Pharmaceutical composition for treating aplastic anemia

Abstract

To provide a pharmaceutical composition for effectively treating aplastic anemia using Romiplostim.SOLUTION: The present invention relates to a pharmaceutical composition for treating aplastic anemia, which comprises Romiplostim as an active ingredient, wherein the pharmaceutical composition is administered subcutaneously once a week, wherein Romiplostim is administered at 10 μg / kg / week for 4 weeks from the start of administration, administered at more than 10 μg / kg / week and at a maximum of 20 μg / kg / week after week 5.SELECTED DRAWING: Figure 1

Description

[Technical field]

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

[0002] Aplastic anemia (AA) is a disease characterized by a decrease in all blood cells in peripheral blood (pancytopenia) and a decrease in cell density in bone marrow (hypoplasia). Subjective symptoms of AA include shortness of breath during exertion, palpitations, dizziness, and other anemic symptoms, fever due to infection, and bleeding tendency such as subcutaneous bleeding spots, gingival bleeding, and nosebleeds. Objective findings include facial pallor, anemic eyelid conjunctiva, subcutaneous bleeding, and gingival bleeding. AA may progress to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), or may lead to death due to bleeding tendency or infection. In Japan, it was designated as an intractable disease by the Ministry of Health, Labor, and Welfare in 1972.

[0003] Treatment for AA includes supportive therapy such as transfusion of platelets and red blood cells and administration of hematopoietic factors such as granulocyte-colony stimulating factor (G-CSF), and treatment aimed at restoring hematopoietic function, such as immunosuppressive therapy, anabolic steroid therapy, and hematopoietic stem cell transplantation. Since the prognosis and treatment policy for AA vary greatly depending on the severity, treatment guidelines are provided according to the severity.

[0004] In Japan's treatment guidelines, it is recommended that AA patients in stages 1 to 2a (mild to moderate, not requiring transfusion) (excluding patients with platelet counts of 100,000 / μL or more, and only anemia and neutropenia) be treated with cyclosporine (CsA) and its effectiveness examined. Since the therapeutic response to cyclosporine appears within 8 weeks at the latest, if no increase in platelet or reticulocyte counts is observed within 8 weeks of treatment, appropriate treatments, such as anti-human thymocyte immunoglobulin (ATG) or eltrombopag (EPAG), will be selected depending on the progression of cytopenia, the need for transfusion, and the presence or absence of subjective symptoms.

[0005] For AA patients in stages 2b to 5 (moderate to very severe disease requiring blood transfusion), the primary treatment is hematopoietic stem cell transplantation for patients under 40 years of age who have an HLA-matched sibling donor. Patients who are not candidates for transplantation and those over 40 years of age are primarily treated with immunosuppressive therapy such as ATG and CsA, with the use of EPAG in combination if necessary.

[0006] However, 10-20% of patients undergo hematopoietic stem cell transplantation and, despite the effectiveness of immunosuppressive therapy, approximately 5-10% of long-term survivors progress to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The response rate of immunosuppressive therapy is approximately 33-57%, and for patients who are refractory to or not eligible for immunosuppressive therapy, life is extended through supportive therapy centered on blood transfusions and administration of hematopoietic factors. When the degree of anemia or thrombocytopenia is severe, or when associated with moderate or severe clinical symptoms, blood transfusions are performed, but transfusions must be kept to a minimum to avoid unknown infections, platelet transfusion refractory due to anti-HLA antibody production, and the risk of rejection during hematopoietic stem cell transplantation. G-CSF is administered to patients with a neutrophil count of 500 / μL or less, who are at high risk of severe infections, but the effect is temporary.

[0007] It was expected that the treatment outcome would be improved by combining EPAG with severe AA patients refractory to immunosuppressive therapy, but clinical trial data of EPAG in Japanese AA patients untreated with ATG showed that there were patients who did not respond to EPAG. In addition, in actual clinical practice, there are patients for whom EPAG administration is a concern, such as patients with liver disorders and elderly patients who have difficulty maintaining compliance with medication due to the oral administration formulation. Thus, there are patients for whom EPAG-based drug therapy aimed at restoring hematopoietic function is not expected to be effective, and safe and more effective treatment methods are needed.

