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Pharmacology: Pharmacodynamics: Mechanism of action: Romiplostim is an Fc-peptide fusion protein (peptibody) that signals and activates intracellular transcriptional pathways via the thrombopoietin (TPO) receptor (also known as cMpl) to increase platelet production. The peptibody molecule is comprised of a human immunoglobulin IgG1 Fc domain, with each single-chain subunit covalently linked at the C-terminus to a peptide chain containing 2 TPO receptor-binding domains.
Romiplostim has no amino acid sequence homology to endogenous TPO. In pre-clinical and clinical trials no anti-romiplostim antibodies cross reacted with endogenous TPO.
Clinical data and safety in patients with ITP: The safety and efficacy of romiplostim have been evaluated for up to 3 years of continuous treatment. In clinical trials, treatment with romiplostim resulted in dose-dependent increases in platelet count. Time to reach the maximum effect on platelet count is approximately 10 - 14 days, and is independent of the dose. After a single subcutaneous dose of 1 to 10 μg/kg romiplostim in ITP patients, the peak platelet count was 1.3 to 14.9 times greater than the baseline platelet count over a 2 to 3 weeks period and the response was variable among patients. The platelet counts of ITP patients who received 6 weekly doses of 1 or 3 μg/kg of romiplostim were within the range of 50 to 450 x 109/L for most patients. Of the 271 patients who received romiplostim in ITP clinical trials, 55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo-controlled studies.
Results from pivotal placebo-controlled studies: The safety and efficacy of romiplostim was evaluated in two placebo-controlled, double-blind studies in adults with ITP who had completed at least one treatment prior to study entry and are representative of the entire spectrum of such ITP patients.
Study S1 (20030212) evaluated patients who were non-splenectomised and had an inadequate response or were intolerant to prior therapies. Patients had been diagnosed with ITP for a median of 2.1 years (range 0.1 to 31.6) at the time of study entry. Patients had received a median of 3 (range, 1 to 7) treatments for ITP prior to study entry. Prior treatments included corticosteroids (90% of all patients), immunoglobulins (76%), rituximab (29%), cytotoxic therapies (21%), danazol (11%), and azathioprine (5%). Patients had a median platelet count of 19 x 109/L at study entry.
Study S2 (20030105) evaluated patients who were splenectomised and continued to have thrombocytopenia. Patients had been diagnosed with ITP for a median of 8 years (range 0.6 to 44.8) at the time of study entry. In addition to a splenectomy, patients had received a median of 6 (range, 3 to 10) treatments for ITP prior to study entry. Prior treatments included corticosteroids (98% of all patients), immunoglobulins (97%), rituximab (71%), danazol (37%), cytotoxic therapies (68%), and azathioprine (24%). Patients had a median platelet count of 14 x 109/L at study entry.
Both studies were similarly designed. Patients (≥ 18 years) were randomised in a 2:1 ratio to receive a starting dose of romiplostim 1 μg/kg or placebo. Patients received single subcutaneous weekly injections for 24 weeks. Doses were adjusted to maintain (50 to 200 x 109/L) platelet counts. In both studies, efficacy was determined by an increase in the proportion of patients who achieved a durable platelet response. The median average weekly dose for splenectomised patients was 3 μg/kg and for non-splenectomised patients was 2 μg/kg.
A significantly higher proportion of patients receiving romiplostim achieved a durable platelet response compared to patients receiving placebo in both studies. Following the first 4-weeks of study romiplostim maintained platelet counts ≥ 50 x 109/L in between 50% to 70% of patients during the 6 months treatment period in the placebo-controlled studies. In the placebo group, 0% to 7% of patients were able to achieve a platelet count response during the 6 months of treatment. A summary of the key efficacy endpoints is presented as follows. (See Table 1.)
Click on icon to see table/diagram/imageResults of studies in adult patients with newly diagnosed and persistent ITP: Study S3 (20080435) was a single arm, open label study in adult patients who had an insufficient response (platelet counts ≤ 30 x 109/L) to first line therapy. The study enrolled 75 patients of whom the median age was 39 years (range 19 to 85) and 59% were female.
