Therapeutic agent for human graft versus host disease and combination thereof

Abstract

In order to provide a novel therapeutic agent for human graft-versus-host disease and a combination thereof, a therapeutic agent according to the present invention is for human graft-versus-host disease and contains, as an active ingredient, tamibarotene or a pharmaceutically acceptable salt thereof.

Description

Therapeutic agents for human graft-versus-host disease and combinations thereof

[0001] The present invention relates to therapeutic agents and combinations thereof for the treatment of human graft-versus-host disease.

[0002] Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used to treat leukemia and other diseases. However, graft-versus-host disease (GVHD) is a complication that has become a problem after allo-HSCT. GVHD is broadly classified into acute GVHD and chronic GVHD based on histopathological or clinical signs (Non-Patent Document 1).

[0003] For example, chronic GVHD occurs in approximately 40% of survivors, often occurring 5 to 6 months after transplantation. It is a condition similar to autoimmune disease, causing lesions and susceptibility to infection in multiple organs, including the skin, mouth, eyes, gastrointestinal tract, liver, joints, and lungs.

[0004] Treatment for GVHD includes first-line systemic therapy, second-line therapy in resistant cases, local therapy, and supportive therapy, but steroid therapy is the standard treatment for moderate to severe GVHD. Second-line therapy is performed if first-line steroid therapy does not improve the condition or if symptoms recur.

[0005] Hematopoietic Cell Transplantation Guidelines for Graft-Vs-Hodgkin's Disease (5th Edition), Japan Society for Hematopoietic Cell Transplantation, November 2022

[0006] However, steroid drugs cause various side effects, and patients may become steroid dependent, intolerant, or refractory to steroid administration. Furthermore, no standard treatment has been established for second-line treatment. For these reasons, the development of more effective and safer therapeutic drugs and the establishment of new treatment methods are desired.

[0007] One aspect of the present invention aims to provide novel therapeutic agents for GVHD and combinations thereof.

[0008] In order to solve the above problems, the present invention includes the following aspects: <1> A therapeutic agent for human graft-versus-host disease, comprising tamibarotene or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] According to one aspect of the present invention, novel therapeutic agents for human graft-versus-host disease and combinations thereof can be provided.

[0010] 1 is a diagram comparing knee joint extension and knee joint flexion at the start of administration and at the end of administration. 2 is a diagram comparing skin symptoms on the lower back and knees at the start of administration and at the end of administration. 3 is a diagram comparing oral symptoms at the start of administration and at the end of administration. 4 is a diagram showing the response rate by organ.

[0011] [1. Therapeutic Drug] The therapeutic drug for human graft-versus-host disease according to this embodiment (hereinafter, may be abbreviated as "GVHD therapeutic drug") is a therapeutic drug for human graft-versus-host disease, which contains tamibarotene or a pharmaceutically acceptable salt thereof as an active ingredient.

[0012] Furthermore, an example of a GVHD treatment drug according to this embodiment contains tamibarotene or a pharmaceutically acceptable salt thereof as an active ingredient, and is used in combination with at least one selected from steroid drugs and immunosuppressants.

[0013] <Active ingredient> Tamibarotene is the generic name for 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid. It is also known as AM80, and formulations are also sold under the name Amnolake (registered trademark). The structural formula of Tamibarotene is shown below.

[0014] Tamibarotene can be produced by the methods described in, for example, Japanese Patent No. 3001632, Japanese Patent Laid-Open No. 61-76440, and International Publication No. 2002 / 018322.

[0015] Pharmaceutically acceptable salts of Tamibarotene include, for example, non-toxic, pharmaceutically acceptable conventional salts, specifically salts with inorganic or organic bases such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), ammonium salts (e.g., triethylamine salt, and amine salts (e.g., N-benzyl-N-methylamine salt, etc.).

[0016] Tamibarotene can also form solvates, which are also included in the scope of Tamibarotene. Preferred solvates include hydrates and ethanolates.

[0017] <Graft-versus-host disease (GVHD)> GVHD is a rejection reaction that occurs during organ transplantation, in which lymphocytes contained in the graft and blood of the donor (organ donor) attack the organs of the recipient (the person receiving the organ). Examples of organs include bone marrow and blood. GVHD is broadly divided into acute GVHD, which occurs early after transplantation, and chronic GVHD, which occurs later after transplantation with autoimmune-like symptoms. It has been shown that in acute GVHD, donor T cells differentiate and activate into Th1 cells due to antigen-presenting cells in the recipient, and tissues are damaged by inflammatory cytokines and cytotoxic cells such as T cells and macrophages. In contrast, in chronic GVHD, autoantigen-reactive T cells are thought to appear during the stage of immune reconstitution in the recipient's body by donor cells, resulting in symptoms similar to those of autoimmune diseases, but the onset and pathology are different from acute GVHD.

[0018] Acute GVHD and chronic GVHD are classified according to histopathological or clinical signs.

[0019] Acute GVHD is further classified into classical acute GVHD, which occurs within 100 days after transplantation, and atypical acute GVHD, which occurs after 100 days. Classical acute GVHD is a group that exhibits typical clinical symptoms such as maculopapular skin rash, nausea, vomiting, emaciation, watery diarrhea, ileus, and cholestatic hepatitis. Atypical acute GVHD includes persistent types in which the clinical symptoms of classical acute GVHD persist after 100 days, recurrent types in which acute GVHD that had once improved recurs after 100 days, and late-onset acute GVHD, which occurs de novo after 100 days.

[0020] On the other hand, the time of onset of chronic GVHD does not matter when it is diagnosed. Chronic GVHD is classified into classical chronic GVHD and overlap syndrome, in which a patient who has been diagnosed with chronic GVHD once has one or more acute GVHD symptoms (regardless of whether they have improved). A diagnosis of overlap syndrome is also made when acute GVHD coexists at the time of diagnosis of chronic GVHD, when acute GVHD appears after the diagnosis of chronic GVHD, or when acute GVHD recurs in a patient who was once diagnosed even though the chronic GVHD symptoms have improved.

[0021] The GVHD therapeutic agent according to this embodiment can be suitably used for treating chronic GVHD, since it can suppress the production of cytokines Th1 and Th17.

[0022] Furthermore, the GVHD therapeutic drug of this embodiment can be suitably used to improve or suppress the progression of lesions resulting from GVHD in at least one selected from the group consisting of the skin, oral cavity, eyeball, fascia, joints, and lungs.

[0023] As used herein, the term "treatment" refers to alleviating or eliminating an existing disease, disorder, or disorder, or the symptoms associated therewith. In addition, the term "treatment" as used herein also encompasses preventing or preventing the onset of a disease, disorder, or disorder.

[0024] <Other Optional Ingredients> In addition to the above-mentioned active ingredients, the GVHD therapeutic agent of this embodiment may contain one or more therapeutically active substances that have a therapeutic effect on other diseases, disorders, and conditions, as long as there is no risk of inhibiting the activity of the active ingredients and they are not harmful to the subject of administration (hereinafter also referred to as the patient).

[0025] The therapeutic agent may also contain a pharmaceutically acceptable carrier that is not harmful to the subject of administration. The carrier that can be used may be solid, semi-solid, or liquid, and examples thereof include, but are not limited to, any of water, electrolyte solutions, and sugar solutions. Furthermore, the therapeutic agent may contain an adjuvant. Examples of adjuvants include lubricants, stabilizers, preservatives, emulsifiers, thickeners (viscosifiers), colorants, flavors (flavoring agents), excipients, preservatives, buffers, flavoring agents, suspending agents, emulsifiers, solubilizers, and lubricants.

