterial oxygen saturation (SpO2), and chest imaging findings, or negativity of the coronavirus.

[0052] The patient to whom Compound A or a salt thereof is administered is preferably a patient complicated with non-severe pneumonia. Among them, non-severe pneumonia means pneumonia that does not appear to the extent of hypoxemia requiring oxygen therapy.

[0053] Compound A or a salt thereof used in the present application can be produced by a method known per se or by appropriately combining those methods. For example, it can be produced according to the method described in International Publication No. 00 / 10569. Furthermore, in Compound A, 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide exists as a tautomer.

[0054] Compound A or a salt thereof used in the present application can be formulated into a pharmaceutical preparation such as an oral preparation (tablet, capsule, powder, granule, fine granule, pill, suspension, emulsion, liquid, syrup, etc.), injection, eye drop, nasal preparation, or transdermal preparation, etc. by blending various pharmaceutical additives such as an excipient, a binder, a disintegrant, a disintegration inhibitor, a solidification / adhesion preventing agent, a lubricant, an absorption / adsorption carrier, a solvent, an extender, an isotonic agent, a cosolvent, an emulsifying agent, a suspending agent, a viscosity increasing agent, a coating agent, an absorption promoting agent, a gelation / solidification promoting agent, a light stabilizing agent, a preservative, a moisture preventing agent, an emulsion / suspension / dispersion stabilizing agent, a coloring preventing agent, a deoxidizing / antioxidizing agent, a flavoring / odor correcting agent, a coloring agent, a foaming agent, an antifoaming agent, a pain relieving agent, an antistatic agent, a buffer / pH adjusting agent, etc. In addition, as the administration preparation for a patient with novel coronavirus infection, an oral preparation or an injection is preferred, an oral preparation is more preferred, a tablet is further more preferred.

[0055] The above-mentioned agent can be formulated by a usual method.

[0056] The method of administration of Compound A is not particularly limited and can be appropriately determined in accordance with the form of preparation, the age, sex or other conditions of the patient, and the degree of the symptoms of the patient.

[0057] The 50% effective concentration (EC50) of Compound A against SARS-CoV-2 using Vero E6 cells was 61.88 μM (Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269-71.). This corresponds to 9.72 μg / mL. However, at the time of publication of the aforementioned literature, it was not possible to predict the effect in the case of actual administration to a patient.

[0058] The amount of Compound A to be administered can be appropriately selected in accordance with the usage, the age, sex, form of disease, other conditions, and the like of the patient, but, for example, for an adult, 10 to 5000 mg or preferably 200 to 2400 mg of Compound A can be administered once a day or divided into several times. Compound A can be administered several times or a single time until the desired therapeutic effect is achieved. The administration is generally monitored and can be repeated as necessary.

[0059] In the present application, for an adult, 1000 to 2400 mg of Compound A can be administered twice a day (on the first day) and 400 to 1200 mg of Compound A can be administered twice a day (from the second day onwards). For an adult, 1600 mg of Compound A can be administered twice a day (on the first day) and 600 mg of Compound A can be administered twice a day (from the second day onwards), and for an adult, 1800 mg of Compound A is preferably administered twice a day (on the first day) and 800 mg of Compound A is preferably administered twice a day (from the second day onwards), and for an adult, 1800 mg of Compound A is more preferably administered twice a day (on the first day) and 800 mg of Compound A is more preferably administered twice a day (from the second day onwards).

[0060] The administration interval of twice a day is preferably an interval of at least 4 hours or more after the first administration and the second administration, and more preferably an interval of 6 hours or more after the first administration and the second administration.

[0061] The administration period can be appropriately determined as the symptoms progress, for example, can be selected from the group consisting of a maximum of 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, and 22 days. A maximum of 10 days, 13 days, 14 days, 22 days is preferred, and a maximum of 13 days, 14 days is more preferred.

[0062] In the present application, the administration of Compound A or a salt thereof can include and use drug and / or concomitant therapy. Specifically, it can include standard treatment for pneumonia. Among them, "standard treatment for pneumonia" means the treatment described in "3. Treatment" of "Guidelines for the diagnosis and treatment of COVID-19 (1st edition)" announced by the Novel Coronavirus Infection Countermeasures Promotion Headquarters, Ministry of Health, Labour and Welfare, March 17, 2020, specifically, "For patients suspected of infection, in the case of being clinically diagnosed as pneumonia, it is desirable to start using an antibacterial drug on an empirical basis without waiting for the results of pathogen diagnosis. Be careful not to overdo the infusion, and start inhaling oxygen as needed. (omit) In addition, for cases where it is suspected that a bacterial infection is combined even after being diagnosed as COVID-19, administer an appropriate antibacterial drug." or treatment based on this. The oxygen therapy can be included. Furthermore, the administration of an interferon alpha preparation, ribavirin, or a drug having an antiviral effect on coronavirus can also be included. As the drug having an antiviral effect on coronavirus, drugs such as the following a) to e) can be mentioned.

