Therapeutic and / or prophylactic agent for mycosis containing isavuconazole or prodrug thereof as active ingredient

Abstract

To provide a therapeutic and / or prophylactic agent for mycosis, which is excellent in safety and effectiveness, is administered to a Japanese mycosis patient, and contains isavuconazole or a prodrug thereof as an active ingredient.SOLUTION: A therapeutic and / or prophylactic agent for mycosis, which is administered according to a loading dosing regimen, and further administered according to a maintenance dosing regimen after a lapse of 12 to 24 hours from the end of the loading dosing regimen. (1) Loading dosing schedule: a dosing schedule in which isavuconazole or a pro-drug thereof is administered in 200mg by oral administration or intravenous drip infusion every 8 hours for a total of 6 times (2) Maintenance dosing schedule: a dosing schedule in which isavuconazole or a pro-drug thereof is administered in 200mg by oral administration or intravenous drip infusion once a day in terms of isavuconazole per dose.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to an agent for treating and / or preventing fungal infections, etc., which contains isavuconazole or a prodrug thereof as an active ingredient. [Background technology]

[0002] Infections caused by fungi localized on the surface of the body are called superficial mycoses, while conditions in which fungi penetrate deep into the body, such as the lungs, liver, kidneys, and brain, and cause infection are called deep mycoses. Deep mycoses can develop in patients with weakened immune systems, such as those after organ transplants.

[0003] The main deep fungal infections experienced in Japan are aspergillosis and candidiasis, followed by cryptococcosis and mucormycosis, although their frequency is significantly lower (Non-Patent Document 1). The various pathological conditions of deep fungal infections are "inflammation" itself, which is an "expression" of the defense reaction that protects the body from damage caused by fungi that act as inflammatory stimuli (Non-Patent Document 1).

[0004] Invasive aspergillosis (IA) has been reported to be the most frequent deep-seated fungal infection in the field of hematology, particularly in patients undergoing chemotherapy for acute leukemia or hematopoietic stem cell transplantation (Non-Patent Document 2). It has also been reported that chronic pulmonary aspergillosis (CPA) includes simple pulmonary aspergilloma (SPA) and chronic progressive pulmonary aspergillosis (CPPA) (Non-Patent Document 1).

[0005] Known antifungal drugs that can be used to treat deep fungal infections include amphotericin B (AMPH-B), liposomal amphotericin B (L-AMB), miconazole (MCZ), fluconazole (FLCZ), fosfluconazole (F-FLCZ), voriconazole (VRCZ), itraconazole (ITCZ), and micafungin (MCFG) (Non-Patent Document 1).

[0006] It has been reported overseas that the novel azole isavuconazole is effective against deep-seated fungal infections, including invasive aspergillosis (IA) (Non-Patent Document 2). For example, in an overseas Phase III trial comparing isavuconazole with voriconazole (VRCZ) in patients with invasive aspergillosis (IA), isavuconazole demonstrated non-inferiority to voriconazole (VRCZ) in terms of efficacy (Non-Patent Document 3).

[0007] In overseas studies, isavuconazole was administered as a prodrug, isavuconazonium sulfate, at a dose of 200 mg three times a day for two days, followed by once a day at a dose of 200 mg (Non-Patent Documents 3 to 5).

[0008] On the other hand, pharmaceutical development is sometimes carried out on a global scale, and clinical trials are generally planned with the aim of developing and approving new drugs on a global scale. Clinical trials in which medical institutions in multiple countries participate in a single clinical trial and are conducted simultaneously and in parallel based on a common clinical trial protocol are called international clinical trials.

[0009] Japan's Ministry of Health, Labour and Welfare has issued a notice entitled "Basic Principles for International Joint Clinical Trials," which points out that in some cases it is difficult to conclude that the recommended dose established based on the results of clinical trials in foreign subjects is the recommended dose for Japanese subjects (Non-Patent Document 7). [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Patent No. 3787307 [Non-patent literature]

[0011] [Non-Patent Document 1] Guidelines for the diagnosis and treatment of deep-seated fungal infections (2014) Kyowa Kikaku [Non-patent document 2] Med.Mycol.J.(2016), Vol.57J, J77-J88 [Non-patent document 3] Lancet(2016), Vol.387, pp760~769 [Non-patent document 4] Lancet Infect Dis(2016), Vol.16, pp828~837 [Non-Patent Document 5] Clin Infect Dis(2016), Vol.63, pp356~362 [Non-patent document 6] CRESEMBA® Package Insert (2015) [Non-Patent Document 7] Basic Principles for Global Clinical Trials, PFSB / ELD Notification No. 0928010 Summary of the Invention [Problem to be solved by the invention]

[0012] An object of the present invention is to provide an agent for treating and / or preventing mycosis, which is excellent in safety and efficacy and which contains an active ingredient, isavuconazole or a prodrug thereof, and which can be administered to Japanese patients suffering from mycosis. [Means for solving the problem]

[0013] One aspect of the present invention is a therapeutic and / or preventive agent for mycosis, which contains an active ingredient, isavuconazole or a prodrug thereof, and is administered to a Japanese patient suffering from mycosis according to a loading dose schedule, followed by a maintenance dose schedule 12 to 24 hours after completion of the loading dose schedule. (1) Loading regimen: A regimen in which isavuconazole or its prodrug is administered orally or intravenously every 8 hours for a total of 6 doses, each dose being 200 mg in terms of isavuconazole. (2) Maintenance dosing regimen: A dosing regimen in which isavuconazole or its prodrug is administered orally or intravenously once a day at a dose of 200 mg in terms of isavuconazole per dose.