[0026] <Dosage form> Dosage form can be tablets, capsules, pills, granules, powders, syrups, suppositories, eye drops, aerosols, lozenges, pellets, emulsions, suspensions, and other known forms.Among these, for example, as oral administration preparations, any of tablets, capsules, pills, granules, powders, liquids, syrups, and jelly are preferred, any of tablets, capsules, and granules are more preferred, and tablets are even more preferred.In addition, as described below, for example, parenteral administration preparations such as injections, suppositories, and transdermal absorption preparations such as patches may also be used.

[0027] <Method for manufacturing the therapeutic drug> The GVHD therapeutic drug according to this embodiment can be manufactured using a known manufacturing method. For example, the active ingredient and any other ingredients are manufactured separately, and then the ingredients are mixed together to achieve the desired content.

[0028] <Subjects to whom the therapeutic drug is administered> The subjects to whom the therapeutic drug for GVHD according to this embodiment is administered are human subjects who are suffering from GVHD or who are at risk of suffering from GVHD.

[0029] <Administration Route / Administration Method> The administration method (administration route) of the GVHD therapeutic agent according to this embodiment can be appropriately determined depending on the age, condition, treatment period, etc. of the subject. Specifically, either oral or parenteral administration may be used, but oral administration is preferred (oral administration is used in the examples). Examples of parenteral administration include injection, administration as a suppository, and administration as a transdermal absorption preparation such as a patch. Examples of types of injection administration include intramuscular, intraperitoneal, subcutaneous, intravenous, and local injection. Furthermore, the GVHD therapeutic agent according to this embodiment can be administered via various routes, such as transdermal, nasal, vaginal, and rectal.

[0030] The dosage, administration period, administration duration, and timing of administration of the therapeutic agent according to this embodiment will be described in detail in the section [3. Treatment method for GVHD] below.

[0031] <Combined Use with At Least One Selected from Steroid Drugs and Immunosuppressants> The GVHD therapeutic drug according to this embodiment may be used in combination with at least one selected from steroid drugs and immunosuppressants. Thus, the GVHD therapeutic drug according to certain embodiments is used in combination with at least one selected from steroid drugs and immunosuppressants.

[0032] Here, "combined use" includes use before, simultaneously with, or after the use of at least one selected from a steroid drug and an immunosuppressant. It also includes use as a combination drug with a steroid drug. By using the compounded drug with at least one selected from a steroid drug and an immunosuppressant, the dose of the steroid or immunosuppressant can be reduced compared to the administration of the steroid or immunosuppressant alone.

[0033] For example, the daily dose of a steroid drug used in combination with the GVHD therapeutic drug of this embodiment can be reduced compared to the daily dose required when the steroid drug is administered alone. Specifically, the daily dose of a steroid drug used in combination with the GVHD therapeutic drug of this embodiment can be reduced by preferably 90% or less, more preferably 50% or less, and even more preferably 10% or less compared to the daily dose required when the steroid drug is administered alone. In other words, the GVHD therapeutic drug of this embodiment can reduce the daily dose of a steroid drug used in combination by preferably 10% or more, more preferably 50% or more, and even more preferably 90% or more compared to the daily dose required for treatment with the steroid drug alone.

[0034] Furthermore, at 24 weeks or later from the start of administration of the GVHD therapeutic drug according to this embodiment, the daily dose of the steroid drug used in combination with the therapeutic drug can be reduced to preferably 90% or less, more preferably 50% or less, and even more preferably 10% or less, compared to the daily dose of the steroid drug used in combination with the therapeutic drug at the start of administration of the therapeutic drug. In other words, at 24 weeks or later from the start of administration of the GVHD therapeutic drug according to this embodiment, the daily dose of the steroid drug used in combination with the therapeutic drug can be reduced to preferably 10% or more, more preferably 50% or more, and even more preferably 90% or more, compared to the daily dose of the steroid drug used in combination with the therapeutic drug at the start of administration of the therapeutic drug.

[0035] Furthermore, the daily dose of the steroid drug used in combination with the GVHD therapeutic drug according to this embodiment may be reduced in stages depending on the pathological condition of the subject.

[0036] An example of the GVHD therapeutic drug according to this embodiment is administered to any of the following subjects 1) to 3) for whom it is difficult to reduce the dose of steroid drugs. By administering the GVHD therapeutic drug according to this embodiment, the dose of steroid drugs administered to the subject can be reduced.

[0037] 1) Subjects whose daily steroid dose is difficult to reduce from 10 mg / kg prednisolone equivalent, 2) Subjects whose symptoms worsen even after two weeks of daily administration at a steroid dose of 1 mg / kg prednisolone equivalent, or 3) Subjects whose symptoms do not improve even after four to eight weeks of daily administration at a steroid dose of 0.5 mg / kg prednisolone equivalent.

[0038] Here, the term "prednisolone equivalent amount" refers to the amount of steroid drug administered when the steroid drug is converted into an amount of prednisolone that has the same efficacy as the steroid drug.

[0039] Examples of steroid drugs include prednisolone, methylprednisolone, clobetasol propionate, diflorasone acetate, betamethasone dipropionate, diflubredonate, diflucortolone valerate, fluocinonide, amcinonide, hydrocortisone butyrate propionate, betamethasone acetate propionate, mometasone furoate, betamethasone valerate-gentamicin sulfate, betamethasone valerate, dexamethasone propionate, beclomethasone propionate, dexamethasone valerate, fluocinolone acetonide, debrodone propionate, triamcinolone acetonide, hydrocortisone butyrate, clobetasone butyrate, alclometasone propionate, prednisolone valerate acetate, and dexamethasone.

[0040] Immunosuppressants include cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, pentostatin, and methotrexate.

[0041] Furthermore, for example, as long as the therapeutic effect of the GVHD therapeutic drug is not impaired, the drug may be used in combination with another drug having a therapeutic effect against GVHD or another drug having a different effect.

[0042] In yet another embodiment, the therapeutic agent has a therapeutic effect not only on GVHD but also on complications associated with GVHD, such as bronchitis, pneumonia, opportunistic infections, thrombosis, and osteoporosis.

[0043] Another embodiment of the therapeutic agent for GVHD of the present invention is a prophylactic agent administered before the onset of GVHD to prevent the onset of GVHD, which has the clinically important significance of preventing the symptoms of GVHD from becoming severe.

[0044] The standard first-line treatment for chronic GVHD is steroid therapy, and it is considered appropriate to reduce the dose of steroid therapy as a second-line treatment. The GVHD therapeutic drug according to this embodiment is expected to play a role as a second-line therapeutic drug for chronic GVHD.

[0045] The GVHD therapeutic drug according to this embodiment can significantly reduce the dose of steroid drugs used in combination. Therefore, when used in combination with the GVHD therapeutic drug according to this embodiment, it may be possible to apply longer-term, low-dose steroid treatment. Furthermore, the occurrence of various adverse events associated with the use of steroid drugs can also be reduced.

[0046] [2. Combination of Therapeutic Agents] The present invention also provides a combination of therapeutic agents for GVHD (hereinafter sometimes simply referred to as "combination") comprising at least one selected from a steroid drug and an immunosuppressant and a GVHD therapeutic agent according to the present invention.

[0047] Examples of steroid drugs and immunosuppressants are as exemplified above.

