A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Abstract

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.

Safety and efficacy of hetrombopag in patients with chronic immune thrombocytopenia: a single-arm, open-label, multi-center phase 1 study

“…It should be noted that the limited follow-up duration of this study may not be enough to detect AEs such as cataract. Results with longer follow-ups can be found in the phase 3 trial in patients with ITP (31). In that study, 1 of 339 patients developed cataract during the 24 weeks of hetrombopag treatment.…”

Dose tapering to withdrawal stage and long‐term efficacy and safety of hetrombopag for the treatment of immune thrombocytopenia: Results from an open‐label extension study

“…7,13,29 Additionally, despite the remarkable usage of rescue therapy in the placebo group, significantly fewer patients in both the HETROM-2.5 group and HETROM-5 groups had bleeding events of WHO bleeding grade 2 or higher compared with the placebo group within 8 weeks of treatment. 15 After entering Stage 2 and Stage 4, the incidence of grade ≥2 bleeding symptoms was consistently low in patients treated with hetrombopag. These findings highlight that platelet count recovery and maintenance at a target level of ≥50 × 10 9 /L with hetrombopag is effective in preventing clinically relevant bleeding events.…”

“…A detailed description of Stages 1 and 2 has been previously published. 15 Herein, we report the efficacy endpoints during Stages 3 and 4 and the safety profile of the whole treatment period. This study was performed in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines.…”

“…These findings are comparable to those of patients receiving placebo during the double-blind treatment and are similar to known toxicities with hetrombopag during the initial 24-week treatment. 15 The most frequent AEs associated with hetrombopag in ITP adults were upper respiratory tract infection, thrombocytopenia, and urinary tract infection during the whole treatment period. No new classes of AEs emerged and AEs did not occur more frequently with prolonged exposure to hetrombopag.…”

Novel therapies for immune thrombocytopenia

“…138 In a very large, well conducted, double-blind, placebocontrolled phase 3 study (NCT03222843), patients over 18 years with primary ITP >6 months having failed ≥1 prior treatment and with platelets <30 9 10 9 /l, received daily placebo (n = 85), hetrombopag 2Á5 mg (n = 168) or hetrombopag 5Á0 mg (n = 171) for 10 weeks. 139 Stable doses of other concurrent treatments except for other TPO-RA were allowed. Over 86% of patients in all three arms completed the 10-week study.…”