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Keywords:

  • romiplostim;
  • immune thrombocytopenia;
  • thrombopoietin-mimetic agents

Summary

  1. Top of page
  2. Summary
  3. Discovery of the pathophysiology of ITP
  4. Thrombopoietin and the first-generation thrombopoietin-mimetic agents
  5. Romiplostim
  6. Clinical development programme
  7. Eltrombopag
  8. Where next in the management of patients with chronic ITP
  9. Acknowledgements
  10. References

Immune thrombocytopenia (ITP) is an autoimmune disorder characterised by abnormally low platelet counts (<100 × 109/l), purpura, and bleeding episodes, and can be categorised in three phases: newly-diagnosed, persistent, and chronic. As many patients become refractory to standard treatments (corticosteroids, danazol, azathioprine, splenectomy), there is an urgent need for alternative treatments. The successful isolation and cloning of thrombopoietin (TPO) in the mid-1990s and identification of its key role in platelet production was a major breakthrough, rapidly followed by the development of the recombinant thrombopoietins, recombinant human TPO and a pegylated truncated product, PEG-rHuMGDF. Both agents increased platelet counts but development was halted because of the development of antibodies that cross-reacted with native TPO, resulting in prolonged treatment-refractory thrombocytopenia. Experimentation with novel platforms for extending the circulating half-life of therapeutic peptides by combining them with antibody fragment crystallisable (Fc) constructs led to the development of a new family of molecules termed ‘peptibodies’. The 60Da recombinant peptibody romiplostim was finally produced by linking several copies of an active TPO-binding peptide sequence to a carrier Fc fragment. In clinical trials, romiplostim was effective in ameliorating thrombocytopenia in patients with chronic ITP, was well tolerated and did not elicit cross-reacting antibodies. Romiplostim has recently been approved for the treatment of adults with chronic ITP.

Idiopathic or primary immune thrombocytopenia (ITP) is an autoimmune disorder characterised by abnormally low platelet counts (<100 × 109/l). Clinical manifestations are related to the severity of thrombocytopenia and include purpura and bleeding episodes, which can be potentially life-threatening and require emergency treatment. ITP may be acute (<6 months), or chronic (>6 months). Acute abrupt-onset ITP occurs mainly in children, often following viral infection or immunisation, with boys and girls being equally affected. Chronic ITP is typically seen in adults, predominantly affecting women of childbearing age. In Europe, the incidence of ITP in adults has been estimated to be between 1 and 4 per 100 000 persons (Frederiksen & Schmidt, 1999; Neylon et al, 2003; Kaye et al, 2007). When a cut-off platelet count of <50 × 109/l was applied, the annual incidence of ITP was estimated to be 2·25 per 100 000 in Denmark and 1·6 per 100 000 in the UK (Neylon et al, 2003).

In chronic ITP, the goal of treatment is to achieve a platelet count that prevents major bleeding, rather than to raise platelet count to the normal range. Management is tailored to the individual patient, taking into account clinical findings (bruising/bleeding and symptomology) and individual lifestyle and risk factors, as well as the platelet count. In general, patients with platelet counts >30 × 109/l do not require treatment unless they are undergoing procedures likely to result in blood loss (e.g. surgery, dental extraction or parturition) (George et al, 1996, British Committee for Standards in Haematology General Haematology Task Force 2003). Most of the available treatments for ITP are aimed primarily at attenuating excessive platelet destruction. Corticosteroids (e.g. prednisolone) are the standard first-line treatment and are effective in approximately two-thirds of patients, but are often associated with intolerable short- and long-term side effects, including hypertension, glaucoma, Cushing’s syndrome, and promotion of osteoporosis and diabetes mellitus. Moreover, suppression of the immune system can predispose patients to infection, which is a major cause of death in ITP patients (Stasi et al, 1995; Portielje et al, 2001). Intravenous (IV) immunoglobulin is usually reserved for ‘rescue’ treatment of acute bleeding episodes and for patients who are refractory to steroids, or require unacceptably high doses of these agents to maintain a safe platelet count. Platelet transfusions, also used for acute treatment of severe episodes, have several limitations, including the risk of transfusion reactions and transmitting infections, as well as supply issues. Other alternative treatments include high-dose corticosteroids (dexamethasone or methylprednisolone), IV anti-D, vinca alkaloids, immunosuppressants (danazol, azathioprine, cyclosporine, mycofenolate mofetil and the anti-CD-20 agent rituximab), dapsone, and cytotoxic chemotherapy combinations (George et al, 1996, British Committee for Standards in Haematology General Haematology Task Force 2003).

Splenectomy is often considered for patients who are refractory to corticosteroid treatment or have experienced relapse. While this procedure can achieve a normal platelet count in approximately two-thirds of patients, the individual risks and benefits, as well as patient preference, must be carefully weighed. Indeed, falling rates of splenectomy over recent years suggest that, with the emergence of alternative therapies, patients and physicians are increasingly opting to delay surgery (Rodeghiero & Ruggeri, 2008). The significant percentage of patients with ITP (approximately 25–30%) who become refractory to standard treatment modalities have long presented a dilemma for physicians (George et al, 1996, British Committee for Standards in Haematology General Haematology Task Force 2003).