[0063] a) hydroxychloroquine sulfate, chloroquine phosphate

[0064] b) lopinavir / ritonavir blend

[0065] c) ciclesonide

[0066] d) nafamostat mesylate

[0067] e) camostat mesylate

[0068] Next, the present application will be described using test examples, but the present application is not limited by these.

[0069] Test Example 1 Adaptive single-blind test randomized multicenter comparative test for evaluating the effectiveness and safety of Compound A for COVID-19 patients with non-severe pneumonia

[0070] [Method]

[0071] 1. Clinical trial design

[0072] 1.1 Type of clinical trial

[0073] Verified test (Phase III)

[0074] 1.2 Clinical trial design

[0075] Stratification, single-blind, randomized, multicenter comparative trial

[0076] 1.3 Composition of Group 1 and method of administration

[0077] [Compound A Group]

[0078] Standard treatment + Compound A 1800 mg x 2 times / day x 1 day + 800 mg x 2 times / day x 13 days (maximum)

[0079] [Control Group]

[0080] Standard treatment + Compound A placebo 9 tablets x 2 times / day x 1 day + 4 tablets x 2 times / day x 13 days (maximum)

[0081] 1.4 Evaluation items

[0082] 1.4.1 Primary evaluation items for effectiveness

[0083] Reduction in body temperature, SpO2, chest imaging findings, and time to SARS-CoV-2 negativity

[0084] 1.4.2 Secondary evaluation items for effectiveness

[0085] (1) Change in patient status according to 7-point scale

[0086] (2) Change in SARS-CoV-2 genome amount

[0087] (3) Time to disappearance of SARS-CoV-2

[0088] (4) Duration of each symptom / finding of body temperature, SpO2, and chest imaging findings

[0089] (5) Change in clinical symptoms / finding

[0090] (6) Change in vital signs

[0091] (7) Change in National Early Warning Score (NEWS)

[0092] (8) Reduction rate of chest imaging findings on day 4, 7, 10, 13, 16, 19, 22, 25, 28

[0093] (9) Ratio and average duration of administration of patients requiring supplementary oxygen therapy

[0094] (10) Ratio and average duration of administration of patients requiring mechanical ventilation therapy

[0095] (11) Changes in white blood cell count, hemoglobin, platelet count, creatinine, blood sugar, total bilirubin, ALT, and AST over time

[0096] 1.4.3 Evaluation items for safety

[0097] (1) Adverse events

[0098] (2) Clinical examination values

[0099] (3) Vital signs

[0100] (4) 12-lead electrocardiogram

[0101] 1.5 Number of target patients

[0102] 96 patients were enrolled (64 patients in the Compound A group and 32 patients in the control group)

[0103] 2. Subjects

[0104] 2.1 Subjects

[0105] COVID-19 patients with non-serious pneumonia

[0106] 2.2 Selection criteria

[0107] (1) Age: 20 to 74 years old (at the time of consent)

[0108] (2) Gender: Not asked

[0109] (3) Outpatient / hospitalization: hospitalized

[0110] (4) Patients who fully meet the following 1), 2), 3) criteria at the time of patient registration

[0111] 1) Patients who are positive for SARS-CoV-2 by RT-PCR (reverse transcription-polymerase chain reaction) examination of respiratory tract specimens such as nasopharyngeal swabs, nasal aspirates, and tracheal aspirates

[0112] 2) Patients who have lung lesions found by chest imaging

[0113] 3) Patients who have a fever of 37.5°C or higher

[0114] (5) In the case of female patients who may be pregnant, patients who are negative by pregnancy test before the start of administration of the clinical trial drug

[0115] (6) Patients who understand the contents of this clinical trial and can obtain written consent from themselves

[0116] 2.3 Exclusion criteria

[0117] (1) Patients who have had fever (37.5°C or higher) for more than 10 days

[0118] (2) Patients who have had fever (37.5°C or higher) for 9 days or less and are using interferon alpha preparations or agents reported to have antiviral effects against SARS-CoV-2 (hydroxychloroquine sulfate, chloroquine phosphate, lopinavir / ritonavir blend, ciclesonide, nafamostat mesylate, camostat mesylate)

[0119] (3) Patients who have had a recurrence or reinfection of SARS-CoV-2 infection in this infection event

[0120] (4) Patients whose SpO2 is less than 95% without oxygen therapy

[0121] (5) Patients whose procalcitonin values are elevated before the start of administration of the test drug and who are suspected of having a bacterial infection

