How to treat idiopathic thrombocytopenic purpura (ITP) with romiplostim

Abstract

The present invention provides a method of treating idiopathic thrombocytopenic purpura (ITP) in a patient with ITP, comprising the steps of: (a) administering romiplostim to said patient weekly; (b) administering romiplostim to a patient with a platelet count of at least about 50×10 9 / L〜200×10 9 (c) increasing the weekly dose until the platelet count reaches 200 × 10 / L for two consecutive weeks; 9 (d) reducing the weekly dose of romiplostim if the platelet count remains above 200 × 10 for two consecutive weeks at a weekly dose of 1 μg / kg; 9 / L or above, or if the platelet count remains 400 × 10 9 / L or greater; and (e) discontinuing romiplostim if platelet count is ≥ 200 x 10 within the first 4 to 12 weeks of treatment. 9 / L or greater, maintaining a treatment-free period of at least about 24 weeks in which the patient is not administered romiplostim.

Description

[Technical Field]

[0001] Primary ITP is an autoimmune disorder characterized by suboptimal platelet production and accelerated platelet destruction, mediated by both antibodies and T cells (Nugent et al, 2009). In adults, ITP often follows a chronic course and leads to an increased risk of subcutaneous and cutaneous bleeding, a reduced quality of life, and, rarely, severe bleeding (Cines & McMillan, 2005). [Background technology]

[0002] The primary treatment goal in these patients is to achieve sustained improvement in platelet count without the need for continuous treatment. Current treatments include first-line treatments such as corticosteroids, anti-D immunoglobulin, and intravenous immunoglobulin (IVIg), and second-line treatments such as romiplostim, eltrombopag, rituximab, and splenectomy. While these first-line treatments can elicit a platelet response in the majority of patients, the response may only be observed for a few weeks to a few months (Provan et al, 2010). For second-line treatments such as rituximab, 15-20% of patients may show significant improvement for up to 5 years. Splenectomy has a long-term response rate of approximately two-thirds (Provan et al, 2010).

[0003] Since adverse effects are associated with all first-line and second-line treatments, the benefits of these treatments must be weighed against their potential risks. Because corticosteroids have well-known side effects, clinicians often seek steroid-saving methods. IVIg and anti-D immunoglobulins are associated with infusion reactions, headaches, and hemolytic anemia. Immunosuppressants are associated with an increased risk of infection. These adverse effects and low response rates limit the usefulness of these methods.

[0004] Romiplostim is a thrombopoietin (TPO) receptor agonist that has been shown to increase and maintain platelet counts for up to 5 years, and to reduce the frequency of bleeding, splenectomy, treatment failure, and rescue medication use (Kuter et al, 2008, 2010, 2013). Romiplostim is approved in various regions worldwide for the treatment of chronic ITP in adults. In the United States, romiplostim is approved for use in adults for the treatment of chronic immune thrombocytopenia that is inadequately responsive to corticosteroids, immunoglobulins, or splenectomy. In Europe, it is approved for use in individuals who have undergone splenectomy and are refractory to other treatments, or as a second-line treatment for patients for whom surgery is contraindicated and who have not undergone splenectomy. Romiplostim is effective for platelet counts of 50 × 10⁶ 9 / L~200×10 9 To achieve and maintain / L, the starting dose is 1 μg / kg, and the weekly dose is adjusted by 1 μg / kg increments.

[0005] Data is emerging regarding the use of romiplostim in children with chronic immune thrombocytopenia (ITP). Treatment of children with ITP is often guided by data from adult trials, preliminary pediatric trials, and expert opinions. Three large randomized controlled trials in children with ITP have demonstrated that treatment with TPO receptor agonists is more effective than placebo and that there are no unexpected or unforeseen adverse events. However, data on the long-term effects of treatment in children with ITP are lacking.

[0006] Romiplostim can induce a platelet response in approximately 80–90% of ITP patients (Bussel et al, 2009; Kuter et al, 2010), but long-term treatment may be necessary to maintain the platelet response. However, long-term treatment can be associated with treatment compliance issues and significant costs (Ghanima et al, 2012).

[0007] The rising data suggest that a certain proportion of patients with recurrent or refractory diseases can achieve remission persistence after discontinuing romiplostim (Vlachaki et al, 2011; Ghadaki et al, 2013; Thachil et al, 2013; Mahevas et al, 2014; Provan et al, 2014; Tarantino et al, 2016, Tarantino et al, ASH 2017, abstract 14 as at: https: / / ash.confex.com / ash / 2017 / webprogram / Paper100126.html). Newland et al., 2016 conducted a systematic prospective evaluation of remission using romiplostim, but ultimately concluded that no statistically significant predictors of remission were identified when examining other demographic or baseline characteristics. However, a higher mean platelet count during the first two months of treatment was associated with remission. The field would benefit from the discovery of predictors of remission and treatment methods that utilize such predictors.