The median time from ITP diagnosis to study enrolment was 2.2 months (range 0.1 to 6.6). Sixty percent of patients (n = 45) had ITP duration < 3 months and 40% (n = 30) had ITP duration ≥ 3 months. The median platelet count at screening was 20 x 109/L. Prior ITP treatments included corticosteroids, immunoglobulins and anti D immunoglobulins. Patients already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the studies. Rescue therapies (i.e., corticosteroids, IVIG, platelet transfusions, anti D immunoglobulin, dapsone, danazol, and azathioprine) were permitted.
Patients received single weekly SC injections of romiplostim over a 12-month treatment period, with individual dose adjustments to maintain platelet counts (50 x 109/L to 200 x 109/L). During the study, the median weekly romiplostim dose was 3 μg/kg (25th-75th percentile: 2 - 4 μg/kg).
Of the 75 patients enrolled in study 20080435, 70 (93%) had a platelet response ≥ 50 x 109/L during the 12-month treatment period. The mean number of months with platelet response during the 12-month treatment period was 9.2 (95% CI: 8.3, 10.1) months; the median was 11 (95% CI: 10, 11) months. The Kaplan Meier estimate of the median time to first platelet response was 2.1 weeks (95% CI: 1.1, 3.0). Twenty-four (32%) patients had sustained treatment-free remission as defined by maintaining every platelet count ≥ 50 x 109/L for at least 6 months in the absence of romiplostim and any medication for ITP (concomitant or rescue); the median time to onset of maintaining every platelet count ≥ 50 x 109/L for at least 6 months was 27 weeks (range 6 to 57).
In an integrated analysis of efficacy, 277 adult patients with ITP duration ≤ 12 months and who received at least one dose of romiplostim from among those patients in 9 ITP studies (inclusive of study S3) were included. Of the 277 romiplostim-treated patients, 140 patients had newly diagnosed ITP (ITP duration < 3 months) and 137 patients had persistent ITP (ITP duration ≥ 3 to ≤ 12 months). The percentage of patients achieving a durable platelet response, defined as at least 6 weekly platelet counts of ≥ 50 x 109/L during weeks 18 through 25 of treatment, was 50% (95% CI: 41.4% to 58.6%) for the 140 patients with newly diagnosed ITP and 55% (95% CI: 46.7% to 64.0%) for the 137 patients with persistent ITP. The median (Q1, Q3) percent time with a platelet response ≥ 50 x 109/L was 100.0% (70.3%, 100.0%) for patients with newly diagnosed ITP and 93.5% (72.2%, 100.0%) for patients with persistent ITP, respectively. Also, the percentage of patients requiring rescue medications was 47.4% for patients with newly diagnosed ITP and 44.9% for patients with persistent ITP.
Results of studies compared to standard of care (SOC) in non-splenectomised patients: Study S4 (20060131) was an open-label randomised 52 week trial in adult subjects who received romiplostim or medical standard of care (SOC) treatment. Patients had been diagnosed with ITP for a median of 2 years (range 0.01 to 44.2) at the time of study entry. This study evaluated non-splenectomised patients with ITP and platelet counts < 50 x 109/L. Romiplostim was administered to 157 subjects by subcutaneous (SC) injection once weekly starting at a dose of 3 μg/kg, and adjusted throughout the study within a range of 1 - 10 μg/kg in order to maintain platelet counts between 50 and 200 x 109/L, 77 subjects received SOC treatment according to standard institutional practice or therapeutic guidelines.
The overall subject incidence rate of splenectomy was 8.9% (14 of 157 subjects) in the romiplostim group compared with 36.4% (28 of 77 subjects) in the SOC group, with an odds ratio (romiplostim vs SOC) of 0.17 (95% CI: 0.08, 0.35).
The overall subject incidence of treatment failure was 11.5% (18 of 157 subjects) in the romiplostim group compared with 29.9% (23 of 77 subjects) in the SOC group, with an odds ratio (romiplostim vs SOC) of 0.31 (95% CI: 0.15, 0.61).
Of the 157 subjects randomised to the romiplostim group, three subjects did not receive romiplostim. Among the 154 subjects who received romiplostim, the total median exposure to romiplostim was 52.0 weeks and ranged from 2 to 53 weeks. The most frequently used weekly dose was between 3 - 5 μg/kg (25th-75th percentile respectively; median 3 μg/kg).
