Therapeutic agent for severe fever with thrombocytopenia syndrome virus infection

Abstract

In the present invention, renal dysfunction patients suffering from severe fever with thrombocytopenia syndrome virus infection can be treated for the severe fever with thrombocytopenia syndrome virus infection by administration of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof.

Description

Treatment for severe fever with thrombocytopenia syndrome (SFS) viral infection

[0001] The present invention relates to a therapeutic agent for severe fever with thrombocytopenia syndrome viral infection, which contains 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (generic name: favipiravir, hereinafter referred to as Compound A) or a salt thereof as an active ingredient.

[0002] Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infection caused by the Dabie bandavirus, a member of the Bunyaviridae family, Fenuiviridae family, and Bandavirus genus. The first case of SFTS virus infection was reported in Japan in January 2013, and since then, additional cases of SFTS virus infection have been confirmed. After an incubation period of 6 days to 2 weeks, SFTS virus infection often presents with fever and gastrointestinal symptoms (loss of appetite, nausea, vomiting, diarrhea, and abdominal pain). Other symptoms include headache, muscle pain, neurological symptoms such as impaired consciousness and aphasia, and bleeding symptoms such as lymphadenopathy, subcutaneous bleeding, and bloody stool. Treatment is limited to symptomatic measures, with no effective drugs or vaccines available. Because of this, the infection is known to have a very high mortality rate.

[0003] Compound A is an antiviral drug created by Fujifilm Toyama Chemical Co., Ltd. (formerly Toyama Chemical Co., Ltd.), and was approved for manufacturing and marketing in Japan in March 2014 with its efficacy limited to "novel or re-emerging influenza virus infections (limited to those for which other anti-influenza virus drugs are ineffective or insufficiently effective)." Furthermore, Compound A received approval in Japan in June 2024 to add the tick-borne infection "severe fever with thrombocytopenia syndrome virus infection" to its indications.

[0004] The mechanism of action of Compound A is that the triphosphorylated form converted in vivo selectively inhibits viral RNA polymerase, and it is known that Compound A is also effective against RNA viruses other than influenza viruses (e.g., the novel coronavirus, etc.) (Patent Document 1).

[0005] Renal dysfunction is a condition in which some abnormality occurs in the kidneys due to disease, trauma, etc., causing impairment of kidney function. Once renal dysfunction has progressed, it is extremely difficult to restore kidney function, so early treatment is important. Renal dysfunction can be evaluated by serum creatinine (s-Cr) levels.

[0006] International Publication No. 2021 / 200651 Pamphlet

[0007] There is no established treatment for SFTS virus infection, and the causal relationship between SFTS virus infection and renal dysfunction has not been known until now.

[0008] The problem to be solved by the present invention is to provide a new use of compound A or a salt thereof, or to provide a therapeutic agent for SFTS virus infection and a method for treating SFTS virus infection in SFTS virus infected patients with renal dysfunction.

[0009] Under these circumstances, the present inventors have discovered that SFTS virus infection can be treated by administering compound A or a salt thereof to SFTS virus-infected patients with renal dysfunction, and have completed the present invention.

[0010] The present invention provides the following: <1> A therapeutic agent for severe fever with thrombocytopenia syndrome virus infection, containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an active ingredient, to be administered to a patient infected with severe fever with thrombocytopenia syndrome virus and having impaired renal function. <2> The therapeutic agent for severe fever with thrombocytopenia syndrome virus infection according to <1>, wherein the patient's renal function classification is G1 or higher. <3> The therapeutic agent for severe fever with thrombocytopenia syndrome virus infection according to <1>, wherein the patient has a serum creatinine (s-Cr) level of >1.07 mg / dL. <4> The therapeutic agent for severe fever with thrombocytopenia syndrome virus infection according to <1> or <2>, wherein the patient is 70 to 99 years old. <5> The therapeutic agent for severe fever with thrombocytopenia syndrome virus infection according to <1> or <2>, wherein the patient is 70 to 89 years old. <6> The therapeutic agent for severe fever with thrombocytopenia syndrome virus infection according to <1> or <2>, wherein the patient is 70 to 79 years old. <7> The therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to <1> or <2>, wherein 1,000 to 2,400 mg of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is administered twice a day on day 1, and 400 to 1,200 mg twice a day from day 2 onwards. <8> The therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to <1> or <2>, wherein 1,800 mg of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is administered twice a day on day 1, and 800 mg twice a day from day 2 onwards. <9> The therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to <7>, wherein the therapeutic agent is administered for 10 days.