Prior Art Documents

Non-Patent Documents

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[0009] In the study on which this specification is based, platelet counts increased to 200 × 10¹⁶ within the first 4 to 12 weeks of treatment. 9 It has been found that reaching a platelet count of 1 / L or higher is a predictor of remission. In this study, remission is defined as a treatment-free period of at least 24 weeks in which the patient does not receive romiplostim or other ITP drug treatments. Accordingly, the present invention relates to a method for treating ITP in a patient having ITP, comprising the steps of (a) administering romiplostim to the patient weekly; and (b) a platelet count of at least about 50 × 10⁶. 9 / L~200×10 9 Steps to increase the weekly dose until the / L is reached; (c) platelet count is 200 × 10 for two consecutive weeks. 9When maintaining at / L or above, the step of reducing the weekly dose of romiplostim; (d) when the weekly dose is 1 μg / kg and the platelet count has been 200×10 9 / L or above for 2 consecutive weeks, or when the platelet count is 400×10 9 / L or above, the step of discontinuing romiplostim; and (e) when the platelet count reaches 200×10 9 / L or above within the first 4 to 12 weeks of treatment, the method includes maintaining a treatment-free period of at least about 24 weeks during which the patient is not administered romiplostim.

[0010] The present invention also relates to the above method including the step of administering an initial dose of 1 μg / kg of romiplostim to the patient.

[0011] The present invention further relates to the above method including the step of maintaining the weekly dose as long as the platelet count is within about 50×10 9 / L to 200×10 9 / L.

[0012] The present invention further relates to the above method wherein the platelet count is 200×10 9 / L or above in the first 4 weeks of treatment.

[0013] The present invention further relates to the above method wherein the increase in the dose of romiplostim is made in increments of 1 μg / kg per week.

[0014] The present invention further relates to the above method wherein the dose in step c is decreased in increments of 1 μg / kg.

[0015] The present invention further relates to the above method wherein the platelet count of the patient is maintained at 50×10 9 / L or above during the treatment-free period.

[0016] The present invention further relates to the above method wherein the patient does not receive ITP drug treatment during the treatment-free period.

Brief Description of the Drawings

[0017] [Figure 1] The flowchart of the trial is shown. Of the 21 patients enrolled in the first extension trial, one withdrew their consent before treatment. Of the 66 patients who moved on to the second extension trial, one withdrew their consent before treatment. [Figure 2] The breakdown of patients enrolled in the trial is as follows: Of the three patients who discontinued romiplostim according to the protocol, two achieved remission, and one had a platelet count of less than 30 × 10⁹ / L despite receiving 10 μg / kg for 10 weeks. The 37 patients who completed romiplostim treatment received the drug until the trial ended in January 2017, 12 months after the last patient was enrolled. [Figure 3A] This graph shows the dose of romiplostim over time. The median dose (Q1, Q3) is shown on the y-axis, and the number of weeks in the study is shown on the x-axis. [Figure 3B] This graph shows platelet counts over time. The median platelet count (Q1, Q3) is shown on the y-axis, and the number of weeks in the study is shown on the x-axis. [Figure 4A] This shows the time course of bleeding for all patients and for patients with grade 2 or higher. [Figure 4B] The patient exhibits bleeding of grade 2 or higher over time. [Figures 5A-5D] Data regarding remission is shown. Figure 5A shows the probability of achieving remission plotted against the time required to achieve remission, with the number of patients at risk at each time point shown along the x-axis. Figure 5B shows the number of patients who achieved remission, categorized by the duration of remission observed in the trial. Figures 5C and 5D show the dosage and platelet count achieved by two individual patients over the period of Phase 1 / 2, the first extension trial, and the second extension trial. [Figure 6] For the selected remission characteristics, the hazard ratio and p-value are shown. [Figure 7A-7M] Furthermore, remission data for 13 patients is shown, as explained in Figures 5C and 5D. [Modes for carrying out the invention]

[0018] TPO receptor agonists are not a foolproof treatment option for ITP because not all patients respond, and even those who do not always maintain that response. The invention in this paper is based on the largest study to date in children using a TPO receptor agonist (65 patients, over 182 patient-years, or 2.8 years of exposure per patient). Importantly, approximately one-quarter of the patients were able to discontinue ITP treatment and still maintained hemostatic platelet counts. The data presented in this paper are large in scale, both in terms of patient number (n=65) and treatment duration (up to 7 years), and demonstrate that romiplostim has an efficacy and safety profile that appears similar to that observed in adults.