Romiplostim (AMG 531, Nplate®; Amgen, Thousand Oaks, CA, USA) is a novel recombinant thrombopoiesis-stimulating Fc-peptide fusion protein (‘peptibody’) which has been developed for the treatment of chronic ITP in adults. This review chronicles the development of romiplostim, from the discovery of the underlying pathophysiology of ITP to the isolation and cloning of thrombopoietin and the subsequent availability of romiplostim in the clinic (Fig 1).

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Figure 1.  Timeline of development of romiplostim as a treatment for chronic ITP.

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Discovery of the pathophysiology of ITP

  1. Top of page
  2. Summary
  3. Discovery of the pathophysiology of ITP
  4. Thrombopoietin and the first-generation thrombopoietin-mimetic agents
  5. Romiplostim
  6. Clinical development programme
  7. Eltrombopag
  8. Where next in the management of patients with chronic ITP
  9. Acknowledgements
  10. References

A clinical syndrome of bleeding and purpura was described as early as 1735 by a German physician, Paul Werlhof (Werlhof, 1735). Subsequently, in the 1880s, Brohm and Kraus and Denys linked thrombocytopenia with ‘Werlhof’s disease’ (Brohm, 1883; Denys, 1887). In the early twentieth century, different hypotheses emerged regarding the underlying pathophysiology of ITP. Frank (Frank, 1915) proposed toxic suppression of megakaryocytes by a factor originating in the spleen as the cause. Shortly afterwards, Kaznelson reported that splenectomy restored platelet counts in thrombocytopenic patients but instead implicated increased platelet destruction by the spleen (Kaznelson, 1916). In 1946, evidence emerged to support megakaryocyte suppression as a cause, when studies of bone marrow from patients with ITP found increased numbers of megakaryocytes, the majority of which did not appear to produce platelets. However, platelet production increased after splenectomy (Dameshek & Miller, 1946).

An immunological role for the accelerated platelet destruction in ITP was confirmed in the early 1950s. Evans et al noted an association between Coombs test–positive haemolytic anaemia and ITP (Evans et al, 1951). Harrington et al published a landmark paper establishing the existence of a ‘thrombocytopenic factor’ in the blood or plasma of patients with ITP, that destroyed platelets (Harrington et al, 1951). These pioneering investigators administered whole blood or plasma from patients with ITP or secondary thrombocytopenias to non-thrombocytopenic individuals (healthy faculty staff and patients with terminal cancer). In most cases, this produced a rapid and dramatic fall in platelet counts that was often apparent within 30–60 min, persisted for 4–7 d (Fig 2) and when severe was associated with prolonged bleeding time. The factor appeared to be located in the globulin fraction and persisted after normalisation of platelet counts by splenectomy.

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Figure 2.  Thrombocytopenic effects of infusing blood/plasma from patients with ITP in non-thrombocytopenic individuals (healthy faculty staff and patients with terminal cancer) (Harrington et al, 1951). Reprinted by permission from Elsevier.

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For many years the prevailing view was that ITP resulted solely from excessive platelet clearance and destruction, mediated by autoreactive antibodies. Kinetic studies conducted in the 1970s, using radiolabelled homologous platelets, demonstrated shortened platelet survival and increased platelet turnover in ITP patients (Harker, 1970; Branehog et al, 1974), consistent with this hypothesis. However, when autologous radiolabelled platelets were studied in the 1980s, it became evident that there was considerable heterogeneity in platelet turnover between patients, with a substantial proportion having impaired platelet production (Stoll et al, 1985; Ballem et al, 1987). More recent evidence indicates that the thrombocytopenic factor described by Harrington is in fact an antibody directed against platelet glycoproteins (Chang et al, 2003; McMillan et al, 2004). Electron microscopy studies have demonstrated the presence of damaged, apoptotic megakaryocytes in ITP patients (Houwerzijl et al, 2004). Direct T-lymphocyte-mediated platelet cytotoxicity has also been implicated in platelet destruction (Olsson et al, 2003). These findings point to considerable heterogeneity of disease in patients with ITP which may contribute to the observed inter-individual differences in response to treatment (Semple & Freedman, 1995).