[0014] One aspect of the present invention is a method for treating and / or preventing mycosis by administering the active ingredient isavuconazole or a prodrug thereof to a Japanese patient suffering from mycosis, the method comprising a loading administration step and a maintenance administration step, wherein the interval between the loading administration step and the maintenance administration step is 12 to 24 hours; (1) Loading administration step: A step in which isavuconazole or a prodrug thereof is administered orally or by intravenous drip infusion six times every eight hours, with each dose being 200 mg in terms of isavuconazole. (2) Maintenance administration step: a step of administering isavuconazole or a prodrug thereof orally or intravenously once a day at a dose of 200 mg in terms of isavuconazole per dose.

[0015] That is, the present invention relates to the following inventions.

[0016] [1] A therapeutic and / or preventive agent for mycosis containing isavuconazole or a prodrug thereof as an active ingredient, which is administered to Japanese patients with mycosis according to a loading dose schedule, and then, 12 to 24 hours after the end of the administration, according to a maintenance dose schedule; (1) Loading regimen: A regimen in which isavuconazole or its prodrug is administered orally or intravenously every 8 hours for a total of 6 doses, each dose being 200 mg in terms of isavuconazole. (2) Maintenance dosing regimen: A dosing regimen in which isavuconazole or its prodrug is administered orally or intravenously once a day at a dose of 200 mg in terms of isavuconazole per dose.

[0017] [2] The agent for treating and / or preventing mycosis according to [1] above, wherein the prodrug of isavuconazole is isavuconazonium sulfate.

[0018] [3] The agent for treating and / or preventing a fungal infection according to [1] or [2] above, wherein the fungal infection is a deep mycosis.

[0019] [4] The agent for treating and / or preventing a fungal infection according to any one of [1] to [3] above, wherein the fungal infection is aspergillosis, mucormycosis, or cryptococcosis.

[0020] [5] The agent for treating and / or preventing mycosis according to any one of [1] to [4] above, wherein the Japanese mycosis patient is a male patient.

[0021] [6] The agent for treating and / or preventing mycosis according to any one of [1] to [5] above, wherein the age of the Japanese mycosis patient is 66 to 75 years old.

[0022] [7] A method for treating and / or preventing mycosis by administering the active ingredient isavuconazole or a prodrug thereof to a Japanese patient suffering from mycosis, the method comprising a loading administration step and a maintenance administration step, wherein the interval between the loading administration step and the maintenance administration step is 12 to 24 hours; (1) Loading administration step: A step in which isavuconazole or a prodrug thereof is administered orally or by intravenous drip infusion six times every eight hours, with each dose being 200 mg in terms of isavuconazole. (2) Maintenance administration step: a step of administering isavuconazole or a prodrug thereof orally or intravenously once a day at a dose of 200 mg in terms of isavuconazole per dose.

[0023] [8] The method for treating and / or preventing a fungal infection according to [7], wherein the prodrug of isavuconazole is isavuconazonium sulfate.

[0024] [9] The method for treating and / or preventing a fungal infection described in [7] or [8] above, wherein the fungal infection is a deep fungal infection.

[0025]

[10] The method for treating and / or preventing a fungal infection according to any one of [7] to [9] above, wherein the fungal infection is aspergillosis, mucormycosis, or cryptococcosis.

[0026]

[11] The method for treating and / or preventing a fungal infection according to any one of [7] to

[10] above, wherein the Japanese patient with a fungal infection is a male patient.

[0027]

[12] The method for treating and / or preventing mycosis according to any one of [7] to

[11] above, wherein the age of the Japanese mycosis patient is 66 to 75 years old. [Brief explanation of the drawings]

[0028] [Figure 1] Figure 1 shows the details of the clinical trial. DETAILED DESCRIPTION OF THE INVENTION

[0029] 1. Active ingredient In the present invention, isavuconazole means a compound represented by the following formula (I): In the present invention, isavuconazole is an active ingredient.

[0030] [ka]

[0031] Isavuconazole is also called isavuconazole or ivuconazole. The CAS number for isavuconazole is 241479-67-4. In the United States, formulations containing isavuconazonium sulfate, a prodrug of isavuconazole, are used clinically (Non-Patent Document 6). Isavuconazonium sulfate is a compound represented by the following formula (II). Isavuconazonium sulfate can be hydrolyzed in vivo to become isavuconazole. The CAS number for isavuconazonium sulfate is 946075-13-4.

[0032] [ka]

[0033] Isavuconazole or a prodrug thereof can be produced or prepared by a method known per se (Patent Document 1, Non-Patent Document 6, etc.) A preferred example of a prodrug of isavuconazole is isavuconazonium sulfate.

[0034] 2.Mycosis Fungal infections can be broadly divided into superficial mycoses, such as tinea, in which the infection is limited to the surface of the body, and deep mycoses, in which fungi invade and cause infection deep within the body, such as the lungs, kidneys, and central nervous system.

[0035] The main deep-seated mycoses are aspergillosis and candidiasis, followed less frequently by cryptococcosis and mucormycosis. Deep-seated mycoses include invasive types that invade tissues and rapidly progress symptoms, and chronic types that progress slowly and experience repeated exacerbations and remissions. An example of an invasive deep-seated mycosis is invasive aspergillosis (IA). An example of a chronic deep-seated mycosis is chronic pulmonary aspergillosis (CPA).

[0036] The mycosis according to the present invention is not particularly limited, but is preferably a deep mycosis. The deep mycosis according to the present invention is also not particularly limited, but is preferably aspergillosis, mucormycosis, or cryptococcosis. Preferred examples of the aspergillosis according to the present invention include invasive aspergillosis, simple pulmonary aspergilloma (SPA), and chronic progressive pulmonary aspergillosis (CPPA). Preferred examples of the cryptococcosis according to the present invention include disseminated cryptococcosis, pulmonary cryptococcosis, and cryptococcal meningitis.