[0019] The objective of the study was to describe the safety and efficacy of long-term use of romiplostim in children with ITP, along with the incidence of adverse events as the primary endpoint. Secondary endpoints included long-term platelet response, bleeding, reduction in the use of concomitant ITP medications (both continuation of baseline medications and rescue medications), and platelet count of 50 × 10¹⁶ over 6 months without ITP medications including romiplostim. 9 The post-progressive evaluation included maintaining a level of / L or higher (defined here as remission).

[0020] method patient Eligible patients are those who have previously participated in the romiplostim ITP trial. 6、7 Participants were required to have completed the study outlined in (Bussel et al., 2011; Tarantino et al., 2016) and to be 18 years of age or younger at the time of enrollment. Exclusion criteria included a history of myelostem cell dysfunction, venous or arterial thrombotic or thromboembolic events, systemic lupus erythematosus, Evans syndrome, or other secondary causes of thrombocytopenia. The study was conducted at each study site in accordance with all regulatory obligations and Institutional Review Board and informed consent procedures. All patients or their legal representatives submitted written informed consent and agreement.

[0021] procedure Patients were recruited from 28 sites in the United States, Canada, Spain, and Australia. The trial (clinicaltrials.gov, identifier: NCT01071954) ran from December 30, 2009 (first subject enrollment) to January 12, 2017 (last patient visit). During the trial period, patients received romiplostim subcutaneously weekly, starting at the same dose as the final dose in the parent trial or 1 μg / kg (if they had previously received placebo or more than 24 weeks had passed since the last dose). The dose was based on a platelet count of 50 × 10⁶. 9 / L~200×10 9 The target was / L, and the dosage was adjusted weekly in 1 μg / kg increments between 1 and 10 μg / kg. Patients were able to continue receiving other ITP drug therapies (e.g., corticosteroids, danazol, or azathioprine) that were stable in dose and schedule before the start of the study. These additional drug therapies reduced platelet counts to 50 × 10 9 After exceeding / L, the dosage could be reduced or discontinued at the discretion of the patient and physician.

[0022] The patient has a platelet count of 10 × 10 9 Rescue treatment was available if the platelet count fell below / L, if bleeding or wet purpura occurred, or if the principal investigator deemed it medically necessary (e.g., before travel or procedure). Rescue treatment was defined as any drug treatment administered to increase platelet count and included intravenous immunoglobulin G (IVIg), anti-D, platelet transfusions, steroids, and antifibrinolytic agents (e.g., epsilon-aminocaproic acid, tranexamic acid).

[0023] Evaluation, outcomes, and statistics Platelet count, concomitant drug therapy, and adverse events were evaluated at each visit. Samples were collected every four weeks for complete blood count and blood chemistry tests, and a physical examination was performed in the first week and every 12 weeks thereafter. Efficacy outcomes included platelet count and platelet response (platelet count of 50 × 10⁶ in the past four weeks without rescue therapy). 9This included platelet counts (≥ / L). Platelet count data within 4 weeks of rescue therapy use were excluded from the continuous summary. Subjects who could not obtain weekly platelet counts due to self-administration or other reasons had their platelet count measurements postponed, provided that rescue therapy was not used within 4 weeks of absence. Other efficacy evaluations included the proportion of patients using other ITP drug therapies and the proportion of patients requiring rescue therapy. Remission was defined as a platelet count of 50 × 10¹⁶ for at least 24 weeks without any ITP drug therapy, including romiplostim. 9 It was defined as / L or higher.

[0024] safety Safety assessments included investigation of adverse events (including bleeding), physical examination, vital signs, serological chemistry, complete blood count, platelet count, and antibody status. Samples were tested for binding antibodies to romiplostim and TPO, and any sample positive for binding antibodies to either was further tested for neutralizing antibodies. Medically significant adverse events considered by the principal investigator to be treatment-related were followed until they resolved or were considered stable. For each adverse event, the principal investigator assigned the following attributes: description; date of onset and resolution; severity; assessment of association with treatment, other suspected drugs or devices; and actions taken (e.g., discontinuation of romiplostim, treatment with another drug, hospitalization, etc.). The severity of toxicity was assessed using the Standard Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 adverse event grading system: 1. Mild, 2. Moderate, 3. Severe, 4. Life-threatening, 5. Fatal. Serious adverse events included any adverse event that was fatal, life-threatening, required hospitalization, or prolonged the current hospital stay. Thromboembolic events were assessed as part of the overall adverse event assessment. Bone marrow aspiration and biopsy were not required at any point, but could be performed at the discretion of the principal investigator if, for example, there were abnormalities in peripheral blood smears (e.g., nucleated or teardrop-shaped red blood cells) or if there was a loss of response to romiplostim despite dose increases. Blood samples for antibody assays against TPO and romiplostim were collected at week 1, week 52, annually, and at the end of the study.