[0008] Romiplostim is a thrombopoiesis stimulating factor preparation that binds to c-Mpl, a 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), it has been approved in more than 60 countries and is manufactured and sold under the trade name Romiplate (registered trademark), etc.

[0009] c-Mpl is expressed not only in megakaryocytic progenitor cells but also in more undifferentiated hematopoietic stem / progenitor cells in the bone marrow, and it has been suggested that TPO promotes the production of multiple lineages of blood cells by activating c-Mpl. Therefore, the effectiveness of romiplostim against AA was expected, and clinical development was started for adult AA patients. A phase II clinical (Ph2) trial of romiplostim for AA patients refractory to immunosuppressive therapy was started in 2014 (Non-Patent Document 1), and a phase II / III clinical (Ph2 / 3) trial was started in 2016 (Non-Patent Document 2). In these clinical trials, romiplostim was administered subcutaneously once a week, and the efficacy was verified using indicators such as platelet, red blood cell, and neutrophil responses, and withdrawal 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 Summary of the Invention [Problem to be solved by the invention]

[0012] An object of the present invention is to provide an effective method for treating aplastic anemia using romiplostim. [Means for solving the problem]

[0013] As a result of intensive research, the inventors have found that administration of romiplostim in a specific dosage and administration method results in high efficacy and safety in the treatment of aplastic anemia, and have completed the present invention.

[0014] That is, the present invention relates to the following (1) to (8). (1) 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 after the start of administration, and at a dose of more than 10 μg / kg / week, up to a maximum of 20 μg / kg / week as romiplostim, from the fifth week onwards. (2) The pharmaceutical composition according to (1), characterized in that the same dosage is continued for at least 4 weeks after the dosage is changed. (3) The pharmaceutical composition according to (1), which is administered at 15 μg / kg / week of romiplostim from the 5th to 8th weeks, and at a maximum of 20 μg / kg / week of romiplostim from the 9th week onwards, and which is characterized in that the same dosage is continued for at least 4 weeks after the dosage change. (4) The pharmaceutical composition according to (1), which is administered at 15 μg / kg / week of romiplostim from weeks 5 to 8, at 20 μg / kg / week of romiplostim from weeks 9 to 12, and at 5 to 20 μg / kg / week of romiplostim from week 13 onwards, and which is characterized in that the same dosage is continued for at least 4 weeks after the dosage change. (5) The pharmaceutical composition according to (1), which is administered at 15 or 20 μg / kg / week of romiplostim from the 5th week onwards, and which is characterized in that the same dosage is continued for 4 or more weeks after the dosage change. (6) The pharmaceutical composition according to any one of (1) to (4), wherein the dosage is increased by 5 μg / kg of romiplostim from the 5th week onwards. (7) A pharmaceutical composition for treating aplastic anemia containing romiplostim as an active ingredient, the pharmaceutical composition being administered subcutaneously once a week at a dose of 10 μg / kg / week of romiplostim for the first four weeks of administration, with the dose being increased by 5 μg / kg of romiplostim from the fifth week onwards. (8) The pharmaceutical composition according to (7), characterized in that the same dosage is continued for 4 weeks or more after the dosage is changed. Effect of the Invention

[0015] According to the present invention, high efficacy can be achieved in the treatment of aplastic anemia patients for whom immunosuppressants are ineffective with romiplostim. [Brief description of the drawings]

