Pharmaceutical composition for treating aplastic anemia

Abstract

The present invention relates to a pharmaceutical composition for treating aplastic anemia containing romiplostim as an active ingredient, which is administered subcutaneously once a week at a dose of 10 μg / kg / week as romiplostim for the first four weeks of administration, and from the fifth week onwards at a dose of more than 10 μg / kg / week up to 20 μg / kg / week as romiplostim.

Description

[Technical Field]

[0001] [Related applications] This specification includes the contents described in the specification of Japanese Patent Application No. 2018-202097 (filed on October 26, 2018), which forms the basis of the priority claim of this application. [Technical field] This invention relates to a pharmaceutical composition for the treatment of aplastic anemia, comprising romiplostim as an active ingredient. [Background technology]

[0002] Aplastic anemia (AA) is a disease characterized by a decrease in all blood cells in the peripheral blood (pancytopenia) and a decrease in bone marrow cell density (hypoplasia). Subjective symptoms of AA include anemic symptoms such as shortness of breath on exertion, palpitations, and dizziness, as well as fever due to infection and bleeding tendencies such as subcutaneous hematomas, gingival bleeding, and epistaxis. Objective findings include facial pallor, anemic conjunctiva, subcutaneous hemorrhage, and gingival bleeding. AA can be fatal due to progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), bleeding tendencies, or infections. In Japan, it was designated as a designated intractable disease by the Ministry of Health, Labour and Welfare in 1972.

[0003] Treatment for AA includes supportive therapies such as platelet and red blood cell transfusions and administration of hematopoietic factors such as granulocyte colony-stimulating factor (G-CSF), as well as therapies aimed at restoring hematopoietic function, such as immunosuppressive therapy, anabolic steroid therapy, and hematopoietic stem cell transplantation. Because the prognosis and treatment approach for AA vary greatly depending on its severity, treatment guidelines are provided for each severity level.

[0004] Japanese treatment guidelines recommend initiating cyclosporine (CsA) treatment and evaluating its effectiveness for AA patients in stages 1-2a (mild to moderate, no transfusion required) (excluding patients with platelet counts of 100,000 / μL or higher, and only anemia and neutropenia). Since the treatment response to cyclosporine appears within 8 weeks at the latest, if an increase in platelet or reticulocyte count is not observed within 8 weeks after treatment, the appropriate treatment method will be selected, such as the combination of anti-human thymocyte immunoglobulin (ATG) or eltrombopag (EPAG), depending on whether cytopenia is progressing, whether transfusions are necessary, and whether there are subjective symptoms.

[0005] For AA patients in stages 2b-5 (moderate to very severe requiring blood transfusions), hematopoietic stem cell transplantation is the primary treatment for patients under 40 years of age with an HLA-matched sibling donor. For patients who are not candidates for transplantation, and for patients over 40 years of age, treatment mainly involves immunosuppressive therapies such as ATG and CsA, with the addition of EPAG considered as needed.

[0006] However, transplant-related death occurs in 10-20% of patients undergoing hematopoietic stem cell transplantation, and in immunosuppressive therapy, approximately 5-10% of long-term survivors progress to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) despite a response to treatment. The response rate to immunosuppressive therapy is approximately 33-57%, and for patients who are refractory to or unsuitable for immunosuppressive therapy, life is prolonged through supportive care centered on blood transfusions and hematopoietic factor administration. Blood transfusions are performed when anemia or thrombocytopenia is severe, or when moderate to severe clinical symptoms are present, but transfusions should be kept to a minimum to avoid the risk of unknown infections, platelet transfusion refractoriness due to anti-HLA antibody production, and rejection during hematopoietic stem cell transplantation. In patients with a neutrophil count below 500 / μL who are at high risk of severe infection, G-CSF is administered, but its effect is temporary.

[0007] While it was expected that combining EPAG with immunosuppressive therapy would improve treatment outcomes in severe AA patients who were refractory to immunosuppressive therapy, clinical trial data on EPAG in Japanese AA patients who had not received ATG treatment showed that some patients did not respond to EPAG. Furthermore, in clinical practice, there are patients for whom EPAG administration is a concern, such as those with liver damage or elderly patients who have difficulty maintaining medication compliance due to the oral administration formulation. Thus, there are patients for whom drug therapy aimed at restoring hematopoietic function with EPAG is not expected to be effective, and there is a need for a safer and more effective treatment method.

[0008] Romiplostim is a platelet hematopoietic stimulating agent that binds to c-Mpl, the receptor for endogenous thrombopoietin (TPO), and enhances platelet production (Patent Document 1). Since its approval in Australia in July 2008 as a treatment for thrombocytopenia in adult patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP), romiplostim has been approved in more than 60 countries and is manufactured and sold under trade names such as Romiplate®.