[0048] In one embodiment, the therapeutic agent for GVHD and at least one selected from a steroid drug and an immunosuppressant are separate pharmaceutical combinations for use in combination. For example, the therapeutic agent for GVHD and the immunosuppressant may each be in the form of a separate composition. Other components and dosage forms contained in the composition may be those described above in [1. Therapeutic Agents].

[0049] The combination product can be suitably used in the GVHD treatment method of this embodiment. A specific example of the combination product is a combination product in which a GVHD therapeutic drug, a steroid drug, and an immunosuppressant are prepared as GVHD treatment pharmaceuticals, each labeled with a pharmaceutical label, and these pharmaceuticals are used in combination. The pharmaceutical labels of the pharmaceuticals may state that they are to be used in combination with each other as a combination product.

[0050] Furthermore, when the therapeutic agent for GVHD and at least one selected from a steroid drug and an immunosuppressant are in the form of separate pharmaceuticals, each composition may contain the same component as the other component, or may contain different components.

[0051] The combination of pharmaceuticals for treating GVHD of this embodiment can be used to administer a GVHD therapeutic drug and at least one drug selected from a steroid drug and an immunosuppressant, each in appropriate amounts at appropriate times, depending on changes in the subject's pathological condition.

[0052] The combination of therapeutic agents for GVHD of this embodiment can be administered over both long and short periods, and therefore can be suitably used for the treatment of GVHD.

[0053] 3. Method for Treating GVHD A method for treating GVHD using the GVHD therapeutic drug according to this embodiment is also within the scope of this embodiment. Details of the method for treating GVHD according to this embodiment will be described below.

[0054] In one embodiment, a method for treating GVHD includes a step of administering the GVHD therapeutic drug according to this embodiment to a human subject (GVHD therapeutic drug administration step). Treating GVHD means improving the symptoms of GVHD to a good or normal state, and is a concept that also includes preventing the onset of GVHD.

[0055] Another method for treating GVHD is a combination therapy of a GVHD therapeutic drug with at least one selected from a steroid drug and an immunosuppressant. In one example, the method for treating GVHD is a combination therapy with a steroid drug. That is, the method for treating GVHD includes, in addition to a step of administering a GVHD therapeutic drug, at least one step of administering a steroid drug to a human subject (a steroid drug administration step) and a step of administering an immunosuppressant to a human subject (an immunosuppressant administration step).

[0056] The therapeutic agent to be administered contains tamibarotene or a pharmaceutically acceptable salt thereof as an active ingredient. The therapeutic agent for GVHD according to this embodiment also includes those described above in the section [1. Therapeutic Agent]. Furthermore, the subjects to which the therapeutic method of this embodiment is applied are as described above in the section <Subjects to which the therapeutic agent is administered> in [1. Therapeutic Agent]. One example of the therapeutic method is a therapeutic method applied to humans.

[0057] As steroid drugs and immunosuppressants, those described in the section [1. Therapeutic Drugs] can be used.

[0058] Each step will be described in more detail below.

[0059] (GVHD therapeutic agent administration step) The GVHD therapeutic agent administration step is a step of administering the GVHD therapeutic agent according to this embodiment to a subject.

[0060] (Dosage of GVHD Therapeutic Drug) The dosage of the therapeutic drug varies depending on the type and severity of GVHD in the patient receiving the therapeutic drug, various test results, the type of active ingredient of the therapeutic drug, and other factors. Furthermore, the dosage of the therapeutic drug also varies depending on the age of the patient to be treated, the number of treatments performed using the treatment method of this embodiment, and various test results. As an example, the GVHD therapeutic drug of this embodiment is administered at a dosage that, in terms of the content of the active ingredient contained in the therapeutic drug, is lower than the dosage used when used as an immunosuppressant in the treatment of living-donor transplants and immune system diseases, etc. For example, when the subject of administration of the GVHD therapeutic drug is a human, the amount of the active ingredient administered is preferably, but not limited to, 0.5 to 10.0 mg, more preferably 0.5 to 8.0 mg, even more preferably 0.5 to 6.0 mg, and even more preferably 0.5 to 4.0 mg per day. A particularly preferred amount is 2.0 to 4.0 mg. Unless otherwise specified, the following descriptions regarding dosages of therapeutic drugs apply to human subjects, and dosages are expressed as the amount of active ingredient.

[0061] In one embodiment, the GVHD therapeutic agent maintains a plasma concentration of the active ingredient in a treated subject, preferably between 1 ng / mL and 200 ng / mL, more preferably between 2 ng / mL and 200 ng / mL, during the administration period.

[0062] For example, the minimum plasma concentration of the active ingredient is maintained at 1 ng / mL or more, 2 ng / mL or more, 5 ng / mL or more, or 8 ng / mL or more during the administration period, and the maximum plasma concentration of the active ingredient is maintained at 200 ng / mL or less, 180 ng / mL or less, 150 ng / mL or less, or 100 ng / mL or less during the administration period.

[0063] However, during the dose reduction period, the plasma concentration of the active ingredient when administered to the subject of treatment may be maintained at 1 ng / mL or higher, or 2 ng / mL or higher. Also, during the drug withdrawal period, the plasma concentration of the active ingredient in the subject of treatment may be 0 ng / mL. The drug administration period, drug reduction period, and drug withdrawal period are described below.

[0064] Furthermore, in the case of oral administration, the number of times of administration per day is preferably 1 to 4 times, more preferably 1 to 3 times, and even more preferably 1 to 2 times. The time of administration per day is not particularly limited, and may be, for example, before meals, after meals, or between meals.

[0065] (Timing and duration of administration of GVHD therapeutic agent) The timing and duration of administration of the GVHD therapeutic agent according to this embodiment vary depending on the type and severity of the disease, disorder, or condition of the patient receiving the therapeutic agent, the results of various tests, the type of active ingredient of the therapeutic agent, and the like. Furthermore, the dosage of the therapeutic agent also varies depending on the age of the patient to be treated, the number of treatments performed using the treatment method of this embodiment, the results of various tests, and the like. For example, when the subject of administration of the therapeutic agent is a human, although not particularly limited, the administration interval is preferably 3 to 180 days, more preferably 60 to 180 days, and even more preferably 120 to 180 days.

[0066] Furthermore, the GVHD therapeutic drug according to this embodiment may be administered to a subject with a drug administration period, a drug holiday period, or a drug reduction period during the administration period. The drug administration period refers to a period during which the drug is actually administered. The drug holiday period refers to a period during which the drug is not administered for one day or more. The drug reduction period refers to a period during which the dose is reduced compared to the dose at the start of treatment. The drug holiday period or drug reduction period can be appropriately selected depending on the pathological condition of the subject, etc. The drug holiday period or drug reduction period is preferably 14 to 56 days, more preferably 14 to 28 days, and even more preferably 14 to 21 days. The drug holiday period and the drug administration period may be repeated. Furthermore, the period during which the dose at the start of treatment is administered and the drug reduction period may be repeated.

[0067] (Administration Period of GVHD Therapeutic Agent) The administration period is not particularly limited, and the agent may be administered continuously or intermittently.

[0068] When the method of this embodiment is a method for treating GVHD in a human subject, the administration period of the GVHD therapeutic agent in the administration step is preferably 4 to 6 months, more preferably 2 to 6 months, and even more preferably 1 to 6 months.