[0016] [Figure 1] Figure 1 shows the change in platelet count over time in Ph2 and Ph2 / 3. In the graph, the lower light-colored line shows the average value for the 10μg / kg starting group (N=10) in the Ph2 (KR001) study, and the upper dark-colored line shows the average value for all subjects (N=31) in the Ph2 / 3 (531-002) study. Error bars show standard deviation. The horizontal axis shows the number of weeks from the start of administration, and the vertical axis shows the platelet count. [Diagram 2] Figure 2 shows the change in hemoglobin levels over time in Ph2 and Ph2 / 3. In the graph, the lower light-colored line shows the average value for the 10μg / kg starting group (N=10) in the Ph2 (KR001) study, and the upper dark-colored line shows the average value for all subjects (N=31) in the Ph2 / 3 (531-002) study. Error bars show standard deviation. The horizontal axis shows the number of weeks from the start of administration, and the vertical axis shows the hemoglobin value. [Diagram 3] Figure 3 shows the transition of neutrophil counts in Ph2 and Ph2 / 3. In the graph, the lower light-colored line shows the average value for the 10μg / kg starting group (N=10) in the Ph2 (KR001) study, and the upper dark-colored line shows the average value for all cases (N=31) in the Ph2 / 3 (531-002) study. Error bars show standard deviation. The horizontal axis shows the number of weeks from the start of administration, and the vertical axis shows the neutrophil count. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] "Romiplostim" Romiplostim is a recombinant fusion protein with a molecular weight of approximately 59 kDa, and is a dimer consisting 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 to 228 are composed of a peptide containing the Fc region of human IgG1, and positions 229 to 269 are composed of a peptide containing the human thrombopoietin receptor (c-Mpl) binding sequence. Romiplostim forms a dimer by disulfide bonding of 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 has thrombopoietic and / or megakaryocytopoietic activity. Romiplostim acts as a thrombopoietin stimulating agent by binding to c-Mpl, the receptor for endogenous thrombopoietin (TPO), and enhancing platelet production. TPO is a human megakaryocyte and thrombopoietin stimulating factor, whose gene was cloned in 1994. Romiplostim is thought to promote cell proliferation and differentiation in the process from bone marrow progenitor cells to megakaryocytes by binding to and activating c-Mpl, 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, so long as it is medicamentously acceptable.

[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 cell density in the bone marrow (hypoplasia). In reality, AA is diagnosed by excluding other diseases with similar characteristics and more clearly defined concepts, but the true nature of the disease can be described as "a state in which hematopoietic stem cells are persistently decreased despite the absence of the effects of bone marrow-toxic drugs."

[0021] To diagnose AA, clinical findings include anemia, bleeding tendency, and sometimes fever, and at least two of the following three conditions must be met: hemoglobin (Hb) concentration less than 10g / 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 that can cause pancytopenia can be ruled out, but it can be difficult to distinguish it from MDS.

[0022] AA can be classified as congenital or acquired depending on the cause. The most common congenital AA is Fanconi anemia, an autosomal recessive genetic disease characterized by bone marrow hypoplasia as well as skeletal deformities, short stature, and gonadal dysfunction. Acquired AA can be idiopathic (primary), secondary due to various drugs, radiation exposure, or chemicals such as benzene, or special types associated with hepatitis or paroxysmal nocturnal hemoglobinuria. In Japan, the majority of acquired AA is considered to be idiopathic (primary).

[0023] Treatment for AA includes supportive therapy such as transfusion of platelets and red blood cells, administration of hematopoietic factors such as G-CSF, and immunosuppressive therapy, anabolic steroid therapy, and hematopoietic stem cell transplantation, which are aimed at restoring hematopoietic function. Since the prognosis and treatment policy of AA vary greatly depending on the severity, treatment guidelines are provided according to the severity. As mentioned above, treatment with CsA is recommended for AA patients in stages 1 to 2a (mild to moderate cases not requiring transfusion), and ATG or EPAG is used in combination as appropriate. For AA patients in stages 2b to 5 (moderate to very severe cases requiring transfusion), hematopoietic stem cell transplantation, immunosuppressive therapy, or a combination of immunosuppressive therapy and EPAG is considered. For patients who are refractory to or for whom immunosuppressive therapy is not applicable, supportive therapy centered on blood transfusions and hematopoietic factors is adopted.

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

[0025] The pharmaceutical composition of the present invention contains one or more pharmacologically acceptable carriers, additives, pH adjusters, etc. Examples of additives include isotonicity agents, buffers, solubilizing agents, and preservatives.

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

[0027] Buffers include, for example, 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 solubilizing agents 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 at the time of use by dissolving diluted or lyophilized romiplostim in an injection solvent such as water.

