Therapeutic agent for hemophagocytic lymphohistiocytosis and use thereof

Abstract

According to the present invention, 6-Fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof has the action of suppressing increased concentration of ferritin in blood, and is effective in a therapeutic agent for hemophagocytic lymphohistiocytosis and in the use of said therapeutic agent.

Description

Hemophagocytic syndrome treatment agent and use thereof

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

[0002] 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 efficacy and effectiveness limited to "novel or re-emerging influenza virus infections (limited to those for which other anti-influenza virus drugs are ineffective or insufficiently effective)."

[0003] 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).

[0004] Hemophagocytic syndrome (HS) is a disease in which immune cells such as macrophages and neutrophils, which are supposed to protect humans, go out of control, and is known as one of the most severe and fatal diseases. Causes of HS include, for example, malignant tumors such as cancer, autoimmune diseases, and infectious diseases. However, HS is not necessarily observed in all patients with these conditions, and the detailed mechanism leading to the onset of the disease has not yet been elucidated (Non-Patent Document 1). While HS is also known as hemophagocytic lymphohistiocytosis, the terms are not used to distinguish between them in this specification.

[0005] A known treatment for hemophagocytic syndrome involves administering steroids to suppress the activation of macrophages and T lymphocytes and reduce the significantly increased amount of ferritin. However, it is generally known that steroid-induced side effects occur in many patients, and there are some problems with this treatment.

[0006] International Publication No. 2021 / 200651 Pamphlet

[0007] A. Hayden et al., Blood Reviews, Vol. 30, 2016, p.411-420

[0008] Compound A is known to have antiviral activity, but is not known to be capable of treating hemophagocytic syndrome.

[0009] 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 new method for treating hemophagocytic syndrome.

[0010] Under these circumstances, the present inventors have found that compound A or a salt thereof suppresses an increase in blood ferritin concentration, and that compound A or a salt thereof is useful as a therapeutic agent for hemophagocytic syndrome and its use, thereby completing the present invention.

[0011] The following aspects of the present invention are provided: <1> A therapeutic or preventive agent for hemophagocytic syndrome, comprising 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an active ingredient. <2> The therapeutic or preventive agent for hemophagocytic syndrome according to <1>, which suppresses an increase in blood ferritin concentration. <3> The therapeutic or preventive agent for hemophagocytic syndrome according to <1>, which is administered at 1,000 to 2,400 mg twice daily as 6-fluoro-3-hydroxy-2-pyrazinecarboxamide on day 1, and at 400 to 1,200 mg twice daily from day 2 onwards. <4> The therapeutic or preventive agent for hemophagocytic syndrome according to <1>, which is administered at 1,800 mg twice daily as 6-fluoro-3-hydroxy-2-pyrazinecarboxamide on day 1, and at 800 mg twice daily from day 2 onwards. <5> The therapeutic or preventive agent for hemophagocytic syndrome according to any one of <1> to <4>, which is administered to a patient with a bunyavirus infection, a patient with an arenavirus infection, a patient with a filovirus infection, a patient with rabies virus infection, a patient with a norovirus infection, a patient with a Zika virus infection, a patient with a coronavirus infection, or a patient with an influenza virus infection. <6> The therapeutic or preventive agent for hemophagocytic syndrome according to any one of <1> to <4>, which is administered to a patient with severe fever with thrombocytopenia syndrome virus infection, a patient with a Lassa fever virus infection, a patient with an Ebola virus infection, a patient with a novel coronavirus infection, or a patient with a novel or re-emerging influenza virus infection. <7> The therapeutic or preventive agent for hemophagocytic syndrome according to any one of <1> to <4>, which is administered to a patient who is not receiving steroids. <8> The therapeutic or preventive agent for hemophagocytic syndrome according to any one of <1> to <4>, which is administered in combination with a steroid.