[0009] c-Mpl is expressed not only in megakaryocyte progenitor cells but also in more undifferentiated hematopoietic stem / progenitor cells in the bone marrow, and it has been suggested that TPO promotes multi-system hematopoietic cell production by activating c-Mpl. Therefore, the efficacy of romiplostim for AA was expected, and clinical development was initiated in adult AA patients. A Phase II (Ph2) clinical trial of romiplostim for immunosuppressive therapy-refractory AA patients was started in 2014 (Non-Patent Literature 1), and a Phase II / III (Ph2 / 3) clinical trial was started in 2016 (Non-Patent Literature 2). In these clinical trials, romiplostim was administered subcutaneously once a week, and the efficacy was verified using indicators such as platelet count, red blood cell count, neutrophil response, and weaning from platelet transfusions, and it was revealed that the initial dose of 10 μg / kg was the most effective. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] WO2000 / 024770 [Non-patent literature]

[0011] [Non-Patent Document 1] Lee et al., “Efficacy and Safety of Romiplostim in Patients with Aplastic Anemia Refractory to Immunosuppressive Therapy: 1-Year Interim Analysis of Phase 2 Clinical Trial” Blood (2016) 128:3910 [Non-Patent Document 2] Lee et al., “Hematologic Response to Romiplostim Treatment Is Associated with Stimulation of Primitive Stem / Progenitor Cells and Stromal Cells in Patients with Aplastic Anemia Refractory to Immunosuppressive Therapy: A 2-Year Interim Exploratory Analysis of a Phase 2 Clinical Trial” Blood (2017) 130:1167 [Overview of the project] [Problems that the invention aims to solve]

[0012] The object of this invention is to provide an effective treatment method for aplastic anemia using romiplostim. [Means for solving the problem]

[0013] As a result of diligent research, the inventors discovered that administering romiplostim in a specific manner and dosage yields high efficacy and safety in the treatment of aplastic anemia, thus completing the present invention.

[0014] That is, the present invention relates to the following (1) to (8). (1) A pharmaceutical composition for treating aplastic anemia, having romiplostim as an active ingredient, which is administered subcutaneously once a week, and is administered at 10 μg / kg / week as romiplostim for 4 weeks from the start of administration, and after the 5th week, it is administered at more than 10 μg / kg / week and up to 20 μg / kg / week as romiplostim. A pharmaceutical composition, characterized in that. (2) The pharmaceutical composition according to (1), characterized in that the same dosage is continued for 4 weeks or more after the dosage change. (3) From the 5th week to the 8th week, it is administered at 15 μg / kg / week as romiplostim, and after the 9th week, it is administered at up to 20 μg / kg / week as romiplostim, and the same dosage is continued for 4 weeks or more after the dosage change. The pharmaceutical composition according to (1), characterized in that. (4) From the 5th week to the 8th week, it is administered at 15 μg / kg / week as romiplostim, from the 9th week to the 12th week, it is administered at 20 μg / kg / week as romiplostim, and after the 13th week, it is administered at 5 to 20 μg / kg / week as romiplostim, and the same dosage is continued for 4 weeks or more after the dosage change. The pharmaceutical composition according to (1), characterized in that. (5) After the 5th week, it is administered at 15 or 20 μg / kg / week as romiplostim, and the same dosage is continued for 4 weeks or more after the dosage change. The pharmaceutical composition according to (1), characterized in that. (6) The pharmaceutical composition according to any one of (1) to (4), characterized in that the increased amount after the 5th week is 5 μg / kg as romiplostim. (7) A pharmaceutical composition for treating aplastic anemia, having romiplostim as an active ingredient, which is administered subcutaneously once a week, and is administered at 10 μg / kg / week as romiplostim for 4 weeks from the start of administration, and the increased amount after the 5th week is 5 μg / kg as romiplostim. A pharmaceutical composition, characterized in that. (8) The pharmaceutical composition according to (7), characterized in that the same dosage is continued for 4 weeks or more after the dosage change.

Effect of the Invention

[0015] According to the present invention, in the treatment of romiplostim in patients with aplastic anemia in whom immunosuppressive agents are ineffective, high drug efficacy can be achieved.

