PHARMACEUTICAL COMPOSITION FOR TREATING APLASTIC ANEMIA
20210379154 · 2021-12-09
Assignee
Inventors
Cpc classification
International classification
Abstract
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.
Claims
1. A method for treating aplastic anemia, comprising administering Romiplostim to a subject in need thereof, wherein Romiplostim is administered subcutaneously once a week, and wherein Romiplostim is administered at 10 μg/kg/week for 4 weeks from the start of administration, and administered at more than 10 μg/kg/week and a maximum of 20 μg/kg/week after week 5.
2. The method according to claim 1, wherein the same dose is maintained for 4 weeks or more after a dose change.
3. The method according to claim 1, wherein Romiplostim is administered at 15 μg/kg/week from week 5 to week 8 and administered at a maximum of 20 μg/kg/week after week 9, and wherein the same dose is maintained for 4 weeks or more after a dose change.
4. The method according to claim 1, wherein Romiplostim is administered at 15 μg/kg/week from week 5 to week 8, administered at 20 μg/kg/week from week 9 to week 12, and administered at 5 to 20 μg/kg/week after week 13, and wherein the same dose is maintained for 4 weeks or more after a dose change.
5. The method according to claim 1, wherein Romiplostim is administered at 15 or 20 μg/kg/week after week 5, and wherein the same dose is maintained for 4 weeks or more after a dose change.
6. The method according to claim 1, wherein a dose increment of Romiplostim after week 5 is 5 μg/kg.
7. A method for treating aplastic anemia, comprising administering Romiplostim to a subject in need thereof, wherein Romiplostim is administered subcutaneously once a week, and wherein Romiplostim is administered at 10 μg/kg/week for 4 weeks from the start of administration, and a dose increment of Romiplostim after week 5 is 5 μg/kg.
8. The method according to claim 7, wherein the same dose is maintained for 4 weeks or more after a dose change.
Description
BRIEF DESCRIPTION OF DRAWINGS
[0026]
[0027]
[0028]
DESCRIPTION OF EMBODIMENTS
“Romiplostim”
[0029] Romiplostim is a genetically-modified fusion protein having a molecular weight of about 59 kDa and is a dimer composed of two subunit molecules consisting of 269 amino acid residues (SEQ ID No. 1). The 2nd to 228th amino acids of the 269 amino acids of the monomer constitute a human IgG1 Fc domain, and the 229th to 269th amino acids constitute a peptide containing a human thrombopoietin receptor (c-Mpl) binding sequence. In Romiplostim, single chains in which a peptide chain containing two c-Mpl binding domains and the C-terminus of the Fc domain of human IgG1 are linked, are linked by a disulfide bond to form a dimer.
##STR00001##
C2634H4086N7220790S18
Mw: 59085
[0030] Romiplostim has platelet-producing activity and/or megakaryocyte-producing activity. Romiplostim acts as a platelet hematopoietic stimulating factor preparation by binding to c-Mpl, which is a receptor for endogenous thrombopoietin (TPO) and enhancing platelet production. TPO is a human megakaryocyte/platelet hematopoietic stimulating factor and was cloned in 1994. Romiplostim is thought to promote cell proliferation and differentiation in the process from bone marrow precursor cells to megakaryocytes and as a result to increase the number of platelets (hereinafter also referred to as PLT), by binding to c-Mpl and activating it.
[0031] In the present invention, the method for producing Romiplostim is not particularly limited as long as it is pharmaceutically acceptable.
“Aplastic Anemia”
[0032] Aplastic anemia (AA) is a disease characterized by a reduction in the number of all blood cells in the peripheral blood (pancytopenia) and a decrease in bone marrow cell density (hypoplasia). In fact, it is diagnosed as AA by excluding other diseases with clearer concepts, which have similar characteristics. However, the essence of the disease can be said to be “a state in which hematopoietic stem cells are continuously decreasing, even though there is no effect of drugs showing bone marrow toxicity.”