[0012] In addition, the following inventions are also provided as other aspects of the present invention: (a) a pharmaceutical composition containing Compound A or a salt thereof for treating or preventing hemophagocytic syndrome. (b) a pharmaceutical composition containing Compound A or a salt thereof and not containing a steroid for treating or preventing hemophagocytic syndrome. (c) Compound A or a salt thereof for treating or preventing hemophagocytic syndrome, which is administered to a patient with a bunyavirus infection, an arenavirus infection, a filovirus infection, a rabies virus infection, a norovirus infection, a Zika virus infection, a coronavirus infection, or an influenza virus infection. (d) Compound A or a salt thereof for treating or preventing hemophagocytic syndrome, which is administered to a patient with a bunyavirus infection, an arenavirus infection, a filovirus infection, a rabies virus infection, a norovirus infection, a Zika virus infection, a coronavirus infection, or an influenza virus infection, and which is not administered to a steroid. (e) A method for treating or preventing hemophagocytic syndrome, which comprises administering Compound A or a salt thereof. (f) A method for treating or preventing hemophagocytic syndrome, which comprises administering Compound A or a salt thereof, wherein a steroid is not administered. (g) A method for treating or preventing hemophagocytic syndrome, which comprises administering Compound A or a salt thereof and administering a steroid. (h) Use of Compound A or a salt thereof for the manufacture of a therapeutic or preventive agent for hemophagocytic syndrome. (i) Use of Compound A or a salt thereof for the manufacture of a therapeutic or preventive agent for hemophagocytic syndrome to be administered to a patient not receiving steroids. (j) Use of Compound A or a salt thereof for the manufacture of a therapeutic or preventive agent for hemophagocytic syndrome to be administered in combination with a steroid.

[0013] Compound A or a salt thereof has the effect of suppressing an increase in blood ferritin concentration, and is useful as a therapeutic or preventive agent for hemophagocytic syndrome and its use. Furthermore, compound A or a salt thereof has the effect of suppressing an increase in blood ferritin concentration without the use of steroids, and is therefore useful as a therapeutic or preventive agent for hemophagocytic syndrome that can reduce the side effects caused by steroids and its use. On the other hand, when the therapeutic effect of hemophagocytic syndrome is prioritized, it is useful to administer the therapeutic or preventive agent for hemophagocytic syndrome of the present invention in combination with a steroid.

[0014] 1 is a graph showing the change in blood ferritin concentration over time in patients with SFTS virus infection.

[0015] The present invention will be described in detail below. Unless otherwise specified, the terms used in this specification have the following meanings.

[0016] 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.

[0017] Compound A refers to 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.

[0018] 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.

[0019] 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.

[0020] Of the above salts, preferred salts include pharmacologically acceptable salts, and more preferred salts include salts with sodium or meglumine.

[0021] 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.

[0022] Compound A or a salt thereof is useful for treatment, such as the prevention or treatment of an RNA virus infection.

[0023] RNA virus infections include Bunyaviruses (Crimean-Congo fever virus, Rift Valley fever virus, La Crosse encephalitis virus, Dobrava virus, Maporal virus, Prospect Hill virus, Andes virus, Sandfly fever virus, Heartland virus, Punta Toro virus, Severe fever with thrombocytopenia syndrome virus (SFTS virus), etc.), Arenaviruses (Junin virus, Pichinde virus, Tacaribe virus, Guanarito virus, Machupo virus, Lymphocytic choriomeningitis virus, Lassa fever virus, etc.), Filoviruses (Ebola virus, Marburg virus, etc.), Rabies virus, Human metapneumovirus, Respiratory syncytial virus, Nipah virus, Hendra virus, Measles virus, Hepatitis A virus, These infectious diseases are caused by hepatitis C virus, hepatitis E virus, chikungunya virus, western equine encephalitis virus, Venezuelan encephalitis virus, eastern equine encephalitis virus, norovirus, poliovirus, echovirus, coxsackievirus, enterovirus, rhinovirus, rotavirus, Newcastle disease virus, mumps virus, vesicular stomatitis virus, Japanese encephalitis virus, tick-borne flavivirus, yellow fever virus, dengue fever virus, West Nile virus, Zika virus, coronaviruses (SARS coronavirus, SARS coronavirus-2, MERS coronavirus, novel coronavirus (SARS-CoV-2 and its mutant viruses)), influenza virus, parainfluenza virus, etc.