Thrombopoietin and the first-generation thrombopoietin-mimetic agents

  1. Top of page
  2. Summary
  3. Discovery of the pathophysiology of ITP
  4. Thrombopoietin and the first-generation thrombopoietin-mimetic agents
  5. Romiplostim
  6. Clinical development programme
  7. Eltrombopag
  8. Where next in the management of patients with chronic ITP
  9. Acknowledgements
  10. References

Thrombopoietin

Existence of a factor that caused the platelet count to rise in response to thrombocytopenic stimuli – thrombopoietin (TPO) – was first demonstrated in 1958 (Kelemen et al, 1958). However, there were many difficulties in the search to purify and clone the TPO molecule. Many unsuccessful attempts were made during the 1980s, as reviewed by Kaushansky (Kaushansky, 1995). A number of cytokines that appeared to be involved in megakaryopoiesis were identified through the late 1980s and early 1990s. These included interleukin (IL)-3, IL-6, stem cell factor (c-kit ligand or steel factor), granulocyte-macrophage colony-stimulating factor and leukaemia inhibitory factor (Kaushansky, 1995).

The cloning of the viral gene v-mpl (Wendling & Tambourin, 1991) and its cellular homologue, c-mpl in 1992, (Souyri et al, 1990; Vigon et al, 1992) were the next steps forward. c-mpl was shown to encode a protein displaying substantial homology with receptors for interleukins and colony-stimulating factors, suggesting that it might have a role as a haematopoietic cytokine receptor (Skoda et al, 1993). Using an antisense strategy, Methia et al, (Methia et al, 1993) provided the first evidence that c-mpl is involved in megakarypoiesis: antisense to CD34+ cells in vitro inhibited only megakaryocyte colonies.

The ligand for c-mpl, TPO (megapoietin; megakaryocyte growth and development factor; MGDF), was finally identified in 1994 – almost 40 years after its existence was first proposed – by several groups working independently of each other and using various methodologies (Bartley et al, 1994; Kuter et al, 1994; Lok et al, 1994; de Sauvage et al, 1994; Wendling et al, 1994). The effects of TPO on megakaryocyte growth and platelet production were demonstrated in vitro and in vivo (Kaushansky et al, 1994; Kuter et al, 1994; de Sauvage et al, 1994; Broudy et al, 1995; Debili et al, 1995; Sheridan et al, 1997; Nichol, 1998). Studies in knockout mice confirmed the role of TPO as the primary growth factor that regulates platelet production: mice that were nullizygous for either TPO (de Sauvage et al, 1996) or c-mpl (Gurney et al, 1994) were severely thrombocytopenic, but without other abnormalities. These findings argued strongly for a single receptor for TPO and a single ligand for c-mpl. However, the persistence of a low number of platelets in both knockout strains implies a residual TPO-independent mechanism for platelet production.

Produced primarily in the liver (Kuter et al, 1994), TPO is a 332-amino acid (95 kDa) glycoprotein consisting of two domains: a receptor-binding domain that shares considerable homology with erythropoietin and a highly glycosylated carbohydrate-rich domain (Bartley et al, 1994; de Sauvage et al, 1994). On binding to mpl, TPO stimulates megakaryopoiesis via tyrosine phosphorylation and triggering of Janus kinase (JAK)-2 and signal transducers and activators of transcription (STAT)-5 (Ezumi et al, 1995). Acting in concert with the early-acting cytokines IL-3 and stem cell factor, and erythropoietin, IL-6 and IL-11 (Broudy et al, 1995), TPO is involved in all stages of megakaryopoiesis, increasing the size, ploidy and number of megakaryocytes. However TPO does not appear to be involved in the late stages of platelet production involving proplatelet formation and platelet shedding and, indeed, may suppress these processes (Choi et al, 1996).

Regulation of TPO occurs via platelet and megakaryocyte-borne c-mpl-mediated clearance (Stoffel et al, 1996). Plasma levels in healthy individuals are thought to be less than 200 pg/ml under normal circumstances and are inversely correlated with the platelet count, generally rising in response to a decrease in platelet production or megakaryocyte mass (Emmons et al, 1996). However, in patients with ITP, TPO levels are generally inappropriately low relative to platelet counts (Nichol, 1997).

The first generation thrombopoietin-mimetic agents: proof of principle

Elucidation of the structure of TPO and its key role in platelet production was rapidly followed by development of the recombinant thrombopoietins. Recombinant human (rHu)TPO, a glycosylated full-length molecule with an amino acid sequence identical to that of native TPO, was produced in mammalian cell culture. PEG-rHuMGDF, a pegylated, truncated product containing part of the native TPO sequence, was produced in Escherichia coli and subsequently modified by the covalent addition of a 20KD polyethylene glycol moiety. These agents were found to increase platelet counts in healthy animals and models of chemo/radiotherapy-induced thrombocytopenia (Hokom et al, 1995; Akahori et al, 1996; Harker et al, 1996; Neelis et al, 1997). Subsequent clinical trials demonstrated that they were effective in accelerating platelet recovery after non-myeloablative chemotherapy (usually in combination with colony-stimulating factors) (Vadhan-Raj et al, 1997; Basser et al, 2000). However, rHuTPO and PEG-rHuMGDF were not effective in attenuating the more profound thrombocytopenia induced by myeloablative chemotherapy (Archimbaud et al, 1999; Bolwell et al, 2000). PEG-rHuMGDF also showed potential for ameliorating the thrombocytopenia associated with ITP, elevating the platelet count in three of four patients with chronic refractory ITP and platelet counts <30 × 109/l (Nomura et al, 2002). Bleeding events decreased after the start of PEG-rHuMGDF therapy. Two patients had platelet counts >700 × 109/l a week after the last administration of PEG-rHuMGDF, with platelet counts returning to baseline levels within 4–6 weeks.