[0032] The pharmaceutical composition of the present invention is provided filled in a glass container, a plastic container, etc. The shape of the container is not particularly limited, and examples thereof include a vial, a syringe, a bag, and a bottle.

[0033] A preferred example of the pharmaceutical composition of the present invention is a powder preparation obtained by freeze-drying romiplostim together with a pharmacologically acceptable additive according to a conventional method.A specific example of such a pharmaceutical composition is Romiplate (registered trademark).Romiplate (registered trademark) contains the freeze-dried product of romiplostim, as additives, D-mannitol, refined sucrose, L-histidine, polysorbate 20, and dilute hydrochloric acid, and is used by being appropriately dissolved in 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 the dose may be increased or decreased as appropriate depending on the patient's symptoms from the fifth week onwards.

[0035] In a first embodiment, the pharmaceutical composition of the present invention is administered at 10 μg / kg / week as romiplostim for the first 4 weeks from the start of administration, and from the 5th week onwards, at more than 10 μg / kg / week up to 20 μg / kg / week as romiplostim.

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

[0037] In a third embodiment, the pharmaceutical composition of the present invention is administered at 10 μg / kg / week as romiplostim for 4 weeks from the start of administration, at 15 μg / kg / week as romiplostim from weeks 5 to 8, and at 20 μg / kg / week as romiplostim from weeks 9 to 12, and the same dosage is continued for 4 weeks or more after the dosage change.

[0038] In a fourth embodiment, the pharmaceutical composition of the present invention is administered at 10 μg / kg / week as romiplostim for 4 weeks from the start of administration, and then at 15 or 20 μg / kg / week as romiplostim from the 5th week onwards, with the same dosage being continued for 4 weeks or more after the dosage change.

[0039] In a fifth embodiment, the pharmaceutical composition of the present invention is administered at 10 μg / kg / week of romiplostim for 4 weeks from the start of administration, and then increased by 5 μg / kg / week of romiplostim from week 5 onwards. Preferably, the same dosage is continued for 4 weeks or more after the dosage change.

[0040] Preferably, the same dosage is continued for at least 4 weeks after the dosage change.

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

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

[0043] The dosage per administration may be increased or decreased as appropriate within a range not exceeding 5 μg / kg of romiplostim. The dosage may be increased, for example, when the same dosage is administered for 4 consecutive weeks without a platelet response (when the platelet count increases by 20,000 / μL or more, or when the platelet count increases by 100% or more from baseline to 10,000 / μL or when the patient is platelet transfusion independent for 8 consecutive weeks) and it is judged that there is no problem with safety.

[0044] When adjusting the dosage, it is preferable to refer to the table below and use the minimum dosage required for treatment.

[0045] [Table 1]

[0046] When the improvement of the blood cell system (e.g., platelet count >50,000 / μL under transfusion independence, hemoglobin concentration >10 g / dL under transfusion independence, and neutrophil count >1,000 / μL) continues for 8 weeks or more, it is preferable to reduce the dose of the pharmaceutical composition of the present invention by not exceeding 5 μg / kg of romiplostim. For example, if the improvement of the three blood cell system is maintained for 4 weeks at the dose after the reduction, the dose is further reduced by not exceeding 5 μg / kg of romiplostim, and reduction is considered every 4 weeks thereafter. In addition, when the improvement of the three blood cell system is maintained for 4 weeks with the dose of romiplostim below 5 μg / kg, it is preferable to suspend the drug. If deterioration of any of the three blood cells is observed during the drug suspension, it can be resumed at the dose before the drug suspension. If no platelet response is observed even after 8 consecutive weeks of administration of the maximum dose of 20 μg / kg / week, appropriate measures such as discontinuing the administration are taken.

[0047] The dosage regimen according to the present invention has a short fixed dose period (allowing for early dose increase), a large dose increase range (allowing for rapid dose increase), and allows for early attainment of the maximum dose. By administering romiplostim according to the dosage regimen according to the present invention, high efficacy (increase in platelet, hemoglobin, and / or neutrophil values, or three-cell reaction) is obtained, and the effect continues even after the maximum dose is reached. Therefore, according to the present invention, excellent improvement effects are 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 with reference to the following examples, but the examples are merely illustrative of the present invention and do not limit the scope of the present invention. In the following examples, Romiplate (registered trademark) was used as a romiplostim formulation, which is an 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 (Phase 2 study) was conducted on patients (hereinafter referred to as subjects) with aplastic anemia refractory to immunosuppressive therapy, according to the following protocol.

