SummaryEltrombopag, a thrombopoietin receptor agonist, raises platelet counts and reduces bleeding in patients with immune thrombocytopenia (ITP). In Chinese patients, eltrombopag was evaluated at an initial dose of 25 mg, vs. 50 mg for non-Asians, because the plasma exposure of eltrombopag is higher in East Asians. A multicentre, double-blind, randomised, placebocontrolled, 8-week, phase III study enrolled 155 patients with chronic, previously treated ITP. Dosage could be adjusted (25-75 mg/day) to maintain platelet counts 50-250 9 10 9 /l. The primary efficacy endpoint was the proportion of patients with a platelet count ≥50 9 10 9 /l after Day 42. Pharmacokinetics and pharmacodynamics of eltrombopag were analysed in an open-label extension. After Day 42, 57Á7% of eltrombopag-treated and 6Á0% of placebo-treated patients achieved platelet counts ≥50 9 10 9 /l.Odds of achieving a platelet count ≥50 9 10 9 /l were 26Á08 times greater with eltrombopag than placebo (P < 0Á001). Compared with placebo, time to response and duration of response were better with eltrombopag (P < 0Á001) and the odds of any bleeding were reduced by 72% (P = 0Á001). Tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics were similar to previous findings in East Asian patients. In conclusion, in Chinese patients with chronic ITP, eltrombopag 25 mg once daily, elevated platelet counts to a safe range and reduced bleeding.

Background Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. Methods Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 109/L) after 8 weeks of treatment. Results The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83–68.63; p < 0.0001) and HETROM-5 (64.3%; OR 32.81, 95% CI 12.39–86.87; p < 0.0001) group than in the Placebo group (5.9%). Hetrombopag was also superior to placebo in achieving a platelet response and in reducing the bleeding risk and use of rescue therapy throughout 8 weeks of treatment. The durable platelet response to hetrombopag was maintained throughout 24 weeks. The most common adverse events were upper respiratory tract infection (42.2%), urinary tract infection (17.1%), immune thrombocytopenic purpura (17.1%) and hematuria (15%) with 24-week hetrombopag treatment. Conclusions In ITP patients, hetrombopag is efficacious and well tolerated with a manageable safety profile. Trial registration Clinical trials.gov NCT03222843, registered July 19, 2017, retrospectively registered.

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.

Epigenetic connection between gut microbiota-derived short-chain fatty acids and chromatin histone modification in kidney diseases

No abstract