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. 2012 Oct;3(5):291–298. doi: 10.1177/2040620712453596

The efficacy and safety of romiplostim in adult patients with chronic immune thrombocytopenia

Nichola Cooper 1, Ilaria Terrinoni 2, Adrian Newland 3,✉
PMCID: PMC3627322  PMID: 23616916

Abstract

Romiplostim is a thrombopoietin peptide mimetic agent recently approved for the treatment of adults with chronic immune thrombocytopenia (ITP). In randomized controlled studies, this agent has demonstrated an increase in the platelet count in the majority of patients with ITP, both in splenectomized and nonsplenectomized patients. In up to 5 years of follow up, its safety profile has been favorable, suggesting this could be a novel therapeutic agent in patients with ITP. This article summarizes the development of this new agent and explores its safety and efficacy in adults with chronic ITP.

Keywords: AMG-531, immune thrombocytopenia, romiplostim, thrombopoietin, thrombopoietin-mimetic agents

Introduction

Immune thrombocytopenia

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a low platelet count (less than 100 × 109/L; normal range 150–400 × 109/L). Depending on the severity of the disease, patients may develop bleeding symptoms, such as petechiae, purpura, ecchymosis, mucocutaneous bleeding and can be at risk of severe hemorrhages. The etiology of primary ITP is multifactorial. It has long been believed that the pathogenesis involves premature destruction of platelets [Kelton, 1982] mediated by antiplatelet antibodies and also by direct T-cell-mediated platelet lysis [Olsson et al. 2003], with a concomitant increase in platelet production. However, megakaryocytes, by virtue of having the same antigens as platelets, are also a target for immune response and there is increasing evidence that decreased platelet production is a prime cause of low platelet counts in ITP [Branehog and Weinfeld, 1974; Branehog et al. 1974; Ballem et al. 1987; Chang et al. 2003].

Chronic immune thrombocytopenia treatment

Patients who do not respond immediately to treatment, and who continue to be thrombocytopenic for more than 12 months, are determined to have chronic ITP [Rodeghiero et al. 2008]. These patients have a higher morbidity and mortality, equally from bleeding and from infectious complications of treatment [Portielje et al. 2001]. The major goal for treatment of chronic ITP is to provide a safe platelet count to prevent or stop hemorrhages and to obtain an acceptable quality of life with minimal drug induced toxicity. The level that is considered safe is open to discussion but most accept a level of 20–30 × 109/L in the patients with stable chronic disease without any underlying bleeding diathesis. In the patient undergoing any operative procedure the levels should be higher and the guidelines recommend that they should be above 30 for dental treatment, 50 for minor surgery and 80 for major surgery. Bleeding may occur in the patient with a rapidly falling level and in such circumstances treatment should be initiated earlier [Provan et al. 2003].

Traditional treatments include immunosuppressive therapy, such as steroids, azathioprine, cyclosporine A, cyclophosphamide, mycophenolate mofetil, rituximab and vinca alkaloids; Fc receptor (FcR) blockade (intravenous immunoglobulin and intravenous anti-D), which prevent macrophage destruction of antibody-coated platelets; and surgical therapy (splenectomy), which prevents platelet sequestration [George et al. 1996]. All these treatments have shown a wide range of side effects, the most severe of which are related to immunosuppression [Stasi et al. 1995]. Following initial therapy in the newly presenting patient there is little consensus on further treatment and few of the options have a significant evidence base.

In patients who are refractory to traditional therapy, or who require high doses of steroids in order to maintain a high count, there has been an unmet need for new, nonimmunosuppressive agents. Following on from the previously controversial understanding of a reduced production of platelets in ITP, new developments have focused on increasing the production of platelets.

Thrombopoietin

Thrombopoietin (TPO or c-MPL ligand) is the main regulator of steady-state megakaryocytes and platelet production [De Sauvage et al. 1994; Kuter et al. 1994]. TPO is a polypeptide of 95 KDa mostly synthesized in the liver. It binds its own receptor through a 153-amino-terminal residues binding domain, interacting with two types of receptor, one low affinity and the other high affinity. Both are necessary to induce the internal signaling pathway. MPL (the TPO receptor) is present on megakaryocyte precursors, megakaryocytes themselves and platelets. It is a member of the type I hematopoietic growth factor family. These molecules contain a transmembrane domain of around 20–25 amino acids with a 70–500-amino-acid intracellular portion. The intracytoplasmic domain contains sequences that bind tyrosine kinases Janus kinase 2 (JAK2) and tyrosine kinase 2, but it appears that only JAK2 is required for signaling. After TPO complexes with SHP2, Gab/insulin receptor substrate and the phosphatidylinositol 3-kinase (PI3K) p85 regulatory subunit, PI3K and Akt (protein kinase B) become activated. In addition to stimulating PI3K, TPO also activates a number of other pathways, including two mitogen-activating protein kinase (MAPK) pathways, that is, p42/p44 ERK1 and ERK2 and p38 MAPK, with phosphorylation of many molecules, including growth factor receptor-bound protein 2, SHC and SOS. The final result of this activation and phosphorylation is induction of the transcription factor HoxB4 and stem cell expansion by p38 MAPK. There is also translocation of transcription factors to the nucleus with release of phosphorylase A2 and subsequent platelet activation [Provan et al. 2007].