[0033] To diagnose AA, it is necessary to observe anemia, a bleeding tendency and sometimes fever as clinical findings, and to meet at least two of these three items: hemoglobin (Hb) concentration less than 10 g/dL, neutrophils less than 1500/μL and platelets less than 100000/μL. Furthermore, it is diagnosed as AA if diseases causing cytopenia, bone marrow hypoplasia and other pancytopenias can be ruled out, but differentiation from MDS can be sometimes difficult.
[0034] AA is divided into congenital AA and acquired AA according to the cause. The most frequent congenital AA is Fanconi anemia, which is an autosomal recessive hereditary disease and is characterized by skeletal deformities, short stature and malformations such as gonadal dysfunction, in addition to bone marrow hypoplasia. In addition, acquired AA includes idiopathic (primary) forms, secondary forms caused by various drugs and radiation exposure/chemical substances such as benzene, and special forms associated with onset after hepatitis and paroxysmal nocturnal hemoglobinuria. Most of acquired AA are considered to be idiopathic (primary) in Japan.
[0035] The treatment of 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 as treatments aiming at the restoration of hematopoietic function. Since the prognosis and treatment policy differ greatly depending on the severity of AA, the treatment guidelines are indicated according to the severity. As described above, treatment with CsA is recommended for AA patients with stages 1 to 2a (mild to moderate with no transfusion required), and ATC or EPAG is used in combination as appropriate. For AA patients with stages 2b to 5 (moderate requiring transfusion to most severe), hematopoietic stem cell transplantation or immunosuppressive therapy or a combination of immunosuppressive therapy and EPAG is considered. For patients who are refractory to immunosuppressive therapy, or for whom immunosuppressive therapy is not indicated, supportive therapy centered on transfusion and hematopoietic factors is adopted.
“Pharmaceutical Composition of the Present Invention”
[0036] The “pharmaceutical composition for treating 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 (subcutaneous injection) to AA patients by intravenous administration (also referred to as intravenous injection) or by intravenous drip infusion (also referred to as intravenous drip injection or drip infusion).
[0037] The pharmaceutical composition of the present invention comprises one or more pharmacologically acceptable carriers, additives, pH adjusters and the like. Examples of additives include tonicity agents, buffers, solubilizers and preservatives.
[0038] A tonicity agent is not particularly limited, and examples thereof include sodium chloride, calcium chloride, potassium chloride, magnesium chloride, fructose, glucose and D-mannitol.
[0039] Examples of buffers include a composition comprising potassium dihydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, sodium dihydrogen phosphate and disodium hydrogen phosphate, sodium citrate and sodium citrate hydrate.
[0040] Examples of solubilizers include ethanol, ethylenediamine, capric acid, L-glutamic acid, L-lysine, calcium oxide, magnesium oxide, sorbitan sesquioleate, D-sorbitol, nicotinic acid amide, propylene glycol, polysorbate 80 and Lauromacrogol (9E.O.).
[0041] Examples of preservatives include phenol, sodium edetate, benzalkonium chloride, chlorocresol, chlorobutanol, sodium salicylate, ethyl para-hydroxybenzoate and butyl para-hydroxybenzoate.
[0042] Examples of pH adjusters include hydrochloric acid, dilute hydrochloric acid, glycine, succinic acid, phosphoric acid, phosphate, acetic acid, tartaric acid and meglumine.
[0043] The form of the pharmaceutical composition of the present invention is not particularly limited, and may be a ready-to use preparation for subcutaneous administration or may be a preparation prepared when needed by diluting or dissolving lyophilized Romiplostim in a solvent for injection such as water.
[0044] The pharmaceutical composition of the present invention is provided by filling in a glass container, a plastic container, and the like. The shape of the container is not particularly limited, and examples thereof include vials, syringes, bags and bottles.