Of the 77 subjects randomised to the SOC group, two subjects did not receive any SOC. Among the 75 subjects who received at least one dose of SOC, the total median exposure to SOC was 51 weeks and ranged from 0.4 to 52 weeks.
Reduction in permitted concurrent ITP medical therapies: In both adult placebo-controlled, double-blind studies, patients already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the study (corticosteroids, danazol and/or azathioprine). Twenty-one non-splenectomised and 18 splenectomised patients received on-study ITP medical treatments (primarily corticosteroids) at the start of study. All (100%) splenectomised patients who were receiving romiplostim were able to reduce the dose by more than 25% or discontinue the concurrent ITP medical therapies by the end of the treatment period compared to 17% of placebo treated patients. Seventy-three percent of non-splenectomised patients receiving romiplostim were able to reduce the dose by more than 25% or discontinue concurrent ITP medical therapies by the end of the study compared to 50% of placebo treated patients (see Interactions).
Bleeding events: Across the entire adult ITP clinical programme an inverse relationship between bleeding events and platelet counts was observed. All clinically significant (≥ grade 3) bleeding events occurred at platelet counts < 30 x 109/L. All bleeding events ≥ grade 2 occurred at platelet counts < 50 x 109/L. No statistically significant differences in the overall incidence of bleeding events were observed between romiplostim and placebo treated patients.
In the two adult placebo-controlled studies, 9 patients reported a bleeding event that was considered serious (5 [6.0%] romiplostim, 4 [9.8%] placebo; Odds Ratio [romiplostim/placebo] = 0.59; 95% CI = (0.15, 2.31)). Bleeding events that were grade 2 or higher were reported by 15% of patients treated with romiplostim and 34% of patients treated with placebo (Odds Ratio; [romiplostim/placebo] = 0.35; 95% CI = (0.14, 0.85)).
Clinical data in patients with Aplastic Anaemia refractory to conventional therapy: Global phase II/III studies: In 31 adult patients, consisting of 24 Japanese and 7 South Korean patients, with aplastic anaemia who were refractory to immunosuppressive therapy including anti-thymocyte immunoglobulin or refractory to cyclosporine and not indicated for anti-thymocyte immunoglobulin, romiplostim was administered at an initial dose of 10 μg/kg once weekly and the dose was adjusted within a range of 5 to 20 μg/kg based on blood count. The haematological response rate at Week 27 was 83.9%, 95% Cl - (66.3, 94.5). A haematological response rate is defined as the rate of patients with improvement in blood count at least 1 blood cell lineage.
The incidence of adverse reactions was 54.8% (17/31 patients). The most frequently observed adverse reactions in Japanese patients were headache and muscle spasms in 16.7% each (4/24 patients), and alanine aminotransferase increased, fibrin D dimer increased, malaise, and pain in an extremely in 8.3% each (2/24 patients). In Korean patients, only platelet count increased was observed in 14.3% (1/7 subjects). (See Table 2.)
Click on icon to see table/diagram/imagePharmacokinetics: The pharmacokinetics of romiplostim involved target-mediated disposition, which is presumably mediated by TPO receptors on platelets and other cells of the thrombopoietic lineage such as megakaryocytes.
Primary Immune Thrombocytopenia (ITP): Absorption: After subcutaneous administration of 3 to 15 μg/kg romiplostim, maximum romiplostim serum levels in ITP patients were obtained after 7 - 50 hours (median 14 hours). The serum concentrations varied among patients and did not correlate with the dose administered. Romiplostim serum levels appear inversely related to platelet counts.
Distribution: The volume of distribution of romiplostim following intravenous administration of romiplostim decreased nonlinearly from 122, 78.8, to 48.2 mL/kg for intravenous doses of 0.3, 1.0 and 10 μg/kg, respectively in healthy subjects. This non-linear decrease in volume of distribution is in line with the (megakaryocyte and platelet) target-mediated binding of romiplostim, which may be saturated at the higher doses applied.
Elimination: Elimination half-life of romiplostim in ITP patients ranged from 1 to 34 days (median, 3.5 days).