The first studies with recombinant thrombopoietins (pegylated recombinant human megakaryocyte growth factor and recombinant human TPO) were discontinued because of problems of immunogenicity, with the development of antibodies that cross-reacted with endogenous TPO and consequent severe thrombocytopenia in healthy controls [Li et al. 2001]. However, these studies showed initial efficacy and led to the formulation of a new category of TPO agonists with a superior profile of efficacy and tolerability. These new agents belong to three categories: TPO nonpeptide mimetics (e.g. eltrombopag), TPO peptide mimetics (e.g. romiplostim) and TPO antibody mimetics. This review article focuses on Romiplostim, a TPO peptide mimetic.

Romiplostim

Romiplostim (AMG 531, N-plate, Amgen, Thousand Oaks, CA, USA) is a recombinant thrombopoiesis-stimulating Fc-peptide fusion protein. The molecule has two domains: a peptide domain that binds to the TPO receptor and activates intracellular pathways stimulating megakaryopoiesis, and a carrier antibody crystallizable (Fc) fragment that undergoes endothelial recirculation, thereby extending its circulating half life. Romiplostim has no sequence homology with endogenous human TPO [Wang et al. 2004], resulting in a very low immunogenicity profile.

In vitro studies in human and murine megakaryocytes indicated that romiplostim binds the TPO receptor in a similar manner to endogenous TPO [Broudy and Lin, 2004].

In vivo work using rhesus monkeys showed that a single dose of romiplostim led to a dose-dependent increase in platelet count at day 5 with a peak between days 7 and 9. No subsequent thrombocytopenia was observed and neutralizing anti-TPO antibodies were not detected. Romiplostim has been shown to stimulate murine megakaryopoiesis [Hartley et al. 2005], and demonstrated a dose-dependent effect on megakaryocyte colony-forming units in murine marrow culture.

Clinical studies

Phase I–II clinical trials

In humans, the first randomized, double-blind, placebo-controlled study was carried out in 2004: 48 healthy volunteers were treated with a single intravenous or subcutaneous dose of romiplostim (0.3–10.0 μg/kg and 0.1–2.0 μg/kg respectively) showing an increase in platelet counts, with a peak count being achieved on days 12–16. The drug showed good tolerability [Wang et al. 2004].

Two phase I–II trials were conducted in the USA [Bussel et al. 2006] and Europe [Newland et al. 2006] in splenectomized patients with ITP, demonstrating dose-dependent efficacy of romiplostim. In the US study (N = 24), a platelet count of at least 50 × 109/L was achieved in 7 of 12 patients treated with 3, 6, or 10 μg/kg romiplostim. The platelet count was within the target range in four patients and above the target range (i.e. >450 × 109/L) in three patients. In the European study, (n = 16; romiplostim dose range 30–500 μg administered on days 1 and 15) platelet responses were seen at all dose levels (30, 100, and 300 μg). Treatment with the 500 μg romiplostim dose was discontinued because of an excessively high platelet count measured in the first patient treated. It was calculated that doses equivalent to at least 1 μg/kg induced platelet responses in 8 of 11 patients.

Transient rebound thrombocytopenia after discontinuation of romiplostim, possibly resulting from enhanced clearance of endogenous TPO by the increased number of megakaryocytes, was reported in approximately 10% (4/41) of patients in a phase I–II study [Bussel et al. 2006]. A gradual de-escalation of the dose is therefore advised rather than abruptly stopping treatment.

Phase III studies

Two multicenter placebo-controlled phase III trials were conducted in parallel. These studies included 63 splenectomized and 62 nonsplenectomized patients who had chronic ITP and a mean of three platelet counts of up to 30 × 109/L [Kuter et al. 2008]. Patient criteria were identical for both studies, with the exception of splenectomy status. The splenectomized patients had a longer duration of ITP (median 7–8 years versus 1–2 years in nonsplenectomized patients) and both groups were heavily pretreated, with over 90% of patients having received at least three previous treatments for ITP.