[0045] One preferable example of the pharmaceutical composition of the present invention is a powdery preparation obtained by lyophilizing Romiplostim with pharmacologically acceptable additives according to a conventional method. Specific examples of such pharmaceutical composition include Romiplate (R). Romiplate (R) is a freeze-dried product of Romiplostim containing D-mannitol, refined sucrose, L-histidine, polysorbate 20 and dilute hydrochloric acid as additives and is used by dissolving it as appropriate in water for injection before administration.
“Dosage and Administration of the Pharmaceutical Composition of the Present Invention”
[0046] The pharmaceutical composition of the present invention is subcutaneously administered once a week at a fixed dose of 10 μg/kg/week of Romiplostim for 4 weeks from the start of administration, and is increased or decreased as appropriate according to the condition of the patient after week 5.
[0047] In a first embodiment, the pharmaceutical composition of the present invention is administered so that Romiplostim is administered at 10 μg/kg/week for 4 weeks from the start of administration, and administered at more than 10 μg/kg/week and a maximum of 20 μg/kg/week after week 5.
[0048] In a second embodiment, the pharmaceutical composition of the present invention is administered so that Romiplostim is administered at 10 μg/kg/week for 4 weeks from the start of administration, administered at 15 μg/kg/week from week 5 to week 8, and administered at a maximum of 20 μg/kg/week after week 9, and the same dose is maintained for 4 weeks or more after a dose change.
[0049] In a third embodiment, the pharmaceutical composition of the present invention is administered so that Romiplostim is administered at 10 μg/kg/week for 4 weeks from the start of administration, administered at 15 μg/kg/week from week 5 to week 8, and administered at 20 μg/kg/week from week 9 to week 12, and the same dose is maintained for 4 weeks or more after a dose change.
[0050] In a fourth embodiment, the pharmaceutical composition of the present invention is administered so that Romiplostim is administered at 10 μg/kg/week for 4 weeks from the start of administration, and administered at 15 or 20 μg/kg/week after week 5, and the same dose is maintained for 4 weeks or more after a dose change.
[0051] In a fifth embodiment, the pharmaceutical composition of the present invention is administered so that Romiplostim is administered at 10 μg/kg/week for 4 weeks from the start of administration, and administered with a dose increment of Romiplostim after week 5 being 5 μg/kg/week. Preferably, the same dose is maintained for 4 weeks or more after a dose change.
[0052] Preferably, the same dose is maintained for 4 weeks or more after the dose change.
[0053] Preferably, the dose increment of Romiplostim after week 5 is 5 μg/kg/week.
[0054] For safe administration, platelet counts are measured at the beginning of use of the pharmaceutical composition of the present invention and at the time of dose adjustment, preferably once a week. Even if the dose is maintained, it is preferable to measure the platelet count roughly once every 4 weeks.
[0055] The dose of Romiplostim can be increased or decreased as appropriate within a range not exceeding 5 μg/kg. For example, the dose is increased when no platelet response (when the platelet count has increased 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 the baseline, or when the patients is platelet transfusion independent for 8 consecutive weeks) is observed even if the same dose is continuously administered for 4 weeks, and when it is considered that there is no problem in safety.
[0056] For the dose adjustment, it is preferable to use the minimal dose necessary for treatment, while referring to the table below.
TABLE-US-00001 TABLE 1 Platelet count Adjustment method 200,000/μL to Decrease the dose 400,000/μL More than Discontinue. After 400,000/μL discontinuation, if the platelet count has decreased to 200,000/μL, in principle, the dose is decreased by 5 μg/kg from the dose before discontinuation and the administration is resumed. When the dose before discontinuation is 5 μg/kg or less, if the platelet count has decreased to 50,000/μL, the administration is resumed at the same dose as before discontinuation.