However, development of both MGDF and rHuTPO was halted after it was discovered that some patients and healthy volunteers developed antibodies to PEG-rHuMGDF on repeated administration, resulting in loss of pharmacological effects. These antibodies cross-reacted with native TPO, resulting in prolonged treatment-refractory thrombocytopenia (Li et al, 2001; Basser et al, 2002). For a review of clinical experience with these two recombinant TPOs see Kuter and Begley (Kuter & Begley, 2002). Another recombinant thrombopoietic protein, the hybrid TPO/IL3 fusion protein promegapoietin, showed promising activity but did not enter clinical trials (Doshi et al, 2001). Nevertheless, this experience provided proof of principle. Research efforts continued and resulted in development of the next generation of thrombopoiesis-stimulating agents – TPO peptide and non-peptide mimetics with little structural homology with native TPO. Of these, romiplostim was the first to reach the clinic.

Romiplostim

  1. Top of page
  2. Summary
  3. Discovery of the pathophysiology of ITP
  4. Thrombopoietin and the first-generation thrombopoietin-mimetic agents
  5. Romiplostim
  6. Clinical development programme
  7. Eltrombopag
  8. Where next in the management of patients with chronic ITP
  9. Acknowledgements
  10. References

Discovery and preclinical development

Using phage display technology, recombinant peptide libraries were screened to identify those without sequence homology with endogenous human TPO, but retaining the ability to bind and activate the TPO receptor (Cwirla et al, 1997). A potent 14-amino acid sequence was identified, and, as dimerisation had been shown to markedly increase the potency of TPO-mimetic peptides, studies were undertaken to determine the optimal number of copies of this sequence to use. As peptides tend to have poor stability and pharmacokinetic properties, a number of options were considered to overcome these problems. Scientists at Amgen were experimenting with novel platforms for extending the circulating half-life of therapeutic proteins by combining them with antibody fragment crystallisable (Fc) constructs which would undergo reticuloendothelial recirculation. Extension of this work to peptides resulted in a new family of molecules termed ‘peptibodies’. The 60Da peptibody romiplostim was finally produced by covalently linking two tandem dimers to the C-terminus of human IgG1 (Fc fragment). Thus, the molecule consists of an active TPO-binding peptide and a carrier Fc domain (Fig 3). Romiplostim is expressed in E. coli.

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Figure 3.  Structure of romiplostim.

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In vitro experiments showed that romiplostim bound and activated the TPO receptor in a similar manner to endogenous TPO, dose-dependently stimulating the growth and maturation of murine colony-stimulating units-megakaryocyte (CFU-Meg). Stimulation of megakaryopoiesis was seen at romiplostim concentrations as low as 30 ng/ml and was maximal at 1000–2000 ng/ml: these effects were enhanced in the presence of erythropoietin, stem cell factor, IL-3, and IL-6. As with native TPO, exposure of cells expressing human mpl (BaF3-mpl) to romiplostim resulted in rapid tyrosine phosphorylation of mpl, JAK2, and STAT5 and stimulation of megakaryopoiesis. Romiplostim displaced recombinant radiolabelled TPO from mpl in these cells, but enhanced the effects of TPO on murine megakaryopoiesis (Broudy & Lin, 2004).

Pharmacodynamic/pharmacokinetic and metabolism studies were subsequently conducted in mice, rats, rabbits, dogs, and monkeys (Data on file, Amgen) (Hartley et al, 2005; Sun et al, 2005). Romiplostim was well tolerated and induced dose-dependent increases in platelet levels in all species, with a wide inter-species difference. It also demonstrated activity in murine models of chemotherapy and radiation-induced thrombocytopenia (Hartley et al, 2005).

The first human study was a double-blind, placebo-controlled study conducted in 48 healthy volunteers (Wang et al, 2004). Based on in vitro potency studies and modelling of pharmacokinetic data from non-human primates, a single IV dose of 10 μg/kg was initially investigated. This was anticipated to be a no-effect dose but was found to elevate platelet counts almost sixfold, to well in excess of 1000 × 109/l. IV and SC doses ranging from 0·1 to 2 μg/kg SC were subsequently evaluated and, unexpectedly, effective doses in humans were found to closely correspond with rodent, rather than non-human primate, data. The pharmacokinetics of romiplostim were nonlinear after IV administration of 0·3–10 mcg/kg. A dose of 1 μg/kg resulted in serum concentrations of 12 900 pg/ml immediately after IV administration, whereas serum romiplostim concentrations were generally below the lower quantitation limit of the assay (18 pg/ml) after SC administration. Absorption from the SC site appeared to be slow, with available data suggesting that peak serum concentrations occur at 24–36 h postdose. Nevertheless, a 1 μg/kg dose induced similar increases in platelet count (approximately doubling the baseline value on average) whether given via the IV or SC route. There was a 3–5-d delay in platelet response, with a peak on days 12–16, and counts returning to near-baseline values by day 28 (Fig 4). These data suggest that the platelet response is driven mainly by the duration that romiplostim concentrations remain above a threshold concentration, rather than by the maximum concentration achieved. This threshold appears to approximate the lower concentration limit of the assay. The most frequently reported adverse events were mild to moderate headache and sore throat.