[0122] (6) Patients whose (1→3)-β-D-glucan values are abnormal before the start of administration of the test drug and who are suspected of having a fungal infection

[0123] (7) Patients whose NT-proBNP (N-terminal pro-brain natriuretic peptide) values are 400 pg / mL or higher (or BNP values are 100 pg / mL or higher) before the start of administration of the test drug and who are suspected of having congestive heart failure

[0124] (8) Patients who have severe liver dysfunction equivalent to Child-Pugh Class C

[0125] (9) Patients with renal dysfunction who require dialysis

[0126] (10) Patients who have developed disturbances of consciousness such as disturbances of orientation

[0127] (11) Pregnant women or patients who have the potential to become pregnant

[0128] (12) Female patients who do not agree to use mechanical contraceptive devices such as oral contraceptives, intrauterine devices, or barrier methods (vaginal rings, condoms), and combinations of these, and the like, for contraception from the start of administration of the test drug to 7 days after the end of administration

[0129] (13) Male patients who do not agree to use the contraceptive methods described in (12) above

[0130] (14) Patients who do not agree to use condoms during the period from the start of administration of the clinical trial drug until 7 days after the end

[0131] (15) Patients with genetic xanthine disease

[0132] (16) Patients who have been diagnosed with hypouricemia (less than 1 mg / dL) or xanthine urinary calculi

[0133] (17) Patients who have a history of gout or are receiving treatment for gout or hyperuricemia

[0134] (18) Patients who are taking immunosuppressants

[0135] (19) Patients who have received administration of Compound A in the past

[0136] (20) Patients who are judged to be ineligible by the clinical trial responsible physician or the clinical trial participating physician

[0137] 3. Clinical trial drug

[0138] Tablet A: 1 tablet containing 200 mg of Compound A (for administration to the Compound A group)

[0139] Tablet B: Same appearance as Tablet A, but does not contain Compound A (for administration to the control group)

[0140] Dosage form: pale yellow film-coated tablet

[0141] Tablet A and Tablet B used in this test were manufactured by the method described in International Publication No. 2010 / 104170, a method well known per se, or a suitable combination of these.

[0142] 4. Method of use / dosage / administration period

[0143] 4.1 Method of use / dosage

[0144] (1) Dosage

[0145] To each administration group, in addition to standard treatment, the following dosage of the clinical trial drug was administered.

[0146] [Compound A group]

[0147] Compound A 1800 mg x 2 times / day x 1 day + 800 mg x 2 times / day x 13 days (maximum)

[0148] [Control group]

[0149] Compound A placebo 9 tablets x 2 times / day x 1 day + 4 tablets x 2 times / day x 13 days (maximum)

[0150] (2) Method of administration

[0151] [Compound A group]

[0152] Tablets A (containing 200 mg of Compound A) were orally administered as 9 tablets at a time, twice on the first day, and 4 tablets at a time, twice a day, for a maximum of 13 days, from the second day onward.

[0153] [Control group]

[0154] Tablets B (placebo not containing Compound A) were orally administered as 9 tablets at a time, twice on the first day, and 4 tablets at a time, twice a day, for a maximum of 13 days, from the second day onward.

[0155] On the first day, the second administration was performed at least 4 hours after the first administration of the clinical trial drug.

[0156] 4.2 During administration

[0157] The period of administration was a maximum of 14 days.

[0158] 5. Evaluation criteria

[0159] 5.1 Sequence of clinical trial implementation

[0160] The present clinical trial was performed in the following order.

[0161] (1) Confirmation of selection / exclusion criteria, explanation of clinical trial, acquisition of consent, implementation of observation / examination before administration

[0162] (2) Enrollment of patients (clinical trial grouping)

[0163] (3) Assignment to treatment

[0164] (4) Prescription of clinical trial drug, start of administration

[0165] (5) Implementation of scheduled observation / examination, evaluation / determination

[0166] (6) Follow-up survey

[0167] 5.2 Evaluation criteria

[0168] 5.2.1 Evaluation criteria for effectiveness

[0169] (1) Criteria for determination of effectiveness

[0170] 1) Criteria for determination of primary evaluation item

[0171] The time from the start of administration of the clinical trial drug to the point at which the body temperature, SpO2, and chest imaging findings were “reduced” and SARS-CoV-2 was “negative” 48 hours later was evaluated as the primary evaluation item.

[0172] "Improvement" of body temperature, SpO2, and chest imaging findings is defined as a case where all of body temperature, SpO2, and chest imaging findings reach the state of a) to c) below and are maintained for 2 days or more (target: 48 hours or more). In addition, "Negativization" of SARS-CoV-2 is defined as a case where SARS-CoV-2 reaches the state of d) below and is maintained for 12 hours or more.