Brief Description of the Drawings

[0016] [Figure 1] Figure 1 shows the change in platelet count in Ph2 and Ph2 / 3. In the graph, the lower light-colored line represents the average value of the Ph2 (KR001) test starting group at 10 μg / kg (N = 10), and the upper dark-colored line represents the average value of all cases in the Ph2 / 3 (531-002) test (N = 31). The error bars indicate the standard deviation. The horizontal axis represents the number of weeks from the start of administration, and the vertical axis represents the platelet count. [Figure 2] Figure 2 shows the change in hemoglobin value in Ph2 and Ph2 / 3. In the graph, the lower light-colored line represents the average value of the Ph2 (KR001) test starting group at 10 μg / kg (N = 10), and the upper dark-colored line represents the average value of all cases in the Ph2 / 3 (531-002) test (N = 31). The error bars indicate the standard deviation. The horizontal axis represents the number of weeks from the start of administration, and the vertical axis represents the hemoglobin value. [Figure 3] Figure 3 shows the change in neutrophil value in Ph2 and Ph2 / 3. In the graph, the lower light-colored line represents the average value of the Ph2 (KR001) test starting group at 10 μg / kg (N = 10), and the upper dark-colored line represents the average value of all cases in the Ph2 / 3 (531-002) test (N = 31). The error bars indicate the standard deviation. The horizontal axis represents the number of weeks from the start of administration, and the vertical axis represents the neutrophil count.

Modes for Carrying Out the Invention

[0017] "Romiplostim" Romiplostim is a recombinant fusion protein with a molecular weight of approximately 59 kDa, and is a dimer composed of two subunit molecules, each consisting of 269 amino acid residues (SEQ ID NO: 1). Of the 269 amino acids in the monomer, positions 2-228 are the Fc region of human IgG1, and positions 229-269 are a peptide containing a human thrombopoietin receptor (c-Mpl) binding sequence. Romiplostim forms a dimer through a disulfide bond between a peptide chain containing two c-Mpl binding regions and a single chain bound to the C-terminus of the Fc region of human IgG1. [ka] C2634H4086N722O790S18 Mw:59085

[0018] Romiplostim possesses platelet-producing and / or megakaryocyte-producing activity. Romiplostim acts as a platelet hematopoietic stimulant by binding to c-Mpl, the receptor for endogenous thrombopoietin (TPO), and enhancing platelet production. TPO is a human megakaryocyte and platelet hematopoietic stimulant, and its gene was cloned in 1994. It is believed that romiplostim, by binding to and activating c-Mpl, promotes cell proliferation and differentiation in the process from bone marrow progenitor cells to megakaryocytes, resulting in an increase in platelets (hereinafter also referred to as PLTs).

[0019] In the present invention, the method for producing romiplostim is not particularly limited, as long as it is permissible as a pharmaceutical product.

[0020] "Aplastic anemia" Aplastic anemia (AA) is a disease characterized by a decrease in all blood cells in the peripheral blood (pancytopenia) and a decrease in bone marrow cell density (hypoplasia). In practice, AA is diagnosed by excluding other diseases with similar characteristics but a clearer concept, but the essence of the disease can be described as "a condition in which hematopoietic stem cells are persistently reduced despite the absence of the effects of myelotoxic drugs."

[0021] A diagnosis of AA requires clinical findings of anemia, bleeding tendency, and sometimes fever, and at least two of the following three criteria: hemoglobin (Hb) concentration less than 10 g / dL, neutrophil count less than 1500 / μL, and platelet count less than 100,000 / μL. Furthermore, AA is diagnosed when cytopenia, bone marrow hypoplasia, and other diseases causing pancytopenia can be ruled out, although differentiation from MDS can sometimes be difficult.

[0022] AA is classified into congenital and acquired types based on its etiology. The most common congenital type is Fanconi anemia, an autosomal recessive genetic disorder characterized by bone marrow hypoplasia, skeletal malformations, short stature, and gonadal dysfunction. Acquired AA includes idiopathic (primary), secondary (caused by various drugs, radiation exposure, benzene, and other chemicals), and special types associated with post-hepatitis development or paroxysmal nocturnal hemoglobinuria. In Japan, the majority of acquired AA cases are considered idiopathic (primary).

[0023] Treatment for AA includes supportive therapies such as platelet and red blood cell transfusions and administration of hematopoietic factors such as G-CSF, as well as therapies aimed at restoring hematopoietic function, such as immunosuppressive therapy, anabolic steroid therapy, and hematopoietic stem cell transplantation. Because the prognosis and treatment strategy for AA vary greatly depending on the severity, treatment guidelines are provided for each severity level. As mentioned above, for AA patients in stages 1-2a (mild to moderate, no transfusion required), treatment with CsA is recommended, with ATG or EPAG used in combination as appropriate. For AA patients in stages 2b-5 (moderate to very severe, requiring transfusion), hematopoietic stem cell transplantation, immunosuppressive therapy, or immunosuppressive therapy combined with EPAG are considered. For patients who are refractory to or unsuitable for immunosuppressive therapy, supportive therapy focusing on transfusions and hematopoietic factors is employed.