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Figure 4.  Platelet counts in healthy volunteers after a single SC or IV dose of romiplostim 1 μg/kg (Wang et al, 2004). Reprinted by permission from Macmillan Publishers Ltd: [Clinical Pharmacology & Therapeutics], Copyright © 2004 by the American Society for Clinical Pharmacology and Therapeutics. http://www.nature.com/clpt/index.html

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A sensitive Biacore immunoassay, able to test simultaneously for antibodies that could bind romiplostim, its peptide or Fc domain or endogenous TPO, was used in this study and subsequent studies. If any binding antibodies were detected, cell-based bioassays were used to test for the ability of sera to neutralise romiplostim or native TPO. Neutralising antibodies were not detected in this study or in any of the subsequent phase I-II studies.

A further double-blind, phase I study evaluated the safety, pharmacodynamic response, and pharmacokinetics of a single SC romiplostim dose (0·3, 1, or 2 μg/kg) in 30 healthy Japanese volunteers (Kumagai et al, 2007). Romiplostim was generally well tolerated, with adverse events similar to placebo. Treatment-related adverse events (headache, ‘feeling hot’, malaise) were reported by 5/24 romiplostim-treated volunteers. Platelet counts were elevated by at least 1·5-fold over baseline in 4/8 subjects receiving 1 μg/kg and 7/8 receiving 2 μg/kg. Serum romiplostim concentrations were undetectable in all but two volunteers.

Clinical development programme

  1. Top of page
  2. Summary
  3. Discovery of the pathophysiology of ITP
  4. Thrombopoietin and the first-generation thrombopoietin-mimetic agents
  5. Romiplostim
  6. Clinical development programme
  7. Eltrombopag
  8. Where next in the management of patients with chronic ITP
  9. Acknowledgements
  10. References

Phase I–II studies

In the US, romiplostim was granted orphan drug status in 2003 and fast-track approval status in December 2004. Two phase I-II clinical trials were conducted in the US (Bussel et al, 2006) and Europe (Newland et al, 2006), respectively, in patients with chronic ITP. Patients were to receive romiplostim 0·2–10 μg/kg (Bussel et al, 2006) or 30–500 μg (Newland et al, 2006) on days 1 and 15 (or day 22 if the platelet count was >50 × 109/l on day 15). Platelet response was defined as a doubling of the baseline platelet count to between 50 and 450 × 109/l (Bussel et al, 2006; Newland et al, 2006).

Romiplostim was well tolerated and increased platelet counts in a dose-dependent manner. In the US study, seven of 12 patients treated with romiplostim 3, 6, or 10 μg/kg achieved a platelet count ≥50 × 109/l: platelet counts were within the target range in four patients and above the target range (i.e. >450 × 109/l) in three patients. Subsequent treatment with romiplostim 1 or 3 μg/kg per week for 6 weeks in phase II of the study induced platelet responses in 10/16 patients, with an additional two patients (both receiving the higher dose) having counts above the target range (Bussel et al, 2006). Transient rebound thrombocytopenia occurred after discontinuation of romiplostim in four patients (10%).

In the European study (n = 16), platelet responses occurred in patients receiving romiplostim 30, 100 or 300 μg. A dosage of 500 μg induced an excessively high platelet count in the first patient and was not studied further. Doses that were equivalent to ≥1 μg/kg induced platelet responses in 8 of 11 patients (Newland et al, 2006) and this dosage level was chosen as an initial starting point for phase III studies.

Phase III studies

Two 24-week, placebo-controlled phase III trials were conducted in parallel at centres in the US and Europe: these studies had identical design except that one enrolled splenectomised, and the other non-splenectomised, patients. Patients were required to have a mean baseline platelet count of <30 × 109/l and were randomised (2:1) to receive romiplostim or placebo once weekly by SC injection for 24 weeks. The initial romiplostim dose was 1 μg/kg and subsequent doses could be adjusted based on platelet response to achieve target counts of 50–200 × 109/l according to the following algorithm: 2 μg/kg every week if the count was 10 × 109/l or less and 2 μg/kg every 2 weeks if the platelet count was 11–50 × 109/l. Once the platelet count was >50 × 109/l, the maintenance algorithm was used: the dose was increased by 1 μg/kg every week if the platelet count was ≤10 × 109/l, increased by 1 μg/kg after 2 weeks if 11–50 × 109/l, reduced by 1 μg/kg after two consecutive weeks at 201–400 × 109/l, withheld if the platelet count had reached >400 × 109/l, and subsequent doses were reduced by 1 μg/kg and given after the platelet count was <200 × 109/l. The maximum permitted dose was 15 μg/kg.