[0025] Data Analysis Statistical analysis was descriptive. Categorical endpoints were summarized by the number and percentage of patients in each category. Continuous endpoints were summarized by the number of patients, mean, standard deviation, median, and the 25th (Q1) and 75th (Q3) percentiles, minimum and maximum values. Adverse events were also summarized as the number of events and the rate per 100 patient-years of exposure.

[0026] For subjects who did not achieve remission and were censored at the time of final platelet count measurement, a proportional hazards model was used to evaluate potential predictors of remission. For univariate models, each potential factor was considered individually (similar to a log-rank test). For events that appeared to contradict the proportional hazards hypothesis, nonparametric tests (Fisher's exact test for categorical variables and the Kruskal-Wallis test for continuous variables) were used instead. For multivariate models, the variable augmentation criterion was used with a significance level of 0.05 at enrollment and termination.

[0027] result Demographics and breakdown The patient flow from the parent trial is shown in Figure 1. 66 patients were enrolled in this extension trial, one withdrew consent before treatment, and 65 received romiplostim for 7 years or less. Of these patients, 15 had previously received placebo and were exposed to romiplostim for the first time in this trial. At baseline, the median (minimum-maximum) age was 11 (3-18) years. 56% were female. 61% were Caucasian, 14% African American, 14% Hispanic / Latin American, 9% Asian, and 3% other. The median (minimum-maximum) baseline platelet count was 27.5 (2-458) × 10⁻⁶. 9 The rate was / L (Table 1). Patients were able to transition to this trial without interrupting romiplostim administration from previous trials. Previous ITP treatments included IVIg, anti-D, corticosteroids, and rituximab, and 9% had previously undergone splenectomy (Table 2).

[0028] Reasons for discontinuing romiplostim (n=28, 42%) included withdrawal of consent (n=10), need for other therapy (n=6), non-compliance with treatment (n=4), protocol (n=3), administrative decision (n=2), adverse events (n=2), and no need for treatment (n=1). Adverse events included asthenia, headache, dehydration, and vomiting in one patient, and anxiety in another. These adverse events were not considered treatment-related by the principal investigator. Romiplostim was administered to 37 patients (56%) until the end of the study (Figure 2).

[0029] Romiprostim exposure The median (minimum-maximum) romiplostim treatment duration was 135 (5-363) weeks, or a median of 2.6 years, per patient, totaling 182 patient-years. The median (minimum-maximum) mean weekly romiplostim dose, including escalations to a stable dose, was 4.8 (0.1-10) μg / kg. The mean maximum weekly romiplostim dose was 6.9 μg / kg, and the median maximum weekly dose was 8.0 μg / kg. Twenty patients started with 1 μg / kg of romiplostim, including 15 patients (23%) who had received placebo in a previous trial. All 65 patients received the protocol dose for more than 90% of the duration. Twenty-one patients missed one or more doses out of a total of 65 due to treatment non-compliance. The dose over time was typically around 4-5 μg / kg, as shown in Figure 3A. After 240 weeks (n≦7), the dosage fluctuated.

[0030] safety The most common adverse events were headache and contusion (Table 3 below). Of the 54 serious adverse events, 19 patients experienced serious adverse events, but only one patient (who had grade 4 thrombocytopenia, grade 3 epistaxis, and grade 2 anemia) was considered treatment-related (a complete list of serious adverse events is in Supplemental Table 1 below). Bleeding adverse events occurred in 57 patients. Three bleeding adverse events were thought to be treatment-related (injection site bleeding, injection site subcutaneous bleeding, and epistaxis). The most common bleeding adverse events were contusion (51%), epistaxis (49%), petechiae (31%), and gingival bleeding (20%). There were no cases of intracranial hemorrhage. Specific bleeding events reported included menorrhagia (n=7, 4%), hematuria (n=4, 2%), rectal bleeding (n=4, 2%), hemoptysis (n=3, 2%), anal bleeding (n=2, 1%), bloody stool (n=2, 1%), and hematemesis (n=1, 0.6%). Seven patients experienced severe or grade 3 bleeding (see Table 2 in the supplement below), and one case of exacerbation of epistaxis was considered treatment-related. No arterial or venous thromboembolic events were reported. Notably, excluding one patient with 499 adverse events would reduce the contusion rate from 239 to 92 per 100 patient-years. One child (a 7-year-old boy who participated in the study for 3.4 years) also experienced several serious adverse events, namely, six cases of decreased platelet count, and one case each of headache, head injury, vomiting, leukopenia, hematoma, streptococcal pharyngitis, and gastroenteritis.