[0069] Administration during the above-mentioned period may be continuous (i.e., daily administration during the period) or intermittent (i.e., days when no administration is performed may be included during the period), and the details are as described in (Timing and period of administration of therapeutic drugs) under [1. Therapeutic drugs]. Specific examples of intermittent administration include administration at regular intervals of a predetermined number of days (1 day, 2 days, 3 days), and administration with one or more predetermined suspension periods consisting of multiple days.

[0070] (Steroid Drug Administration Step and Immunosuppressant Drug Administration Step) The steroid drug administration step is a step of administering a steroid drug to a human subject, and the immunosuppressant drug administration step is a step of administering an immunosuppressant drug to a human subject.

[0071] (Dosage of Steroid Drug) The dosage of the steroid drug varies depending on the type and severity of GVHD in the patient receiving the GVHD therapeutic drug, various test results, the type of active ingredient of the therapeutic drug, and other factors. Furthermore, the dosage of the therapeutic drug also varies depending on the age of the patient to be treated, the number of treatments performed using the treatment method of this embodiment, and various test results. As an example, the steroid drug is administered at a dose that, in terms of the content of the active ingredient contained in the therapeutic drug, is lower than the dosage used when used as an immunosuppressant in the treatment of living-donor transplants and immune system diseases, etc. For example, when the subject of administration of the GVHD therapeutic drug is a human, the amount administered per day, in terms of prednisolone equivalent, is preferably 1.0 to 60.0 mg, more preferably 1.0 to 40.0 mg, and even more preferably 1.0 to 20.0 mg, although not particularly limited thereto.

[0072] (Dosage of Immunosuppressant) Like steroid drugs, the dosage of an immunosuppressant varies depending on the type of GVHD of the patient receiving the GVHD therapeutic drug.

[0073] (Timing of combined administration of at least one selected from steroid drugs and immunosuppressants with a GVHD therapeutic drug) The GVHD therapeutic drug and at least one selected from steroid drugs and immunosuppressants may be administered simultaneously or separately.

[0074] When the GVHD therapeutic agent and the steroid drug are contained in separate pharmaceuticals, the GVHD therapeutic agent and the steroid drug may be administered simultaneously, or the steroid drug may be administered before or after the administration of the GVHD therapeutic agent. For example, when the GVHD therapeutic agent is administered orally, the GVHD therapeutic agent may be administered within 0 to 2 hours after the administration of the steroid drug, 0 to 2 hours before, or 0 to 2 hours after the administration of the GVHD therapeutic agent.

[0075] In the GVHD therapeutic agent administration step and at least one step selected from the steroid drug administration step and the immunosuppressant administration step, the GVHD therapeutic agent and at least one selected from the steroid drug and the immunosuppressant may be administered simultaneously or in mixture, or the GVHD therapeutic agent and at least one selected from the steroid drug and the immunosuppressant may be administered at different times.

[0076] Furthermore, the number of steroid drugs or immunosuppressants administered during a certain treatment period may be one or more.

[0077] In addition, the components of the composition to be administered may be changed, for example, by administering a certain drug for a certain period of time and then administering another steroid drug for a further certain period of time, and the composition of the administered active ingredients over a certain period of time may be changed in a desired cycle and order.

[0078] Furthermore, the treatment method according to this embodiment may further include a step of measuring a marker related to the onset of thrombosis, in addition to the step of administering a GVHD therapeutic agent.

[0079] (Step of Measuring Markers Related to the Onset of Thrombosis) The step of measuring factors involved in the onset of thrombosis is a step of measuring markers related to the onset of thrombosis, such as D-dimer.

[0080] It is known that the incidence of thrombosis is high in patients who have developed GVHD. By measuring markers related to the onset of thrombosis, such as D-dimer, it is possible to consider changing the dosage of a therapeutic drug or using it in combination with an anticoagulant. Markers related to the onset of thrombosis can be measured using known measurement methods. For example, they can be measured by quantifying D-dimer in the blood.

[0081] Furthermore, the treatment method according to this embodiment may include a step of administering an anticoagulant as necessary based on the measurement results obtained in the step of measuring the markers described above.

[0082] (Administration Schedule) The treatment method according to this embodiment may be carried out according to any one of the following administration schedules (1) to (5), or a combination thereof.

[0083] (1) The therapeutic agent is orally administered daily at a dose of 4 mg per day for 24 consecutive weeks.

[0084] (2) In the first administration period, the therapeutic agent is orally administered daily at 4 mg per day for four consecutive weeks, and in the second administration period, the therapeutic agent is orally administered daily at 6 to 8 mg per day for four consecutive weeks.

[0085] (3) During the first administration period, the therapeutic agent is orally administered daily at 4 mg per day for four consecutive weeks, and during the second administration period, the therapeutic agent is orally administered daily at 2 mg or less per day for four consecutive weeks.

[0086] (4) In the first administration period, the therapeutic agent is orally administered at 4 mg per day for four consecutive weeks, and in the second administration period, the therapeutic agent is orally administered at 2 mg or less per day every day. A two-week washout period is provided between the first administration period and the second administration period. The second administration period and the two-week washout period are repeated depending on the grade of adverse events occurring during the second administration period.

[0087] (5) In the first administration period, the therapeutic agent is orally administered at 4 mg per day for four consecutive weeks, and in the second administration period, the therapeutic agent is orally administered at 2 mg or less per day every day. A two-week washout period is provided between the first administration period and the second administration period. The second administration period and the two-week washout period are repeated depending on the grade of adverse events occurring during the second administration period. In the third administration period, the therapeutic agent is orally administered at 2 mg or less per day every other day.

[0088] An "adverse event" is any undesirable or unintended sign (including abnormal laboratory test values), symptom, or illness that occurs when Tamibarotene is administered, regardless of whether it is causally related to Tamibarotene. However, findings that were present before Tamibarotene administration and that do not worsen after administration are not considered adverse events. Furthermore, if the exacerbation of the underlying disease during Tamibarotene administration is within the range of expected fluctuations and can be medically justified by increasing the steroid dose by no more than 1 mg / kg, it is not considered an adverse event.

[0089] The severity of adverse events can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE).

[0090] 4. Other Aspects In some embodiments, the present invention encompasses methods for reducing the incidence of conditions or complications associated with GVHD, such as bronchitis, pneumonia, opportunistic infections, thrombosis, and osteoporosis.

[0091] The use of at least one compound selected from tamibarotene or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent is also included in the scope of this embodiment.