The elimination of serum romiplostim is in part dependent on the TPO receptor on platelets. As a result for a given dose, patients with high platelet counts are associated with low serum concentrations and vice versa. In another ITP clinical trial, no accumulation in serum concentrations was observed after 6 weekly doses of romiplostim (3 μg/kg).
Aplastic anaemia: For 13 Japanese and Korean adult patients with aplastic anaemia, who had inadequate response to immunosuppressive therapy and had been administered with Romiplate at a dose of 10 μg/kg once a week by subcutaneous injection for 4 weeks, the serum pharmacokinetics parameters of Romiplate are shown as follows.
The serum pharmacokinetics parameters of romiplostim at Week 4 in patients with aplastic anaemia who did not respond well to immunosuppressive therapy after subcutaneous injection of 10 μg/kg once a week for 4 consecutive weeks. (See Table 3.)
Click on icon to see table/diagram/imageThe data is presented as "mean ± standard deviation", 13 subjects include "8 subjects in Japan and 5 subjects in Korea".
Regarding 31 Japanese and Korean adult patients with aplastic anaemia who had inadequate response to immunosuppressive therapy, the Serum Ctrough-time curve of Romiplostim for once-weekly subcutaneous administration at 10 μg/kg from Week 1 to 4 and once-weekly adjustment at 5 μg/kg (acceptable dose adjustment range: 5-20 μg/kg) based on platelet response and blood count from Week 5 to 52 are ad shown as follows. (See Table 4.)
Click on icon to see table/diagram/imageThe serum Ctrough-time curve of Romiplostim (mean + standard deviation) from Week 1 to 56 for patients with aplastic anaemia who have inadequate response to immunosuppressive therapy. (See figure.)
Click on icon to see table/diagram/imageSpecial patient populations: Pharmacokinetics of romiplostim in patients with renal and hepatic impairment has not been investigated. Romiplostim pharmacokinetics appear not affected by age, weight and gender to a clinically significant extent.
Toxicology: Preclinical safety data: Multiple dose romiplostim toxicology studies were conducted in rats for 4 weeks and in monkeys for up to 6 months. In general, effects observed during these studies were related to the thrombopoietic activity of romiplostim and were similar regardless of study duration. Injection site reactions were also related to romiplostim administration. Myelofibrosis has been observed in the bone marrow of rats at all tested dose levels. In these studies, myelofibrosis was not observed in animals after a 4-week post-treatment recovery period, indicating reversibility.
In 1-month rat and monkey toxicology studies, a mild decrease in red blood cell count, haematocrit and haemoglobin was observed. There was also a stimulatory effect on leukocyte production, as peripheral blood counts for neutrophils, lymphocytes, monocytes, and eosinophils were mildly increased. In the longer duration chronic monkey study, there was no effect on the erythroid and leukocytic lineages when romiplostim was administered for 6 months where the administration of romiplostim was decreased from thrice weekly to once weekly. Additionally, in the phase 3 pivotal studies, romiplostim did not affect the red blood cell and white blood cells lineages relative to placebo treated subjects.
Due to the formation of neutralising antibodies pharmacodynamic effects of romiplostim in rats were often decreasing at prolonged duration of administration. Toxicokinetic studies showed no interaction of the antibodies with the measured concentrations. Although high doses were tested in the animal studies, due to differences between the laboratory species and humans with regard to the sensitivity for the pharmacodynamic effect of romiplostim and the effect of neutralising antibodies, safety margins cannot be reliably estimated.
Carcinogenesis: The carcinogenic potential of romiplostim has not been evaluated. Therefore, the risk of potential carcinogenicity of romiplostim in humans remains unknown.
Reproductive toxicology: In all developmental studies neutralising antibodies were formed, which may have inhibited romiplostim effects. In embryo-foetal development studies in mice and rats, reductions in maternal body weight were found only in mice. In mice there was evidence of increased post-implantation loss. In a prenatal and postnatal development study in rats an increase of the duration of gestation and a slight increase in the incidence of peri-natal pup mortality was found. Romiplostim is known to cross the placental barrier in rats and may be transmitted from the mother to the developing foetus and stimulate foetal platelet production. Romiplostim had no observed effect on the fertility of rats.
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