Editor's Note: The annual meeting of the European Hematology Association (EHA) is a premier international conference that gathers experts and scholars from around the globe to share and discuss innovative ideas and advancements in scientific and clinical research in the field of hematology. This year, the research on spleen tyrosine kinase (SYK) inhibitors has garnered significant attention. HMPL-523 (Solepinib), the first domestically produced SYK inhibitor from China to apply for market approval (*as of the press date), presented multiple research results at the EHA conference. "Oncology Frontier - Hematology Frontier" invited Dr. Zeping Zhou from The Second Affiliated Hospital of Kunming Medical University to interpret the ESLIM-01 study (NCT05029635) on Solepinib for primary immune thrombocytopenia (ITP), aiming to provide clinical practice references.

Differentiating Mechanisms in ITP Treatment Drugs

Oncology Frontier – Hematology Frontier: How does the mechanism of action of the SYK inhibitor Solepinib in the ESLIM-01 study differ from existing treatments like TPO/TPO-RA?

Dr. Zeping Zhou: Solepinib, as a selective oral SYK inhibitor, works by inhibiting SYK activity, disrupting B-cell receptor and Fc receptor signaling, thus weakening immune responses. Solepinib exhibits a dual mechanism, particularly targeting B cells and macrophages.

SYK inhibitors differ from thrombopoietin (TPO) and thrombopoietin receptor agonists (TPO-RA), which primarily mimic or enhance TPO’s role to promote platelet production. Specifically, TPO binds to the TPO receptor (c-MPL) to stimulate the differentiation and maturation of megakaryocytes in the bone marrow, thereby increasing platelet production. TPO-RA directly activates c-MPL, stimulating megakaryocytes to produce more platelets. This mechanism results in a rapid increase in platelet count, leading to significant fluctuations in the PLT curve. In contrast, SYK inhibitors do not directly stimulate platelet production. By inhibiting immune signaling pathways in B cells and Fc receptors, SYK inhibitors reduce antibody-mediated platelet destruction, leading to a gradual increase in platelet count. Thus, the PLT curve with Solepinib treatment is relatively stable.

Anti-CD20 antibodies like rituximab primarily work by binding to the CD20 molecule on B cells, mediating their apoptosis and clearance. Since B cells are the primary producers of antibodies, reducing their number can lower autoantibody production, thus decreasing platelet destruction. SYK inhibitors act directly on immune signaling pathways, specifically targeting B cells and macrophages to reduce platelet loss and increase platelet counts. Unlike broad immunosuppression, SYK inhibitors have a more targeted effect on the immune system.

Additionally, the onset speed of SYK inhibitors and anti-CD20 antibodies in ITP treatment differs. SYK inhibitors, by directly inhibiting B cell and macrophage activation, can quickly reduce platelet destruction. Anti-CD20 antibodies may take varying times to show effects, with some patients seeing increased platelet counts within four weeks, while others may need up to three months. The ESLIM-01 study showed that Solepinib could raise platelet counts to or above 50×10⁹/L within approximately one week (eight days).

ESLIM-01 Study Design and Results

Oncology Frontier – Hematology Frontier: At EHA 2024, the ESLIM-01 study on Solepinib’s innovative mechanism was formally presented. Could you elaborate on the study design and main results?

Dr. Zeping Zhou: The ESLIM-01 study enrolled adult ITP patients who had received at least one prior treatment and allowed for one ITP maintenance treatment, with a disease duration of over 12 months. The study compared Solepinib to a placebo. The primary endpoint focused on the durable response rate, defined as achieving a platelet count of at least 50×10⁹/L in at least four out of six visits between weeks 14 and 24 without emergency treatment. Secondary endpoints included overall response rate, response time, frequency of emergency treatments, reduction in concomitant ITP medications, WHO bleeding scores, and quality of life based on the SF-36 survey.

The ESLIM-01 study achieved its primary and all secondary endpoints. Solepinib raised platelet counts to 50×10⁹/L within a median of eight days. The overall response rate for Solepinib was 71%, compared to 16% in the placebo group. The median platelet count in the Solepinib group stabilized between 50 and 90×10⁹/L. The durable response rate was 48%, with responders maintaining platelet counts between 80 and 100×10⁹/L.

Additionally, Solepinib demonstrated good results in reducing bleeding risk. Compared to the placebo group, there was a statistically significant improvement in WHO bleeding scores at 12 and 24 weeks (P=0.0002). Solepinib also showed potential in improving patients’ quality of life, including physical function, fatigue, and overall health status.

Analyzing the Overall Safety of Solepinib

Oncology Frontier – Hematology Frontier: How does Solepinib perform in terms of safety, particularly concerning infection, liver function abnormalities, and thrombosis risks?

Dr. Zeping Zhou: Analyzing the safety data of the ESLIM-01 study, it’s essential to consider that this study was conducted during the global COVID-19 pandemic. Given the lack of efficacy in the placebo group, most non-responders in the placebo group exited the study by week 12. Consequently, the drug exposure time for Solepinib was twice that of the control group (24.1 weeks vs. 12.1 weeks). Despite increased exposure, the incidence of ≥3 grade treatment-emergent adverse events (TEAEs) was comparable between Solepinib and placebo groups (25.4% vs. 24.2%), with serious TEAEs also similar (20.6% vs. 17.7%). No deaths occurred during the analysis.