[0037] Diagnosis of deep-seated mycoses can be appropriately performed by clinicians and other skilled artisans. Definitive diagnostic methods include, for example, culture tests, microscopic tests, and histopathological diagnostic methods, while auxiliary diagnostic methods include serodiagnosis, genetic diagnosis, imaging diagnostics, and antifungal drug susceptibility testing. When a definitive diagnostic method cannot be used due to clinical constraints or when a clear result cannot be obtained, a provisional diagnosis can be made by combining an auxiliary diagnostic method with clinical information (Non-Patent Document 1).

[0038] 3. Treatment and prevention of fungal diseases The treatment of deep fungal infections according to the present invention is not particularly limited, but specific examples include empirical treatment and early predicted treatment for deep fungal infections. The prevention of deep fungal infections according to the present invention is also not particularly limited, but means prevention of the onset of deep fungal infections, and examples of application include prevention of onset in cases with a high risk of developing deep fungal infections, such as bone marrow transplants and organ transplants.

[0039] The presence or absence and degree of effectiveness of treatment for deep fungal infections can be appropriately judged by clinicians, etc., and the presence or absence and degree of effectiveness of treatment can be judged, for example, based on the effectiveness rate of clinical symptoms, the effectiveness rate of imaging diagnostic effects, the disappearance rate of mycological effects, and all-cause mortality rate.

[0040] For example, in cases of invasive aspergillosis, mucormycosis, and disseminated cryptococcosis, the mycological effect can be judged to be effective if fungi detected by culture or direct microscopic examination before the start of administration disappear after administration (disappearance), or if fungi detected by culture or direct microscopic examination before the start of administration are clinically determined to have disappeared even though there is no evidence of elimination due to the difficulty in obtaining specimens for culture due to the disappearance of the infection focus, etc.

[0041] For example, in cases of invasive aspergillosis, mucormycosis, disseminated cryptococcosis, etc., if the imaging findings of fungal infections before the start of administration improve after administration, the imaging diagnostic effect can be determined to be effective. Here, improvement means, for example, a reduction of the long diameter of the lesion on the imaging findings by 50% or more.

[0042] 4. Usage and dosage The agent for treating and / or preventing mycosis of the present invention is administered according to a loading regimen, and then, 12 to 24 hours after the end of the administration, it is further administered according to a maintenance regimen.

[0043] The method for treating and / or preventing mycosis of the present invention comprises a loading administration step and a maintenance administration step, and the interval between the loading administration step and the maintenance administration step is 12 to 24 hours.

[0044] Generally, loading doses are understood as a dosage regimen in which the target drug blood concentration is reached early by increasing the dose per administration or the number of daily administrations in the early stages of treatment. Among antifungal drugs, voriconazole and itraconazole, for example, are known to require loading doses. Furthermore, maintenance doses are generally understood as a dosage regimen in which a drug is repeatedly administered to roughly maintain a desired drug blood concentration.

[0045] The loading dose regimen of the present invention is "a regimen in which isavuconazole or a prodrug thereof is administered orally or by intravenous drip infusion six times every eight hours, with each dose being 200 mg in terms of isavuconazole." Here, the loading dose step refers to the process of administration according to the loading dose regimen.

[0046] The maintenance administration regimen of the present invention is "a regimen in which isavuconazole or a prodrug thereof is administered orally or by intravenous drip infusion once daily at a dose of 200 mg in terms of isavuconazole per administration." Here, the maintenance administration step refers to the course of administration according to the maintenance administration regimen.

[0047] When isavuconazonium sulfate is used as isavuconazole or a prodrug thereof, it is understood that the amount of isavuconazonium sulfate 372.6 mg corresponds to 200 mg of isavuconazole.

[0048] The period from the end of administration according to the loading regimen to the start of administration according to the maintenance regimen is 12 to 24 hours, i.e., the time elapsed from the end of the loading regimen to the start of the maintenance regimen is 12 to 24 hours.

[0049] From the viewpoint of the efficacy and safety of the agent for treating and / or preventing mycosis of the present invention, this elapsed time is more preferably 14 to 22 hours, and most preferably 16 to 20 hours.

[0050] During the administration period according to the loading regimen of the present invention or the administration period according to the maintenance regimen of the present invention, a change from oral administration to intravenous drip administration, or from intravenous drip administration to oral administration, is permitted, although when changing the administration route during the administration period according to the maintenance regimen of the present invention, a change from intravenous drip administration to oral administration is more preferable than a change from oral administration to intravenous drip administration.

[0051] In carrying out the present invention, when isavuconazole or a prodrug thereof is administered intravenously, the time elapsed from the start to the end of each administration is not particularly limited, but is preferably at least one hour, and more preferably exceeds one hour.

[0052] 5. Target of administration One feature of the agent for treating and / or preventing mycosis of the present invention is that it is administered to mycosis patients with specific backgrounds, most typically Japanese patients.

[0053] A Japanese person is someone who has lived in Japan since ancient times and whose origins, ancestry, or origins lie in the Japanese archipelago, and generally refers to someone who has Japanese nationality.

[0054] The recipient may be of any gender or age, but is preferably male and / or between 66 and 75 years old. Male adult heights may be approximately 165 to 175 cm, and female adult heights may be approximately 153 to 163 cm. The weight of the recipient is not particularly limited, but is preferably 40 kg or more, and more preferably 50 kg or more.

[0055] When the subject of administration is a woman, the woman is preferably a non-pregnant woman, a woman of no possibility of pregnancy, or a woman who is willing to use appropriate contraception.

[0056] 5.1. Indications for treatment of invasive aspergillosis In the present invention, when the treatment of invasive aspergillosis is aimed at, the subjects to be administered may be those who are determined to be invasive aspergillosis patients by definitive diagnosis, those who are determined to have invasive aspergillosis by clinical diagnosis, or those who are determined to have the possibility of having invasive aspergillosis.