[0031] Post-administration antibodies were assayed annually in 60 patients. One patient withdrew from the study to receive other therapy, and anti-romiplostim neutralizing antibodies were detected; however, these neutralizing antibodies were not found in follow-up tests at 3 and 6 months. This girl required several additional therapies and is stable with mycophenolic acid. Despite annual antibody assays over 200 patient-years of exposure (including the period of previous romiplostim trials), no patients had anti-TPO neutralizing antibodies.

[0032] Bone marrow biopsies were performed in two patients with further cytopenia. Both patients were found to have iron deficiency anemia and had neither fibrosis nor malignant tumors. The first biopsy was performed two years after the start of the study to evaluate persistent anemia in a 17-year-old girl. Her anemia improved with regular iron supplementation and reduced menstrual bleeding. The second biopsy was performed six weeks after the start of the study in an 11-year-old girl who had developed neutropenia and anemia. This patient received iron for anemia and had intermittent neutropenia, but eventually recovered.

[0033] Effectiveness From the second week of the trial, the median platelet count was 50 × 10 9 The platelet count remained above / L, and the median platelet count was 100 × 10 from week 24 to week 260. 9 The values ​​exceeded / L (Figure 3B). Almost all patients (94%, 61 out of 65) had a platelet response of 1 or higher (platelet count 50 × 10⁻¹⁰). 9 (Excluding counts with doses of ≥ / L and within 4 weeks after rescue treatment). The majority of patients (72%, 47 out of 65) had a platelet response of ≥75% during the period, and more than half of patients (58%, 38 out of 65) had a platelet response of ≥90% during the period. 60 patients (92%) (or caregivers) self-administered romiplostim (i.e., at home rather than in the hospital). 23 patients (35%) received rescue treatment (Table 4 below), with its use most frequently occurring in the first few months. At baseline, 5 patients were receiving other ITP drug therapy, including aminocaproic acid, prednisolone, prednisone, and tranexamic acid. Overall, 48% (31 out of 65) of patients were receiving other ITP drug therapy (from baseline or as rescue). The proportion of patients receiving these drug therapies decreased during the study period. Both overall bleeding and grade 2 or higher bleeding decreased over time (Figures 4A and B).

[0034] Remission / treatment-free period Fifteen patients (23%) had platelet counts of 50 x 10⁶ for more than 24 weeks without ITP drug treatment. 9The platelet count remained above 1 / L (i.e., the treatment-free period, defined here as remission; Table 5, Figures 5A-D). At the start of the treatment-free period, these patients (9 girls and 6 boys) had ITP for a median (minimum-maximum) of 4 (1-12) years and had been receiving romiplostim for 3 (1-7) years. None of these patients had previously undergone splenectomy. The median (minimum-maximum) baseline platelet count was 14 (1-44) × 10⁶ 9 The value was / L. These treatment-free periods lasted a median (minimum-maximum) of 1 (0.6-2.1) year, and all but one patient still had a platelet count of 50 × 10 at the end of the study without receiving any treatment. 9 The value is greater than / L. In the last few months of dose reduction, the median (minimum-maximum) peak platelet count was 299 (217-730) × 10⁻¹⁶. 9 The value was / L. One month after discontinuation, i.e., when drug effects / rebound phenomena were no longer expected, the median (minimum-maximum) peak platelet count was 249 (150-450) × 10⁻¹⁴. 9 / L, median (minimum-maximum) minimum platelet count is 113 (77-311) × 10 9 The platelet count was / L (as seen in the individual patient plots, Figures 5A-D). All 15 of these patients had platelet counts of 100 × 10⁶ for more than 3 months without ITP drug treatment, and 12 of the 15 had platelet counts of 100 × 10⁶ for more than 6 months. 9 The levels exceeded / L. These 15 patients were 100 × 10 9 The median (minimum-maximum) period for periods above / L was 42 weeks (13-109 weeks).