[0024] "The Pharmaceutical Composition of the Present Invention" The "pharmaceutical composition for the treatment of aplastic anemia comprising romiplostim as an active ingredient" according to the present invention (hereinafter referred to as "the pharmaceutical composition of the present invention") is administered subcutaneously (subcutaneously by injection) to AA patients by intravenous injection (also referred to as transvenous administration or intravenous injection) or intravenous drip infusion (also referred to as intravenous drip infusion or drip infusion).

[0025] The pharmaceutical composition of the present invention comprises one or more pharmacologically acceptable carriers, additives, or pH adjusters. Examples of additives include isotonic agents, buffers, solubilizers, and preservatives.

[0026] The isotonic agent is not particularly limited, but examples include sodium chloride, calcium chloride, potassium chloride, magnesium chloride, fructose, glucose, and D-mannitol.

[0027] Examples of buffering agents include compositions containing potassium dihydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, sodium dihydrogen phosphate, and disodium hydrogen phosphate, sodium citrate, and sodium citrate hydrate.

[0028] Examples of solubilizers include ethanol, ethylenediamine, capric acid, L-glutamic acid, L-lysine, calcium oxide, magnesium oxide, sorbitan sesquioleate, D-sorbitol, nicotinamide, propylene glycol, polysorbate 80, and lauromacrogol (9E.O.).

[0029] Examples of preservatives include phenol, sodium edetate, benzalkonium chloride, chlorocresol, chlorobutanol, sodium salicylate, ethyl parahydroxybenzoate, and butyl parahydroxybenzoate.

[0030] Examples of pH adjusters include hydrochloric acid, dilute hydrochloric acid, glycine, succinic acid, phosphoric acid, phosphates, acetic acid, tartaric acid, and meglumine.

[0031] The form of the pharmaceutical composition of the present invention is not particularly limited, and may be a form prepared in advance for subcutaneous administration, or a form prepared by dissolving diluted or lyophilized romiplostim in an injectable solvent such as water at the time of use.

[0032] The pharmaceutical composition of the present invention is provided filled in glass containers, plastic containers, etc. The shape of the container is not particularly limited and examples include vials, syringes, bags, and bottles.

[0033] A preferred example of the pharmaceutical composition of the present invention is a powdered preparation obtained by freeze-drying romiplostim with pharmacochemically acceptable additives according to a conventional method. A specific example of such a pharmaceutical composition is Romiplate®. Romiplate® contains freeze-dried romiplostim with additives including D-mannitol, purified sucrose, L-histidine, polysorbate 20, and dilute hydrochloric acid, and is used after being appropriately dissolved in sterile water for injection before administration.

[0034] "Dosage and Administration of the Pharmaceutical Composition of the Present Invention" The pharmaceutical composition of the present invention is administered subcutaneously once a week at a fixed dose of 10 μg / kg / week of romiplostim for the first four weeks after the start of administration, and from the fifth week onward, the dose may be increased or decreased as appropriate according to the patient's symptoms.

[0035] In the first embodiment, the pharmaceutical composition of the present invention is administered at a dose of 10 μg / kg / week as romiplostim for the first four weeks from the start of administration, and at a dose greater than 10 μg / kg / week, up to a maximum of 20 μg / kg / week, from the fifth week onward.

[0036] In the second embodiment, the pharmaceutical composition of the present invention is administered at a dose of 10 μg / kg / week as romiplostim for 4 weeks from the start of administration, at a dose of 15 μg / kg / week as romiplostim from week 5 to week 8, and at a maximum dose of 20 μg / kg / week as romiplostim from week 9 onward, with the same dose being continued for at least 4 weeks after the dose change.

[0037] In the third embodiment, the pharmaceutical composition of the present invention is administered at a dose of 10 μg / kg / week as romiplostim for the first four weeks from the start of administration, at a dose of 15 μg / kg / week as romiplostim from weeks 5 to 8, and at a dose of 20 μg / kg / week as romiplostim from weeks 9 to 12, with the same dose being continued for at least four weeks after the dose change.

[0038] In the fourth embodiment, the pharmaceutical composition of the present invention is administered at a dose of 10 μg / kg / week as romiplostim for the first four weeks from the start of administration, and at a dose of 15 or 20 μg / kg / week as romiplostim from the fifth week onward, with the same dose being continued for at least four weeks after the dose change.