[0057] In diagnosing invasive aspergillosis, the host factor criteria can be (1) prolonged neutropenia associated with the onset (a period of less than 500 / μL for 10 days or more), (2) recipient of allogeneic hematopoietic stem cell transplant, (3) use of corticosteroids equivalent to 0.3 mg / kg / day or more of prednisolone for 3 weeks or more, (4) a history of administration of cellular immunosuppressants within the past 90 days, or (5) severe congenital immunodeficiency.

[0058] In diagnosing invasive aspergillosis, the clinical criteria can be (1) lower respiratory tract fungal infection, (2) tracheobronchitis, (3) sinus infection, or (4) central nervous system infection.

[0059] In the diagnosis of invasive aspergillosis, the mycological criteria can be (1) direct tests (cytology, direct microscopy, or culture), or (2) indirect tests (detection of Aspergillus antigens).

[0060] Patients who have been diagnosed with invasive aspergillosis include: 1) Those who have confirmed mycelia in histopathological examination, cytopathological examination, or direct microscopic examination of needle aspiration or biopsy specimens obtained from an essentially sterile site within 14 days prior to administration, and who have confirmed associated tissue damage (confirmation of infiltration or lesions by microscopy or imaging tests), or 2) Those who have had filamentous fungi (Aspergillus genus) detected in a culture test of a specimen obtained by aseptic technique from an area that was originally sterile or from an area with clinical / radiographic abnormalities associated with infectious symptoms within 14 days prior to administration of the drug. It can be said that:

[0061] Patients who are clinically diagnosed as having invasive aspergillosis and who satisfy at least one of the host factors, clinical criteria, and mycological criteria are eligible for administration.

[0062] A subject who is judged to have a possibility of invasive aspergillosis may be one who satisfies one or more of the host factors and clinical criteria.

[0063] 5.2. Indications for treatment of chronic pulmonary aspergillosis In the present invention, when the treatment of chronic pulmonary aspergillosis is aimed at, the subject of administration can be a patient who has been determined to have chronic pulmonary aspergillosis by a definitive diagnosis, or a patient who has been determined to have chronic pulmonary aspergillosis by a clinical diagnosis.

[0064] A patient with a definitive diagnosis of chronic pulmonary aspergillosis can be one who meets both the host factor and clinical criteria, and also meets one or more of the mycological criteria for "direct examination."

[0065] A patient who is clinically diagnosed as having chronic pulmonary aspergillosis may meet both the host factor and clinical criteria and also meet one or more of the mycological criteria for "indirect testing."

[0066] In diagnosing chronic pulmonary aspergillosis, host factors can be those with risk factors for chronic pulmonary aspergillosis (such as old pulmonary tuberculosis, COPD, bronchiectasis, cavitary lesions, pulmonary nontuberculous mycobacterial disease, interstitial pneumonia, or a history of thoracic surgery).

[0067] The clinical criteria for diagnosing chronic pulmonary aspergillosis are (1) chronic clinical symptoms and (2) chest imaging (CT) showing shadows, with other causes ruled out.

[0068] In the diagnosis of chronic pulmonary aspergillosis, mycological criteria can be direct tests (direct microscopy, culture, or histopathological examination), indirect tests (detection of Aspergillus antigens or antibodies).

[0069] 5.3. Targets for administration in the treatment of mucormycosis In the present invention, when the treatment of mucormycosis is aimed at, the subject of administration can be a person who is strongly suspected of having a fungal infection based on clinical symptoms or images, etc., and who falls under any of the following categories. (1) Mucorales elements are confirmed in direct microscopic examination of a specimen obtained within 14 days prior to administration, or Mucorales are detected in a culture test. (2) Mucorales are detected in histopathological examination of specimens obtained within 14 days prior to administration.

[0070] 5.4. Indications for treatment of cryptococcosis When the present invention is directed to treating cryptococcosis, the subject of administration may be a person who has been determined to be a cryptococcosis patient by a definitive diagnosis, or a person who has been determined to have cryptococcosis by a clinical diagnosis.

[0071] In diagnosing cryptococcosis, a person who is determined to be a cryptococcosis patient by a definitive diagnosis can be a person who is strongly suspected of having a fungal infection based on clinical symptoms or images, etc., and who also meets the mycological criteria through direct testing.

[0072] In the diagnosis of cryptococcosis, a person who is clinically diagnosed as a cryptococcosis patient is one in whom fungal infection is strongly suspected based on clinical symptoms or images, etc., and who also meets the indirect mycological criteria.

[0073] In the diagnosis of cryptococcosis, mycological criteria can be direct tests (direct microscopy, culture, or histopathological examination), indirect tests (detection of cryptococcal antigens).

[0074] 6.Safety Generally, any undesirable or unintended disease or symptom that occurs in a person who has been administered a drug can be called an adverse event (AE). Adverse events that occur after drug administration are sometimes called treatment-emergent adverse events (TEAE).

[0075] Adverse events for which a causal relationship with a drug cannot be denied can be called side effects. Here, "a causal relationship cannot be denied" includes not only cases where a causal relationship is recognized as being reasonably possible, but also cases where it cannot be evaluated as being reasonably possible that a causal relationship does not exist.

[0076] Adverse events can be classified into "serious adverse events" and "non-serious adverse events." The severity of adverse events can be classified into "mild," "moderate," and "severe." Such classification can be made, for example, in a clinical trial by a principal investigator or a subinvestigator according to a method commonly used in the art.

[0077] Adverse events can also be classified over time and their outcomes can be categorized, for example, as recovered / resolved, recovering / resolving, not recovered / not resolved, recovered / resolved with sequelae, death, or unknown.

[0078] The method for comparing the safety of one drug with another is not particularly limited. For example, a comparison can be made by focusing on a certain adverse event and comparing its frequency, severity, causality, outcome, and / or severity. Alternatively, the two drugs can be compared in terms of all or some of the adverse events, or administration discontinuation due to all or some of the side effects. Adverse events can include abnormalities in clinical test values ​​and vital signs.

