NPLATE Powder for solution for injection Ref.[9452] Active ingredients: Romiplostim

Pharmacotherapeutic group: Antihaemorrhagics, other systemic haemostatics
ATC code: B02BX04

Mechanism of action

Romiplostim is an Fc-peptide fusion protein (peptibody) that signals and activates intracellular transcriptional pathways via the 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 efficacy and safety

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 mcg/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 week period and the response was variable among patients. The platelet counts of ITP patients who received 6 weekly doses of 1 or 3 mcg/kg of romiplostim were within the range of 50 to 450 × 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 (212) evaluated patients who were non-splenectomised and had an inadequate response or were intolerant to prior therapies. Patients had been diagnosed with ITP for approximately 2 years at the time of study entry. Patients had 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 × 10⁹/L at study entry.

Study S2 (105) evaluated patients who were splenectomised and continued to have thrombocytopenia. Patients had been diagnosed with ITP for approximately 8 years at the time of study entry. In addition to a splenectomy, patients had 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 × 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 mcg/kg or placebo. Patients received single subcutaneous weekly injections for 24 weeks. Doses were adjusted to maintain (50 to 200 × 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 mcg/kg and for non-splenectomised patients was 2 mcg/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 × 10⁹/L in between 50% to 70% of patients during the 6 month treatment period in the placebo-controlled studies. In the placebo group, 0% to 7% of patients were able achieve a platelet count response during the 6 months of treatment. A summary of the key efficacy endpoints is presented below.

Summary of key efficacy results from placebo-controlled studies

^a Durable platelet response was defined as weekly platelet count ≥50 × 10⁹/L for 6 or more times for study weeks 18-25 in the absence of rescue therapies any time during the treatment period.
^b Overall platelet response is defined as achieving durable or transient platelet responses. Transient platelet response was defined as weekly platelet count ≥50 × 10⁹/L for 4 or more times during study weeks 2-25 but without durable platelet response. Patient may not have a weekly response within 8 weeks after receiving any rescue medicinal products.
^c Number of weeks with platelet response is defined as number of weeks with platelet counts ≥50 × 10⁹/L during study weeks 2-25. Patient may not have a weekly response within 8 weeks after receiving any rescue medicinal products.
^d Rescue therapies defined as any therapy administered to raise platelet counts. Patients requiring rescue medicinal products were not considered for durable platelet response. Rescue therapies allowed in the study were IVIG, platelet transfusions, anti-D immunoglobulin, and corticosteroids.
^e Stable dose defined as dose maintained within ± 1 mcg/kg during the last 8 weeks of treatment.

Results of studies compared to standard of care (SOC) in non-splenectomised patients

Study S3 (131) was an open-label randomised 52 week trial in adult subjects who received romiplostim or medical standard of care (SOC) treatment. This study evaluated non-splenectomised patients with ITP and platelet counts <50 × 10⁹/L. Romiplostim was administered to 157 subjects by subcutaneous (SC) injection once weekly starting at a dose of 3 mcg/kg, and adjusted throughout the study within a range of 1-10 mcg/kg in order to maintain platelet counts between 50 and 200 × 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 mcg/kg (25th-75th percentile respectively; median 3 mcg/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 section 4.5).

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 × 10⁹/L. All bleeding events ≥ grade 2 occurred at platelet counts <50 × 10⁹/L. No statistically significant differences in the overall incidence of bleeding events were observed between Nplate 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)).

Paediatric population

The European Medicines Agency has waived the obligation to submit data for children <1 year.

The safety and efficacy of romiplostim was evaluated in two placebo-controlled, double-blind studies. Study S4 (279) was a phase 3 study with 24 weeks of romiplostim treatment and study S5 (195) was a phase ½ study with 12 weeks of romiplostim treatment (up to 16 weeks for eligible responders who enter a 4-week pharmacokinetic assessment period).

Both studies enrolled paediatric subjects (≥1 year to <18 years of age) with thrombocytopenia (defined by a mean of 2 platelet counts ≤30 × 10⁹/L with neither count >35 × 10⁹/L in both studies) with ITP, regardless of splenectomy status.

In study S4, 62 subjects were randomised in a 2:1 ratio to receive romiplostim (n=42) or placebo (n=20) and stratified into 1 of 3 age cohorts. The starting dose of romiplostim 1 mcg/kg and doses were adjusted to maintain (50 to 200 × 10⁹/L) platelet counts. The most frequently used weekly dose was 3-10 mcg/kg and the maximum allowed dose on study was 10 mcg/kg. Patients received single subcutaneous weekly injections for 24 weeks. Of those 62 subjects, 48 subjects had ITP > 12 months of duration (32 subjects received romiplostim and 16 subjects received placebo).

The primary endpoint was the incidence of durable response, defined as achieving at least 6 weekly platelet counts of ≥50 × 10⁹/L during weeks 18 through 25 of treatment. Overall, a significant greater proportion of subjects in the romiplostim arm achieved the primary endpoint compared with subjects in the placebo arm (p=0.0018). A total of 22 subjects (52%) had durable platelet response in the romiplostim arm compared with 2 subjects (10%) in the placebo arm: ≥1 to <6 years 38% versus 25%; ≥6 to <12 years 56% versus 11%; ≥12 to <18 years 56% versus 0.

In the subset of subjects with ITP >12 months of duration, the incidence of durable response was also significantly greater in the romiplostim arm compared with the placebo arm (p=0.0022). A total of 17 subjects (53.1%) had durable platelet response in the romiplostim arm compared with 1 subject (6.3%) in the placebo arm: ≥1 to <6 years 28.6% versus 25%; ≥6 to <12 years 63.6% versus 0%; ≥12 to <18 years 57.1% versus 0%.

