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Thrombopoietin Receptor Agonists as a Novel Treatment for Immune Thrombocytopenia

Romiplostim Pharmacology

Romiplostim (formerly AMG 531), developed by Amgen, is a recombinant protein known as a ‘peptibody’. It is made up of two disulphide-bonded immunoglobulin G1 (IgG1) heavy-chain and kappa light-chain constant regions (Fc fragments). Each of these is covalently bound at residue 228 of the heavy chain with two identical peptide sequences linked via polyglycine.33

The carrier Fc component

of the molecule binds to the FcRn salvage receptor and undergoes endothelial recirculation, resulting in a substantially longer half-life (t½) than the peptide alone.34

The peptide component binds to and

activates the human TPO-R in a similar manner to endogenous TPO via activation of signalling pathways, including tyrosine phosphorylation of TPO-R, janus kinase 2 and signal transducer and activator of transcription 5 (STAT5).35

The peptibody exerts a dose-dependent effect on the growth of megakaryocytic colony-forming units from murine marrow cells. It also increased megakaryocyte ploidy and maturation in vitro. Furthermore, it effectively competed with TPO for binding to human TPO-R in vitro.35

Phase I–II Clinical Trials

In healthy volunteers, single intravenous or subcutaneous doses of romiplostim ranging from 0.3 to 10.0µg/kg and from 0.3 to 2.0µg/kg, respectively, were well tolerated. The drug-induced dose-dependent increases in platelet counts, with peak counts being achieved on days 12–16.33

Two phase I–II clinical trials were conducted in the US36 and Europe37 in

splenectomised adult patients with ITP. Platelet response was defined as a doubling of the baseline platelet count to between 50 and 450x109/l.

In phase I of the US study,36 seven of 12 patients treated with

romiplostim 3, 6 or 10µg/kg achieved platelet counts within the target range. Three of the patients achieved counts above the target range (i.e. >450x109/l). In phase II of the same trial, 21 patients were randomly assigned to receive six weekly subcutaneous injections of romiplostim (1, 3 or 6µg/kg) or placebo. However, the highest-dose cohort was closed after the platelet count increased to 520x109/l in one patient on day 21.

In the European study37 (n=16, romiplostim dose range 30–500µg

administered on days 1 and 15), platelet responses were seen at all dose levels (30, 100 and 300µg). Treatment with the 500µg romiplostim dose was discontinued because of an excessively high platelet count measured in the first patient treated. It was calculated that doses equivalent to ≥1µg/kg induced platelet responses in eight out of 11 patients. Transient rebound thrombocytopenia (defined as a platelet count <10x109/l or below baseline) occurred after discontinuation of romiplostim in four patients (10%) in the US study and in one patient in the European study. This suggests that abrupt cessation of romiplostim without tapering or reinitiation of other ITP treatments should be avoided.

Phase III Studies

Two similarly designed, multicentre, randomised, placebo-controlled, double-blind phase III trials were conducted in parallel. One trial enrolled patients with a prior splenectomy (n=63) and the other enrolled patients who had not undergone splenectomy (n=62).38


• adverse events; •

• • • •

proportion of transient responses (four or more weekly platelet responses without a durable platelet response from week 2 to 25);

changes in concurrent ITP therapies; number of weekly platelet responses;

proportion of patients receiving rescue medications; and overall platelet response (durable and transient responses).

The splenectomised patients had a longer duration of ITP (median eight years versus 2.1 years in non-splenectomised patients) and were more heavily pre-treated. More than 90% of splenectomised patients had received more than three previous treatments for ITP compared with 32% of non-splenectomised patients. Patients receiving no current treatment or concurrent ITP treatment with corticosteroids, azathioprine or danazol at a constant dose and schedule were permitted to enter the study. The starting dose of romiplostim or placebo was 1µg/kg (with a maximum dose of 10µg/kg) and was adjusted to keep platelet counts within a target range of 50–200x109/l. Romiplostim increased and sustained platelet counts in both splenectomised and non-splenectomised patients during the study period (see Figure 1). A platelet count ≥50x109/l was maintained for a mean of 15.2 (standard deviation [SD] 7.5) and 12.3 (SD 7.9) weeks for non-splenectomised and splenectomised patients, respectively, over the 24-week course. This was compared with 1.3 (SD 3.5) or 0.2 (SD 0.5) weeks, for the non-splenectomised and splenectomised patients receiving placebo. Most of the romiplostim patients (20 out of 23 patients [87%], 12 out of 12 splenectomised and eight out of 11 non-splenectomised) were able to discontinue or substantially reduce concomitant ITP medications (by >25%) by the end of the study. This was compared with only 38% of the placebo patients (six out of 16 patients, one in six splenectomised and five in 10 non-splenectomised). Romiplostim also reduced the percentage of patients requiring rescue medications (immunoglobulins, corticosteroids and platelet transfusions) compared with placebo (26.2 versus 57.1% of splenectomised and 17.1 versus 61.9% of non-splenectomised patients).

Data pooled from the two trials mentioned above, adjusted for splenectomy status, showed significant improvement in health-related quality of life (HRQoL) in patients treated with romiplostim.39

The study enrolled 234 adult ITP patients at 85 sites in North America, Europe and Australia. Treatment was considered to be ineffective if platelet levels remained low (≤20x109/l) for four consecutive weeks or if participants experienced major bleeding events or required changes in therapy, including splenectomy.


In a recently-published trial, non-splenectomised patients with ITP were randomly assigned to either the standard care medications prescribed by their treating physicians or weekly romiplostim injections.40

trials included adult patients who had chronic ITP, a mean of three platelet counts ≤30x109/l despite treatment for ITP and were over 18 years of age. Patients were randomised 2:1 to receive romiplostim (n=42 splenectomised, n=41 non-splenectomised) or placebo (n=21 in each study) once weekly for 24 weeks.

The primary end-point was a durable platelet response. This was defined as a weekly platelet count of ≥50x109/l at a weekly study visit for six or more of the final eight weeks of treatment. Secondary objectives included:

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