Hetrombopag Added to Immunosuppressive Therapy in First-Line Treatment of Severe Aplastic Anemia: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial
Authors: Zhang Fengkui , Zhao Xin , Chang Hong , Han Bing , Gao Sujun , Miao Miao , Hu Jianda , Lin Yanjuan , Liu Xinjian , Zhang Lina , Jin Chenghao , Li Yingmei , Lin Shengyun , Jia Jinsong , Wang Yi , Chang Chunkang , Ge Zheng , He Guangsheng , Xia Ruixiang , Fu Xiangjun , Li Yuhua , Liu Hong , Sun Kai , Wang Shunqing , Xia Linghui , Zhang Weihua , Li Runzi , Xiong Junye , Zhai Wanyi 
Published: December 2024

Introduction: Immunosuppressive therapy (IST) combined with the thrombopoietin receptor agonist (TPO-RA) is the first-line recommendation for patients with severe aplastic anemia (SAA) who are not eligible for hematopoietic stem cell transplantation (HSCT). Hetrombopag, a novel small molecule TPO-RA, has demonstrated promising efficacy in IST-refractory SAA in our previous single-arm phase 2 study (NCT03557099). To further evaluate the efficacy and safety of hetrombopag in combination with standard IST as first-line treatment for untreated SAA patients, we conducted this randomized, double-blind, placebo-controlled phase 3 study (NCT03825744) and reported the results.

Methods: Eligible patients aged 15-75 years with untreated SAA according to the Camitta criteria and ineligible for HSCT were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either hetrombopag plus IST (antithymocyte globulin [ATG] and cyclosporine [CsA]) or placebo plus IST. Randomization was stratified based on the source of ATG (rabbit or pig-derived). Hetrombopag or placebo was administered orally on an empty stomach at a daily dose of 15 mg for 6 months. ATG was administered intravenously for 5 consecutive days, and CsA was given orally for 6 months. The primary endpoint was hematologic complete response (CR) rate at 6 months.

Results: A total of 240 patients were randomized, with 160 patients in the hetrombopag group and 80 in the placebo group. At 6 months, the CR rate was 28.1% (95% CI 21.2-35.1) in the hetrombopag group and 13.8% (95% CI 6.2-21.3) in the placebo group, indicating a significant between-group difference of 14.4% (95% CI 4.1-24.6, 2-sided p=0.0129). The OR rate at 6 months was 63.8% in the hetrombopag group and 42.5% in the placebo group. At 3 months, the CR rate was 8.8% and 5.0%, and the OR rate was 50.6% and 25.0% in the hetrombopag and placebo group, respectively. The median time to a first hematologic response was 87.0 days (95% CI 86.0-111.0) in the hetrombopag group and 141.0 days (95% CI 113.0-NA) in the placebo group. At 6 months, the proportion of patients who were red-cell transfusion independent was 69.0% in the hetrombopag group and 48.7% in the placebo group, respectively. Platelet transfusion independence was achieved in 69.0% and 50.6% of patients, respectively. At 3 months, the proportions were 56.8% in the hetrombopag group and 27.6% in the placebo group for red-cell transfusion independence, and 54.4% vs 31.2% for platelet transfusion independence, respectively. The incidence of adverse events was comparable between the two groups, with no unexpected safety signals observed for hetrombopag. Grade ≥3 treatment-related adverse events (TRAE) were reported in 15.6% of patients in the hetrombopag group and 19.2% in the placebo group, with serious TRAE reported in 2.5% and 2.6% of patients, respectively. There were no treatment-related deaths reported. The incidence of abnormal hepatic function was 41.9% in the hetrombopag group and 48.7% in the placebo group; 35.0% and 34.6% in each group were considered treatment-related. Additionally, myelodysplastic syndromes were observed in one (0.6%) patient in the hetrombopag group and not reported in the placebo group, while myelofibrosis was reported in 0.6% of patients in the hetrombopag group and 2.6% of patients in the placebo group, respectively.

Conclusions: The addition of hetrombopag to IST as first-line treatment for SAA patients led to a significantly higher hematologic response rate. These findings support hetrombopag as an effective and safe therapy for SAA patients ineligible for HSCT. Further studies are necessary to assess the long-term efficacy and safety of this treatment approach.