[0079] Adverse events are not particularly limited and can also be classified by system organ class (SOC). Examples of system organ classes related to adverse events include the following:

[0080] 1) Infectious and parasitic diseases 2) Gastrointestinal disorders 3) Musculoskeletal and connective tissue disorders 4) Disorders, addictions, and procedural complications 5) General and systemic disorders and conditions at the injection site 6) Skin and subcutaneous tissue disorders 7) Nervous system disorders 8) Respiratory, thoracic and mediastinal disorders 9) Eye disorders 10) Metabolic and nutritional disorders 11) Clinical testing 12) Benign, malignant, and unspecified neoplasms (including cysts and polyps) 13) Ear and labyrinth disorders 14) Heart disorders 15) Vascular disorders

[0081] 7. Preparation The agent for treating and / or preventing fungal infections of the present invention is not particularly limited as long as it can be administered orally or by intravenous drip infusion, and examples of dosage forms include tablets, capsules, granules, powders, oral liquids, syrups, and injections.

[0082] A preferred example of the therapeutic and / or preventive agent for intravenous drip administration of mycosis of the present invention is an infusion set for intravenous drip administration that includes at least an infusion containing 200 mg of isavuconazole or a prodrug thereof in isavuconazole equivalent, a bottle needle, an infusion tube, a clamp, an infusion filter with an air vent, a venous needle, and an infusion tube.

[0083] A preferred example of the therapeutic and / or preventive agent for mycosis of the present invention for intravenous administration is a lyophilized preparation containing isavuconazole or a prodrug thereof for producing an infusion solution containing 200 mg of isavuconazole or a prodrug thereof in isavuconazole equivalent. The composition of the lyophilized preparation is not particularly limited, but reference can be made to a lyophilized preparation of isavuconazonium sulfate that has been used clinically overseas (CRESEMBA®; Non-Patent Document 6). Specifically, the lyophilized preparation of the present invention can be produced by blending mannitol and sulfuric acid as a pH adjuster with the active ingredient of the present invention and using a conventional method.

[0084] When the agent for treating and / or preventing mycosis of the present invention is made into a capsule, it can be prepared with reference to an isavuconazonium sulfate preparation that has been used clinically overseas (CRESEMBA (registered trademark); Non-Patent Document 6). Specifically, for example, the capsule of the present invention can be produced by mixing the active ingredient and additives (magnesium citrate, crystalline cellulose, talc, light anhydrous silicic acid, stearic acid) using a conventional method and filling them into a capsule base material whose main component is hypromellose. [Example]

[0085] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples and can be implemented in any form without departing from the spirit of the present invention.

[0086] 1. Test Method 1.1 Overview The safety and efficacy of intravenous or oral administration of 372.6 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) was investigated in Japanese patients with deep fungal infections. This study (hereafter sometimes referred to as the clinical trial) consisted of a screening period, a treatment period, and a follow-up period (Figure 1). During the treatment period, the study drug (isavuconazonium sulfate or voriconazole) was administered for up to 84 days. The administration route was selected from two options: intravenous or oral, and switching from intravenous to oral administration was possible within the same patient.

[0087] The therapeutic effects were evaluated in a blinded manner by a committee composed of specialists on days 42 and 84 after the start of treatment, and at the end of treatment (hereinafter referred to as EOT (End of Treatment)). The follow-up period was 28 days after the end of treatment, and all adverse events up to the end of the follow-up period were investigated. The follow-up period lasted up to 112 days from the start of treatment. The primary endpoint of this trial was the proportion of subjects (those who received the study drug) who experienced adverse events from the start of treatment to the end of the follow-up period.

[0088] 1.2 Selection Criteria Patients who met all of the following criteria (1) to (3) were included in the clinical trial. (1) Japanese men and women aged 20 or older (2) Patients with invasive aspergillosis, chronic pulmonary aspergillosis, mucormycosis, or cryptococcosis. (3) In the case of women, women who are not pregnant, women who are not likely to become pregnant, and women who are willing to use appropriate contraception

[0089] 1.3 Exclusion criteria Patients who met any of the following criteria (1) to (16) were excluded from the clinical trial. (1) Pregnant or lactating female patients (2) Patients with hypersensitivity to azole antifungal drugs or components of the investigational drug (3) Patients at high risk for QT / QTc prolongation or patients with risk factors for torsade de pointes (4) Patients with a history of short QT syndrome (5) Subjects with liver dysfunction at the time of registration (6) Patients with moderate to severe renal dysfunction at the time of enrollment (7) Patients who have received efavirenz, ritonavir, rifampicin, rifabutin, ergot alkaloids (excluded only for Cohort A subjects described below), long-acting barbiturates, carbamazepine, pimozide (excluded only for Cohort A subjects described below), quinidine (excluded only for Cohort A subjects described below), triazolam (excluded only for Cohort A subjects described below), olmesartan medoxomil / azelnidipine (excluded only for Cohort A subjects described below), or St. John's wort within 5 days prior to administration of the study drug. (8) Patients whose causative fungi are other than Aspergillus, Mucorales, and Cryptococcus (9) Patients who are considered unlikely to survive the clinical trial period (10) Patients with underlying diseases, complications, or general conditions that make it difficult to evaluate efficacy and safety (11) Patients who have received voriconazole for deep fungal infections and who were ineffective or intolerant to this treatment, or all patients who received voriconazole within 14 days prior to the administration of the study drug (excludes only Cohort A subjects described below). (12) Patients who are currently receiving systemic antifungal drugs other than voriconazole and who are unable to discontinue these drugs before starting the study drug, or whose symptoms of deep fungal infection are improving due to these drugs. (13) Patients with a strong suspicion of cryptococcal meningitis (14) Patients who have received other investigational drugs within 30 days prior to the administration of the investigational drug (15) Patients who have previously participated in this clinical trial (16) Patients who are otherwise deemed inappropriate for the implementation of this clinical trial by the investigator or clinical investigator.

