First‐in‐patient study of hetrombopag in patients with chronic idiopathic thrombocytopenic purpura

Abstract

Background: Idiopathic thrombocytopenic purpura (ITP) especially refractory and (or) relapsed ITP, is a serious and global health burden and its clinical treatment is far from being satisfied. Hetrombopag is a novel, small-molecule thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura (CITP). Objectives: This first-in-patient study aimed to investigate the safety, pharmacokinetics, and anticipated therapeutic dose of hetrombopag in CITP patients. Methods: In this multicenter, first-in-patient study, CITP patients received hetrombopag in a dose escalation (2.5 mg/day, 5 mg/day, or 7.5 mg/day) cohort. All patients received hetrombopag in fasting condition once daily for 2 weeks. Results: Of 44 patients screened, 32 were enrolled and treated. Most adverse events were graded 1 to 2 (ie, mild to moderate), and the incidence and severity were similar for three study cohorts. The pharmacokinetics of hetrombopag were found to be nonlinear with greater than dose-proportional: 12.5% of patients (1/8) in the 2.5 mg/d cohort, 58.3% of patients (7/12) in the 5 mg/d cohort, 66.7% of patients (8/12) in the 7.5 mg/d cohort reached the primary study endpoint of a platelet count exceeding 50 × 10 9 /L on day 28. Conclusion: Hetrombopag was well tolerated and preliminarily efficacious. Efficacy, safety, and pharmacokinetic data suggest that 7.5 mg hetrombopag once daily was the anticipated therapeutic dose of hetrombopag in CITP patients and has been recommended for investigation in a later confirmatory clinical study of hetrombopag.

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

“…Only one patient's dose of hetrombopag was modified due to an AE. Liver toxicity in this study was not a new safety signal since it had been observed in a previous first-in-patient trial of hetrombopag in ITP patients (24). In the current study, most of the treatment-related increased transaminases were grades 1-2, and only 1 patient had grade 3 increased alanine aminotransferase.…”

“…Preclinical studies have shown that hetrombopag has a similar mechanism of action as eltrombopag, but its pharmacological performance in vivo (nude mice) is superior to that of eltrombopag (23). In the first-in-patient study, hetrombopag was found to be well-tolerated and have preliminary efficacy in ITP patients (24). Thus, we conducted this phase 1 trial (NCT02614846) to further assess the activity and safety of hetrombopag in ITP patients who had an insufficient response or had progressed on a previous standard ITP treatment.…”

Novel therapies for immune thrombocytopenia

“…There were minimal adverse events. At the lowest dose of 2·5 mg, there was a minimal rise in platelet count and only 1/8 (12·5%) had a platelet count rise over 50 × 10 9 /l; but at doses of 5·0 and 7·5 mg there was a dose‐dependent rise in platelet count with response rates of 7/12 (58·3%) and 8/12 (66·7%), respectively, beginning on day 4–5 and reaching a peak on about day 14, then falling to baseline after discontinuation of therapy 138 …”

“…At the lowest dose of 2Á5 mg, there was a minimal rise in platelet count and only 1/8 (12Á5%) had a platelet count rise over 50 9 10 9 /l; but at doses of 5Á0 and 7Á5 mg there was a dosedependent rise in platelet count with response rates of 7/12 (58Á3%) and 8/12 (66Á7%), respectively, beginning on day 4-5 and reaching a peak on about day 14, then falling to baseline after discontinuation of therapy. 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.…”

Commentary on: First‐in‐patient study of hetrombopag in patients with chronic idiopathic thrombocytopenic purpura

“…Because this is a new drug and there is not yet enough information, the need to find the correct doses for CITP treatment is essential. The present study by Wang et al is the first‐in‐patient report of this novel drug, which was aimed to investigate the safety, pharmacokinetics, and anticipated therapeutic dose in CITP patients 9 . The authors reported that oral hetrombopag, administered in fasting conditions, was mostly well tolerated by CITP patients, they also evaluated the anticipated therapeutic dose using three dose cohorts that consisted of 2.5, 5, and 7.5 mg/d.…”