Effect of Eltrombopag on Platelet Response and Safety Results in Chinese Adults with Chronic ITP-Primary Result of a Phase III Study

Abstract

INTRODUCTION: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline) is a non peptide, oral thrombopoietin receptor agonist which promotes the differentiation and proliferation of megakaryocytes and increases platelet counts. In previous studies, East Asians ITP subjects had an approximately 1.85 fold higher plasma eltrombopag AUC (0-τ) and 1.6 fold higher plasma eltrombopag Cmax than non-East Asian ITP subjects who were predominantly Caucasian. An initial dose of 25mg once daily has not been studied in a randomized fashion in East Asian subjects with ITP. METHODS: This is a randomized study comprising a double-blind (DB), placebo (PBO)-controlled phase, followed by an open-label (OL) phase in previously treated Chinese patients with chronic ITP who had failed ≥1 previous treatment. Subjects were stratified at baseline by use of ITP medication, splenectomy status and platelet count ≤15×109/L. In the DB phase, Chinese Adults with Chronic ITP and platelet counts <30 ×109/L received standard of care and were randomized (2:1) to receive either an initial dose of 25mg of eltrombopag or matching placebo once daily. The dose was increased every 2 weeks by 25 mg once daily increments up to a maximum of 75 mg once daily if the desired platelet response (> 50×109/L) was not achieved. The primary efficacy endpoint was the proportion of patients achieving a platelet count of ≥50×109/L and ≤250×109/L after the first 6 weeks of study treatment using a logistic regression model adjusted for stratification factors . All subjects completing the DB phase entered the OL phase where they initiated (if they were on placebo) or continued (if they were on eltrombopag) to receive eltrombopag (25, 50 or 75 mg/day) based on individual platelet counts. RESULTS: 155 subjects were randomized to receive 6 weeks of once daily eltrombopag (n=104) or matching placebo (n=51) in 2:1 ratio. Of 155 subjects randomized, 81 subjects (52.3%) were receiving concomitant ITP medication at baseline, 25 subjects (16.1%) had prior splenectomy, and 82 subjects (52.9%) had baseline platelet count ≤15×109/L. A total of 53/104 (51%) subjects on eltrombopag were receiving concomitant ITP medication at baseline vs 28/51 (54.9%) subjects on placebo. A total of 18/104 (17.3%) subjects on eltrombopag had prior splenectomy vs 7/51 (13.7%) subjects on placebo. A total of 54/104 (51.9%) subjects on eltrombopag had baseline platelet counts ≤15×109/L vs 28/51 (54.9%) subjects on placebo. The primary efficacy analysis showed that eltrombopag statistically significantly increased platelet counts in patients with chronic ITP: 57.7% (60/104) of subjects in eltrombopag group, and 6% (3/50) of subjects in placebo group achieved a platelet count of ≥50×109/L after the first 6 weeks of study treatment. (Odds ratio= 26.08, 95% CI [7.29, 93.26]; p <0.001). 63.5% (66/104) of patients in eltrombopag group and 66.7% (34/51) of patients in placebo group experienced adverse events. The most common (≥3% total incidence) adverse events are hypokalaemia [10.6% (11/104) in eltrombopag group, 15.7% (8/51) in placebo group], alanine aminotransferase increased [8.7% (9/104) in eltrombopag group, 15.7% (8/51) in placebo group], and nasopharyngitis [10.6% (11/104) in eltrombopag group, 9.8% (5/51) in placebo group]. The AEs were mostly mild to moderate. Only 4.9% (4/104) of patients on eltrombopag and 9.8% (5/51) of patients on placebo experienced serious adverse events. Additional safety and efficacy results will be presented at meeting. CONCLUSION: This is the first study to evaluate eltrombopag at an initial dose of 25mg once daily in a randomized fashion in East Asian patients with previously treated chronic ITP. Eltrombopag statistically significantly increased platelet counts in Chinese adults with chronic ITP when compared to placebo. Eltrombopag was well-tolerated and these results are consistent with the known clinical benefit: risk profile of eltrombopag in patients with chronic ITP. Eltrombopag may be a new treatment option for Chinese patients with chronic ITP. Disclosures No relevant conflicts of interest to declare.

Systematic literature review of treatments used for adult immune thrombocytopenia in the second‐line setting

“…Among the remaining non‐surgical therapies, we identified 12 prospective RCTs with a placebo or SOC arm evaluating the safety and efficacy of eltrombopag (5 studies), rituximab (2 studies), or romiplostim (5 studies, with one publication reporting on two studies conducted in parallel). (No head‐to‐head RCTs directly comparing one second‐line therapy of interest to another were found.)…”

“…These studies are summarized in more detail in Table , and study‐specific definitions of the outcomes/endpoints common to at least two of the studies are provided in Table . Two studies were prospective phase 2, placebo‐controlled RCTs (1 eltrombopag and 1 romiplostim); one was a prospective SOC‐controlled, open label RCT (romiplostim); one was a prospective placebo‐controlled pilot RCT (rituximab); and the remaining eight studies were prospective phase 3, placebo‐controlled RCTs (4 eltrombopag, 1 rituximab, and 3 romiplostim).…”

“…Across TPO‐RA studies, which enrolled both splenectomized and non‐splenectomized patients, the overall platelet response tended to be higher in patients receiving eltrombopag or romiplostim compared with patients in the respective placebo/SOC arms (Figure ). The calculated response ratio comparing the rate of overall platelet response in eltrombopag vs placebo patients ranged from 1.40 (95% CI: 0.27‐7.18) to 13.24 (95% CI: 1.98‐88.62) . For studies of romiplostim, the response ratio ranged from 1.50 (95% CI: 0.22‐10.22) to 34.28 (95% CI: 2.20‐533.41) .…”

“…In terms of efficacy, the most compelling evidence stems from the trials of eltrombopag and romiplostim . Without exception, across the 10 studies, patients treated with one of these therapies tended to have higher rates of overall and complete platelet responses compared with patients receiving placebo or SOC.…”

Primary Immune Thrombocytopenia: Novel Insights into Pathophysiology and Disease Management

“…Randomized controlled studies showed that eltrombopag achieved early platelet response in 70–80% of the patients and a remission rate of 20–30% [ 119 , 120 , 121 , 122 ]. In an open-label extension study, 85% of the patients achieved a platelet response, and 52% of them had a continuous response of 25 weeks or longer [ 123 ].…”