[0090] 1.4 Diagnostic criteria Subjects were recruited if they met the diagnostic criteria for invasive aspergillosis, chronic pulmonary aspergillosis, mucormycosis, or cryptococcosis. The diagnostic criteria for each fungal infection were as follows:

[0091] 1.4.1 Invasive aspergillosis (Cohort A) (1) Confirmed cases 1) Subjects with mycelia identified in histopathological, cytopathological, or direct microscopic examination of needle aspiration or biopsy specimens from otherwise sterile sites obtained within 14 days prior to administration of the investigational drug, along with associated tissue damage (microscopic or imaging studies of infiltration or lesions), or 2) Subjects who have filamentous fungi (Aspergillus genus) detected in cultures of specimens obtained by aseptic techniques from sites that are normally sterile or have clinical / radiographic abnormalities associated with infectious symptoms within 14 days prior to administration of the study drug

[0092] (2) Clinical diagnosis Clinically diagnosed cases were defined as subjects who met at least one of the host factors, clinical criteria, and mycological criteria.

[0093] (3) Possibility example Subjects who met at least one host factor and one clinical criterion. However, among subjects registered as probable cases, if they met the criteria for confirmed or clinically diagnosed cases by testing within 7 days of starting treatment with the study drug, they were treated as confirmed or clinically diagnosed cases.

[0094] The host factor criteria for the diagnosis of invasive aspergillosis were (1) prolonged neutropenia associated with the onset (a period of <500 / μL for 10 days or more), (2) recipient of allogeneic hematopoietic stem cell transplant, (3) use of corticosteroids equivalent to 0.3 mg / kg / day or more of prednisolone for 3 weeks or more, (4) history of administration of cellular immunosuppressants within the past 90 days, and (5) severe congenital immunodeficiency.

[0095] The clinical criteria for the diagnosis of invasive aspergillosis were (1) lower respiratory tract fungal infection, (2) tracheobronchitis, (3) sinus infection, and (4) central nervous system infection.

[0096] The mycological criteria for the diagnosis of invasive aspergillosis were (1) direct tests (cytology, direct microscopy, or culture) and (2) indirect tests (detection of Aspergillus antigen).

[0097] 1.4.2 Chronic pulmonary aspergillosis (Cohort A) (1) Confirmed cases Subjects who meet both the host factor and clinical criteria and also meet one or more of the mycological criteria for "direct testing"

[0098] (2) Clinical diagnosis Subjects who meet both the host factor and clinical criteria and also meet one or more of the mycological criteria for "indirect testing"

[0099] For the diagnosis of chronic pulmonary aspergillosis, host factors were those with risk factors for chronic pulmonary aspergillosis (old pulmonary tuberculosis, COPD, bronchiectasis, cavitary lesions, pulmonary nontuberculous mycobacterial disease, interstitial pneumonia, history of thoracic surgery, etc.).

[0100] The clinical criteria for the diagnosis of chronic pulmonary aspergillosis were (1) subjects with chronic clinical symptoms and (2) subjects with opacities on chest CT scans, with other causes ruled out.

[0101] The mycological criteria for the diagnosis of chronic pulmonary aspergillosis were direct examination (direct microscopy, culture, or histopathological examination) and indirect examination (detection of Aspergillus antigen or antibody).

[0102] 1.4.3 Mucormycosis (Cohort B) Subjects were strongly suspected of having a fungal infection based on clinical symptoms or images, and met any of the following criteria: (1) Mucorales elements are confirmed in direct microscopic examination of specimens obtained within 14 days prior to administration of the investigational drug, or Mucorales are detected in culture. (2) Mucorales are detected in histopathological examination of specimens obtained within 14 days prior to administration of the investigational drug.

[0103] 1.4.4 Cryptococcosis (Cohort B) (1) Confirmed cases Subjects who are strongly suspected of having a fungal infection based on clinical symptoms or imaging, etc., and who meet the mycological criteria for direct testing.

[0104] (2) Clinical diagnosis Subjects who are strongly suspected of having a fungal infection based on clinical symptoms or imaging, etc., and who also meet the indirect mycological criteria.

[0105] The mycological criteria for the diagnosis of cryptococcosis were direct tests (direct microscopy, culture, or histopathological examination) and indirect tests (detection of Aspergillus antigen).

[0106] 1.5 Investigational Drugs The subjects were administered the test drug and the control drug as investigational drugs.

[0107] 1.5.1 Study Drug The test drug was a lyophilized formulation containing 372.6 mg of isavuconazonium sulfate (200 mg of isavuconazole) for intravenous administration, and two capsule formulations containing 186.3 mg of isavuconazonium sulfate (100 mg of isavuconazole) for oral administration. Both formulations were manufactured by conventional methods.

[0108] 1.5.2 Control The control drugs were a lyophilized formulation containing 200 mg of voriconazole for intravenous administration and tablets containing 200 mg or 50 mg of voriconazole for oral administration. These formulations, such as Vfend tablets 200 mg or 50 mg, were readily available and were used as control drugs in the clinical trial.

[0109] 1.6 Dosage and administration of investigational drug 1.6.1 Dosage and administration of the investigational drug Loading doses were administered on the first and second days of administration, and maintenance doses were administered from the third day onwards, 12 to 24 hours after the end of the loading doses.

[0110] The loading dose was administered approximately every 8 hours for a total of 6 times (48 hours). For each dose, one vial of the test drug (lyophilized formulation) was dissolved immediately before use, and the solution was placed in an intravenous infusion container and administered intravenously. Alternatively, two capsules of the test drug (capsules) were administered orally.