Both studies used a rigorous primary endpoint: durable platelet response, defined as a platelet count ≥50 × 109/l during at least 6 of the last 8 weeks of treatment, without having received rescue medication at any point in the trial. A transient response was defined as four or more weekly platelet responses without a durable response from week 2–25. Patients assessed as having had a transient response were not allowed to have received rescue medications within 8 weeks of the response.

A total of 125 patients were enrolled in the studies (Kuter et al, 2008). These patients had severe and refractory ITP, with baseline platelet counts ranging from 2 to 31 (median 16) × 109/l. Almost two-thirds had received at least three previous ITP treatments and almost one-third were receiving concomitant ITP therapy (Table I). The median duration of ITP was approximately 8 years in splenectomised, and approximately 2 years in non-splenectomised, patients. Romiplostim achieved a durable platelet response in 16/42 (38%) splenectomised and 25/41 (61%) non-splenectomised patients. Corresponding figures for the placebo group were 0/21 (0%) and 1/21 (5%), respectively (Fig 5). The results show a treatment difference of 38% (95% CI 23·4–52·8; P = 0·0013) in splenectomised, and 56% (38·7–73·7; P < 0·0001) in non-splenectomised, patients. Overall, durable or transient (≥4 weeks with counts ≥50 × 109 without use of rescue medication in the previous 8 weeks) platelet responses were achieved in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients treated with romiplostim, compared with only 14% (3 of 21) of non-splenectomised and 0% (0) splenectomised placebo recipients (P < 0·0001). Romiplostim-treated patients were able to maintain a platelet count ≥50 × 109/l for a mean of 15·2 weeks (non-splenectomised patients) or 12·3 weeks (splenectomised patients), compared with only 1·3 or 0·2 weeks for placebo recipients.

Table I.   Characteristics of the patients participating in two phase III studies of romiplostim* (Kuter et al, 2008).
 SplenectomisedNon-splenectomisedAll patients
PlaceboRomiplostimPlaceboRomiplostimPlaceboRomiplostimAll
  1. *Median (range) or number of patients (%).

Age, years56 (26–72)51 (27–88)46 (23–88)52 (21–80)52 (23–88)52 (21–88)52 (21–88)
Platelets × 109/l15 (2–28)14 (3–29)19 (5–31)19 (2–29)18 (2–31)16 (2–29)16 (2–31)
Years since diagnosis 8·50 (1·1–31·4) 7·75 (0·6–44·8) 1·60 (0·1–16·2) 2·20 (0·1–31·6)NANANA
≥3 previous treatments20 (95%)39 (93%)5 (24%)15 (37%)26 (60%)54 (65%)79 (63%)
Concurrent ITP treatment6 (29%)12 (29%)10 (48%)11 (27%)16 (38%)23 (28%)39 (31%)
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Figure 5.  Incidence of durable response (defined as a platelet count ≥50 × 109/l during at least 6 of the last 8 weeks of treatment, without having received rescue medication at any point in the trial) in patients with ITP treated with romiplostim or placebo in a phase III study (Kuter et al, 2008).

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Almost one-third of patients were taking concomitant ITP medications (corticosteroids, azathioprine, danazol) at baseline: of these, most of the romiplostim-treated patients (87%) were able to discontinue such treatments or substantially reduce dosage (by >25%) compared with only 38% of placebo recipients. Moreover, fewer romiplostim-treated patients required rescue medications (increased doses of corticosteroids, or IV immunoglobulins/Anti D) compared with placebo recipients (26·2% vs. 57·1% of splenectomised and 17·1% vs. 61·9% of non-splenectomised patients).

Romiplostim was well tolerated in these two 24-week clinical trials (Kuter et al, 2008). While adverse events were reported in almost all patients treated with romiplostim or placebo (100% and 95%, respectively), most events were mild to moderate and appeared to be related to the underlying disease. Among those treated with romiplostim, there were few serious treatment-related adverse events (n = 2; 2%: increased bone marrow reticulin and arterial embolism, respectively) or discontinuations because of adverse events (n = 3; 4%). Bleeding events of at least grade 3 severity were more common with placebo than with romiplostim (12% vs. 7%). There was no evidence of an increased risk of thromboembolic events during romiplostim treatment: such events were equally uncommon in patients receiving romiplostim or placebo (≈ 2·5%) (Kuter et al, 2008). No antibodies against romiplostim or TPO were detected.