[0092] [5. Examples of Specific Embodiments of the Present Invention] In order to solve the above-mentioned problems, the present invention includes any one of the following embodiments. <1-1> A therapeutic agent for human graft-versus-host disease, comprising tamibarotene or a pharmaceutically acceptable salt thereof as an active ingredient. <1-2> The therapeutic agent according to <1-1>, wherein the human graft-versus-host disease is chronic graft-versus-host disease. <1-3> The therapeutic agent according to <1-1> or <1-2>, which improves or inhibits the progression of lesions resulting from the human graft-versus-host disease in at least one selected from the group consisting of skin, oral cavity, eyeball, fascia, joints, and lungs. <1-4> The therapeutic agent according to <1-1> to <1-3>, wherein the plasma concentration of the active ingredient in the subject to be treated is maintained at 1 ng / mL to 200 ng / mL during the administration period. <1-5> The therapeutic agent according to <1-1> to <1-4>, which is administered to the subject with a drug-withdrawal period or a drug-reduction period. <1-6> The therapeutic agent according to <1-5>, wherein the plasma concentration of the active ingredient when administered to the subject is maintained at 1 ng / mL or more during the dose tapering period. <1-7> The therapeutic agent according to <1-1> to <1-6>, to be administered to any of the following subjects: 1) a subject for whom it is difficult to reduce a daily steroid dose from 10 mg / kg in prednisolone equivalent, 2) a subject whose condition worsens despite daily administration for two weeks at a daily steroid dose of 1 mg / kg in prednisolone equivalent, or 3) a subject whose symptoms do not improve despite daily administration for four to eight weeks at a daily steroid dose of 0.5 mg / kg in prednisolone equivalent. <2-1> A therapeutic agent for human graft-versus-host disease, comprising tamibarotene or a pharmaceutically acceptable salt thereof as an active ingredient, and used in combination with at least one selected from a steroid drug and an immunosuppressant. <2-2> The therapeutic agent according to <2-1>, wherein the human graft-versus-host disease is chronic graft-versus-host disease. <2-3> The therapeutic agent according to <2-1> or <2-2>, which ameliorates or inhibits progression of a lesion resulting from the human graft-versus-host disease in at least one selected from the group consisting of the skin, oral cavity, eyeball, fascia, joint, and lung.<2-4> The steroid drug is selected from the group consisting of prednisolone, methylprednisolone, clobetasol propionate, diflorasone acetate, betamethasone dipropionate, diflubredonate, diflucortolone valerate, fluocinonide, amcinonide, hydrocortisone butyrate propionate, betamethasone acetate propionate, mometasone furoate, betamethasone valerate-gentamicin sulfate, betamethasone valerate, dexamethasone propionate, beclomethasone propionate, dexamethasone valerate, fluocinolone acetonide, debrodone propionate, triamcinolone acetonide, hydrocortisone butyrate, clobetasone butyrate, alclometasone propionate, prednisolone valerate acetate, and dexamethasone; The therapeutic agent according to any one of <2-1> to <2-3>, wherein the immunosuppressant is selected from the group consisting of cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, pentostatin, and methotrexate. <2-5> The therapeutic agent according to any one of <2-1> to <2-4>, wherein the daily dose of the steroid drug used in combination is reduced compared to the daily dose of the steroid drug used alone for treatment. <2-6> The therapeutic agent according to any one of <2-1> to <2-5>, wherein the daily dose of the steroid drug used in combination is reduced by 10% or more compared to the daily dose of the steroid drug used alone for treatment. <2-7> The therapeutic agent according to any one of <2-1> to <2-6>, wherein the daily dose of the steroid drug used in combination is reduced by 10% or more at 24 weeks or later from the start of administration of the therapeutic agent compared to the daily dose of the steroid drug used in combination at the start of administration of the therapeutic agent. <2-8> The therapeutic agent according to any one of <2-1> to <2-7>, wherein the daily dose of the steroid drug used in combination is reduced stepwise.<2-9> The therapeutic agent according to <2-1> to <2-8>, which is administered to any of the following subjects: 1) a subject for whom it is difficult to reduce the daily steroid drug dose from 10 mg / kg in prednisolone equivalent, 2) a subject for whom the condition worsens despite daily administration for two weeks at a daily steroid drug dose of 1 mg / kg in prednisolone equivalent, or 3) a subject for whom the condition does not improve despite daily administration for four to eight weeks at a daily steroid drug dose of 0.5 mg / kg in prednisolone equivalent. <2-10> The therapeutic agent according to <2-1> to <2-9>, which is administered to a subject with a drug-free period or a drug-reducing period. <2-11> A combination of therapeutic agents for human graft-versus-host disease, comprising at least one selected from a steroid drug and an immunosuppressant and the therapeutic agent according to <2-1> to <2-10>. <3-1> A therapeutic agent for human graft-versus-host disease, comprising tamibarotene or a pharmaceutically acceptable salt thereof as an active ingredient. <3-2> The therapeutic agent for human graft-versus-host disease according to <3-1>, which is used in combination with at least one selected from a steroid drug and an immunosuppressant. <3-3> The therapeutic agent according to <3-1> or <3-2>, wherein the human graft-versus-host disease is chronic graft-versus-host disease. <3-4> The therapeutic agent according to any of <3-1> to <3-3>, which improves or inhibits the progression of lesions caused by the human graft-versus-host disease in at least one selected from the group consisting of skin, oral cavity, eyeball, fascia, joints, and lungs. <3-5> The therapeutic agent according to any of <3-1> to <3-4>, wherein the plasma concentration of the active ingredient in the subject to be treated is maintained at 1 ng / mL to 200 ng / mL during the administration period. <3-6> The therapeutic agent according to any one of <3-1> to <3-5>, which is administered to a subject with a withdrawal period or a tapering period. <3-7> The therapeutic agent according to <3-6>, wherein, during the tapering period, the plasma concentration of the active ingredient when administered to the subject is maintained at 1 ng / mL or more.<3-8> The steroid drug is selected from the group consisting of prednisolone, methylprednisolone, clobetasol propionate, diflorasone acetate, betamethasone dipropionate, diflubredonate, diflucortolone valerate, fluocinonide, amcinonide, hydrocortisone butyrate propionate, betamethasone acetate propionate, mometasone furoate, betamethasone valerate-gentamicin sulfate, betamethasone valerate, dexamethasone propionate, beclomethasone propionate, dexamethasone valerate, fluocinolone acetonide, debrodone propionate, triamcinolone acetonide, hydrocortisone butyrate, clobetasone butyrate, alclometasone propionate, prednisolone valerate acetate, and dexamethasone; The therapeutic drug according to any one of <3-2> to <3-7>, wherein the immunosuppressant is selected from the group consisting of cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, pentostatin, and methotrexate. <3-9> The therapeutic drug according to any one of <3-2> to <3-8>, wherein the daily dose of the steroid drug used in combination is reduced compared to the daily dose of the steroid drug used alone for treatment. <3-10> The therapeutic drug according to any one of <3-2> to <3-9>, wherein the daily dose of the steroid drug used in combination is reduced by 10% or more compared to the daily dose of the steroid drug used alone for treatment. <3-11> The therapeutic agent according to any one of <3-2> to <3-10>, wherein, at 24 weeks or later from the start of administration of the therapeutic agent, the daily dose of the steroid drug used in combination is reduced by 10% or more compared to the daily dose of the steroid drug used in combination at the start of administration of the therapeutic agent. <3-12> The therapeutic agent according to any one of <3-2> to <3-11>, wherein the daily dose of the steroid drug used in combination is reduced in a stepwise manner.<3-13> The therapeutic agent according to any one of <3-1> to <3-12>, to be administered to any of the following subjects: 1) a subject for whom it is difficult to reduce the daily steroid drug dose from 10 mg / kg in prednisolone equivalent, 2) a subject for whom the condition worsens despite daily administration for two weeks at a daily steroid drug dose of 1 mg / kg in prednisolone equivalent, or 3) a subject for whom the condition does not improve despite daily administration for four to eight weeks at a daily steroid drug dose of 0.5 mg / kg in prednisolone equivalent. <3-14> A combination of therapeutic agents for human graft-versus-host disease, comprising at least one selected from steroid drugs and immunosuppressants, and the therapeutic agent according to any one of <3-2> to <3-13>.

[0093] The following examples are provided to further explain the embodiments of the present invention. Of course, the present invention is not limited to the following examples, and various modifications are possible in detail. Furthermore, the present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed herein are also included in the technical scope of the present invention. Furthermore, all of the documents cited in this specification are incorporated by reference.