[0039] In the fifth embodiment, the pharmaceutical composition of the present invention is administered at a dose of 10 μg / kg / week as romiplostim for the first four weeks from the start of administration, and the dose is increased by 5 μg / kg / week as romiplostim from the fifth week onward. Preferably, the same dose is continued for at least four weeks after the dose change.

[0040] Preferably, the same dosage should be continued for at least four weeks after the dosage change.

[0041] Preferably, the dose increase from week 5 onwards is 5 μg / kg / week of romiplostim.

[0042] For safe administration, the platelet count of the pharmaceutical composition of the present invention should be measured, preferably once a week, at the start of use and when adjusting the dose. Even when the dose is maintained, it is preferable to measure the platelet count approximately once every four weeks.

[0043] The single dose can be increased or decreased as appropriate, but not exceeding 5 μg / kg of romiplostim. Dose increases should be made, for example, when no platelet response (platelet count increases by 20,000 / μL or more, or when the platelet count is 10,000 / μL or more and has increased by 100% or more from baseline, or when platelet transfusion independence is observed for 8 consecutive weeks) is observed after administering the same dose for 4 consecutive weeks, and when it is judged that there are no safety concerns.

[0044] When adjusting the dosage, it is preferable to use the minimum therapeutically necessary dose, referring to the table below.

[0045] [Table 1]

[0046] If the pharmaceutical composition of the present invention shows improvement in blood cell lineage (for example, platelet count exceeding 50,000 / μL, hemoglobin concentration exceeding 10 g / dL, and neutrophil count exceeding 1,000 / μL in a transfusion-independent state) for 8 weeks or more, it is preferable to reduce the dose of romiplostim by a range not exceeding 5 μg / kg. For example, if improvement in the three blood cell lineages is maintained for 4 weeks at the reduced dose, the dose should be further reduced by a range not exceeding 5 μg / kg of romiplostim, and further reduction should be considered every 4 weeks thereafter. Also, if improvement in the three blood cell lineages is maintained for 4 weeks at a dose below 5 μg / kg of romiplostim, it is preferable to discontinue the drug. If deterioration is observed in any of the three blood cell lineages during the drug discontinuation period, the dose can be resumed at the dose before the discontinuation. If no platelet response is observed even after continuous administration of a maximum dose of 20 μg / kg / week for 8 weeks, appropriate measures should be taken, such as discontinuing administration.

[0047] The dosage and administration method of the present invention allows for a short dose fixation period (allowing for early dose increases), a large dose increase range (allowing for rapid dose increases), and early attainment of the maximum dose. By administering romiplostim according to the dosage and administration method of the present invention, high efficacy (increases in platelet, hemoglobin, and / or neutrophil levels, or tricellular blood cell responses) is obtained, and this effect continues even after reaching the maximum dose. Therefore, according to the present invention, excellent improvement effects can be achieved even in AA patients who are refractory to immunosuppressive therapy or for whom immunosuppressive therapy is not applicable. [Examples]

[0048] The present invention will be specifically described by the following examples, but these examples are merely illustrative and do not limit the scope of the present invention. In the following examples, Romiplate (registered trademark) was used as the romiplostim preparation, which is one example of a pharmaceutical composition containing romiplostim as an active ingredient. [Examples]

[0049] Phase II Clinical Trial (Ph2) A randomized, open-label, parallel-group comparative dose-finding study (Ph2 trial) was conducted in patients with aplastic anemia who were refractory to immunosuppressive therapy (hereinafter referred to as subjects) according to the following protocol.

[0050] Duration of administration • Fixed dose period (initial dose evaluation period): Weeks 1-8 Romiplostim was administered once a week for 8 weeks at one of the following doses: 1 μg / kg, 3 μg / kg, 6 μg / kg, or 10 μg / kg. Except in cases where the drug-free period criteria in 3) below were met, the initial dose was maintained during this period and no dose adjustments were made. • Continuing treatment period: Weeks 9-52 The starting dose for the continuation phase was determined for each patient based on efficacy and safety data from the fixed-dose phase (initial dose evaluation phase). If a platelet response was not obtained in Week 9, the dose was increased by one step according to the dose adjustment table (continuation phase). If platelet counting was not possible due to platelet transfusion, it was assumed that no platelet response was observed during that week.