[0050] Treatment period -Dose fixation period (initial dose evaluation period): Week 1~8 Romiplostim was administered once weekly for 8 weeks at doses of 1 μg / kg, 3 μg / kg, 6 μg / kg, or 10 μg / kg. Except when the drug discontinuation criteria in 3) below were met, the initial dose was maintained during this period and no dose adjustments were made. ·Continuation period: Week 9~52 The starting dose in the extension phase was determined for each patient based on efficacy and safety data from the dose fixing phase (initial dose evaluation phase). If no platelet response was achieved at Week 9, the dose was increased by one step based on the dose adjustment table (extension phase). If platelet counts could not be obtained due to platelet transfusion, the week was considered to have no platelet response.

[0051] How to adjust dosage (Week 9~52) 1) Increasing the dose During the continued administration period, the dose may be increased by one step, referring to the dose adjustment table (continuation administration period). If no platelet response was obtained after 4 weeks of romiplostim administration after the dose increase, the dose may be increased by one step at a time up to a maximum of 20 μg / kg. After 4 weeks of continuous administration of the same dose, the necessity and timing of dose increases were determined by the physician based on the safety and efficacy data for each patient. 2) Dose adjustment If a platelet response was observed in a patient, efficacy and safety data for each patient were referred to, and the dose was increased or decreased by one step at the doctor's discretion in accordance with the "Dosage Adjustment Table (Continuation Administration Period)" (Table 2) to adjust the dose appropriately so that the platelet response could be maintained. The maximum dose was 20 μg / kg.

[0052] [Table 2]

[0053] 3) Criteria for drug suspension and resumption Platelet count is 400 x 10 9 If the platelet count was greater than 200 × 10 9 If the platelet count fell below 50 × 10 / L, administration was resumed at a dose one level lower than the dose before discontinuation, according to the dosage adjustment table (Table 2). 9 / L or less, the dosage was restored to the dose at which it was discontinued.

[0054] Platelet count is 200 x 10 9 If the dose exceeded 1 μg / L, the dose was reduced by one level according to the dosage adjustment table (Table 2). If the dose at the time of withdrawal was 1 μg / kg, the dose at the time of resumption of administration was 1 μg / kg. If safety concerns arise for reasons other than those mentioned above, doctors may reduce the dose at any time.

[0055] 3. Criteria for blood cell reaction The primary endpoint was the proportion of subjects who showed a platelet response at Week 9, and the main secondary endpoints were the proportion of subjects who showed a platelet response, the time to a platelet response, the proportion of subjects who were withdrawn from platelet transfusions, and the proportion of subjects who showed an erythrocyte response and / or neutrophil response. These endpoints were defined as follows: A triple blood cell reaction, or a positive triple blood cell reaction, means that a reaction was observed in all three blood cells: platelets, red blood cells, and neutrophils.

[0056] Defining the evaluation indicators Platelet response: When any of the following conditions are met Platelet count increased by 20 x 10 from baseline (value before starting romiplostim administration) 9 / L or more increase Platelet count is 10 x 10 9 / L or higher and increased by 100% or more from baseline However, the evaluation results for subjects within 7 days after platelet transfusion were recorded as "no response."

[0057] ◆ Red blood cell reaction: When any of the following conditions are met - An increase in hemoglobin concentration of at least 1.5 g / dL from baseline without red blood cell transfusions in subjects with hemoglobin concentrations less than 9.0 g / dL before romiplostim administration A continuous reduction in transfusion volume of 4 units or more for 8 weeks compared to the amount of red blood cell transfusions in the 8 weeks prior to romiplostim administration However, the evaluation results for subjects within 28 days after red blood cell transfusion were recorded as "no response."