Patients were randomized (2:1) to receive romiplostim (splenectomized n = 42; nonsplenectomized n = 41) or placebo (n = 21 in each study) once weekly for 24 weeks. All patients were permitted to receive concurrent ITP therapy with corticosteroids, azathioprine, and danazol. The starting dose of romiplostim or placebo was 1 μg/kg and was adjusted to maintain platelet counts within a target range of 50–200 × 109/L. The primary endpoint was considered a durable platelet response, defined as a platelet count of at least 50 × 109/L during at least 6 of the last 8 weeks of treatment, in the absence of rescue medication. A transient response was defined as four or more weekly platelet responses without a durable response from week 2 to week 25 without receiving rescue medications.

Efficacy

Romiplostim showed efficacy in both splenectomized and nonsplenectomized patients. A platelet count of at least 50 × 109/L was maintained for a mean of 15.2 and 12.3 weeks for nonsplenectomized and splenectomized patients respectively compared with 1.3 or 0.2 weeks for placebo recipients.

Most romiplostim-treated patients (87%: 12/12 splenectomized and 8/11 nonsplenectomized) were able to discontinue or substantially reduce concomitant ITP medications (corticosteroids, azathioprine, danazol). In comparison, concomitant ITP medications were discontinued or reduced in 38% of placebo recipients (1/6 splenectomized; 5/10 nonsplenectomized). Romiplostim also reduced the percentage of patients requiring rescue medications (immunoglobulins, corticosteroids, platelet transfusions) compared with placebo (26.2% versus 57.1% of splenectomized and 17.1% versus 61.9% of nonsplenectomized patients). Highlighting the main rescue medication, during the 24-week study intravenous immunoglobulin therapy was administered to only 14% of romiplostim recipients but in 50% of those on placebo, with adjustment for age and gender this reached significance at p < 0.001 [Pullarkat et al. 2009].

Similar efficacy results were reported in a further randomized study of splenectomized and nonsplenectomized Japanese patients treated over a 12-week period. Using similar criteria the median number of weeks with the platelet count in the target range (>50 × 109/L) was significantly higher in the romiplostim arm than in those on placebo and the mean change from baseline was also significantly greater (110 versus 2 × 109/L) with a p value of 0.0003 [Shirasugi et al. 2011].

Tolerability

Romiplostim was well tolerated during the two phase III, 24-week clinical trials [Kuter et al. 2008]. Although adverse events were reported in almost all patients treated with either romiplostim (83/83; 100%) or placebo (39/41; 95%), most events were mild to moderate. Very few patients (three patients; 4%) discontinued romiplostim because of adverse events. Headache was the most common adverse event reported by the romiplostim-treated patients (29/84; 35%) followed by fatigue (28/84; 33%), epistaxis (27/84; 32%), and arthralgia (22/84; 26%). Increases in dizziness, insomnia, myalgia, and pain in the extremities and abdomen were noted in the romiplostim-treated patients, the clinical significance of which could not be determined due to the small study size. Thromboembolic events are a concern in patients with ITP, but there was no evidence in the phase III studies that romiplostim treatment increased the risk of such events – the overall incidence of thromboembolic events was 2.4% in both the romiplostim and placebo groups.

Clinically significant bleeding adverse events (severity grade ≥2, where 2 = moderate, 3 = severe, 4 = life threatening, or 5 = fatal) were observed in 16% of romiplostim- and 34% of placebo-treated patients (p = 0.018). The percentage of patients who had bleeding events of severity grade 3 or higher was 7% and 12% in the romiplostim and placebo groups respectively (p = 0.36). None of the patients with bleeding events of grade 3 or higher had achieved a durable platelet response during the study period.

Serious treatment-related adverse events occurred in two romiplostim-treated patients. After 7 weeks of treatment, increased baseline bone marrow reticulin was noted in one patient. This particular patient had increased bone marrow reticulin at baseline and was unresponsive to romiplostim treatment. Following discontinuation of romiplostim, reticulin levels returned to baseline 14 weeks later. Similar reversible increases in bone marrow reticulin have been noted previously in animals and humans exposed to other thrombopoetic agents (recombinant human TPO, interleukin 3, and interleukin 11 [Kuter et al. 2007]. The second patient with a serious treatment-related adverse event was an 82-year-old man who experienced a right popliteal arterial embolism. This patient (who had a history of extensive peripheral vascular disease and atrial fibrillation), underwent successful embolectomy and anticoagulation treatment, and continued the study.

