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

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.