[0024] In the present invention, compound A or a salt thereof is preferably administered to, but is not particularly limited to, patients with bunyavirus infection, arenavirus infection, filovirus infection, rabies virus infection, norovirus infection, Zika virus infection, coronavirus infection, or influenza virus infection. Compound A or a salt thereof is preferably administered to patients with SFTS virus infection, Lassa fever virus infection, Ebola virus infection, COVID-19 infection, or novel or re-emerging influenza virus infection, more preferably to patients with SFTS virus infection, COVID-19 infection, or novel or re-emerging influenza virus infection, and even more preferably to patients with SFTS virus infection.

[0025] In the present invention, when the patient to be administered compound A or a salt thereof is a patient with SFTS virus infection, the patient is preferably 70 to 109 years old, more preferably 70 to 99 years old, even more preferably 70 to 89 years old, and even more preferably 70 to 79 years old.

[0026] In the present invention, when the patient to be administered compound A or a salt thereof is a patient with an SFTS virus infection, the patient is preferably not suffering from sepsis accompanied by secondary bacteremia during or even during treatment.

[0027] 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 SFTS.

[0028] 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.

[0029] "Treatment" refers to the alleviation or amelioration of one or more symptoms resulting from a specific disease suffered by a subject, as well as the suppression of 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), the treatment refers to the suppression of an increase in ferritin concentration in the blood, thereby treating hemophagocytic syndrome. In another embodiment of the present invention, for example, in a patient with an infection caused by the SFTS virus (Davidson-Banda virus), the treatment 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), as well as the suppression of an increase in ferritin concentration in the blood, thereby treating or preventing hemophagocytic syndrome. In another embodiment of the present invention, in a patient with an infectious disease caused by, for example, SFTS virus (Davidson-Banda virus), the treatment or prevention of hemophagocytic syndrome means, for example, improvement in body temperature, percutaneous arterial oxygen saturation (SpO2), and chest imaging findings, or SFTS virus (Davidson-Banda virus) negativity, as well as suppression of an increase in ferritin concentration in the blood.

[0030] 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.

[0031] In the present invention, the therapeutic or preventive agent for hemophagocytic syndrome is a drug for treating or preventing a condition in which an abnormal increase in blood ferritin concentration occurs.

[0032] 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.

[0033] 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 SFTS patients, oral preparations or injections are preferred. The above-mentioned drugs are formulated by conventional methods.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] In the present invention, steroids may be used in combination to treat or prevent hemophagocytic syndrome. From the viewpoint of further suppressing an increase in blood ferritin concentration, it is preferable to use steroids in combination. From the viewpoint of reducing side effects caused by steroids, it is preferable not to use steroids in combination.

[0038] In the present invention, steroid means a drug having a steroid skeleton, and examples thereof include dexamethasone palmitate, dexamethasone, betamethasone, hydrocortisone, prednisolone, and methylprednisolone.

[0039] In the present invention, administration of Compound A or a salt thereof may include concomitant medications and / or concomitant therapies other than steroids. Concomitant medications include, for example, acetaminophen, loperamide, or antiemetics. Antiemetics include, for example, diphenidol hydrochloride or metoclopramide. Concomitant therapies include, for example, oxygen administration or blood transfusion therapy.

[0040] These steroids and concomitant drugs may be produced by combining known methods, or commercially available products may be used.

[0041] Next, the present invention will be described with reference to test examples, but the present invention is not limited to these.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 5. Study Design 5.1 Detailed Study Design Multicenter, open-label, uncontrolled study

[0047] 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.