[0058] Neutrophil reaction: When any of the following conditions are met Neutrophil count before romiplostim administration was 0.5×10 9 ≥100% increase in neutrophil count from baseline in subjects <100 / L Neutrophil count before romiplostim administration was 1.0 × 10 9 Subjects with neutrophil counts < 0.5 × 10 9 / L or more increase However, the evaluation results for subjects within 7 days after G-CSF administration were recorded as "no response."

[0059] Weaning from blood transfusions In subjects who received a platelet or red blood cell transfusion as pretreatment within 8 weeks prior to romiplostim administration, platelet or red blood cell transfusions have not been received for 8 or more consecutive weeks.

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

[0061] Subcutaneous administration was initiated once weekly at a dose of 1, 3, 6, or 10 μg / kg, and no dose adjustments (increases or decreases) were permitted during the dose-fixed period (initial dose evaluation period) up to Week 8. The proportion of subjects who showed a platelet response at Week 9, the primary efficacy endpoint, increased with increasing dose, being 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. The proportion of subjects who showed an erythrocyte and / or neutrophil response during the initial dose evaluation period also increased with increasing dose, being 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 the above results, 10 μg / kg was determined to be the starting dose for treatment in the Phase II / III clinical trials (Ph2 / 3), as it was shown to produce significant platelet, red blood cell, and / or neutrophil responses during the initial dose evaluation period. EXAMPLES

[0062] Phase II / III clinical trial (Ph2 / 3) An international, open-label, intra-individual dose-adjusted Phase II / III clinical trial was conducted in patients with aplastic anemia who were refractory to immunosuppressive therapy or for whom immunosuppressive therapy was not applicable, according to the following protocol.

[0063] Administration period (Week 1~52) Romiplostim will be administered subcutaneously once weekly as follows: ·Dose fixed phase (Week 1~4) The initial dose will be 10 μg / kg, and will be a fixed dose during Weeks 1-4. ·Continuation period (Week 5~52) After Week 5, the dose may be adjusted according to the dose adjustment methods below.

[0064] Dose adjustment method 1) Increasing the dose If no platelet response was observed for 4 consecutive weeks, the dose was increased by one step in accordance with 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 dose of the investigational drug may be maintained at the discretion of the physician. In addition, even if a platelet response is observed, the dose may be increased by one step every four weeks if the physician deems it necessary.

[0065] [Table 3]

[0066] 2) Dose reduction and drug suspension When the dosage was 10-20 μg / kg, if the same dosage was administered for 8 or more consecutive weeks, and all the following 3 blood cell values ​​were maintained for 8 weeks during that period, and no blood transfusions were received, the dosage was reduced by one level according to the dosage adjustment table (Table 3). If the reduced dosage was administered for 4 consecutive weeks, and all the following 3 blood cell values ​​were maintained during that period, and no blood transfusions were received, the dosage was reduced by another level according to the dosage adjustment table (Table 3). In addition, when the dosage was 5 μg / kg, romiplostim was discontinued if the same dose had been administered for four or more consecutive weeks, all of the following three blood cell values ​​were met for four weeks during that period, and no blood transfusions were received. However, during the extended treatment period, if a doctor determines that the values ​​of the following three blood cells cannot be maintained by reducing the dose or suspending the medication, the reduction or suspension may be postponed. Platelet count: >50×109 / L Hemoglobin concentration: >10.0 g / dL Neutrophil count: >1×10 9 / L

[0067] 3) Criteria for re-escalation and resumption of administration During tapering, if the platelet count, hemoglobin concentration, or neutrophil count reached 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 withdrawal, if the platelet count, hemoglobin concentration, or neutrophil count reached any of the following values, administration was resumed at 5 μg / kg. Platelet count: <30×10 9 / L Hemoglobin concentration: <9.0 g / dL Neutrophil count: <0.5×10 9 / L

[0068] 4) Dose maintenance criteria During tapering, if the criteria for tapering or re-escalation were not met, the dose was maintained and treatment continued.