[0057] When the improvement of the blood cell lineages (for example, platelet count over 50,000/μL under transfusion independence, hemoglobin concentration over 10 g/dL under transfusion independence, and neutrophil count over 1,000/μL) lasts for 8 weeks or more, it is preferable to reduce the pharmaceutical composition of the present invention within a range not exceeding 5 μg/kg of Romiplostim. For example, if the improvement of the tri-lineage is maintained for 4 weeks with the reduced dose, the dose of Romiplostim is further decreased within a range not exceeding 5 μg/kg, and the dose reduction is considered every 4 weeks thereafter. In addition, it is preferable to discontinue if the improvement of the tri-lineage is maintained for 4 weeks with a dose of less than 5 μg/kg Romiplostim. If deterioration of any of the 3 blood cells is observed during discontinuation, the treatment can be resumed with the dose before discontinuation. If no platelet response is observed even if a maximum dose of 20 μg/kg/week is administered for 8 consecutive weeks, appropriate measures are taken, such as stopping the administration.
[0058] The dose and administration according to the present invention has a short fixed dose period (the dose can be increased early on), a large increase range (the dose can be increased at once), and can reach the maximum dose early on. By administering Romiplostim according to the dose and administration of the present invention, high drug efficacy (increased platelet, hemoglobin level and/or neutrophil level, or tri-lineage response) can be obtained, and the effect continues even after reaching the maximum dose. Therefore, according to the present invention, an excellent improvement effect is achieved even in AA patients who are refractory to immunosuppressive therapy or for whom immunosuppressive therapy is not indicated.
EXAMPLES
[0059] The present invention will be described specifically by the following Examples, but these Examples are merely illustrative examples of the present invention and do not limit the scope of the present invention. In the following Examples, Romiplate (R) was used as a Romiplostim preparation, and this is one example of the pharmaceutical composition comprising Romiplostim as an active ingredient.
Example 1
[0060] Phase II Clinical (pH2) Trial
[0061] A randomized open-label parallel-group comparative dose-finding study (Ph2 trial) was conducted according to the following protocol, targeting at subjects with aplastic anemia who are refractory to immunosuppressive therapy (hereinafter also referred to as subjects).
Administration Period
[0062] Fixed dose period (initial dose evaluation period): Weeks 1 to 8
[0063] Romiplostim was administered at a dose of either 1 μg/kg, 3 μg/kg, 6 μg/kg or 10 μg/kg once a week for 8 weeks.
The initial dose was maintained during this period, and no dose adjustment was performed, except when satisfying the criteria for discontinuation in 3) below. [0064] Extension period: Weeks 9 to 52
[0065] The initial dose for the extension period was decided for each patient based on the efficacy and safety data of the fixed dose period (initial dose evaluation period). If a subject does not show a platelet response at week 9, the dose was increased by one level according to the dose adjustment table (extension period). If no platelet measurement is available due to the platelet transfusion, then that week's platelet response was considered as having no response.
Method for Adjusting Dose and Administration (Weeks 9 to 52)
1) Dose Escalation
[0066] During the extension period, dose escalation was allowed by one level according to the dose adjustment table (extension period). After the dose was increased, if a subject does not show a platelet response even after 4 weeks of administration of Romiplostim, it was allowed to increase the dose by one level, with the highest dose being 20 μg/kg. The necessity and timing of dose escalation after administering the same dose continuously for 4 weeks was decided by a doctor based on the safety and drug efficacy data for each subject.
2) Dose Adjustment
[0067] If a subject showed a platelet response, the dose was increased or decreased by one level according to the “Dose adjustment table (extension period)” (Table 2) and adjusted to an appropriate dose, at the discretion of a doctor to maintain the platelet response while referring to the efficacy and safety data of each subject. The highest dose was set to 20 μg/kg.
TABLE-US-00002 TABLE 2 Dose adjustment table (extension period) Romiplostim Dose 1 μg/kg 3 μg/kg 6 μg/kg 10 μg/kg 13 μg/kg 16 μg/kg 20 μg/kg
3) Criteria for Discontinuation and Resuming
[0068] If the platelet count exceeded 400×10.sup.9/L, the treatment was temporarily discontinued. When the platelet count fell to below 200×10.sup.9/L, administration was resumed at a reduced dose by one level from the dose before discontinuation, according to the dose adjustment table (Table 2). Once the platelet count fell to 50×10.sup.9/L or less at that dose, the dosing was changed to the temporarily discontinued dose.
