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Thrombopoietin Receptor Agonists as a Novel Treatment for Immune Thrombocytopenia

After seven weeks of treatment, increased bone marrow reticulin (thought to result from increased transforming growth factor-β released from megakaryocytes within the bone marrow) was noted in one patient. This particular patient had bone marrow reticulin present at baseline and was unresponsive to romiplostim treatment. Reticulin returned to baseline 14 weeks after discontinuation of romiplostim. Similar reversible increases in bone marrow reticulin have been noted previously in animals and humans exposed to other thrombopoetic agents (rhTPO, interleukin [IL]-3 and IL-11).43

treatment-related adverse events occurred in two romiplostim- treated patients.38

However, in a mouse model expression of a constitutively active mutant TPO-R, TPO-RW515A, resulted in the development of a myelofibrosis-like disease.44

The second patient with a serious treatment-related adverse event was a man 82 years of age 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.

In the long-term extension study, romiplostim was generally well tolerated by patients.41

Eight patients were found to have bone

marrow reticulin present or at increased levels. Six of these patients had mild to moderate reticulin reported (grade 2 or lower or within the normal range). Follow-up bone marrow biopsies in two patients revealed that one patient showed improvement in the amount of reticulin present over time, while the other patient had no change. All of the patients affected continue to be monitored for clinical signs of any progressive bone marrow abnormalities.

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, will have to be followed closely in future studies of patients with ITP treated with romiplostim.

Twelve thromboembolic events were reported in seven patients (5%) on long-term treatment with romiplostim. Six of these had pre-existing risk factors for thrombosis including congestive heart failure, antiphospholipid antibodies, coronary artery disease, hypertension, cancer and/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 (thrombosed inflammatory fibrosis at the site of a central line).

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 (167x109/l). All of the events resolved. One patient developed transient neutralising antibodies to romiplostim, but these did not cross-react with endogenous TPO or affect the platelet response. There were no clinically significant changes in laboratory parameters, blood coagulation or platelet aggregation in any of the studies.


There was a dose-dependent increase in the proportion of responders, with a statistically significant effect in the 50 and 75mg arms compared with placebo. The median platelet count on day 43 was 16x109/l in the placebo group and 26x109/l, 128x109/l and 183x109/l in the 30, 50 and 75mg groups, respectively. Furthermore, there were fewer bleeding events in those receiving the 50mg (7%) and 75mg (4%) doses than in those receiving placebo (14%) or 30mg eltrombopag (17%). The occurrence of bleeding symptoms gradually


In a phase II, placebo-controlled, double-blind trial, the platelet counts of 118 patients with chronic ITP were analysed after six weeks of daily oral treatment with placebo or eltrombopag at doses of 30, 50 or 75mg.53

Eltrombopag Pharmacology

Eltrombopag (formerly SB497115) is a non-peptide TPO-R agonist developed by GlaxoSmithKline (see Table 1). It is administered as a daily oral tablet. In pre-clinical studies, eltrombopag was shown to stimulate human megakaryocyte differentiation and proliferation in a dose-dependent manner via stimulation of the TPO-R. Eltrombopag displays high receptor-specific and species-specific binding selectivity for human TPO-R. The response of normal human TPO-R has been elucidated by measuring growth and differentiation of human bone marrow in vitro: these studies demonstrated human and chimpanzee-specific activation of TPO-R-expressing cells via activation of STAT5.45

By contrast, no eltrombopag-induced

platelet activation was observed in other species tested, including cynomolgus macaques, rhesus monkeys, pigs, dogs, ferrets, rabbits, rats and mice.46

Since eltrombopag and TPO do not bind to the same site, competitive binding is avoided and eltrombopag and TPO confer additive cell-signalling effects.48

The pharmacokinetics of eltrombopag were studied in a phase I study in healthy volunteers and in ITP patients.49,50

The terminal t½ averaged

more than 12 hours on day 10 across all doses, with the exception of the 5mg dose (which had a t½ of nine hours). Limited pharmacology data suggest that in patients of East Asian ethnicity, exposure to eltrombopag expressed as area under the serum concentration-time curve was approximately 70–80% higher than in non-Asian patients who were predominantly Caucasian. An initial dose decrease to 25mg/day is therefore recommended in East Asian patients.51

Phase I–II Clinical Trials

Eltrombopag increased platelet counts in a dose-dependent manner in healthy, non-Asian adults, but the drug only appeared to be active at doses >20mg.49

A consistent increase in platelet count started after eight days of repeat dosing with eltrombopag and the time from first dose to peak platelet count was 16 days. By day 22 (12 days after the last dose of eltrombopag) platelet counts had returned to baseline values, with no evidence of rebound thrombocytopenia following discontinuation of treatment. Eltrombopag did not prime platelets for activation and did not adversely affect platelet function.52

The mechanisms leading to activation of the TPO-R on eltrombopag binding are different from those of romiplostim. Eltrombopag interacts with the TPO-R at a binding site distant from that of TPO and appears to initiate signal transduction by a mechanism different from that of endogenous TPO. In fact, Erhardt et al. reported that eltrombopag induced the phosphorylation of STAT proteins, but not of AKT, whereas hrTPO induced the phosphorylation of AKT in addition to the STAT proteins.47

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