The composite bleeding episode was defined as clinically significant bleeding events or the use of a rescue medication to prevent a clinical significant bleeding event during weeks 2 through 25 of the treatment period. A clinically significant bleeding event was defined as a Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grade ≥2 bleeding event. The mean (SD) number of composite bleeding episodes was 1.9 (4.2) for the romiplostim arm and 4.0 (6.9) for the placebo arm with a median (Q1, Q3) number of bleeding events of 0.0 (0, 2) for the romiplostim arm and 0.5 (0, 4.5) in the placebo arm. In the subset of subjects with ITP >12 months of duration, the mean (SD) number of composite bleeding episodes was 2.1 (4.7) for the romiplostim arm and 4.2 (7.5) for the placebo arm with a median (Q1, Q3) number of bleeding events of 0.0 (0, 2) for the romiplostim arm and 0.0 (0, 4) in the placebo arm. Because the statistical testing for the incidence of rescue medication use was not significant, no statistical test was done for the number of composite bleeding episodes endpoint.

In study S5, 22 subjects were randomised in a 3:1 ratio to receive romiplostim (n=17) or placebo (n=5). Doses were increased in increments of 2 mcg/kg every 2 weeks and the target platelet count was ≥50 × 10⁹/L. Treatment with romiplostim resulted in statistically significantly greater incidence of platelet response compared with placebo (p=0.0008). Of those 22 subjects, 17 subjects had ITP >12 months of duration (14 subjects received romiplostim and 3 subjects received placebo). Treatment with romiplostim resulted in statistically significantly greater incidence of platelet response compared with placebo (p=0.0147).

Paediatric subjects who had completed a prior romiplostim study (including study S4) were allowed to enroll in study S6 (340), an open-label extension study evaluating the safety and efficacy of long-term dosing of romiplostim in thrombocytopenic paediatric subjects with ITP.

A total of 66 subjects were enrolled in this study, including 54 subjects (82%) who had completed study S4. Of these, 65 subjects (98.5%) received at least 1 dose of romiplostim. The median (Q1, Q3) duration of treatment was 135.0 weeks (95.0 weeks, 184.0 weeks). The median (Q1, Q3) average weekly dose was 4.82 mcg/kg (1.88 mcg/kg, 8.79 mcg/kg). The median (Q1, Q3) of most frequent dose received by subjects during the treatment period was 5.0 mcg/kg (1.0 mcg/kg, 10.0 mcg/kg). Of the 66 subjects enrolled in the study, 63 subjects had ITP >12 months of duration. All the 63 subjects received at least 1 dose of romiplostim. The median (Q1, Q3) duration of treatment was 138.0 weeks (91.1 weeks, 186.0 weeks). The median (Q1, Q3) average weekly dose was 4.82 mcg/kg (1.88 mcg/kg, 8.79 mcg/kg). The median (Q1, Q3) of most frequent dose received by subjects during the treatment period was 5.0 mcg/kg (1.0 mcg/kg, 10.0 mcg/kg).

Across the study, the overall subject incidence of platelet response (1 or more platelet count ≥50 × 10⁹/L in the absence of rescue medication) was 93.8% (n=61) and was similar across age groups. Across all subjects, the median (Q1, Q3) number of months with platelet response was 30.0 months (13.0 months, 43.0 months) and the median (Q1, Q3) time on study was 34.0 months (24.0 months, 46.0 months). Across all subjects, the median (Q1, Q3) percentage of months with platelet response was 93.33% (67.57%, 100.00%) and was similar across age groups.

In the subset of subjects with ITP >12 months of duration, the overall subject incidence of platelet response was 93.7% (n=59) and was similar across age groups. Across all subjects, the median (Q1, Q3) number of months with platelet response was 30.0 months (13.0 months, 43.0 months) and the median (Q1, Q3) time on study was 35.0 months (23.0 months, 47.0 months). Across all subjects, the median (Q1, Q3) percentage of months with platelet response was 93.33% (67.57%, 100.00%) and was similar across age groups.

A total of 31 subjects (47.7%) used concurrent ITP therapy during the study including 23 subjects (35.4%) who used rescue medication and 5 subjects (7.7%) who used concurrent ITP medication at baseline. The subject prevalence of concurrent ITP medication use showed a trend towards a reduction over the course of the study: from 30.8% (weeks 1 to 12) to <20.0% (weeks 13 to 240), and then 0% from week 240 to the end of the study.

In the subset of subjects with ITP >12 months of duration, 29 subjects (46.0%) used concurrent ITP therapy during the study including 21 subjects (33.3%) who used rescue medication and 5 subjects (7.9%) who used concurrent ITP medication at baseline. The subject prevalence of concurrent ITP medication use showed a trend towards a reduction over the course of the study: from 31.7% (weeks 1 to 12) to <20.0% (weeks 13 to 240), and then 0% from week 240 to the end of the study.

The subject prevalence of rescue medication use showed a trend towards a reduction over the course of the study: from 24.6% (weeks 1 to 12) to <13.0% (weeks 13 to 216), then 0% after week 216 until the end of the study. Similar reduction of the subject prevalence of rescue medication over the course of the study was seen in the subset of subjects with ITP >12 months of duration: from 25.4% (weeks 1 to 12) to ≤13.1% (weeks 13 to 216), then 0% after week 216 until the end of the study.