[0035] Baseline characteristics and early treatment outcomes, such as ITP duration, previous ITP treatment, and platelet count in the first four weeks, were evaluated in a post-hoc analysis. A younger age at diagnosis, a younger age at initial administration, and a platelet count of 200 × 10¹¹ in the first four weeks were also considered important factors. 9 All factors, including a platelet count of ≥ / L and a higher mean platelet count during the first four weeks, were associated with a higher likelihood of remission in univariate analysis (Table 5, Figure 3). In multivariate analysis, age at initial administration (p=0.001) and platelet count of 200 × 10¹⁶ during the first four weeks were associated with a higher likelihood of remission. 9A platelet count of ≥ / L (p=0.004) was a predictor of remission. Notably, the models for prior rituximab use (p=1.0) and prior splenectomy (p=0.32) were non-proportional hazards, and therefore no hazard ratios were found. When multivariate analysis was performed based on baseline age, patients who were under 10 years old at the time of initial administration (N=32) had less than 3 prior ITP treatments and a platelet count of 200 × 10¹⁶ in the first 12 weeks. 9 A platelet count of 200 × 10¹⁶ / L or higher was a prediction of remission. For patients who were under 10 years old at the time of diagnosis (N=49), the age at the time of the first dose was lower, and the platelet count was 200 × 10¹⁶ in the first four weeks. 9 / L or higher, mean platelet count of 100 × 10¹⁶ in the first 12 weeks 9 A blood glucose level of ≥ / L and the use of rescue therapy in the first six months were also predictive factors, although the use of rescue therapy was a negative predictor. Patients aged 10 years or older were too few to be used as a model for predicting remission.

[0036] Consideration Effectiveness As evidenced by the fact that the majority of children (72%) had a platelet response of 75% or higher during the period, and more than half of the children (58%, 38 out of 65) had a platelet response of 90% or higher during the period, romiplostim treatment frequently led to a sustained platelet response. Furthermore, the median platelet count reached the desirable range (50 × 10) from the second week onward. 9 / L~200×10 9 It was maintained at / L) and from week 24 to week 260 it was 100 × 10 9 It exceeded / L.

[0037] Patients in this trial were also able to reduce their use of other ITP drug therapies and reported fewer bleeding events over time, particularly clinically significant bleeding (grade 2 or higher).

[0038] safety The data from this trial showed that romiplostim was well-tolerated, with no thrombotic events, myeloma changes, deaths, or new safety concerns, despite 182 patient-years, or nearly three years, of exposure to romiplostim per patient.

[0039] The median dose was similar to that of the Phase 3 trial (approximately 4-5 μg / kg).

[0040] Approximately 30% of patients experienced serious adverse events, but only one patient experienced treatment-related serious adverse events (thrombocytopenia, epistaxis, and anemia).

[0041] Despite a large number of patient-years of treatment, only one patient was confirmed to have developed anti-romiplostim neutralizing antibodies, and no patients had neutralizing antibodies against TPO. This is consistent with observations made in adults treated for ITP. In the integrated database of romiplostim ITP trials, anti-romiplostim neutralizing antibodies were found in 4 out of 1046 patients with a total exposure of 1832 patient-years. 9 All four patients continued to show a platelet response to romiplostim.

[0042] Bone marrow biopsies were performed when the principal investigator deemed them clinically necessary. Two patients underwent bone marrow biopsies due to further cytopenia; both had iron deficiency anemia.

[0043] No cases of thrombosis were observed. In adult trials of romiplostim, the incidence of thrombosis was low, and there was no significant difference between placebo and standard treatment (Cines et al., 2015). 10

[0044] Only two patients discontinued the trial due to adverse events, but overall, 42% (28 out of 66 patients) dropped out before the end of the trial. The most common reasons for dropping out were withdrawal of consent (n=10) and the need for alternative therapy (n=4).

[0045] Remission / treatment-free period A pleasant surprise was that nearly a quarter of the patients (15 out of 65) were able to discontinue all ITP treatment (including romiplostim) after 0.7 to 6 years of romiplostim administration, and still maintained a hemostatic platelet count (50 x 10) for at least 6 months. 9 The goal was to maintain a platelet count of ≥ / L (defined here as remission). Only one out of 15 patients relapsed and required further treatment with 1 μg / kg romiplostim. At the last time contact was made, this patient had a platelet count of 400 × 10¹⁶ 9 I had stopped taking Romiprostim again because I reached / L.