[0069] If the platelet count exceeded 200×10.sup.9/L, the dose was decreased by one level, according to the dose adjustment table (Table 2). If the temporarily discontinued dose was 1 μg/kg, the dose when resuming administration was set to 1 μg/kg.
[0070] Other than the reasons above, the doctor can reduce the dose at any time if safety concerns arose.
Criteria for Tri-Lineage Response
[0071] The primary endpoint was set to the proportion of subjects achieving a platelet response at week 9, and the main secondary endpoints were set to the proportion of subjects achieving a platelet response, the time to platelet response, the proportion of subjects who became platelet transfusion independent, and the proportion of subjects achieving erythroid response and/or neutrophil response. These evaluation indicators were defined as follows.
[0072] Achieving tri-lineage response or tri-lineage response positive is defined as achieving platelet response, erythroid response and neutrophil response all together.
[0073] Definition of Evaluation Indicators [0074] Platelet response: when any of the following applies [0075] the platelet count has increased by 20×10.sup.9/L or more above baseline (the level before start of administration of Romiplostim) [0076] the platelet count is 10×10.sup.9/L or more, and has increased by 100% or more from baseline
[0077] However, the evaluation result for subjects within 7 days after platelet transfusion was set as “no response”. [0078] Erythroid response: when any of the following applies [0079] the hemoglobin concentration has increased by 1.5 g/dL or more above baseline without red blood cell transfusion in subjects with a hemoglobin concentration of less than 9.0 g/dL before Romiplostim administration [0080] the transfusion unit has reduced by 4 units or more for 8 consecutive weeks compared with the red blood cell transfusion requirement in the 8 weeks prior to Romiplostim administration
[0081] However, the evaluation result for subjects within 28 days after red blood cell transfusion was set as “no response”. [0082] Neutrophil response: when any of the following applies [0083] the neutrophil count has increased by 100% or more over the baseline in subjects with a neutrophil count of less than 0.5×10.sup.9/L before Romiplostim administration [0084] the neutrophil count has increased by 0.5×10.sup.9/L or more over the baseline in subjects with a neutrophil count of less than 1.0×10.sup.9/L before Romiplostim administration
[0085] However, the evaluation result for subjects within 7 days after G-CSF administration was set as “no response”. [0086] Transfusion Independence
[0087] Platelet transfusion or red blood cell transfusion free period of at least 8 consecutive weeks is achieved in subjects who received platelet transfusion or red blood cell transfusion as pretreatment 8 weeks prior to Romiplostim administration.
Results
[0088] The results of the Ph2 trial are shown in Table 4 and
[0089] Subcutaneous administration was started once a week at any dose of 1, 3, 6, or 10 μg/kg, and no dose adjustment (increase or decrease) was observed during the fixed dose period (initial dose evaluation period) until week 8. The proportion of subjects showing a platelet response at week 9, which was the primary endpoint of efficacy, increased with the dose escalation, and was 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. In addition, the proportion of subjects showing an erythroid response and/or neutrophil response during the initial dose evaluation period also increased with dose escalation, and was 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. From the above results, 10 μg/kg was found to achieve a significant platelet response, erythroid response and/or neutrophil response during the initial dose evaluation period and was set as the treatment starting dose of the Phase II/III clinical (Ph2/3) trial described later.
Example 2
[0090] Phase II/III Clinical (pH2/3) Trial
[0091] An international joint open-label intra-individual dose adjustment phase II/III clinical trial was conducted according to the following protocol, targeting at subjects with aplastic anemia who were refractory to immunosuppressive therapy or for whom immunosuppressive therapy is not indicated.
