A Multicenter, Open-Label, Single-Arm, Phase 2 Study to Evaluate the Efficacy and Safety of Hetrombopag in Patients with Severe Aplastic Anemia (SAA)

Introduction: Severe aplastic anemia (SAA) is a hematologic disorder characterized by bone marrow hypoplasia and peripheral pancytopenia. Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CsA) is the standard first-line treatment for patients with SAA who are ineligible for hematopoietic stem cell transplantation (HSCT). For those refractory to or relapsed after IST, eltrombopag (an oral thrombopoietin receptor agonist) were recommended as the second-line therapy by US FDA and European Medicines Agency (EMA). However, in several countries including China, eltrombopag has not been approved for use in patients with SAA, so there is an urgent unmet medical need for additional efficient treatment options. Hetrombopag, another oral thrombopoietin receptor agonist, has similar mechanism in stimulating thrombopoietin receptor signaling pathway as eltrombopag and better pharmacological performance than eltrombopag in pre-clinical study (Xie et al, JCMM 2018). In a phase 1 trial, hetrombopag was safe and well-tolerated in healthy subjects with potent thrombopoietic activity and acceptable pharmacokinetic profiles (Zheng et al, BCPT 2017). Here, in this phase 2 trial (NCT03557099), we aimed to assess the activity and safety of hetrombopag in patients with SAA who have had an insufficient response to IST.

Methods: This open-label, single-arm, phase 2 study enrolled patients with SAA who have had an insufficient response to IST and were ineligible for transplantation. Patients were given hetrombopag orally at an initial dose of 7.5 mg once daily after overnight fasting. If increase of platelet count was less than 20×10⁹/L from baseline, the dose of hetrombopag was gradually up-titrated by 2.5 mg every 2 weeks to a maximum of 15 mg once daily, for a total of 52 weeks. The primary endpoint was proportion of patients achieving hematologic responses in at least one lineage at week 18.

Results: Between June 20, 2018 and May 24, 2019, 55 eligible patients were enrolled and received hetrombopag treatment. The median age was 40 years (range 19–65) and 34 (61.8%) patients were male. As of data cutoff on June 12, 2020, 52 (94.5%) patients received the maximum dose of 15 mg once daily, and the final dose of the other three patients was 7.5 mg, 10 mg, and 12.5 mg, respectively. A total of 24 (43.6%, 95% CI 30.3–57.7) of the 55 patients met primary endpoint, achieving at least one lineage hematologic response at week 18 after the initiation of hetrombopag treatment (Figure 1). Of them, 11 (20.0%) patients had unilineage responses, 7 (12.7%) had bilineage responses, and 6 (10.9%) had trilineage responses. Twenty-four (43.6%, 95% CI 30.3–57.7) patients responded in at least one lineage at week 24 and 27 (49.1%, 95% CI 35.4–62.9) patients responded in at least one lineage at week 52 (Figure 1). Of the 32 patients with responses at week 18, 24, or 52, median time to initial hematologic response was 7.9 weeks (range 2.0–32.1). The responses were durable in majority of patients who remained on hetrombopag treatment, with only six patients relapsed, achieving a probability of recurrence-free survival at 12-month of 79.5% (95% CI 59.9–90.3). Adverse events of any attribution were reported in 54 (98.2%) of the 55 patients, with the most common ones being upper respiratory tract infection (22, 40.0%), increased aspartate aminotransferase (12, 21.8%), and pyrexia (12, 21.8%). Twenty-eight (50.9%) patients had treatment-related adverse events. Adverse events of grade 3 or higher occurred in 17 (30.9%) patients, with only one (1.8%) related to hetrombopag. Three (5.5%) patients underwent dose reduction or treatment interruption and three (5.5%) patients were discontinued from treatment because of adverse events, but none of which was considered as drug-related. Fifteen (27.3%) patients had serious adverse events. Three (5.5%) deaths were reported, and all of them were judged to be not treatment-related. Clonal cytogenetic evolution occurred in two (3.6%) patients during hetrombopag administration, with one patient had a loss of chromosome 7 and one had an increase of chromosome 8.

Conclusions: Hetrombopag showed encouraging activity with multilineage hematologic responses in patients with SAA who have had an insufficient response to prior IST. Hetrombopag was well-tolerated and safe. This study provided evidences that hetrombopag might represent a novel treatment option for patients with SAA.