[0051] How to adjust dosage and administration (Weeks 9-52) 1) Increase the dosage During the continuation phase, the dosage may be increased by one step, referring to the dosage adjustment table (continuation phase). If a platelet response is not obtained after 4 weeks of administration of romiplostim after the increase, the maximum dose may be increased by one step at a time, up to 20 μg / kg. After administering the same dose continuously for 4 weeks, the necessity and timing of further dose increases were determined by the physician based on individual patient safety and efficacy data. 2) Dosage adjustment If a platelet response was observed in a patient, the physician, referring to efficacy and safety data for each patient, adjusted the dose by increasing or decreasing it one step at a time according to the "Dosage Adjustment Table (Continued Administration Phase)" (Table 2) to maintain the platelet response. The maximum dose was 20 μg / kg.

[0052] [Table 2]

[0053] 3) Criteria for discontinuing and resuming medication Platelet count: 400 × 10 9 If the platelet count exceeded / L, the medication was discontinued. 9 If the platelet count fell below / L, administration was restarted at a dose one step lower than the dose before discontinuation, according to the dosage adjustment table (Table 2). At that dose, the platelet count was 50 × 10 9 If the dose fell below / L, the dosage was changed to the dose used when the drug was discontinued.

[0054] Platelet count: 200 × 10 9 If the dose exceeded / L, the dose was reduced by one step according to the dosage adjustment table (Table 2). If the dose at the time of drug discontinuation was 1 μg / kg, the dose at the time of restarting administration was 1 μg / kg. For reasons other than those mentioned above, if safety concerns arise, physicians may reduce the dosage at any time.

[0055] Criteria for 3 blood cell reactions The primary evaluation item was defined as the percentage of subjects who showed a platelet response at Week 9, and the main secondary evaluation items were set as the percentage of subjects who showed a platelet response, the period until a platelet response was shown, the percentage of subjects who discontinued platelet transfusions, and the percentage of subjects who showed a red blood cell response and / or a neutrophil response. These evaluation indicators were defined as follows. Showing a three-blood-cell response, or being positive for a three-blood-cell response, means showing a response in all of platelets, red blood cells, and neutrophils.

[0056] Definition of evaluation metrics ◆ Platelet response: When any of the following apply · The platelet count increases by 20 × 10 9 / L or more from the baseline (the value before the start of romiplostim administration) · The platelet count is 10 × 10 9 / L or more and increases by 100% or more from the baseline. However, the evaluation result for subjects within 7 days after platelet transfusion was defined as "no response".

[0057] ◆ Red blood cell response: When any of the following apply · For subjects with a hemoglobin concentration of less than 9.0 g / dL before romiplostim administration, the hemoglobin concentration increases by 1.5 g / dL or more from the baseline without red blood cell transfusion. · The blood transfusion volume decreases by 4 units or more continuously for 8 weeks compared to the red blood cell transfusion volume in the 8 weeks before romiplostim administration. However, the evaluation result for subjects within 28 days after red blood cell transfusion was defined as "no response".

[0058] ◆ Neutrophil response: When any of the following apply · For subjects with a neutrophil count of less than 0.5 × 10 9 / L before romiplostim administration, the neutrophil count increases by 100% or more from the baseline. · For subjects with a neutrophil count of less than 1.0 × 10 9 / L before romiplostim administration, the neutrophil count increases by 0.5 × 10 9 / L or more from the baseline. However, the evaluation results for subjects within 7 days of G-CSF administration were classified as "no response."

[0059] ◆Weaning off blood transfusions In subjects who received platelet or red blood cell transfusions as prior treatment within 8 weeks prior to romiplostim administration, when platelet or red blood cell transfusions were not received for 8 consecutive weeks or more.

[0060] result The results of the Ph2 test, along with the results of the Ph2 / 3 test in Example 2, are shown in Table 4 and Figures 1-3.

[0061] Subcutaneous administration was initiated once weekly at one of the following doses: 1, 3, 6, or 10 μg / kg. No dose adjustments (increase or decrease) were observed during the fixed-dose period (initial dose evaluation period) up to Week 8. The percentage of subjects showing a platelet response at Week 9, the primary efficacy endpoint, increased with increasing dose: 0% in the 1 and 3 μg / kg groups, 33.3% in the 6 μg / kg group, and 70.0% in the 10 μg / kg group. Similarly, the percentage of subjects showing a erythrocyte and / or neutrophil response during the initial dose evaluation period also increased with increasing dose: 14.3% in the 1 μg / kg group, 57.1% in the 3 μg / kg group, 55.6% in the 6 μg / kg group, and 70.0% in the 10 μg / kg group. Based on these results, it became clear that significant platelet, erythrocyte, and / or neutrophil responses were observed during the initial dose evaluation phase. Therefore, 10 μg / kg was set as the starting dose for the Phase II / III clinical trial (Ph2 / 3) described later. [Examples]

[0062] Phase II / III Clinical Trial (Ph2 / 3) In patients with aplastic anemia who are refractory to or for whom immunosuppressive therapy is not indicated, an international, collaborative, open-label, intracellular dose-adjusted Phase II / III clinical trial was conducted according to the following protocol.