Administration Period (Weeks 1 to 52)
[0092] Romiplostim is administered subcutaneously once a week according to the following. [0093] Fixed dose period (Weeks 1 to 4)
The initial dose is set to 10 μg/kg, and the dose was fixed between weeks 1 and 4. [0094] Extension period (Weeks 5 to 52)
After week 5, the dose may be adjusted according to the following dose adjustment.
Dose Adjustment
1) Dose Escalation
[0095] If a subject does not show a platelet response for 4 consecutive weeks, the dose was increased by one level according to the dose adjustment table (Table 3). However, even if a subject does not show a platelet response, if there were concerns about the expression of adverse events, deterioration, or the like, the dose of the study drug may be maintained at the discretion of a doctor.
[0096] In addition, even if a subject shows a platelet response, if deemed necessary by the doctor, it was allowed to increase the dose by one level every 4 weeks.
TABLE-US-00003 TABLE 3 Dose adjustment table Romiplostim Dose 5 μg/kg 10 μg/kg 15 μg/kg 20 μg/kg
2) Dose Decrease and Discontinuation
[0097] At a dose of 10 to 20 μg/kg, if the same dose was administered for 8 consecutive weeks or more, and during this period, all the following tri-lineage values were maintained for 8 weeks without transfusion, the dose was decreased by one level according to the dose adjustment table (Table 3). Furthermore, if the decreased dose was administered for 4 consecutive weeks, and during this period, all the following tri-lineage values were maintained without transfusion, the dose was further decreased by one level according to the dose adjustment table (Table 3).
[0098] In addition, at a dose of 5 μg/kg, if the same dose was administered for 4 consecutive weeks or more, and during this period, all the following tri-lineage values were satisfied for 4 weeks without transfusion, Romiplostim was discontinued.
[0099] However, during the extended administration period, if the doctor considered that the following tri-lineage values could not be maintained due to dose decrease or discontinuation, it was allowed to postpone dose decrease or discontinuation. [0100] Platelet count: >50×10.sup.9/L [0101] Hemoglobin concentration: >10.0 g/dL [0102] Neutrophil count: >1×10.sup.9/L
3) Criteria for Dose Re-Escalation and Resuming Administration
[0103] While tapering, if either of the platelet count, hemoglobin concentration or neutrophil count dropped to the following values, tapering was stopped and the dose was increased by one level according to the dose adjustment table (Table 3). While discontinuation, if either of the platelet count, hemoglobin concentration or neutrophil count dropped to the following values, administration was resumed at 5 μg/kg. [0104] Platelet count: <30×10.sup.9/L [0105] Hemoglobin concentration: <9.0 g/dL [0106] Neutrophil count: <0.5×10.sup.9/L
4) Criteria for Dose Maintenance
[0107] While tapering, if a subject does not meet the criteria for tapering or re-escalation the dose, the dose was kept stable and administration was continued.
Criteria for Tri-Lineage Response
[0108] Platelet response: when any of the following is satisfied [0109] the platelet count has increased by 20×10.sup.9/L or more above the baseline [0110] the platelet count is 10×10.sup.9/L or more, and has increased by 100% or more from the baseline [0111] no platelet transfusion has been performed for 8 consecutive weeks in subjects who received platelet transfusion as pretreatment in the 8 weeks prior to the first administration [0112] Erythroid response: when any of the following is satisfied [0113] the hemoglobin concentration has increased by 1.5 g/dL or more without red blood cell transfusion in subjects with a baseline hemoglobin concentration of less than 9.0 g/dL [0114] the volume of transfusion has cumulatively decreased by 800 mL or more for 8 consecutive weeks in subjects who received red blood cell transfusion as pretreatment in the 8 weeks prior to the first administration [0115] Neutrophil response: when any of the following is satisfied [0116] in subjects with a baseline neutrophil count of less than 0.5×10.sup.9/L, the neutrophil count has increased by 100% or more from the baseline [0117] in subjects with a baseline neutrophil count of less than 1×10.sup.9/L, the neutrophil count has increased by 0.5×10.sup.9/L or more over the baseline
[0118] Achieving tri-lineage response or tri-lineage response positive is defined as achieving platelet response, erythroid response and neutrophil response all together. [0119] Transfusion Independence
[0120] Platelet transfusion or red blood cell transfusion free period of at least 8 consecutive weeks is achieved in subjects who received platelet transfusion or red blood cell transfusion as pretreatment in 8 weeks prior to Romiplostim administration.