[0011] The present invention also provides the following: (a) a pharmaceutical composition containing compound A or a salt thereof, which is administered to a patient infected with severe fever with thrombocytopenia syndrome virus and having renal impairment. (b) compound A or a salt thereof, which is administered to a patient infected with severe fever with thrombocytopenia syndrome virus and having renal impairment. (c) a method for treating a severe fever with thrombocytopenia syndrome virus infection by administering compound A or a salt thereof, the method comprising administering compound A or a salt thereof to a patient infected with severe fever with thrombocytopenia syndrome virus and having renal impairment. (d) use of compound A or a salt thereof for the manufacture of a therapeutic agent for severe fever with thrombocytopenia syndrome virus infection, which is administered to a patient infected with severe fever with thrombocytopenia syndrome virus and having renal impairment. (e) a preventive agent for severe fever with thrombocytopenia syndrome virus infection, which contains compound A or a salt thereof, which is administered to a patient with renal impairment. (f) a pharmaceutical composition containing compound A or a salt thereof, which is administered to a patient with renal impairment for the prevention of a severe fever with thrombocytopenia syndrome virus infection. (g) Compound A or a salt thereof, administered to patients with renal impairment for the prevention of severe fever with thrombocytopenia syndrome viral infection. (h) A method for preventing severe fever with thrombocytopenia syndrome viral infection by administering compound A or a salt thereof, the method comprising administering compound A or a salt thereof to a patient with renal impairment. (i) Use of compound A or a salt thereof for the manufacture of an agent for preventing severe fever with thrombocytopenia syndrome viral infection, to be administered to patients with renal impairment.

[0012] SFTS virus infection can be treated or prevented by administering compound A or a salt thereof to patients with renal dysfunction.

[0013] The present invention will be described in detail below. Unless otherwise specified, the terms used in this specification have the following meanings.

[0014] In this specification, a numerical range indicated using "to" means a range that includes the numerical values ​​written before and after "to" as the minimum and maximum values, respectively. In one embodiment, either or both of the minimum and maximum values ​​may be excluded (i.e., "equal to or greater than x" can be read as "greater than x," and "equal to or less than x" can be read as "less than x"). In this specification, when a composition contains multiple substances corresponding to each component, the amount of each component in the composition means the total amount of the multiple substances present in the composition, unless otherwise specified.

[0015] Compound A refers to 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.

[0016] Salts of Compound A include commonly known salts with a basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group. Salts with a basic group include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids 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 salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

[0017] Examples of salts of acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases 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.

[0018] Of the above salts, preferred salts include pharmacologically acceptable salts, and more preferred salts include salts with sodium or meglumine.

[0019] When compound A or a salt thereof has isomers (for example, optical isomers, geometric isomers, tautomers, etc.), the present invention includes all of these isomers, as well as hydrates, solvates, and all crystalline forms.

[0020] In the present invention, the patient to whom Compound A or a salt thereof is administered is preferably a patient aged 70 to 109 years, more preferably a patient aged 70 to 99 years, even more preferably a patient aged 70 to 89 years, and even more preferably a patient aged 70 to 79 years.

[0021] The patient to whom Compound A or a salt thereof is administered is preferably a patient who is not suffering from sepsis with secondary bacteremia during / even during treatment.

[0022] Sepsis with secondary bacteremia refers to a condition presenting with severe organ damage caused by a mixed infection resulting from the invasion of other microorganisms into the bloodstream after contracting an SFTS virus infection.

[0023] Compound A or a salt thereof may be administered to a patient complicated with at least one disease selected from digestive diseases, respiratory diseases, neurological diseases, cardiac diseases, musculoskeletal diseases, blood diseases, immune diseases, cancer, lifestyle-related diseases, skin diseases, urinary diseases, sleep disorders, eye diseases, and dental diseases. Among these, compound A or a salt thereof is preferably administered to a patient complicated with a digestive disease that is frequently seen in patients with SFTS virus infection.

[0024] "Treatment" refers to the alleviation or amelioration of one or more symptoms resulting from a specific disease in a subject, as well as the slowing of the progression of the disease. In an embodiment of the present invention, for example, in a patient with an infection caused by the SFTS virus (Davidson-Banda virus), it refers to the alleviation or amelioration of one or more symptoms, such as fever, gastrointestinal symptoms (loss of appetite, nausea, vomiting, diarrhea, abdominal pain), and neurological symptoms (disturbance of consciousness, aphasia), and also refers to, for example, improvement in body temperature, percutaneous arterial oxygen saturation (SpO2), and chest imaging findings, or negativity for the SFTS virus (Davidson-Banda virus). In another embodiment of the present invention, it refers to the reduction of the mortality rate in a patient with an infection caused by the SFTS virus (Davidson-Banda virus).