[0173] a) Body temperature: 37.4°C or less (measurement value within 4 hours after use of antipyretic analgesic is not used)

[0174] b) SpO2: 96% or more (under the condition of no oxygen therapy)

[0175] c) Chest imaging findings: improvement from the worst

[0176] d) SARS-CoV-2: negative in RT-PCR (qualitative) examination

[0177] 2) Criteria for evaluation of secondary evaluation items

[0178] a) Time until disappearance of SARS-CoV-2

[0179] The time from the start of administration of the clinical trial drug until the "negativization" of SARS-CoV-2 is evaluated as the time until the disappearance of SARS-CoV-2.

[0180] b) Duration of each symptom / finding of body temperature, SpO2, and chest imaging findings

[0181] The time from the start of administration of the clinical trial drug until the achievement of the state of a) to c) above and the maintenance for 2 days or more (target: 48 hours or more) is evaluated as the duration of each symptom / finding of body temperature, SpO2, and chest imaging findings.

[0182] c) NEWS classification

[0183] The scores of each parameter of the NEWS classification are derived from the clinical symptoms / findings (state of consciousness) and vital signs (SpO2, body temperature, blood pressure, pulse rate, respiratory rate) and the like recorded by the clinical trial responsible physician or the clinical trial participating physician, and the total value is calculated.

[0184] 5.2.2 Criteria for evaluation of safety

[0185] The clinical trial responsible physician or the clinical trial participating physician determines the degree and causal relationship of adverse events exhibited in the clinical trial.

[0186] [Results]

[0187] The therapeutic effect of Compound A when added to the standard treatment for pneumonia in COVID-19 patients with non-severe pneumonia can be verified by the primary evaluation item and / or the secondary evaluation item. Specifically, for example, in the case of analyzing the results of the test on an appropriately defined effective analysis target population, the therapeutic effect of the Compound A group exceeds that of the control group, and it can be confirmed that there is a statistically significant effect by the primary evaluation item and / or the secondary evaluation item.

[0188] Based on the method described in Test Example 1, the effectiveness and safety of Compound A were evaluated in 156 COVID-19 patients (107 in the Compound A group and 49 in the control group). As an index for estimating the state of COVID-19 patients, body temperature, SpO2, reduction in chest imaging findings, and SARS-CoV-2 negativity were set in the evaluation items, and the time from the start of administration of the clinical trial drug until the complete reduction in body temperature, SpO2, and chest imaging findings, and then the time until SARS-CoV-2 negativity were evaluated. Patients who discontinued the clinical trial or administration of the clinical trial drug due to insufficient effect stopped at day 28. The results are shown in Table 1 and Figure 1 . The median was about 3 days earlier in the Compound A group than in the control group, and the time until 75% of the patients were reduced was 15.6 days in the Compound A group, while even if 28 days were observed, more than 25% of the patients were not reduced in the control group.

[0189] It can be confirmed that the therapeutic effect of the Compound A group statistically significantly exceeds that of the control group. In addition, there were no clinically significant safety problems in the Compound A group.

[0190] [Table 1]

[0191]

[0192] a. Log-rank test using a weighted test statistic based on "Lu Cui, H.M. James Hung, Sue-Jane Wang, Modification of sample size in group sequential clinical trials. Biometrics, 1999, 55, 853-857".

[0193] b. Hazard ratio using the Cox proportional hazards model, with the time until COVID-19 reduction as the target variable and gender, age, and administration group as explanatory variables.

Claims

1. A therapeutic agent for coronavirus infectious disease, which is administered to a patient with non-severe pneumonia, and contains 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an effective ingredient.

2. The therapeutic agent for coronavirus infectious disease according to claim 1, wherein the patient is a patient with novel coronavirus infectious disease.

3. The therapeutic agent for coronavirus infectious disease according to claim 1 or 2, wherein the patient is a patient who fully satisfies the criteria of (1) to (3) below, (1) is positive for coronavirus, (2) lung lesion is found from a chest image, (3) fever of 37.5°C or higher is found.

4. The therapeutic agent for coronavirus infectious disease according to any one of claims 1 to 3, wherein 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is administered at 1000 to 2400 mg twice a day (on day 1); 400 to 1200 mg twice a day (on day 2 and thereafter) as a 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.

5. The therapeutic agent for coronavirus infectious disease according to any one of claims 1 to 3, wherein 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is administered at 1800 mg twice a day (on day 1); 800 mg twice a day (on day 2 and thereafter) as a 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.

6. The therapeutic agent for coronavirus infectious disease according to any one of claims 1 to 5, wherein 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof is administered for 14 days.

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