[0094] Example 1: Examination of efficacy and safety of tamibarotene for chronic GVHD Tamibarotene was administered to patients with chronic graft-versus-host disease (chronic GVHD) after allogeneic hematopoietic stem cell transplantation, and its efficacy was examined.

[0095] <Subject Selection Criteria> The main selection criteria for subjects are as follows:

[0096] (A) Age ≥ 18 years and < 85 years (B) Karnofsky performance status (KPS) ≥ 60 (C) Patients who initiated treatment with ≥ 0.5 mg / kg prednisolone (PSL) (or equivalent steroid treatment) as first-line treatment and met any of the following criteria (1) to (4): (1) Patients whose condition worsened after 2 weeks of PSL at ≥ 1 mg / kg and who required additional treatment; (2) Patients whose condition did not improve after 4 weeks of treatment, including 2 weeks of PSL at ≥ 0.5 mg / kg and who required additional treatment; (3) Patients whose GVHD symptoms recurred or worsened within the period in which the steroid dose was reduced; or (4) Patients whose steroid-dependent condition was difficult to reduce from 10 mg / day (or equivalent steroid treatment) <Study Design> Tamibarotene was administered to 18 subjects. Tamibarotene 2 mg tablets were administered orally for 24 weeks. The dose is twice a day after breakfast and dinner (2 mg tablets twice a day), i.e., 4 mg (3 mg / m ２ The treatment was started with daily administration of 4 mg (3 mg / m2). PSL or steroid administration continued daily. <Administration method and schedule> Tamibarotene 2 mg tablets were administered orally for 24 weeks. The administration was at a dose of 4 mg (3 mg / m2) daily. ２ The initial dose was 2 mg twice a day (one 2 mg tablet in the morning and one in the evening) after breakfast and dinner. If adverse events were mild (grade 0-1), the dose could be increased to 8 mg per day (two 2 mg tablets in the morning and one in the evening) after 4 weeks of treatment (if taking 6 mg per day, two 2 mg tablets should be taken after breakfast and one 2 mg tablet after dinner).

[0097] In the case of grade 2 unexpected adverse events (for which a causal relationship could not be denied) or grade 3 expected adverse events (for which a causal relationship could not be denied), the dose was reduced to 2 mg per day (one tablet once after breakfast) and continued. Alternatively, after a 2-week drug withdrawal, treatment was resumed at 2 mg per day after confirming improvement to one grade lower than before drug withdrawal. However, for grade 3 liver dysfunction, patients with grade 3 liver dysfunction due to chronic GVHD prior to enrollment were allowed to continue treatment without dose reduction or drug suspension, even if their liver dysfunction remained at grade 3. If repeated drug suspension and resumption at 2 mg per day due to adverse events was required, the dose was allowed to be reduced to 2 mg per day every other day.

[0098] Adverse events include any untoward or unintended sign (including abnormal laboratory values), symptom, or illness that occurs when tamibarotene is administered.

[0099] The severity of adverse events was assessed by grading according to the Common Terminology Criteria for Adverse Events v 4.0 (CTCAE (CTCAE v4.03 / MedDRA v12.0 (Japanese: MedDRA / J v16.0)).

[0100] <Study Evaluation Items> (FFS) The survival rate without treatment failure (death, recurrence, or additional treatment) at the end of tamibarotene administration (week 24), i.e., failure-free survival (FFS), was evaluated. If additional treatment was administered for chronic GVHD, it was considered to be treatment failure at that point. Regarding additional treatment here, changes in steroid dosage were not taken into account, but if the dose was increased to more than 1 mg / kg / day, it was considered that additional treatment had been administered.

[0101] (Therapeutic Effect on Chronic GVHD in Each Organ) The therapeutic effect on chronic GVHD in each organ was evaluated according to the criteria shown in Table 1.

[0102] In Table 1, CR indicates complete response, PR indicates partial response, SD indicates stable disease, and PD indicates progressive disease. Furthermore, S indicates the start point, E indicates the end point, and ULN indicates the upper limit of normal. For example, "S: 3" indicates that the score was 3 points at the start point. CR alone indicates the absence of PR.

[0103] For the skin, eyes, and gastrointestinal tract, the NIH organ-specific scores described in Biol. Blood Marrow Transplant, 2005 11(12), 945-56 were used. For the skin, the therapeutic effect was further evaluated using the total skin score. For the oral cavity, the 15-point Schubert scale shown in Table 2 was used. For liver function, laboratory test values ​​of T-Bil, ALP, and ALT were used, and for lung function, the 12-point LFS (lung function score) was used.

[0104] For the total skin score, the body surface was divided into 10 areas (head and neck, chest, abdomen / genitals, back / buttocks, right arm, right hand, left arm, left hand, right lower leg, and left lower leg), and the skin chronic GVHD grade in each area was classified from 0 to 4 as follows. The percentage of the total area occupied by each grade was also calculated. Grade 0: Normal skin; Grade 1: Skin discoloration, depigmentation or hyperpigmentation, or hair loss; Grade 2: Lichenoid plaques, skin thickening, or mobile induration; Grade 3: Skin with reduced mobility, but the skin can be grasped; Grade 4: Tough, contracted skin with no mobility, making it impossible to grasp the skin. Furthermore, if grade 3 or 4 lesions were present, the extent of the erythema within the lesion was classified as 0%, 25%, 50%, 75%, or 100%.

[0105] (Chronic GVHD Therapeutic Effect) Based on the criteria for chronic GVHD therapeutic effect for each organ shown in Table 1, the chronic GVHD therapeutic effect was evaluated 24 weeks after the start of tamibarotene administration using the evaluation criteria shown in Table 3.

[0106] (Response rate) Based on the criteria shown in Table 3, the response rate was calculated using the following formula: Response rate = [number of patients judged to have a complete response (CR) + number of patients judged to have a partial response (PR)] / number of patients who received treatment. Note that if leukemia or other diseases that are "primary diseases suitable for hematopoietic stem cell transplantation" recurred, the treatment was considered unsuccessful in the evaluation of FFS. However, if additional treatment such as retransplantation or anticancer drug therapy was not performed despite the recurrence, and if chronic GVHD was controlled and it was determined that continuation of tamibarotene was desirable, administration was continued without discontinuation, and the response rate was assessed.

[0107] (Secondary endpoints) The FFS and response rate at 12 weeks after the start of tamibarotene administration, as well as the FFS at 24 weeks after the start of tamibarotene administration, and the proportion of subjects who were able to reduce their PSL dose by 50% or more were also evaluated.

[0108] (Significance Level for Efficacy Analysis) Based on a model using Simon's two-stage design, a test was judged to be effective if there were 7 or more effective cases among a total of 18 subjects.

[0109] Results: Nine of the 18 subjects completed the 24-week trial. Five subjects achieved a PR score at 12 and 24 weeks after Tamibarotene administration. Seven subjects achieved SD scores at 12 and 24 weeks after Tamibarotene administration. The full-fledged survival (FFS) and response rate at 24 weeks after Tamibarotene administration were 28% (5 / 18), respectively.

[0110] In three subjects, the PSL dose was reduced by 50% or more at 24 weeks after Tamibarotene administration compared to the dose at the start of Tamibarotene administration, and in seven subjects, the PSL dose was reduced at 24 weeks after Tamibarotene administration compared to the dose at the start of treatment.

[0111] (Overall response rate) The overall response rate in the entire treatment population at the time of final analysis was 33.3% (6 / 18 cases, 95% confidence interval: 13.3-59.0%).