[0111] Maintenance administration was once daily, with one vial of the study drug (lyophilized formulation) being dissolved immediately before use and the solution placed in an intravenous infusion container and administered intravenously, or two capsules of the study drug (capsules) being administered orally. When administering one vial of the study drug (lyophilized formulation) intravenously, it was administered over a minimum of one hour. Patients were permitted to switch from the lyophilized formulation to capsules, but not from capsules to the lyophilized formulation.

[0112] 1.6.2 Control drug dosage and administration A loading dose was administered on the first day of administration, and maintenance doses were administered from the second day onwards, 12 to 24 hours after the end of the loading dose.

[0113] The loading dose was administered twice, approximately 12 hours apart (over a total of 24 hours). For each dose, the control drug (lyophilized formulation) was dissolved immediately before use, and the solution was placed in an intravenous infusion container and administered intravenously at a dose of 6 mg / kg. Alternatively, the control drug (tablet) was administered orally at a dose of 300 mg.

[0114] Maintenance dosing was administered twice daily, with the control drug (lyophilized formulation) being dissolved immediately before use and placed in an intravenous infusion container and administered intravenously at a dose of 4 mg / kg, or the control drug (tablets) being administered orally at a dose of 200 mg. Switching from the lyophilized formulation to tablets was permitted, but switching from tablets to the lyophilized formulation was not. The dosage was adjusted based on the subject's weight, liver function, etc., and plasma concentrations were monitored as necessary.

[0115] 1.7 Study drug groups and allocation In Cohort A, subjects who met the diagnostic criteria for invasive aspergillosis and subjects who met the diagnostic criteria for chronic pulmonary aspergillosis were randomly assigned to the investigational drug and control groups. Cohort B consisted of subjects who met the diagnostic criteria for mucormycosis and subjects who met the diagnostic criteria for cryptococcosis. All subjects in Cohort B were assigned to the investigational drug group.

[0116] 1.8 Efficacy Assessment The efficacy evaluation items were the following four items. (1) Therapeutic efficacy rate based on the results of the Data Review Committee (DRC) assessment (the overall efficacy rate at Day 42, Day 84, and EOT (End of Treatment) (2) DRC (Data Review Committee) assessment (effectiveness rate of clinical symptoms, effective rate of diagnostic imaging, and disappearance rate of mycological effects) (3) Investigator's assessment (effectiveness rate of overall effect, effectiveness rate of clinical symptom effect, effectiveness rate of imaging diagnostic effect, disappearance rate of mycological effect) (4) All-cause mortality rate, etc.

[0117] 1.9 Safety Assessment The primary endpoint of this study was the proportion of subjects who experienced TEAEs (TEAE incidence rate). Other safety endpoints included clinical test values, vital signs, and 12-lead electrocardiograms.

[0118] 1.9.1 Clinical Test Items Clinical test items included general blood tests (red blood cell count, hemoglobin, hematocrit, white blood cell count, white blood cell differential, platelet count), blood biochemistry tests (AST, ALT, γ-GTP, ALP, total bilirubin, direct bilirubin, creatinine phosphokinase, LDH, serum creatinine, BUN, calcium, uric acid, electrolytes, albumin, blood glucose), and urinalysis (pH, protein, sugar, occult blood, urobilinogen).

[0119] 2. Test Results 2.1 Analysis population The numbers of analysis populations (ITT, mITT, SAS) for efficacy and safety are shown in Table 1.

[0120] [Table 1]

[0121] The background information for Cohort A and Cohort B is as shown in Table 2. In Cohort A, there were no significant differences in background information between the investigational drug group and the control drug group.

[0122] The intention-to-treat (ITT) analysis set consisted of all randomized patients who received at least one dose of the study drug. The modified intention-to-treat (mITT) analysis set consisted of all patients in the intention-to-treat (ITT) analysis set who were classified as "confirmed" or "clinically diagnosed" with deep fungal infection by the DRC. The safety analysis set (SAS) consisted of all randomized patients who received at least one dose of the study drug.

[0123] [Table 2]

[0124] 2.2 Administration period of test drug and control drug There were no significant differences in the duration of treatment between the test drug and control drug groups in Cohort A or Cohort B (Table 3).

[0125] [Table 3]

[0126] 2.3 Effectiveness rate of chronic pulmonary aspergillosis treatment as determined by DRC (effectiveness rate of overall effect) The therapeutic effectiveness rates (total effectiveness rate) for chronic pulmonary aspergillosis on day 42, day 84, and EOT are shown in Table 4, demonstrating that the test drug is effective in treating chronic pulmonary aspergillosis.

[0127] [Table 4]

[0128] As mentioned above, in an overseas Phase III trial comparing isavuconazole with voriconazole (VRCZ) in patients with invasive aspergillosis, isavuconazole demonstrated non-inferiority to voriconazole (VRCZ) in terms of efficacy (Non-Patent Document 3).

[0129] Non-Patent Document 3 shows the therapeutic effectiveness rate (at EOT) of invasive aspergillosis as determined by DRC, which was effective (35%) and ineffective (65%; the sum of unchanged and worsening cases) (Non-Patent Document 3; Table 2). In the present invention, the therapeutic effectiveness rate (at EOT) of chronic pulmonary aspergillosis as determined by DRC was effective (approximately 83%) and ineffective (approximately 10%; the sum of unchanged and worsening cases). In light of the above results, the inventors believe that Table 4 suggests that the therapeutic and / or preventive agent for mycosis according to the present invention is extremely superior in terms of efficacy.

