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.

Keywords: Hetrombopag; Immune thrombocytopenia; Platelet response; Thrombopoietin receptor agonists.

Conflict of interest statement

Junye Xiong, Runzi Li, and Jianjun Zou are employees of Jiangsu Hengrui Medicine Co., Ltd. All other coauthors declare no competing interests.

Figures

Fig. 1

Trial profile. HETROM-2.5, the dose was titrated from an initial dosage of once-daily 2.5 mg hetrombopag; HETROM-5, the dose was titrated from an initial dosage of once-daily 5 mg hetrombopag; AEs, adverse events. *Eligible patients were randomly allocated at a ratio of 4:4:1:1 to the HETROM-2.5 group, the HETROM-5 group, and matching placebo groups. The two matching placebo groups were pooled as the Placebo group

Fig. 2

Platelet counts at every scheduled visit during the 10-week double-blind treatment period. HETROM-2.5, the dose was titrated from an initial dosage of once-daily 2.5 mg hetrombopag; HETROM-5, the dose was titrated from an initial dosage of once-daily 5 mg hetrombopag. The data are shown as means (standard errors)

Fig. 3

Proportions of patients achieving a first response (a platelet count of ≥ 50 × 109/L) during the 8-week double-blind treatment period after the first dose of the study treatment. HETROM-2.5, the dose was titrated from an initial dosage of once-daily 2.5 mg hetrombopag; HETROM-5, the dose was titrated from an initial dosage of once-daily 5 mg hetrombopag