[0063] Duration of administration (Week 1-52) Romiplostim is administered subcutaneously once a week according to the following instructions. ·Dose fixed phase (Week 1~4) The initial dose will be 10 μg / kg, and a fixed dose will be maintained from Week 1 to Week 4. • Continued administration period (Weeks 5-52) From Week 5 onward, you may adjust the dosage according to the following dosage adjustment method.

[0064] Dose adjustment method 1) Increase the dosage If no platelet response was observed for four consecutive weeks, the dose was increased one step at a time according to the dose adjustment table (Table 3). However, even if no platelet response was observed, if there was concern about the occurrence or worsening of adverse events, the physician may maintain the investigational drug dose at their discretion. Furthermore, even if a platelet response is observed, the dosage may be increased by one step every four weeks if the physician deems it necessary.

[0065] [Table 3]

[0066] 2) Dose reduction and discontinuation of medication When the administered dose was 10-20 μg / kg, if the same dose was administered continuously for 8 weeks or more, and all three of the following blood cell values ​​were maintained for 8 weeks during that period, and no blood transfusions were received, the dose was reduced by one step according to the dose adjustment table (Table 3). Furthermore, if the reduced dose was administered continuously for 4 weeks, and all three of the following blood cell values ​​were maintained during that period, and no blood transfusions were received, the dose was reduced by another step according to the dose adjustment table (Table 3). Furthermore, when the dose was 5 μg / kg, if the same dose was administered continuously for more than 4 weeks, and during that period all three of the following blood cell values ​​were met for 4 weeks, and no blood transfusions were received, romiplostim was discontinued. However, during the extended administration period, if the physician determines that the following three blood cell values ​​cannot be maintained by reducing the dosage or discontinuing the medication, the reduction or discontinuation of the medication may be postponed. • Platelet count: >50 × 109 / L • Hemoglobin concentration: >10.0 g / dL • Neutrophil count: >1 × 10⁻⁶ 9 / L

[0067] 3) Criteria for increasing the dose again and resuming administration During tapering, if the platelet count, hemoglobin concentration, or neutrophil count fell to any of the following values, tapering was discontinued and the dose was increased by one step according to the dose adjustment table (Table 3). During drug-free periods, if the platelet count, hemoglobin concentration, or neutrophil count fell to any of the following values, administration was restarted at 5 μg / kg. • Platelet count: <30 × 10 9 / L • Hemoglobin concentration: <9.0 g / dL • Neutrophil count: <0.5 × 10⁻⁶ 9 / L

[0068] 4) Criteria for maintaining the dosage If the criteria for gradual reduction or dose increase were not met during the tapering process, the dose was maintained and administration continued.

[0069] Criteria for 3 blood cell reactions ◆Platelet reaction: When any of the following conditions are met • Platelet count increased by 20 × 10 compared to baseline. 9 Increase of / L or more • Platelets 10 x 10 9 / L or higher, and an increase of more than 100% from baseline. • Subjects who had received platelet transfusions as prior treatment in the 8 weeks prior to the first dose, and who have not received platelet transfusions for 8 consecutive weeks.

[0070] ◆Red blood cell reaction: When any of the following conditions are met • In subjects with a baseline hemoglobin concentration of less than 9.0 g / dL, hemoglobin concentration increased by 1.5 g / dL or more without red blood cell transfusion. • In subjects who received red blood cell transfusions as prior treatment in the 8 weeks prior to the initial dose, the cumulative amount of transfused blood decreased by 800 mL or more over a continuous 8-week period.

[0071] ◆Neutrophil reaction: When any of the following conditions are met • Baseline neutrophil count was 0.5 × 10 9 In subjects with a neutrophil count of less than / L, when the neutrophil count increased by more than 100% from baseline. • Baseline neutrophil count 1 × 10 9 In subjects with a neutrophil count less than / L, the neutrophil count was 0.5 × 10⁶ higher than baseline. 9 Increase by / L or more A positive three-cell blood cell reaction (TRIC reaction) means that all three cells—platelets, red blood cells, and neutrophils—showed a reaction.

[0072] ◆Weaning off blood transfusions In patients who received platelet transfusion or red blood cell transfusion as prior treatment in the 8 weeks prior to romiplostim administration, when platelet transfusion or red blood cell transfusion was not performed for 8 consecutive weeks or more.