[0025] In the present invention, the time of initiation of treatment means when treatment is initiated, and includes, for example, when a definitive diagnosis is made and when a therapeutic agent is administered.

[0026] In the present invention, a patient with renal dysfunction refers to a patient in a state where some abnormality has occurred in the kidney due to disease, trauma, or the like, causing impairment of renal function. In another embodiment, a patient with renal dysfunction refers to a patient with a serum creatinine (s-Cr) level of >1.07 mg / dL (renal function classification G1 or higher, as described below). The s-Cr level can be measured by a method known per se, for example, an enzymatic method (creatininase-saloxidase-POD method).

[0027] In the present invention, a patient without renal dysfunction refers to a patient other than a patient with renal dysfunction. In another embodiment, a patient without renal dysfunction refers to a patient with a serum creatinine (s-Cr) level of 1.07 mg / dL or less.

[0028] Patients with impaired kidney function can be classified into five stages, from stage 1 (G1) to stage 5 (G5), depending on the level of their kidney function: G1 (impairment, but normal or high kidney function), G2 (mildly impaired kidney function), G3 (moderately impaired kidney function), G4 (severely impaired kidney function), and G5 (renal failure) (see, for example, "An Easy Kidney Disease Course: Everything You Need to Know, from Early Symptoms to Treatment and Diet"; https: / / www.kidney-trouble.info / syokisyoujyou / ckd_stage.html).

[0029] Compound A or a salt thereof used in the present invention can be produced by a method known per se or an appropriate combination thereof. For example, it can be produced by the method described in WO 00 / 10569. Compound A also exists as a tautomer, 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide.

[0030] Compound A or a salt thereof used in the present invention can be formulated with various pharmaceutical additives, such as excipients, binders, disintegrants, disintegration inhibitors, anti-caking / adhesion agents, lubricants, absorption / adsorption carriers, solvents, bulking agents, isotonicity agents, solubilizers, emulsifiers, suspending agents, thickeners, coating agents, absorption promoters, gelation / coagulation promoters, light stabilizers, preservatives, moisture-proofing agents, emulsifying / suspension / dispersion stabilizers, color inhibitors, oxygen absorbers / antioxidants, flavoring / odor masking agents, colorants, foaming agents, antifoaming agents, soothing agents, antistatic agents, and buffer / pH adjusters, to form pharmaceutical preparations such as oral preparations (tablets, capsules, powders, granules, fine granules, pills, suspensions, emulsions, liquids, syrups, etc.), injections, eye drops, intranasal preparations, or transdermal preparations. For administration to patients with SFTS virus infection, oral preparations or injections are preferred. The above-mentioned drugs are formulated by conventional methods.

[0031] The method of administering Compound A is not particularly limited, and is determined appropriately depending on the form of the preparation, the age, sex and other conditions of the patient, and the severity of the patient's symptoms.

[0032] The dosage of Compound A is appropriately selected depending on the dosage method, the patient's age, sex, type of disease, and other conditions, but for example, 10 to 6000 mg, or preferably 200 to 2400 mg, of Compound A can be administered to an adult once or several times a day. Compound A can be administered once or multiple times until the desired therapeutic effect is achieved. Administration is typically monitored, and can be repeated as necessary.

[0033] In the present invention, Compound A may be administered to an adult at a dose of 1000 to 2400 mg twice daily (Day 1) and 400 to 1200 mg twice daily (Day 2 and thereafter). It is preferable to administer Compound A at a dose of 1600 mg twice daily (Day 1) and 600 mg twice daily (Day 2 and thereafter), and it is also preferable to administer Compound A at a dose of 1800 mg twice daily (Day 1) and 800 mg twice daily (Day 2 and thereafter), and it is more preferable to administer Compound A at a dose of 1800 mg twice daily (Day 1) and 800 mg twice daily (Day 2 and thereafter). Regarding the twice-daily administration interval, it is preferable that the second administration be given at least 4 hours after the first administration on Day 1, and that the administration be given at 12-hour intervals from Day 2 onwards. The administration period is determined appropriately depending on the progression of symptoms, and can be selected from, for example, a maximum of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22 days. A maximum of 8, 9, 10, 11, 12, 13, or 14 days is preferred, with a maximum of 10 days being more preferred.