[0048] Test Example 2 Phase III clinical trial of Compound A in patients with SFTS virus infection <Method> 1. Objective of the trial Compound A will be orally administered to SFTS patients for 10 days, and the cumulative mortality rate up to Day 28 will be used as an indicator to verify its efficacy against SFTS.

[0049] 2. Clinical trial design 2.1 Types of clinical trials Confirmatory trials (Phase III)

[0050] 2.2 Detailed design of the clinical trial Multicenter, open-label, historically controlled comparative study

[0051] 2.3 Primary efficacy endpoint: Cumulative mortality up to Day 28

[0052] 3. Subjects: Patients suspected of having SFTS who are not complicated with sepsis at the start of treatment will be included.

[0053] 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.

[0054] 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.

[0055] 5.2 Administration period: 10 days

[0056] 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.

[0057] <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.

[0058]

[0059] 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).

[0060] 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.

[0061] 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).

[0062]

[0063] 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.

[0064] Test Example 3: Ferritin Measurement in Patients with SFTS Virus Infection The SFTS virus infection patients in Test Example 2 were divided into three groups: patients who received steroids (methylprednisolone sodium succinate) without Compound A (● in Figure 1), patients who received Compound A but not steroids (▲ in Figure 1), and patients who received Compound A and steroids (methylprednisolone sodium succinate) (■ in Figure 1). The time course of ferritin concentrations (ng / mL) in the blood after administration of a therapeutic agent (compound A and / or steroids) is shown in Table 4. Furthermore, these results are shown in Figure 1, with the ferritin concentration before administration of a therapeutic agent (compound A and / or steroids) as the baseline. Note that steroids were administered in accordance with general dosages and by general administration methods.

[0065] From these results, it was confirmed that Compound A significantly suppresses the increase in blood ferritin concentration compared to steroids. From these results, it was confirmed that Compound A is effective as a therapeutic agent for hemophagocytic syndrome and its use. Furthermore, since Compound A has the effect of significantly suppressing the increase in blood ferritin concentration without the use of steroids, it was confirmed that Compound A is effective as a therapeutic agent for hemophagocytic syndrome that can reduce the side effects caused by steroids and its use. Furthermore, it was confirmed that Compound A further suppresses the increase in blood ferritin concentration when used in combination with steroids.

[0066] Compound A or a salt thereof has the effect of suppressing an increase in blood ferritin concentration, and is useful as a therapeutic agent for hemophagocytic syndrome and for use therein, and therefore can be used in the field of pharmaceutical industry.

Claims

1. A therapeutic or preventive agent for hemophagocytic syndrome, which contains 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an active ingredient.

2. The therapeutic or preventive agent for hemophagocytic syndrome according to claim 1, which suppresses an increase in blood ferritin concentration.

3. The agent for treating or preventing hemophagocytic syndrome according to claim 1, 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 from the second day onwards.

4. The agent for treating or preventing hemophagocytic syndrome according to claim 1, wherein 1800 mg of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is administered twice daily on the first day, and 800 mg twice daily from the second day onwards.

5. The therapeutic or preventive agent for hemophagocytic syndrome according to any one of claims 1 to 4, which is administered to a patient with a bunyavirus infection, an arenavirus infection, a filovirus infection, a rabies virus infection, a norovirus infection, a Zika virus infection, a coronavirus infection, or an influenza virus infection.

6. The therapeutic or preventive agent for hemophagocytic syndrome according to any one of claims 1 to 4, which is administered to patients with severe fever with thrombocytopenia syndrome virus infection, patients with Lassa fever virus infection, patients with Ebola virus infection, patients with COVID-19 infection, or patients with novel or re-emerging influenza virus infection.

7. The therapeutic or preventive agent for hemophagocytic syndrome according to any one of claims 1 to 4, which is administered to a patient to whom steroids are not administered.

8. The therapeutic or preventive agent for hemophagocytic syndrome according to any one of claims 1 to 4, which is administered in combination with a steroid.

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