[0112] (Overall response rate according to the NIH Consensus Development Project Criteria (2014)) As the above response was assessed according to the NIH Consensus Development Project Criteria (2005), a sensitivity analysis was performed in which response was assessed according to the NIH Consensus Development Project Criteria (2014), which was revised after the start of the study. The overall response rate according to the NIH Consensus Development Project Criteria (2014) in the entire treatment population at the time of tumor evaluation was 38.9% (7 / 18 cases, 95% confidence interval: 17.3-64.3%), which was similar to the overall response rate according to the NIH Consensus Development Project Criteria (2005).

[0113] Of the 11 subjects who achieved a PR overall, one was able to reduce the PSL dose without worsening chronic GVHD two years after the end of treatment, and another was able to discontinue PSL and reduce the FK506 dose without worsening chronic GVHD two years after the end of treatment.

[0114] (Chronic GVHD Therapeutic Effect on Each Organ) <Skin> At 24 weeks after administration of Tamibarotene, the therapeutic effect was confirmed in 16 subjects. One of the 16 subjects was evaluated as CR, and three of the 16 subjects were evaluated as PR, resulting in an NIH response rate of 25%. Furthermore, when evaluated by total skin score, improvement in the score was observed in eight of the 16 subjects. In particular, Tamibarotene administration resulted in significant improvement in edema, skin hardening, pigmentation, or erythema in several subjects.

[0115] Oral Cavity: After 24 weeks of Tamibarotene treatment, the therapeutic effect was confirmed in 16 subjects. Two of the 16 subjects were evaluated as CR, and two of the 16 subjects were evaluated as PR, resulting in a 25% NIH response rate. Furthermore, when assessed using the 15-point Schubert scale, improvement in scores was observed in 10 of the 16 subjects. In particular, healing of ulcers and significant improvement in erythema were observed in several subjects.

[0116] Eyes: At 24 weeks after administration of Tamibarotene, the therapeutic effect was confirmed in 14 subjects. No subjects were evaluated as CR, and only 2 of the 14 subjects were evaluated as PR, resulting in an NIH response rate of 14%. Furthermore, Schirmer test results showed improvement in 5 of 18 right eyes and 7 of 18 left eyes.

[0117] <Other Organs> The NIH response rate for the gastrointestinal tract was 20%, the genital tract was 17%, and the liver was 23%. The number of subjects available for evaluation was small for the gastrointestinal tract (n=5) and genital tract (n=6). The liver response rate was 23%, but it was difficult to consider the influence of other diseases. The pulmonary function score response rate remained unchanged. The NIH response rate for the joints and fascia was 11%, while subjects who demonstrated a confirmed therapeutic effect showed a significant improvement in joint range of motion.

[0118] Summary of Example 1 The above results demonstrated the effectiveness of tamibarotene against chronic GVHD. In particular, significant improvements were observed in many subjects with skin and oral lesions, and in some subjects with ocular lesions.

[0119] Furthermore, most of the subjects were able to reduce their steroid dose, and it was found that the combined use of Tamibarotene and steroids allowed for a reduction in steroid doses compared to the administration of steroids alone.

[0120] Example 2: Therapeutic effect on each organ against chronic GVHD The therapeutic effect on each organ against chronic GVHD in the specific case of Example 1 was examined.

[0121] <Case 1: Improvement in range of motion of knee joint> The patient was administered the following dosages: At the start of administration (tamibarotene / steroid / tacrolimus): 4 mg / 15 mg / 4 mg At the end of administration (tamibarotene / steroid / tacrolimus): 2 mg (alternate days) / 3 mg / 3 mg Steroid: prednisolone Administration period: 200 days (total tamibarotene dose: 356 mg) Figure 1 is a diagram comparing knee joint extension and knee joint flexion at the start and end of administration.

[0122] As shown in Figure 1, administration of tamibarotene resulted in significant improvements in knee joint extension and knee joint flexion.

[0123] <Case 2: Improvement of skin symptoms> The patient was administered the following dosages: At the start of administration (Tamibarotene / steroid / tacrolimus): 4 mg / 11 mg / 0.2 mg At the end of administration (Tamibarotene / steroid / tacrolimus): 0 mg / 9 mg / 0.6 mg Steroid: Prednisone Administration period: 137 days (total Tamibarotene dose: 386 mg) Figure 2 compares the skin symptoms on the lower back and knees at the start and end of administration.

[0124] As shown in FIG. 2, administration of tamibarotene resulted in significant improvement in pigmentation and skin thickening below the waist and in pigmentation and skin thickening on the knees.

[0125] <Case 3: Improvement of oral symptoms> The patient was administered the following dosages: At the start of administration (Tamibarotene / steroid / tacrolimus): 4 mg / 10 mg / 0.6 mg At the end of administration (Tamibarotene / steroid / tacrolimus): 4 mg / 10 mg / 0.6 mg Steroid: Prednisolone Administration period: 83 days (total dose of Tamibarotene: 332 mg) Figure 3 is a diagram comparing oral symptoms at the start and end of administration.

[0126] As shown in Figure 3, healing of oral ulcers and significant improvement of erythema were observed. <Other Functions> The response rate for each organ was calculated from all cases in Example 1. Figure 4 shows the response rate for each organ.

[0127] As shown in the graph in Figure 4, in addition to the skin and oral cavity, chronic GVHD of the eyes and liver has also shown efficacy or progressed without deterioration. <Summary of Example 2> As a primary treatment for chronic GVHD, steroids are administered to suppress the inflammatory response, but no secondary treatment has been established for when side effects from steroid administration occur or the condition worsens. Although there are individual differences, damage to each organ (inflammatory response) repeatedly worsens and improves, and the condition progresses over the long term.

[0128] Before the administration of tamibarotene, none of the patients in the examples showed any improvement in the lesions in each organ despite the administration of various drugs, but after the administration of tamibarotene, all of the patients showed improvement in their symptoms.

[0129] It is believed that chronic GVHD presents a clinical picture similar to that of autoimmune disease due to the emergence of autoantigen-reactive T cells during the process of immune reconstitution in the recipient's body by donor cells. Th17 cells, a subset of helper T cells, are known to be involved in autoimmune diseases. Tamibarotene is thought to suppress autoimmune diseases by inhibiting the differentiation of T cells into Th17 cells. If such an effect is observed, it is likely that this new mechanism of action could improve chronic GVHD, leading to a reduction in the dosage of steroids and immunosuppressants currently administered to alleviate the symptoms of chronic GVHD.

[0130] Example 3: Investigation of plasma concentration of active ingredient A total of 11 patients were given a single dose of 2.0 mg, 4.0 mg or 6.0 mg of tamibarotene.

[0131] Additionally, a total of six patients received repeated administration of 8.0 mg or 10.0 mg of tamibarotene.

[0132] The 2.0 mg dose was administered using a 2 mg Tamibarotene tablet, with one tablet (2 mg Tamibarotene) being administered after breakfast; the 4.0 mg dose was administered using one tablet (2 mg Tamibarotene) after breakfast and one tablet (2 mg Tamibarotene) after dinner; and the 6.0 mg dose was administered using two tablets (4 mg Tamibarotene) after breakfast and one tablet (2 mg Tamibarotene) after dinner.