[0034] In the present invention, administration of Compound A or a salt thereof may include concomitant medication and / or concomitant therapy. Concomitant medications include, for example, acetaminophen, loperamide, or antiemetics. Antiemetics include, for example, diphenidol hydrochloride or metoclopramide. Concomitant therapy includes, for example, oxygen administration or blood transfusion therapy.

[0035] These concomitant drugs may be produced by combining known methods, or commercially available drugs may be used.

[0036] Next, the present invention will be described with reference to test examples, but the present invention is not limited to these.

[0037] Test Example 1 Clinical trial of Compound A in patients with SFTS virus infection [Method] 1. Objective Compound A will be orally administered for 10 to 14 days to patients who have been definitively diagnosed with SFTS virus infection or who are strongly suspected of having SFTS virus infection, and its efficacy and safety will be examined. The primary endpoint of this test will be the patient survival rate 28 days after the start of administration.

[0038] 2. Subjects The study will target patients who have been definitively diagnosed with SFTS virus infection or who are strongly suspected of having SFTS virus infection and who do not have sepsis.

[0039] 3. Efficacy evaluation item Patient survival rate for 28 days after the start of administration [Evaluation method] This evaluation item will be the primary evaluation item of this study. The principal investigator or co-researcher will record the progress of symptoms and clinical test values, whether the patient is alive or dead, their condition, and other special notes from the date of consent acquisition of patients enrolled in this study until 28 days after the start of administration or until discontinuation. Death due to SFTS virus infection will be defined as "patient death," and the patient survival rate for 28 days after the start of administration will be calculated.

[0040] 4. Information on the test drug The test drug is a tablet containing 200 mg of compound A. The tablets used in this study will be manufactured by the method described in WO 2010 / 104170, a method known per se, or an appropriate combination of these methods.

[0041] 5. Study Design 5.1 Detailed Study Design Multicenter, open-label, uncontrolled study

[0042] 5.2 Dosage and Administration Period Compound A will be orally administered twice, at 1800 mg on Day 1, and twice, at 800 mg, from Day 2 onwards, for 10 to 14 days. On Day 1, the second dose will be orally administered at least 4 hours after the first dose.

[0043] Test Example 2 Phase III clinical trial of Compound A for SFTS virus infection [Method] 1. Objective of the trial Compound A will be orally administered to patients with SFTS virus infection for 10 days, and the cumulative mortality rate up to Day 28 will be used as an indicator to verify its efficacy against SFTS virus infection.

[0044] 2. Clinical trial design 2.1 Types of clinical trials Confirmatory trials (Phase III)

[0045] 2.2 Detailed design of the clinical trial Multicenter, open-label, historically controlled comparative study

[0046] 2.3 Primary efficacy endpoint: Cumulative mortality up to Day 28

[0047] 3. Subjects: Patients suspected of having SFTS virus infection who are not complicated with sepsis at the start of treatment.

[0048] 4. Information on the investigational drug The investigational drug is a tablet containing 200 mg of Compound A. The tablets used in this clinical trial will be manufactured by the method described in WO 2010 / 104170, a method known per se, or an appropriate combination of these methods.

[0049] 5. Dosage and Administration 5.1 Dosage and Administration (1) Dosage Day 1: 1800 mg of favipiravir administered twice a day Days 2-10: 800 mg of favipiravir administered twice a day (2) Administration Method Administer orally twice daily. On Day 1, 9 tablets containing compound A are administered twice, and on Days 2-10, 4 tablets containing compound A are administered twice, with as few as 12-hour intervals between doses. If the first dose on Day 1 is administered in the evening, the second dose should be administered orally at least 4 hours later, taking into account the half-life of favipiravir in the blood.

[0050] 5.2 Administration period: 10 days

[0051] 6. Evaluation criteria for efficacy The cumulative mortality rate is defined as the ratio of all deaths up to Day 28 to the number of patients.

[0052] [Results] Based on the method described in Test Example 1 or Test Example 2, the efficacy (mortality rate) of Compound A was evaluated in patients with SFTS virus infection who were free of sepsis at the start of treatment and who were free of sepsis accompanied by secondary bacteremia. The results are shown in Table 1. The numbers in parentheses in Table 1 are the results based on the method described in Test Example 2. For example, "17 (11)" for surviving cases aged 70 to 79 years means that the total number of cases based on the method described in Test Example 1 or Test Example 2 is "17 cases," of which "11 cases" were based on the method described in Test Example 2.

