Efficacy and safety of hetrombopag, a novel thrombopoietin receptor agonist, in children and adolescents with immune thrombocytopenia: Results from a randomized, multicenter, placebo-controlled phase 3 trial

Abstract Introduction: Hetrombopag is a novel oral thrombopoietin receptor agonist (TPO-RA) approved in China for adults with chronic immune thrombocytopenia (ITP) who have not responded to or have relapsed after prior treatment. This study aimed to evaluate the efficacy and safety of hetrombopag in children and adolescents with chronic primary ITP. Methods: Part B of this clinical trial (ClinicalTrials.gov: NCT04737850) was a multicenter, randomized, double-blind, placebo-controlled phase 3 study conducted at 17 sites across China. It included a 12-week double-blind core treatment period followed by a 12-week open-label extension. Eligible patients were aged 6–17 years with primary ITP lasting ≥6 months and had failed or relapsed after at least one prior first-line therapy (e.g., corticosteroids, IVIg) or splenectomy. Patients were randomized in a 2:1 ratio to receive hetrombopag or placebo during the core period, stratified by age group (6–11 vs 12–17 years) and disease duration (6–12 vs >12 months). Treatment was initiated at 2.5 mg once daily and titrated up to 7.5 mg to maintain platelet counts between 50×10⁹/L and 250×10⁹/L. In the open-label extension, patients continued or initiated hetrombopag at 2.5 mg. A treatment response was defined as a platelet count ≥50×10⁹/L. The primary endpoint was the proportion of responders at Week 10. The key secondary endpoint was the proportion of patients achieving a sustained platelet response (≥50×10⁹/L for ≥6 weeks without rescue therapy) from Week 5 to 12. Results: Between July 30, 2022, and June 17, 2025, 88 eligible patients were randomized and received at least one dose of study treatment (hetrombopag, n = 57; placebo, n = 31). The median age was 10.0 years (67% aged 6–11), median weight 39.5 kg, median baseline platelet count 15.0 × 10⁹/L, and median ITP duration 2.7 years; 55 patients (62.5%) had bleeding symptoms at baseline. The primary endpoint was achieved by 61.4% (35/57) of patients receiving hetrombopag versus 9.7% (3/31) receiving placebo, an absolute difference of 52.7 percentage points (95% CI, 35.9–69.5; two-sided p < 0.0001). The key secondary endpoint—sustained platelet response from Weeks 5 to 12—was met by 43.9% (25/57) in the hetrombopag group and none in the placebo group, for a difference of 43.7 percentage points (95% CI, 28.5–58.9; two-sided p < 0.0001). Additional secondary endpoints during the core treatment period also favored hetrombopag, including a higher proportion of patients with platelet responses lasting ≥4 consecutive weeks between Weeks 5 and 12 (43.9% vs 0), at least one response (91.2% vs 64.5%), responses at ≥75% of scheduled visits (26.3% vs 0), and platelet counts ≥30 × 10⁹/L with ≥2-fold increase from baseline (93.0% vs 64.5%). The median time to first documented response was 20 days (95% CI, 16–23) with hetrombopag and 43 days (95% CI, 24–not reached) with placebo. Median maximum continuous response duration was 29.0 vs 8.0 days, and total response duration was 38.0 vs 14.0 days, respectively. Fewer patients receiving hetrombopag required rescue therapy (21.1% vs 45.2%). At Week 12, bleeding symptoms (grades 1–4, per the 2021 Chinese guideline for childhood ITP) were less frequent with hetrombopag (15.8% [9/57]) than with placebo (48.4% [15/31]). The platelet response to hetrombopag remained durable through Week 24. Among the 52 patients who achieved platelet responses at consecutive visits within the 24-week period, the median maximum continuous response duration was 44.5 days, and the median total response duration was 85.0 days. During the 12-week double-blind period, the overall incidence of adverse events (AEs) was comparable between the hetrombopag (87.7% [50/57]) and placebo (96.8% [30/31]) groups, with most events being grade 1 or 2. Serious adverse events (SAEs) occurred in 6 (10.5%) patients receiving hetrombopag and 4 (12.9%) receiving placebo; all SAEs were assessed by investigators as unrelated or possibly unrelated to the study drug. Safety profiles were consistent across both the core and open-label extension periods. No deaths, malignancies, or thrombotic events were reported during the 24-week treatment period. Conclusions: Once-daily oral hetrombopag produced durable platelet responses and demonstrated a favorable safety profile in children and adolescents with chronic ITP, supporting its potential as a novel oral second-line treatment option in this population.