Other than abnormal platelet counts, no clinically significant treatment-related changes in vital signs, or in hematological or serum chemistry values were seen in any of the patients participating in the phase III studies. No antibodies against romiplostim or thrombopoietin were detected.

Long-term extension study

Patients from the phase III studies could enter a long-term, open-label, extension study [Newland, 2009]. As of July 2007, 143 patients (60% splenectomized; median baseline platelet count 17 × 109/L; range 1–50 × 109/L) were enrolled and 142 had been treated with romiplostim for up to 3 years (median 65 weeks). These figures were updated at the American Society of Hematology (ASH) in 2010 and have recently been submitted for publication [Kuter et al. 2010b, 2012a].

The study compared four treatment cohorts entered into studies over a 4-year period. All patients had previously been entered into romiplostim studies (whether on placebo or an active drug). The initial cohorts were more refractory patients and the maximum dose allowed was 30 µg/kg with a baseline count of up to 50 × 109/L whereas in cohort 4 the dose was restricted to 10 µg/kg with no baseline platelet requirement. The median duration of disease had also reduced from 9 years in cohort 1 to 3 years in cohort 4. Whereas initially 77% had undergone splenectomy, this had fallen to 2% in cohort 4. Over a 5-year follow up 292 patients were followed. Platelet counts of at least 50 × 109/L were achieved in 94.5% of patients. A significant proportion transferred successfully to home injection without loss of effect and no new safety concerns have been raised [Kuter et al. 2010b, 2012a].

Efficacy

In the phase III placebo-controlled, randomized study a platelet response (>50 × 109/L and double the baseline value) was observed in 87% (124/142) of patients: 30% (42/138) of patients responded after the first dose, and 51% (71/138) after the third dose of romiplostim. Ad hoc analysis revealed that platelet counts above 50 × 109/L were maintained for at least 10, 25, and 52 consecutive weeks by 78% (102/131), 54% (66/122), and 35% (29/84) of patients, respectively. Altogether 84% (27/32) of patients receiving concurrent ITP medications at baseline either discontinued these or reduced their dosage by more than 25% and the use of rescue medications decreased from 23% (33/142) of patients during weeks 1–12 to 15% (18/124) during weeks 24–36 [Kuter et al. 2008].

Tolerability

In the long-term extension study, romiplostim was generally well tolerated by the patients, several of whom were treated for up to 3 years. Eight patients were found to have bone marrow reticulin present or increased [Newland, 2009]. Six patients had mild to moderate reticulin levels (≤ grade 2 or within the normal range). Follow-up bone marrow biopsies in two patients revealed that one patient showed improvement in the amount of reticulin while the other patient had no change. All of the affected patients continue to be monitored for clinical signs of any progressive bone marrow abnormalities, and to date there has been no evidence of progression to collagen fibrosis, myelofibrosis, or clonal myeloproliferative disorder. The incidence and clinical significance of bone marrow reticulin as well as the extent of regression that occurs following discontinuation of romiplostim treatment requires further follow up in large numbers of patients.

Thromboembolic events were reported in 7 (4.9%) patients, 6 of whom had pre-existing risk factors for thrombosis, including congestive heart failure, antiphospholipid antibodies, coronary artery disease, hypertension, cancer, or a history of thrombotic events. Five thromboembolic events were assessed as being serious treatment-related events: one patient with myocardial infarction, one patient with portal vein thrombosis and deep vein thrombosis, one patient with transverse sinus thrombosis, and one patient with thrombosis. Thromboembolic events did not appear to be related to higher than normal platelet counts, with most events occurring at counts below the median peak platelet count (167 × 109/L). All of the events resolved.

One patient developed transient neutralizing antibodies to romiplostim, but these did not cross-react to endogenous TPO or affect the platelet response and disappeared when retested.

Quality-of-life analyses

Patients with ITP have been shown to have significantly impaired health-related quality of life (HRQoL), worse than patients with hypertension, arthritis, or cancer. These relate to fatigue, concerns over appearance due to bruising and impaired ability to conduct routine daily activities [Mathias et al. 2008; Snyder et al. 2008]. HRQoL changes were studied, using an ITP Patient Assessment Questionnaire (ITP-PAQ), in both of the phase III studies [George et al. 2009] and in the open-label romiplostim extension study [Tarantino et al. 2007].