[0053]

[0054] When Compound A was administered to SFTS virus infection patients aged 70 years or older who were free of sepsis at the start of treatment and did not have sepsis with secondary bacteremia, the mortality rate was 4.2% (1 death; total 24 deaths) (Table 1). On the other hand, when symptomatic treatment was administered to SFTS virus infection patients aged 70 years or older, the mortality rate was 15% (78 deaths; total 508 deaths) (Table 2). Furthermore, a non-patent document (Y. Yuan et al. Clinical efficacy and safety evaluation of favipiravir in treating patients with severe fever with thrombocytopenia syndrome. EBioMedicine 72 (2021) 103591) reported that when Compound A was administered to patients aged 70 years or older, no therapeutic effect against SFTS virus was observed, and the mortality rate was approximately 20.2% (19 deaths; total 94 deaths) (e.g., Fig. 2.C).

[0055] From the above results, it was confirmed that Compound A is highly effective for SFTS virus infected patients aged 70 years or older who are not complicated with sepsis at the start of treatment.

[0056] Furthermore, among SFTS virus infection patients aged 70 years or older who were free of sepsis at the start of treatment and free of sepsis accompanied by secondary bacteremia, 23 patients survived after administration of Compound A (Table 1). These surviving patients (23 cases) included patients who were also suffering from at least one or more of the diseases listed in Table 3 (Table 3).

[0057]

[0058] From these results, it was confirmed that Compound A is also very effective for patients with at least one or more diseases selected from digestive diseases, respiratory diseases, neurological diseases, cardiac diseases, musculoskeletal diseases, blood diseases, immune diseases, cancer, lifestyle-related diseases, skin diseases, urinary diseases, sleep disorders, eye diseases, and dental diseases. In particular, it was confirmed that Compound A is very effective for patients with digestive diseases that are often seen in patients with SFTS virus infection.

[0059] Test Example 3: Effect of Compound A on SFTS virus infected patients with renal dysfunction The SFTS virus infected patients from Test Examples 1 and 2 were divided into three groups: patients with renal dysfunction who were administered Compound A (Patient Group 1), patients with renal dysfunction who received conventional treatment without administering Compound A (Patient Group 2), and patients without renal dysfunction who received conventional treatment without administering Compound A (Patient Group 3). The fatality rates (%) were calculated and shown in Table 4. The conventional treatments were performed in accordance with standard treatment methods (e.g., "Guide to the Treatment of Severe Fever with Thrombocytopenia Syndrome (SFTS) Revised Edition 2019, page 11, 3. Treatment"; https: / / dcc.ncgm.go.jp / information / pdf / SFTS_2019.pdf).

[0060] The mortality rate of Patient Group 2 was significantly high at 35.3%. On the other hand, the mortality rate of Patient Group 1 was 13.3%, which was similar to the mortality rate of Patient Group 3 (13.1%) and significantly lower. In other words, it was confirmed that Compound A is highly effective for SFTS virus infection patients with renal dysfunction.

[0061] Furthermore, a comparison between Patient Group 2 and Patient Group 3 revealed that the mortality rate in patients receiving conventional treatment who had impaired renal function rose significantly from 13.1% to 35.3%. On the other hand, a comparison between Patient Group 1 and Patient Group 2 confirmed that Compound A had the effect of significantly reducing the mortality rate (35.3% → 13.3%) in SFTS virus infection patients with impaired renal function.

[0062] By administering Compound A or a salt thereof to a patient infected with SFTS virus and having impaired renal function, the SFTS virus infection can be treated, and therefore Compound A or a salt thereof is useful in the field of pharmaceutical industry.

Claims

1. A therapeutic agent for severe fever with thrombocytopenia syndrome (SFSS) viral infection, which contains 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an active ingredient, and is administered to patients with severe fever with thrombocytopenia syndrome (SFSS) viral infection who have renal dysfunction.

2. The therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to claim 1, wherein the patient's renal function classification is G1 or higher.

3. A therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to claim 1, for patients with a serum creatinine (s-Cr) level of >1.07 mg / dL.

4. A therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to claim 1 or 2, wherein the patient is 70 to 99 years old.

5. A therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to claim 1 or 2, wherein the patient is 70 to 89 years old.

6. A therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to claim 1 or 2, wherein the patient is 70 to 79 years old.

7. The therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to claim 1 or 2, wherein 1000 to 2400 mg of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is administered twice a day (on the first day) and 400 to 1200 mg twice a day (on the second day and thereafter).

8. The therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to claim 1 or 2, wherein 1800 mg of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is administered twice a day (on the first day) and 800 mg twice a day (on the second day and thereafter).

9. The therapeutic agent for severe fever with thrombocytopenia syndrome viral infection according to claim 7, which is administered for 10 days.

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