[0046] In multivariate analysis, both a younger age at initial administration and a higher mean platelet count during the first eight weeks were associated with a higher likelihood of remission. This is particularly interesting because, while a previous adult study had also observed a higher mean platelet count during the first eight weeks being associated with a higher likelihood of remission, the authors ultimately concluded that no statistically significant predictors of remission were found when other demographic or baseline characteristics were examined (Newland et al., 2016).

[0047] Regarding the analysis of remission, it should be noted that even if the factors were not judged to be predictive of remission in this study, the possibility remains. This is because the population was small in size or not a suitable population for the study. The absence of evidence is not evidence of non-existence.

[0048] Furthermore, it should be noted that the definition of remission can vary considerably, and in some cases, the platelet threshold may be higher (e.g., 50 × 10⁻⁶). 9 / L is not 100x10 9 / L), and / or the duration may be longer (e.g., 1 year instead of 6 months). For the purposes of this specification, remission is defined as a platelet threshold of 50 × 10⁶ months (24 weeks) without ITP drug treatment. 9This is defined as maintaining the / L level.

[0049] The occurrence of remission was not entirely predicted, and although remission was not a designated test evaluation item, it was an observed phenomenon.

[0050] While remission in children may differ significantly from that observed in adults, this finding is consistent with previous romiplostim trials in adults with ITP (including a trial in which 75 patients with ITP for 6 months or less were treated with romiplostim for 12 months or less, followed by forced tapering) (Newland et al., 2016). 11 Remission was observed in 24 patients (32%), and there were no significant predictors. The majority of patients (20 out of 24) began remission before forced tapering.

[0051] The treatment-free period was also observed in adults with ITP in the eltrombopag extension trial (Saleh et al., 2013). 12 Among these, long-term response (more than 12 weeks without ITP drug treatment including eltrombopag, platelet count 50 × 10 9 ITP (defined as ≥ / L) was observed in 13 out of 325 patients (4%). The median (minimum-maximum) time from ITP diagnosis was 26 months (9-128), and the median (minimum-maximum) duration of eltrombopag treatment in the extension trial prior to the long-term response was 160 days (14-1107).

[0052] In a retrospective evaluation of adults with ITP treated with eltrombopag, 80 out of 201 patients showed marked improvement (platelet count 100 × 10⁶). 9 The result was (exceeding / L), and Eltrombopag was discontinued (Gonzalez-Lopez et al., 2015). 13 Of the 49 evaluable patients, 26 showed a sustained response for at least 6 months after discontinuation of eltrombopag without additional ITP therapy. No predictors of a sustained response after discontinuation of eltrombopag were identified.

[0053] As stated above, the definitions of response, remission, and sustained response can vary considerably. In the studies reported herein, a response was defined as a platelet count of 50 × 10⁶. 9 For platelet counts of 50 × 10¹ / L or higher, and for remission, platelet counts of 50 × 10¹² / L or higher without ITP drug treatment for 6 months or more. 9 A value of 1 / L or higher was selected. Other studies used different platelet thresholds for response and different treatment-free periods. For example, the response by IWG (Rodeghiero et al.) 14 There is a 30x10 9 / L and 100×10 9 The threshold of / L was used for both response and marked efficacy in a state where there was no bleeding, or in long-term rituximab trials (Patel et al., 2012). 15 As in the above, a treatment-free period of at least one year was used.

[0054] As seen in the inventors' trials, the longer duration of ITP before remission suggests that this remission is likely not spontaneous but attributable to romiplostim, indicating that romiplostim may be a disease-altering agent. This is unexpected, as romiplostim is not known to be immunomodulatory. While not bound by theory, possible mechanisms of action include: • Enhancement of regulatory T cell function (Bao et al., 2010; Chong, 2010; Son et al., 2015) 16~18 • Natural killer T cells (Johansson et al., 2005) 19 • Regulatory B cell activity (Li et al., 2012) 20 • Induction of crystallizable fragment receptor IIb (FcRIIb) and inhibitory FcR (Liu et al., 2016) 21

[0055] The occurrence of remission in nearly a quarter of patients suggests that maintenance with romiplostim is not an unclear "lifelong treatment"; the response in the first eight weeks may indicate whether a patient is more likely to enter remission.