Long-term extension study

An ongoing open-label extension study in Europe and the US is evaluating the safety and efficacy of long-term romiplostim treatment. Patients who had completed a previous romiplostim study and had platelet counts ≤50 × 109/l were eligible to enter (Bussel et al, 2009a). Interim data from 142 patients treated with romiplostim for periods of up to 3 years have recently been published (Bussel et al, 2009a). 60% of patients had undergone splenectomy and median baseline platelet count was 17 × 109/l (range 1–50 × 109/l). 87% of patients (n = 124) achieved a platelet response (≥50 × 109/l and double the baseline value in the absence of rescue medication in the previous 8 weeks) and, on average, this response occurred for 67% of the weeks on study in patients who responded. Approximately 60% of patients were able to self-administer their romiplostim injections. Most of those patients who were receiving concurrent ITP medications at baseline either discontinued these or reduced their dosage by ≥25% (84%; 27/32). Use of rescue medications decreased from 23% (33/142) of patients during weeks 1–12 to 15% (18/124) during weeks 24–36.

Long-term romiplostim treatment was generally well tolerated, with only seven patients (5%) discontinuing treatment because of adverse events. Treatment-related serious events occurred in 13 patients (9%). The proportion of patients experiencing bleeding events decreased from 42% (60/142) in the first 24 weeks to 20% (13/65) during weeks 72–96, with only 12 (9%) patients experiencing severe bleeding events. Thromboembolic events occurred in seven (5%) patients, six of whom had pre-existing risk factors such as cardiovascular disease and/or a history of thrombosis.

Bone marrow samples were taken from 16 patients: eight patients were found to have presence of/increased bone marrow reticulin. Reticulin deposition is often present in the bone marrow of healthy individuals and patients with ITP, and increased reticulin has been observed in patients treated with various TPO mimetics (Kuter et al, 2007). The clinical significance of these findings is unknown, but close monitoring of affected patients has shown no evidence of progression to collagen fibrosis, or clonal myeloproliferative disorder after romiplostim treatment. One patient transiently developed neutralising antibodies to romiplostim (absent on retesting ≈ 4 months after discontinuation of treatment), but these did not cross-react with endogenous TPO or affect the platelet response.

Quality of life analyses

Not surprisingly, patients with chronic ITP experience impaired health-related quality of life (HRQoL), related to fatigue, concerns over their appearance due to bruising, as well as impaired ability to conduct routine daily activities (Mathias et al, 2008; Snyder et al, 2008). Indeed, it was recently reported that such patients have worse HRQoL than do patients with hypertension, arthritis, or cancer (McMillan et al, 2008). HRQoL changes were specifically studied in patients participating in the two phase III studies (George et al, 2009) and the open-label, romiplostim extension study (Tarantino et al, 2007), using a specific validated instrument, the ITP Patient Assessment Questionnaire (ITP-PAQ). Results demonstrated that treatment with romiplostim significantly improved patient HRQoL in this setting.

Ongoing clinical programme

Because of the urgent need for new treatments for ITP, regulatory authorities in several countries granted priority review of romiplostim. It has now been approved for treatment of adult chronic ITP in Australia, Canada, the USA and the European Union. Romiplostim is currently being evaluated in a 52-week phase IIIb trial versus medical standard of care in adult patients with ITP, with one of the two primary endpoints being the number of splenectomies in each treatment group. Another study is ongoing in children with ITP. Romiplostim is also being investigated for the treatment of other thrombocytopenic conditions, including patients with myelodysplastic syndromes and chemotherapy-induced thrombocytopenia (US National Institutes of Health. Available at: http://www.clinicaltrials.gov/ct/show/NCT00415532).

Eltrombopag

  1. Top of page
  2. Summary
  3. Discovery of the pathophysiology of ITP
  4. Thrombopoietin and the first-generation thrombopoietin-mimetic agents
  5. Romiplostim
  6. Clinical development programme
  7. Eltrombopag
  8. Where next in the management of patients with chronic ITP
  9. Acknowledgements
  10. References

