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304 Hetrombopag Added to Immunosuppressive Therapy in First-Line Treatment of Severe Aplastic Anemia: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 508. Bone Marrow Failure: Acquired: Emerging Data in the Treatment of Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria
Hematology Disease Topics & Pathways:
Research, Clinical trials, Drug development, Bone Marrow Failure Syndromes, Aplastic Anemia, Clinical Research, Diseases, Treatment Considerations
Saturday, December 7, 2024: 4:45 PM

Fengkui Zhang1*, Xin Zhao1, Hong Chang2*, Bing Han3*, Sujun Gao4*, Miao Miao, MD5*, Jianda Hu, PhD6, Yanjuan Lin6*, Xinjian Liu7*, Lina Zhang7*, Chenghao Jin8*, Yingmei Li9*, Shengyun Lin10*, Jinsong Jia11*, Yi Wang12*, Chunkang Chang13*, Zheng Ge, MD, PhD14, Guangsheng He15*, Ruixiang Xia16*, Xiangjun Fu17*, Yuhua Li18*, Hong Liu19*, Kai Sun20*, Shunqing Wang21*, Linghui Xia22*, Weihua Zhang23*, Runzi Li24*, Junye Xiong24* and Wanyi Zhai24*

1National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
2West China Hospital of Sichuan University, Chengdu, China
3Department of Hematology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
4The First Hospital of Jilin University, Changchun, China
5The First Affiliated Hospital of Soochow University, Suzhou, China
6Fujian Medical University Union Hospital, Fuzhou, China
7Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
8Jiangxi Provincial People's Hospital, Nanchang, China
9The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
10The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
11Peking University People’s Hospital, Beijing, China
12Shaanxi Provincial People's Hospital, Xi'an, China
13Shanghai Sixth People's Hospital, Shanghai, China
14Zhongda Hospital Southeast University, Nanjing, China
15The First Affiliated Hospital with Nanjing Medical University, NANJING, China
16The First Affiliated Hospital of Anhui Medical University, Hefei, China
17Hainan General Hospital, Haikou, China
18Zhujiang Hospital, Southern Medical University, Guangzhou, China
19Affiliated Hospital of Nantong University, Nantong, China
20Henan Provincial People's Hospital, Zhengzhou, China
21Guangzhou First People's Hospital, Guangzhou, China
22Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
23First Hospital of Shanxi Medical University, Taiyuan, China
24Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China

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.

Disclosures: He: LongBioPharmaceuticals: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Li: Jiangsu Hengrui Pharmaceuticals Co., Ltd.: Current Employment. Xiong: Jiangsu Hengrui Pharmaceuticals Co., Ltd.: Current Employment. Zhai: Jiangsu Hengrui Pharmaceuticals Co., Ltd.: Current Employment.

*signifies non-member of ASH