-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

16 Safety, Pharmacokinetics and Preliminary Efficacy of HMPL-523 in Adult Patients with Primary Immune Thrombocytopenia: A Randomized, Double-Blind and Placebo-Controlled Phase 1b Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 311. Disorders of Platelet Number or Function: Clinical and Epidemiological: Treatment of Immune Thrombocytopenia
Hematology Disease Topics & Pathways:
Clinical Trials, Autoimmune Disorders, Clinical Research, Diseases, Immune Disorders
Saturday, December 11, 2021: 10:15 AM

Renchi Yang, MD1*, Hu Zhou, MD2*, Yu Hu3*, Jie Yin, MD4*, Junmin Li, MD5*, Wenming Chen, MD6*, Ruibin Huang, MD7*, Yuping Gong, MD8*, Chenwei Luo, MD9*, Liu Xiaofan, MD1*, Heng Mei3*, Bingjie Ding, MD2*, Chengyuan Gu, MD4*, Huiping Sun, MD5*, Leng Yun, MD6*, Dexiang Ji, MD7*, Yan Li, MD8*, Haiyan Shi, MD10*, Hongyan Yin, MD10*, Songhua Fan, MD10*, Jian Wang, PhD10* and Weiguo Su, PhD10*

1Hematology Hospital of Chinese Academy of Medical Sciences, Beijing, China
2Henan Cancer Hospital/The Affiliated Cancer Hospital of Zheng Zhou University, Zhengzhou, China
3Union Hospital of Tongji Medical College; Huazhong University of Science and Technology, Wuhan, China
4First Affiliated Hospital of Soochow University, Suzhou, China
5Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
6Affiliated Beijing Chaoyang Hospital of Capital Medical University, Beijing, China
7The First Affiliated Hospital of Nanchang University, Nanchang, China
8West China Hospital of Sichuan University, Chengdu, China
9Guangdong Provincial People's Hospital, Guangzhou, China
10HUTCHMED MediPharma Ltd, Shanghai, China

Background: Primary immune thrombocytopenia (ITP) is characterized by increased platelet destruction and impaired platelet production, resulting in decreased platelet counts and increased bleeding risk. Spleen Tyrosine Kinase (Syk) plays a pivotal role in the regulation of downstream signals in immune receptors, including B cell receptors (BCRs) and has been implicated in autoantibody production. On the other hand, all activating Fc receptors signal via Syk, which has roles in cellular proliferation, differentiation, survival, immune regulation, and cytoskeletal rearrangements during phagocytosis. This randomized, double-blind, placebo-controlled phase 1b study (NCT03951623) aimed to assess the safety, pharmacokinetics (PK), determine the recommended phase 2 dose (RP2D) and evaluate preliminary efficacy of HMPL-523, a novel, potent and highly selective Syk inhibitor, in patients with ITP.

Methods: Relapsed/refractory ITP patients with platelet counts less than 30×109/L were eligible for the study. This randomized study (3:1) consists of two stages with dose escalation (DES) and dose expansion (DEX). Four dose groups were set (100, 200, 300 and 400mg QD) and patients were randomized to either HMPL-523 or placebo in each dose group (n=8) to determine the RP2D in DES. Additional 12 patients were enrolled at RP2D to further assess the safety and efficacy in DEX. Each patient received an 8-week double blind treatment (8w-DB), followed by a 16-week, open-label HMPL-523 treatment (16w-OL), except for all patients of 100mg cohort and 2 patients of 200mg cohort (only received 8w-DB per protocol v1.0). Treatment-emergent adverse events were graded using the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0. The efficacy of overall response rate was defined as the proportion of patients with at least one platelet counts ≥50×109/L, and durable response rate was defined as the proportion of patients with platelet counts ≥50×109/L for at least 4 of the last 6 scheduled visits.

Results: As of data cutoff (June 23, 2021), 33 patients (24:9) were enrolled in DES at 100-400mg. And 300mg QD was determined as RP2D. Additional 12 patients (10:2) were enrolled in DEX at 300mg QD. Main baseline patient characteristics are shown in Table 1. During 8-w DB treatment period, the overall response rate was 3 (50.0%), 2 (33.3%), 11 (68.8%) and 2 (33.3%) at 100-400mg dose cohorts, respectively, compared to 1 (9.1%) in the placebo. The durable response rate at 300mg was 5 (31.3%), compared to 1 (9.1%) in placebo. For all patients enrolled in 300mg cohort with at least one dose of HMPL-523 (n=20), including both 8w-DB and 16w-OL treatment period, the overall response rate was 80%; the durable response rate was 27.8% in the durable response-evaluable set (defined as patients received HMPL-523 treatment and completed at least 6 scheduled visits or discontinued during HMPL-523 treatment, n=18). No DLTs were observed at 100-400mg dose cohorts. The most common TEAEs (≥2 patients) related with HMPL-523 in 8w-DB were LDH increased (6 [17.6%]), ALT increased (5 [14.7%]), amylase increased (5 [14.7%]), AST increased (4 [11.8%]), neutrophil count decreased (3 [8.8%]), hypokalemia (3 [8.8%]), urine protein detection (3 [8.8%]), WBC count decreased (3 [8.8%]), gamma-glutamyl transferase (2 [5.9%]), asthenia (2 [5.9%]), dizziness (2 [5.9%]), total bile acid increased (2 [5.9%]), diarrhea (2 [5.9%]), abdominal pain (2 [5.9%]), hypertriglyceridemia (2 [5.9%]) and hyperlipidemia (2 [5.9%]). For all patients enrolled in 300mg cohort (n=20) throughout HMPL-523 treatment period (up to 24 weeks), ALT increased (5 [25.0%]), LDH increased (5 [25.0%]), AST increased (4 [20.0%]), total bile acid increased (4 [20.0%]), amylase increased (3 [15.0%]), TBiL increased (2 [10.0%]), hyperlipemia (2 [10.0%]) and hypertension (2 [10.0%]) were the most frequently reported HMPL-523-related TEAEs (≥2 patients). At the dose of 100-400mg QD, the exposure of HMPL-523 (Cmax and AUCtau) in plasma increased dose proportionally. Median Tmax was 4 h and mean T1/2 was 11-13 h across all four dose levels.

Conclusion: HMPL-523 was well tolerated at all dose levels within the range of 100 mg to 400 mg. HMPL-523 300mg QD for ITP treatment is an efficacious and safe dose and recommended as RP2D. A randomized phase 3 study will commence to further confirm the efficacy of HMPL-523 in primary ITP.

Disclosures: Shi: HUTCHMED: Current Employment. Yin: HUTCHMED: Current Employment. Fan: Hutchmed: Current Employment.

*signifies non-member of ASH