The non-peptide, synthetic TPO-receptor agonist, eltrombopag, (Revolade®, GSK, London, UK; Promacta®, Research Triangle Park, NC, USA), is administered as a once-daily oral dose. It activates the TPO receptor by binding to the transmembrane region. Although eltrombopag binds differently to the receptor than eTPO or romiplostim, signal transduction and the final pathways seem to be identical (Stasi et al, 2008). Results from a 6-week treatment-period, placebo-controlled phase II trial (n = 118 patients) showed that 28%, 70%, and 81% of patients receiving, respectively, 30, 50 or 75 mg of eltrombopag daily (vs. 11% in the placebo group) achieved a platelet count ≥50 × 109/l at day 43 of treatment (Bussel et al, 2007). Mild to moderate headache was the most commonly reported adverse event, followed by aspartate aminotransferase elevation, constipation, fatigue, and rash. A phase III, randomised, double-blind, placebo-controlled study was conducted in 114 patients (39% splenectomised) who received eltrombopag (initial dose 50 mg/d; n = 76) or placebo (n = 38) for up to 6 weeks (Bussel et al, 2009b). A total of 43 (59%) eltrombopag vs. 6 (16%) placebo recipients achieved platelet counts ≥50 × 109/l at day 43; odds ratio [OR] 9·61 [95% CI 3·31–27·86]; P < 0·0001). As reported by investigators, bleeding was significantly less common with eltrombopag than with placebo (as measured by the WHO bleeding scale), at any point in time during treatment (OR 0·49 [95% CI 0·26–0·89]; P = 0·021) The frequency of grade 3–4 adverse events during treatment (eltrombopag, 2 [3%]; placebo, 1 [3%]) and withdrawal because of adverse events (eltrombopag, 3 [4%]; placebo, 2 [5%]), was similar in both groups. Consistent with the phase II study, hepatotoxicity was more common with eltrombopag than with placebo, with elevated transaminase concentrations twice the upper limit of normal detected in six eltrombopag and one placebo recipient. Cataracts (which were also noted in preclinical studies) occurred in a small proportion of patients in both treatment groups (cataracts: eltrombopag, n = 3, placebo, n = 1; progression of existing cataracts: eltrombopag n = 2; placebo n = 1) (Bussel et al, 2009b).

Where next in the management of patients with chronic ITP

  1. Top of page
  2. Summary
  3. Discovery of the pathophysiology of ITP
  4. Thrombopoietin and the first-generation thrombopoietin-mimetic agents
  5. Romiplostim
  6. Clinical development programme
  7. Eltrombopag
  8. Where next in the management of patients with chronic ITP
  9. Acknowledgements
  10. References

The current management of ITP varies considerably and is not always evidence-based, due to the lack of good quality comparative study data. Indeed, a number of treatments which are used for ITP are not actually licensed for this indication. Furthermore, several of the existing treatment options for ITP are based on suppressing the immune system, which can predispose patients to infection. Indeed, it has been reported that infections account for approximately half of all deaths in patients with ITP (Stasi et al, 1995; Portielje et al, 2001). Therefore, as many treatments for ITP can contribute substantially to morbidity and mortality, a proportion of patients may be left untreated and at risk of developing dangerously low platelet levels or experiencing serious bleeding episodes. Evaluation of clinical trial data has been hampered by the wide variation in criteria used for patient characteristics and response to treatment (Ruggeri et al, 2008). Recently, an international working group has proposed standardised terminology and definitions for primary ITP, as well as criteria for grading severity, and clinically meaningful outcomes and response (Rodeghiero et al, 2008). Following on from these publications an international group of experts in ITP have updated the guidelines previously produced by the American Society of Haematology and the British Committee for Standards in Haematology (George et al, 1996, British Committee for Standards in Haematology General Haematology Task Force 2003) in an attempt to provide an agreed consensus document on primary ITP. It is anticipated that this will act as a basis for the diagnosis, investigation and treatment of the disease and will provide an evidence base for the use of established and novel treatments that will allow future evaluation and a more rigorous approach to management (Provan et al, 2010).

The prolonged search for the elusive growth factor that stimulates megakaryopoiesis eventually culminated in the development of TPO mimetics, five decades after the existence of TPO was first postulated. The development of romiplostim has provided the clinician with a novel approach to treating ITP – namely, by enhancing platelet production. Romiplostim is administered by weekly subcutaneous injection and many patients are able to self-administer their injections at home. Its place in treatment and that of the newer thrombopoietin receptor agonists, such as the oral agent eltrombopag, will need to be determined by ongoing studies. It is clear from current studies that most patients can reduce or discontinue concomitant immunosuppressive treatment and require less rescue medication. Ongoing studies will shed some light on the influence of this new class of drugs on the course of the disease, quality of life, and life expectancy in patients with chronic ITP.

Acknowledgements

  1. Top of page
  2. Summary
  3. Discovery of the pathophysiology of ITP
  4. Thrombopoietin and the first-generation thrombopoietin-mimetic agents
  5. Romiplostim
  6. Clinical development programme
  7. Eltrombopag
  8. Where next in the management of patients with chronic ITP
  9. Acknowledgements
  10. References

This article was supported by Amgen Europe GmbH, Zug, Switzerland. Dr Graham Molineux is an employee of Amgen. Professor Adrian Newland is a consultant and speaker for Amgen, and has received research support from Amgen. The authors thank Julia Balfour, Medical Writer, Kilconquhar, Scotland and Claire Foster, Amgen Europe GmbH, for their assistance with the preparation of the manuscript.

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  2. Summary
  3. Discovery of the pathophysiology of ITP
  4. Thrombopoietin and the first-generation thrombopoietin-mimetic agents
  5. Romiplostim
  6. Clinical development programme
  7. Eltrombopag
  8. Where next in the management of patients with chronic ITP
  9. Acknowledgements
  10. References
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