[0069] 3. Criteria for blood cell reaction ◆ Platelet response: When any of the following is met - Platelet count increased by 20×10 compared to baseline 9 / L or more increase Platelets are 10×10 9 / L or higher and increased by 100% or more from baseline - Subjects who had received a platelet transfusion as pretreatment within 8 weeks prior to the first dose and had not received a platelet transfusion for 8 consecutive weeks

[0070] ◆ Red blood cell reaction: When any of the following is met In subjects with baseline hemoglobin levels <9.0 g / dL, hemoglobin levels increased by ≥1.5 g / dL without red blood cell transfusions - A cumulative reduction in transfusion volume of 800 mL or more over a consecutive 8-week period in subjects who had received red blood cell transfusions as pretreatment in the 8 weeks prior to the first dose

[0071] ◆Neutrophil response: When any of the following is met Baseline neutrophil count 0.5×10 9 In subjects with neutrophil counts < 100% increase from baseline Baseline neutrophil count 1×10 9 / L, subjects with neutrophil counts 0.5 × 10 9 / L or more increase A triple blood cell reaction, or a positive triple blood cell reaction, means that a reaction was observed in all three blood cells: platelets, red blood cells, and neutrophils.

[0072] Weaning from blood transfusions In patients who received a platelet or red blood cell transfusion as pretreatment within 8 weeks prior to romiplostim administration, if they have not received a platelet or red blood cell transfusion for 8 consecutive weeks or more

[0073] result The results of the Ph2 / 3 test are shown in Table 4 and Figures 1 to 3 together with the results of the Ph2 test of Example 1.

[0074] [Table 4]

[0075] The overall percentage of subjects who showed a hematological response (platelet response, red blood cell response, or neutrophil response) at Week 27 was 83.9%. The results of this study demonstrated that in AA patients who were refractory to or for whom immunosuppressive therapy, including ATG, was not applicable, significant hematological responses (platelet response, red blood cell response, and / or neutrophil response) could be achieved by initiating weekly subcutaneous administration of 10 μg / kg romiplostim, and then adjusting the dose of romiplostim appropriately between 5 and 20 μg / kg based on platelet response, platelet count, and adverse events.

[0076] Consideration In the Ph2 / 3 study, the dose escalation was larger (5μg / kg vs. 3-4μg / kg), the initial dose fixation period was shorter (4 weeks vs. 8 weeks), and the time to reach the maximum dose of 20μg / kg was shorter (minimum 9 weeks vs. 17 weeks).

[0077] The proportion of patients with positive hemocyte reactions was higher in the Ph2 / 3 study (31 patients in total) than in the Ph2 study (10 patients in the group starting with an initial dose of 10μg / kg, hereafter referred to as the Ph2 (10μg / kg) group) at 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 the difference in the duration of the fixed dose period and the dose adjustment method. According to the administration method of the Ph2 / 3 study, by increasing the dose from 10μg / kg at the start of administration to 20μg / kg in a short period of time, it was found that the drug showed a stronger efficacy than the known administration method, and that the efficacy was maintained even after one year. In addition, the difference in efficacy between the Ph2 / 3 group and the Ph2 (10μg / kg) group was observed for a long time even after 17 weeks, when the Ph2 (10μg / kg) group could be administered at 20μg / kg. Looking at the trends in platelet, hemoglobin, and neutrophil values ​​in Figures 1 to 3, the platelet count (Figure 1), hemoglobin value (Figure 2), and neutrophil count (Figure 3) continued to be higher in the Ph2 / 3 group than in the Ph2 (10 μg / kg group) up until Week 53.

[0078] According to the dosage and administration method of the Phase 2 / 3 trial, the fixed dose period (10μg / kg) is set for 4 weeks, and then the dose is adjusted in increments of 5μg / kg / week, allowing the maximum dose to be reached quickly. This dosage and administration method achieved high efficacy (increase in platelet, hemoglobin, and neutrophil values), and the effect continued even after the maximum dose was reached. As a result, excellent improvement effects can be expected even in AA patients who are refractory to immunosuppressive therapy 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 effective treatment can be provided to patients with aplastic anemia in whom conventional treatment methods such as immunosuppressant therapy have not been sufficient.

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

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

Claims

[Claim 1] The invention described in the specification.

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