Common TEAEs included upper respiratory tract infection (29%) and COVID-19 infection (24%), likely related to the immunosuppressive mechanism of SYK inhibitors, which increases infection risk. The incidence of infection-related TEAEs did not exceed 30%, with ≥3 grade being 1% to 2%. Clinicians are advised to closely monitor patients to effectively prevent and manage potential infection risks.

Biochemical markers indicated that 24% of patients had elevated lactate dehydrogenase (LDH), and 15% had elevated alanine aminotransferase (ALT). These elevations suggest liver function impairment, but no ≥3 grade serious adverse events were reported. Elevated LDH and ALT often signal liver cell damage or destruction, potentially due to SYK inhibitor metabolism or immune-mediated liver cell damage. Continuous monitoring of liver function indicators is recommended to identify and address potential issues promptly.

The ESLIM-01 study did not observe thromboembolic events, indicating that Solepinib’s stable increase in platelet count might avoid sharp hemodynamic changes, reducing thrombosis risk. Additionally, gastrointestinal toxicity and hypertension incidences were low. Overall, the ESLIM-01 study data suggest that Solepinib demonstrates good safety in treating ITP.

Secondary Endpoint Results

Oncology Frontier – Hematology Frontier: Could you share the secondary endpoint results of the ESLIM-01 study, such as emergency treatments, WHO bleeding scores, and quality of life?

Dr. Zeping Zhou: The core goal in treating ITP is to increase platelet counts and reduce bleeding risk. In addition to efficacy and safety data suggesting Solepinib may become a treatment option for adult ITP patients, the ESLIM-01 study also explored secondary endpoints. The need for emergency treatment was reduced in the Solepinib group (22% vs. 35%), indicating Solepinib’s potential in improving disease control and reducing additional treatment needs. WHO bleeding scores improved significantly at 12 and 24 weeks (0.56 vs. 0.79), indicating better control of bleeding severity and frequency. Additionally, Solepinib reduced the dose of concomitant ITP medications (27% vs. 10%), potentially lowering the risk of drug side effects and simplifying treatment regimens, positively impacting long-term management and quality of life.

Quality of life, based on the SF-36 survey, showed improvements in physical functioning, role limitations due to emotional problems, vitality/fatigue, general health, role limitations due to physical health, emotional well-being, and social functioning. These results suggest Solepinib positively affects patients’ daily lives and psychological state, potentially enhancing social participation.

Patient Adherence and Treatment Management

Oncology Frontier – Hematology Frontier: How do you view Solepinib’s potential impact on patient adherence and treatment management in terms of convenience and applicability to different patient groups?

Dr. Zeping Zhou: Solepinib’s once-daily oral administration enhances patient adherence and improves the treatment experience due to its convenience. Good adherence is crucial for achieving therapeutic efficacy, helping patients consistently benefit from the medication.

Moreover, Solepinib requires no dosage adjustments, simplifying treatment. For patients, this reduces the need for regular blood monitoring and dosage adjustments, lowering the frequency of medical visits and treatment complexity. This administration method is easy for elderly patients to understand and follow, making it suitable for chronic disease patients needing long-term management. Solepinib has not been specifically noted for interactions with certain foods in related studies, potentially indicating no need for patients to adjust their diet significantly during treatment.

In summary, Solepinib’s characteristics, such as administration method, convenience, applicability, and potential to enhance patient adherence, collectively support its potential to improve overall ITP treatment outcomes. We look forward to Solepinib becoming a new treatment option for ITP patients.

Zeping Zhou

• PhD, Chief Physician, Doctoral Supervisor, Postdoctoral Supervisor
• Director of Hematology, Second Affiliated Hospital of Kunming Medical University
• Vice Chair, Subcommittee on Pediatric Hematologic Malignancies, National Health Commission Expert Committee
• Vice Chair, Tumor Immunotherapy Committee, Chinese Elderly Care Association
• Standing Member, Hematology Physician Branch, Chinese Medical Doctor Association, Yunnan Province Chair
• Standing Member, Lymphoma Committee, Chinese Anti-Cancer Association, Yunnan Province Chair
• Deputy Chair, Hematology Branch, Yunnan Medical Association
• Deputy Leader, Aplastic Anemia Collaboration Group, China Hematology Specialized Alliance
• Leading Talent, Academic and Technical Leaders of Middle-aged and Young People in Yunnan Province
• Principal Investigator of six National Natural Science Foundation projects
• Published 87 papers (BJH, Haemophilia, TR, etc.; SCI: 40)
• Editorial Board Member, “Journal of Immunology Research”
• Corresponding Editorial Board Member, “Chinese Journal of Hematology”; Executive Editorial Board Member, “Journal of Thrombosis and Hemostasis”
• Editorial Board Member, “Oncology Pharmacy,” “Chinese Journal of Clinical Oncology and Rehabilitation”