[0073] result The results of the pH2 / 3 test, along with the results of the pH2 test in Example 1, are shown in Table 4 and Figures 1-3.

[0074] [Table 4]

[0075] At Week 27, 83.9% of subjects showed a hematological response (platelet response, erythrocyte response, or neutrophil response). The results of this study revealed that in AA patients who are refractory to immunosuppressive therapy including ATG or for whom immunosuppressive therapy is not applicable, initiating romiplostim subcutaneous administration at 10 μg / kg once a week, and then adjusting the romiplostim dose between 5 and 20 μg / kg as appropriate based on platelet response, platelet count, and adverse events, can lead to a significant hematological response (platelet response, erythrocyte response, and / or neutrophil response).

[0076] Consideration In the Ph2 / 3 trial, the dose increase was larger compared to the Ph2 trial (5 μg / kg vs. 3-4 μg / kg), and the initial dose fixation period was shorter (4 weeks vs. 8 weeks). Furthermore, the time to reach the maximum dose of 20 μg / kg was also shorter (shortest at 9 weeks vs. 17 weeks).

[0077] The proportion of patients with positive triglyceride reactions was higher in the Ph2 / 3 trial (31 patients in total) than in the 10 patients in the Ph2 trial who started with an initial dose of 10 μg / kg (hereinafter also referred to as the Ph2 (10 μg / kg group)) in both Week 27 and Week 53, and further increased from Week 27 to Week 53. The difference in efficacy between Ph2 and Ph2 / 3 is thought to be due to differences in the duration of the fixed-dose period and the method of dose adjustment. Following the administration method of the Ph2 / 3 trial, increasing the dose from 10 μg / kg at the start of administration to 20 μg / kg in a short period of time showed a stronger efficacy compared to known administration methods, and it was revealed that this efficacy was maintained even after one year. Furthermore, even after 17 weeks, when the Ph2 (10 μg / kg group) was able to receive 20 μg / kg, the difference in efficacy with the Ph2 / 3 group was observed for a long period. Looking at the changes in platelet count, hemoglobin level, and neutrophil level in Figures 1 to 3, the platelet count (Figure 1), hemoglobin level (Figure 2), and neutrophil count (Figure 3) were consistently higher in the Ph2 / 3 group than in the Ph2 (10 μg / kg group) up to Week 53.

[0078] Following the dosage and administration guidelines of the Ph2 / 3 trial, a fixed dose period (10 μg / kg) was established for 4 weeks, followed by dose increases of 5 μg / kg / week, which allowed for early attainment of the maximum dose. This dosage and administration method resulted in high efficacy (increases in platelet, hemoglobin, and neutrophil levels), and this effect persisted even after reaching the maximum dose. As a result, excellent improvement can be expected even in AA patients who are refractory to or for whom immunosuppressive therapy is not applicable. [Industrial applicability]

[0079] According to the present invention, high efficacy can be achieved in the treatment of aplastic anemia with romiplostim, and an effective treatment can be provided even to patients with aplastic anemia who have not achieved sufficient results with conventional treatment methods such as immunosuppressive therapy.

[0080] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety. [Sequence Listing Free Text]

[0081] SEQ ID NO: 1: Thrombopoietin fusion protein analog

Claims

1. A pharmaceutical composition for the treatment of aplastic anemia, comprising romiplostim as the active ingredient, characterized in that it is administered subcutaneously once a week, with 10 μg / kg / week of romiplostim administered for the first four weeks from the start of administration, and from the fifth week onward, with a dose increase of more than 10 μg / kg / week, up to a maximum of 20 μg / kg / week, wherein the increase from the fifth week onward is 5 μg / kg of romiplostim, and the same dose is continued for at least four weeks after the dose change.

2. The pharmaceutical composition according to claim 1, characterized in that it is administered at a dose of 15 μg / kg / week as romiplostim from week 5 to week 8, and at a maximum dose of 20 μg / kg / week as romiplostim from week 9 onward.

3. The pharmaceutical composition according to claim 1, characterized in that it is administered as romiplostim at a dose of 15 or 20 μg / kg / week from the fifth week onward.

4. A pharmaceutical composition for the treatment of aplastic anemia, comprising romiplostim as the active ingredient, characterized in that it is administered subcutaneously once a week, with a dose of 10 μg / kg / week of romiplostim for the first four weeks from the start of administration, and the dose can be increased from the fifth week onward, with the increase being 5 μg / kg of romiplostim, and the same dose is continued for at least four weeks after the dose change.

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