The ITP-PAQ study looks at physical health, emotional health, work, social activity and women’s reproductive health. In splenectomized patients significantly greater improvements were seen for symptoms, bother, social activity, and reproductive health in the romiplostim group and in the nonsplenectomized group scores for activity were significantly improved (p < 0.05) over placebo [George et al. 2009; Sanz et al. 2011].

These studies were taken further in the randomized, open-label, multicentre, 52-week study comparing romiplostim with standard of care in nonsplenectomized patients. The overall results were better, with fewer experiencing treatment failure or proceeding to splenectomy with associated clinically important improvements in their ITP-PAQ scores. Statistically significant improvements in symptoms, bother, activity, psychological health, fear, social activity and overall HR-QOL were seen (p < 0.05) [Kuter et al. 2010a, 2012b], confirming the impact on quality of life in patients with thrombocytopenia and the importance to the patient in its reversal.

Conclusions

Romiplostim is one of a number of new molecules made available for clinical use due to advances in molecular biology, biochemistry, and pharmacology. It was specifically engineered to produce an increase in the production of platelets by activation of the TPO receptor, whilst avoiding the immunogenicity of previous agents. Early phase I/II studies showed the promise of these agents in ITP. Subsequent phase III randomized controlled studies, which are amongst the largest clinical studies performed in ITP, confirmed these findings, with 80% of patients responding to romiplostim. The trials, including 5-year follow up presented at ASH 2010, show these agents are well tolerated, with few side effects [Kuter et al. 2010a]. Responses continue, with the majority of patients being able to be maintained on romiplostim once a week, and with some patients being able to decrease doses over time. In addition, bleeding events appear to be reduced and quality of life improved.

Over the course of the studies, despite good tolerability, some potential adverse effects have been highlighted. For example, there was a surprisingly high incidence of thromboembolic disease in patients included in both of the TPO studies. Events occurred on the placebo arm and on the treatment arm and were not related to the platelet count, suggesting the embolic events may reflect the nature of the disease rather than the treatment itself [Sarpatwari et al. 2010]. It is notable that these studies have collected data in a prospective manner in a large number of patients with ITP, hence otherwise unnoticed complications of the disease may be highlighted. A second concern is one of bone marrow changes; reticulin deposition has been reported, although the incidence and severity of this event is not clear and the effects appear to resolve on stopping the medications (this is the subject of ongoing evaluation).

Another theoretical concern is whether long-term use of the agents will result in impairment of the stem cell pool, or stimulation of blast production. No immediate effects have been noted in this regard. Furthermore, it is not yet clear how long patients will require therapy. At European Hematology Association 2011, a poster presentation described four patients with previously chronic and refractory ITP who were able to discontinue romiplostim after a short course of treatment [Newland et al. 2011]. These observations were supported by a report of long-term response of treatment in nine patients in the long-term follow-up study reported at the ASH in 2011 [Bussel et al. 2011]. The same finding has been reported for eltrombopag. This raises the question of how these agents work. As well as increasing the megakaryocyte mass, and producing extra platelets, it is possible that these agents could allow resolution of a megakaryocyte defect, or induce tolerance by increasing the antigen load. Early work on regulatory T cells suggests this may be the case [Bao et al. 2010]; however, it remains speculation as to the importance of this observation in the overall mechanisms of action and it is clear that increased platelet production is the initial desired effect in the patient refractory to initial therapy. A number of groups are now exploring further the potential pathophysiology of these agents.

Overall, these agents are very promising, with a good side-effect profile and excellent responses. A global and rigorous pharmacovigilance is ongoing to fully evaluate the real and potential adverse events with long-term use of romiplostin [Kuter et al. 2010a], although the long-term studies, with follow up of over 5 years have not highlighted any new or unexpected safety issues [Kuter et al. 2012a]. While these agents have been licensed for use in patients with chronic and refractory ITP, further safety and efficacy data and analysis of their use within either persistent or newly diagnosed ITP may allow us to use these agents earlier on in the disease course, with the potentiation to induce tolerance and to further reduce the use of steroids.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: Nichola Cooper has been a speaker and has consultancies with Amgen and GSK. Adrian Newland has participated in advisory boards and/or as a speaker at medical education events supported by Amgen, GSK and Roche and has received research support from Amgen, Eisai, Genetech, GSK and Shionogi.

Contributor Information

Nichola Cooper, Department of Haematology, Hammersmith Hospital, London, UK.

Ilaria Terrinoni, Department of Haematology, Hammersmith Hospital, London, UK.

Adrian Newland, Centre for Haematology, Barts and The London, Queen Mary’s School of Medicine and Dentistry, Turner Street, London E1 2AD, UK.

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