[0130] 2.4 Effectiveness rate of invasive aspergillosis treatment as determined by DRC (effectiveness rate of overall effect) The therapeutic effectiveness rate (total effectiveness rate) for invasive aspergillosis on day 42 and at EOT is shown in Table 5, and the test drug was considered to be effective in treating invasive aspergillosis. [Table 5]

[0131] Non-Patent Document 3 shows the therapeutic effectiveness rate (at EOT) of invasive aspergillosis as determined by DRC, which was ineffective (65%; the sum of unchanged and worsening cases) (Non-Patent Document 3; Table 2). In the present invention, the therapeutic effectiveness rate (at EOT) of invasive aspergillosis as determined by DRC was ineffective (approximately 33%; the sum of unchanged and worsening cases). In light of the above results, the inventors believe that Table 5 suggests that the therapeutic and / or preventive agent for mycosis according to the present invention is extremely superior in terms of efficacy.

[0132] 2.5 Cryptococcosis treatment effectiveness rate as determined by DRC (effectiveness rate of overall effectiveness) The therapeutic effectiveness rates (total effectiveness rate) for cryptococcosis on day 42, day 84, and EOT are shown in Table 6, demonstrating that the test drug is effective in treating cryptococcosis.

[0133] [Table 6]

[0134] As mentioned above, in overseas studies, isavuconazole was administered as the prodrug isavuconazonium sulfate at 200 mg isavuconazole equivalent three times a day for two days, followed by once a day at 200 mg isavuconazole equivalent (Non-Patent Documents 4-5). Non-Patent Document 5 reports the DRC assessment results (total efficacy at EOT) for cryptococcosis treatment, which were effective (approximately 67%) and ineffective (approximately 33%; this is the sum of unchanged and worsening cases) (Non-Patent Document 5; Table 2).

[0135] On the other hand, in the present invention, the therapeutic effectiveness rate for cryptococcosis (at EOT) as determined by DRC was effective (90%) and ineffective (10%; this is the sum of unchanged and worsened cases). In light of the above results, the inventors believe that Table 6 suggests that the therapeutic and / or preventive agent for fungal infection according to the present invention is extremely superior in terms of efficacy.

[0136] 2.6 Mucormycosis treatment effectiveness rate as determined by DRC (effectiveness rate of overall effect) The therapeutic effectiveness rate (total effectiveness rate) for mucormycosis on day 42, day 84, and EOT was as shown in Table 7, demonstrating that the test drug was effective in treating mucormycosis.

[0137] [Table 7]

[0138] Non-Patent Document 4 shows the effectiveness rate of mucormycosis treatment (at EOT) as determined by DRC, which was ineffective (69%; however, this is the sum of unchanged and worsened cases) (Non-Patent Document 4; Table 3).

[0139] On the other hand, in the present invention, the mucormycosis treatment effectiveness rate (at EOT) as determined by DRC was ineffective (0%; the sum of unchanged and worsened cases). In light of the above results, the inventors believe that Table 7 suggests that the agent for treating and / or preventing fungal infections according to the present invention is extremely superior in terms of efficacy.

[0140] 2.7 Effectiveness of chronic pulmonary aspergillosis treatment as determined by DRC (overall effectiveness rate, by subgroup) The therapeutic effectiveness rate (overall effectiveness rate) by subgroup of chronic pulmonary aspergillosis at EOT is shown in Table 8. It was revealed that the test drug was effective in treating chronic pulmonary aspergillosis in all subgroups. The inventors believe that this suggests that the test drug may be particularly effective in male patients and patients aged 66 to 75 years.

[0141] [Table 8]

[0142] 2.8 TEAE incidence TEAEs (adverse events occurring after drug administration) were defined as adverse events observed in each patient from the time administration of the test drug or control drug began (the start of observation) until 35 days after the end of administration (the end of observation). The incidence rates (%) of TEAEs for all adverse events, as well as eye disorders, hepatic and biliary disorders, gastrointestinal disorders, and musculoskeletal disorders, are shown in Table 9. The incidence rates (%) of constipation, nausea, photosensitivity, pneumonia, and visual impairment are also shown in Table 10.

[0143] [Table 9]

[0144] Non-patent document 3 discloses not only efficacy but also safety information (Table 3).

[0145] In the present invention, the incidence of TEAEs related to skeletal and connective tissue disorders generally tended to be kept low in all fungal infection treatments (5.8, 0.0, 10.0, 0.0). On the other hand, in the safety information disclosed in Non-Patent Document 3, the incidence of skeletal and connective tissue disorders following administration of isavuconazole was 27% (Musculoskeletal and connective disorders column; Table 3). As exemplified by this example, the inventors believe that the therapeutic and / or preventive agent for fungal infection according to the present invention is extremely excellent not only in efficacy but also in safety.

[0146] [Table 10]

[0147] 2.9 TEAE incidence (incidence rate during loading dose and maintenance dose) The results of observing the TEAE incidence rate for each loading dose and maintenance dose are shown in Table 11. Conversely, the TEAE incidence rate tended to be lower during the loading dose, in which the daily dose was higher (i.e., the drug burden on patients was greater).

[0148] [Table 11] [Industrial Applicability]

[0149] The therapeutic and / or preventive agent for mycosis of the present invention containing isavuconazole or a prodrug thereof as an active ingredient is excellent in safety and efficacy, and is therefore extremely useful in the pharmaceutical industry.

Claims

[Claim 1] A therapeutic and / or preventive agent for mycosis, which contains isavuconazole or a prodrug thereof as an active ingredient, and is administered to a Japanese patient suffering from mycosis according to a loading dosage regimen, and then, 12 to 24 hours after the completion of said dosage regimen, is further administered according to a maintenance dosage regimen; (1) Loading regimen: A regimen in which isavuconazole or a prodrug thereof is administered orally or intravenously every 8 hours, a total of 6 times, with each dose being 200 mg of isavuconazole. (2) Maintenance dosing regimen: A dosing regimen in which isavuconazole or a prodrug thereof is administered orally or by intravenous drip infusion once daily at a dose of 200 mg in terms of isavuconazole per dose.

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