[0056] [Table 1]

[0057] [Table 2]

[0058] [Table 3]

[0059] [Table 4]

[0060] [Table 5]

[0061] [Table 6]

[0062] Supplementary table

[0063] [Table 7]

[0064] [Table 8]

[0065] [Table 9]

[0066] To confirm that the results observed in the above pediatric trials correlate with those in the adult population, retrospective statistical analyses were performed on two adult trials (clinical trials 20080009 and 20080435). Trial 0009, reported by Janssens et al. (2016), concerned chronic ITP treated with romiplostim for up to 3 years. Trial 0435, reported by Newland et al. (2015), was a specific attempt to confirm whether subjects achieved remission with tapering in early ITP treatment with romiplostim for up to 1 year. In both trials, individually, platelet counts increased by 200 × 10⁶ within the first 4, 8, and 12 weeks of romiplostim treatment. 9 The study showed that having a platelet count of 200 × 10¹⁶ / L or higher was associated with a higher remission rate. In the "0009 trial," a second, more conservative related trial was used. In both adult trials, a platelet count of 200 × 10¹⁶ within the first 8 weeks was associated with a higher remission rate. 9 Reaching a level of / L or higher is the strongest predictor of entering remission. The analysis results are shown in Tables A to D below.

[0067] [Table 10]

[0068] [Table 11]

[0069] [Table 12]

[0070] [Table 13]

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Provan,D.,Taylor,L.,Nandigham,R.,Doobaree,U.,Kalkur,P.& Newland,A.(2014).Sustained responses following treatment with romiplostim in immune thrombocytopenia: a single-centre experience.Journal of Hematology & Thromboembolic Diseases,2,147 Rodeghiero F.,Stasi R.,Gernsheimer T.et al.(2009).Standardization of terminology,definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.Blood 113:2386-93. Saleh M.N.,Bussel J.B.,Cheng G.et al.(2013).Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term,open-label EXTEND study.Blood 121:537-45. Son B.R.,Kim J.Y.(2015).Association of CD4(+)CD25(+)FoxP3(+)regulatory T cells with natural course of childhood chronic immune thrombocytopenic purpura.Korean J Pediatr 58: 178-82. 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[0072] Each reference cited herein is incorporated by reference in its entirety. Naturally, the specific methodologies, protocols, and materials described may vary, and the disclosed invention is not limited thereto. Furthermore, naturally, the terms used herein are for the purpose of describing specific embodiments and do not limit the scope of the appended claims.

[0073] Those skilled in the art will be able to recognize or confirm, by mere routine experimentation, many equivalents to the specific embodiments of the present invention described herein. Such equivalents shall be covered by the following claims.

Claims

1. A pharmaceutical composition comprising romiplostim for treating idiopathic thrombocytopenic purpura (ITP) in patients with ITP, a. A step of administering romiplostim to a patient weekly, including administering an initial dose of 1 μg / kg of romiplostim to the patient; b. Platelet count is at least approximately 50 × 10 ９ / L~200×10 ９ The step of increasing the weekly dose until it reaches / L, where the increase in the dose of romiplostim is an increase of 1 μg / kg per week; c. Platelet count was 200 x 10 for two consecutive weeks. ９ If the level remains above / L, reduce the weekly dose of romiplostim. Here, in either step b or c, (i) When the weekly dose is 1 μg / kg, the platelet count is 200 × 10 for two consecutive weeks. ９ If the level remains above / L, (ii) Platelet count 400 × 10 ９ / If it is L or more The administration of romiplostim is discontinued; and d. A step in which patients are analyzed as remission factors if their platelet count reaches 200 × 10⁹ / L or higher within the first 4 to 12 weeks of treatment, where remission is defined as a platelet count of 50 × 10⁹ / L without ITP drug treatment for at least 24 weeks. ９ It is defined as maintaining a level of / L or higher; A pharmaceutical composition administered by a method comprising [a specific substance].

2. The method involves determining the platelet count to be approximately 50 x 10 ９ / L~200×10 ９ The pharmaceutical composition according to claim 1, comprising the step of maintaining a weekly dose as long as it is within / L.

3. If the platelet count reaches 200 × 10 ９ / L or more within the first 4 to 12 weeks of treatment, administration of romiplostim is discontinued, and the platelet count is 200 × 10 ９ / L or more in the first 4 weeks of treatment. The pharmaceutical composition according to claim 1.

4. Platelet count 200 x 10¹⁶ within the first 4-12 weeks of treatment ９ If the platelet count reaches 200 x 10⁶ / L or higher, administration of romiplostim should be discontinued, and the platelet count should be 200 x 10⁶ during the first 8 weeks of treatment. ９ The pharmaceutical composition according to claim 1, wherein the amount is 1 / L or more.

5. The pharmaceutical composition according to claim 1, wherein the dose in step c is reduced in increments of 1 μg / kg.

6. The pharmaceutical composition according to claim 1, wherein the patient does not receive ITP drug treatment during the treatment-free period.

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