Results
[0121] The results of the Ph2/3 trial are shown in Table 4 and
TABLE-US-00004 TABLE 4 Proportion of subjects showing tri-lineage response in Ph2 (10 μg/kg group) and all cases in Ph2/3 Week 27 Week 53 Ph2 (10 μg/kg group) 0% (0/10 subjects) 10.0% (1/10 subjects) Ph2/3 25.8% (8/31 subjects) 38.7% (12/31 subjects)
[0122] The proportion of subjects showing hematological response (either platelet response, erythroid response or neutrophil response) at week 27 was 83.9% in total. From the results of the present study, it became clear that a significant hematologic response (platelet response, erythroid response and/or neutrophil response) could be obtained by starting subcutaneous weekly administration of Romiplostim at 10 μg/kg to AA patients who are refractory to immunosuppressive therapy including ATG or for whom immunosuppressive therapy is not indicated, and then adjusting the dose of Romiplostim as appropriate to 5 to 20 μg/kg, with platelet response and platelet count, and adverse events as indicators.
Discussion
[0123] In the Ph2/3 trial, the dose increment is larger (5 μg/kg vs. 3 to 4 μg/kg) and the initial fixed dose period is shorter (4 weeks vs. 8 weeks) compared to the Ph2 trial. Moreover, the period up to the maximum dose of 20 μg/kg is also short (at least 9 weeks vs. 17 weeks).
[0124] The proportion of patients with a tri-lineage response positive was higher in the Ph2/3 trial (31 subjects in total) than in 10 subjects of the group starting with 10 μg/kg initial dose in the Ph2 trial (hereinafter also referred to as Ph2 (10 μg/kg group)) both at week 27 and week 53. The proportion was further increased from week 27 to week 53. It is considered that the difference in drug efficacy between Ph2 and Ph2/3 is based on the differences in the duration of the fixed dose period and the dose adjustment method. It was found that a strong drug efficacy is exhibited compared to known administration methods, and that the drug efficacy is maintained even after one year, by increasing the initial dose of 10 μg/kg to 20 μg/kg in a short time period according to the administration method of the Ph2/3 trial. In addition, even after week 17, when the dose could be increased to 20 μg/kg in the Ph2 (10 μg/kg group), the difference in drug efficacy with the Ph2/3 group was observed for a long time. When considering the transition of platelet, hemoglobin level and neutrophil level in
[0125] It is possible to reach the maximum dose early on by setting the fixed dose period (10 μg/kg) to 4 weeks, then adjusting the dose by a dose increment of 5 μg/kg/week according to the dose and administration of the Ph2/3 trial. According to this dose and administration, high drug efficacy (increased platelet, hemoglobin level and/or neutrophil level) can be achieved, and the effect continues even after reaching the maximum dose. As a result, an excellent improvement effect can be expected even in AA patients who are refractory to immunosuppressive therapy or for whom immunosuppressive therapy is not indicated.
INDUSTRIAL APPLICABILITY
[0126] According to the present invention, high drug efficacy can be achieved in the treatment of aplastic anemia with Romiplostim; and a treatment effective for aplastic anemia patients for whom sufficient effect was not obtained with conventional treatment such as immunosuppressive therapy can be provided.
[0127] All publications, patents and patent applications cited in the present description are incorporated herein by reference in their entirety.
Sequence Listing Free Text
[0128] SEQ ID No.1: Thrombopoietin fusion protein analog