[0133] The 8.0 mg dose was administered using 2 mg Tamibarotene tablets, with two tablets (4 mg Tamibarotene) administered after breakfast and two tablets (4 mg Tamibarotene) administered after dinner for 35 to 46 days. The 10.0 mg dose was administered using 2 mg Tamibarotene tablets, with three tablets (6 mg Tamibarotene) administered after breakfast and two tablets (4 mg Tamibarotene) administered after dinner for 34 to 59 days.

[0134] After administration of tamibarotene to each patient, blood samples were taken at 0, 2, 4, 8, 10, and 24 hours on a specific day, and the tamibarotene concentration in human plasma was measured by high performance liquid chromatography (HPLC).

[0135] <Results of Example 3> In all patients, the plasma concentration of the active ingredient was maintained at 1 ng / mL to 200 ng / mL during the administration period.

[0136] <Measurement results of minimum plasma concentration of active ingredient> Plasma concentration at 24 hours after a single dose of 6.0 mg: 1.08 ng / mL Plasma concentration at 24 hours after a single dose of 6.0 mg: 1.14 ng / mL Plasma concentration at 24 hours after a single dose of 4.0 mg: 2.09 ng / mL Plasma concentration at 24 hours after a single dose of 6.0 mg: 2.50 ng / mL Plasma concentration at 10 hours after a single dose of 2.0 mg: 2.23 ng / mL Plasma concentration at 10 hours after a single dose of 2.0 mg: 3.05 ng / mL Plasma concentration at 8 hours after a single dose of 2.0 mg: 3.26 ng / mL Plasma concentration at 24 hours after a single dose of 4.0 mg: 4.95 ng / mL Plasma concentration at 10 hours after a single dose of 2.0 mg: Plasma concentration at 8 hours after a single 2.0 mg dose: 5.04 ng / mL Plasma concentration at 24 hours after repeated 8.0 mg doses (46 days): 2.92 ng / mL Plasma concentration at 4 hours after a single 2.0 mg dose: 8.98 ng / mL Plasma concentration at 10 hours after a single 4.0 mg dose: 9.56 ng / mL Plasma concentration at 10 hours after a single 4.0 mg dose: 8.03 ng / mL Plasma concentration at 10 hours after a single 4.0 mg dose: 7.01 ng / mL Plasma concentration at 6 hours after a single 6.0 mg dose: 7.42 ng / mL Plasma concentration at 10 hours after a single 6.0 mg dose: 7.72 ng / mL <Measurement results of maximum plasma concentration of active ingredient> Plasma concentration at 2 hours after repeated administration of 10.0 mg (58 days): 199.2 ng / mL Plasma concentration at 4 hours after repeated administration of 10.0 mg (36 days): 161.1 ng / mL Plasma concentration at 2 hours after repeated administration of 10.0 mg (59 days): 118.8 ng / mL Plasma concentration at 2 hours after repeated administration of 8.0 mg (46 days): 100.09 ng / mL Plasma concentration at 8 hours after repeated administration of 10.0 mg (36 days): 111.99 ng / mL Plasma concentration at 4 hours after repeated administration of 6.0 mg (47 days): 92.53 ng / mL Plasma concentration at 4 hours after repeated administration of 10.0 mg (58 days): 88.74 ng / mL Plasma concentration at 4 hours after repeated administration of 10.0 mg (59 days): 82.06 ng / mL Plasma concentration at 2 hours after repeated administration of 10.0 mg (34 days): 88.02 ng / mLPlasma concentration at 4 hours after repeated administration of 10.0 mg (34 days): 85.64 ng / mL Plasma concentration at 4 hours after repeated administration of 8.0 mg (35 days): 84.6 ng / mL Plasma concentration at 4 hours after repeated administration of 8.0 mg (46 days): 85.21 ng / mL Plasma concentration at 4 hours after single administration of 6.0 mg: 80.21 ng / mL <Other measurement results> Plasma concentrations ranged from 10 ng / mL to 80 ng / mL at 2, 4, 8, and 10 hours after a single administration of 2.0 mg, at 2, 4, and 8 hours after a single administration of 4.0 mg, at 2, 4, 8, and 10 hours after a single administration of 6.0 mg, at 0, 2, 4, 8, and 10 hours after repeated administration of 8.0 mg, and at 0, 2, 4, 8, and 10 hours after repeated administration of 10.0 mg.

[0137] The present invention can be used, for example, in the treatment and research of graft-versus-host disease.

Claims

1. A therapeutic agent for human graft-versus-host disease, comprising tamibarotene or a pharma- ceutical acceptable salt thereof as an active ingredient.

2. The therapeutic agent for human graft-versus-host disease according to claim 1, which is used in combination with at least one selected from steroid drugs and immunosuppressants.

3. The therapeutic agent according to claim 1 or 2, wherein the human graft-versus-host disease is chronic graft-versus-host disease.

4. The therapeutic agent according to claim 1, which ameliorates or inhibits the progression of lesions resulting from the human graft-versus-host disease in at least one selected from the group consisting of the skin, oral cavity, eyeball, fascia, joints, and lungs.

5. The therapeutic agent according to claim 1, wherein the plasma concentration of the active ingredient in the subject of said treatment is maintained at 1 ng / mL to 200 ng / mL during the administration period.

6. The therapeutic agent described in claim 1, which is administered to a subject with a drug-free period or a drug-reducing period.

7. The therapeutic agent described in claim 6, wherein the plasma concentration of the active ingredient when administered to the subject is maintained at 1 ng / mL or more during the tapering period.

8. The steroid drug is selected from the group consisting of prednisolone, methylprednisolone, clobetasol propionate, diflorasone acetate, betamethasone dipropionate, diflubredonate, diflucortolone valerate, fluocinonide, amcinonide, hydrocortisone butyrate propionate, betamethasone acetate propionate, mometasone furoate, betamethasone valerate gentamicin sulfate, betamethasone valerate, dexamethasone propionate, beclomethasone propionate, dexamethasone valerate, fluocinolone acetonide, debrodone propionate, triamcinolone acetonide, hydrocortisone butyrate, clobetasone butyrate, alclometasone propionate, prednisolone valerate acetate and dexamethasone; The therapeutic agent of claim 2, wherein the immunosuppressant is selected from the group consisting of cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, pentostatin, and methotrexate.

9. The therapeutic agent according to claim 2, wherein the daily dose of the steroid drug used in combination is reduced compared with the daily dose of the steroid drug required for treatment alone.

10. The therapeutic agent according to claim 2, wherein the daily dose of the steroid drug used in combination is reduced by 10% or more compared with the daily dose required for treatment with the steroid drug alone.

11. The therapeutic drug according to claim 2, wherein the daily dosage of the concomitant steroid drug at or after 24 weeks from the start of administration of the therapeutic drug is reduced by 10% or more compared to the daily dosage of the concomitant steroid drug at the start of administration of the therapeutic drug.

12. The therapeutic agent according to claim 2, wherein the daily dose of the steroid drug used in combination is gradually reduced.

13. The therapeutic drug according to claim 1, which is administered to any of the following subjects: 1) a subject for whom it is difficult to reduce the daily steroid dosage from 10 mg / kg in prednisolone equivalent, 2) a subject whose condition worsens even after two weeks of daily administration of a steroid dosage of 1 mg / kg in prednisolone equivalent, or 3) a subject whose condition does not improve even after four to eight weeks of daily administration of a steroid dosage of 0.5 mg / kg in prednisolone equivalent.

14. A combination of therapeutic agents for human graft-versus-host disease, comprising at least one selected from steroid drugs and immunosuppressants, and the therapeutic agent according to claim 2.

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