Shanghai, China---Shanghai Haihe Biopharma Co., Ltd (referred as "Haihe Biopharma" or the “Company”), today announced that the preliminary results from the Phase 1 Part of a First-in-Human Phase I/II Study of EZH1/2 Inhibitor HH2853 in the Epithelioid Sarcoma Population is selected to present at the American Society of Clinical Oncology (ASCO) Annual Meeting 2023. This report summarized the preliminary safety and preliminary clinical efficiency of HH2853, an EZH1/2 inhibitor, in patients with epithelioid sarcoma.

Epithelioid sarcoma (ES) is a rare and aggressive subtype of soft-tissue sarcoma of high heterogeneity. Loss of expression of integrase interactor 1 (INI1), the core subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex and a tumor suppressor, occurs in over 90% of ES tumors. The SWI/SNF complex has an antagonistic relationship with the polycomb repressive complex (PRC2), which contains catalytic subunits enhancer of zeste homolog (EZH)1/2, and plays an essential role in maintaining transcriptional repression via the methylation of histone H3 lysine 27 and regulating the expression of multiple genes. Due to the reciprocal interference and compensatory action of EZH1 and EZH2, the dual-targeted inhibition of EZH1/2 is more effective than EZH2 inhibition alone. Tazemetostat (an only EZH2 inhibitor) has received accelerated approval from FDA in ES indication.

HH2853-G101 is a first-in-human, open-label, multi-center, Phase (Ph) I/II study in patients (pts) with relapsed/refractory non-Hodgkin lymphomas or advanced solid tumors. Ph I is composed of two parts: dose escalation and dose extension part. Local pathologically documented, advanced recurrent or metastatic ES ptsfrom prior systemic anti-tumor therapies and with no standard therapy afterward are eligible for this trial. HH2853 was administered orally twice daily (BID) in a continuous 28-day treatment cycle. Safety and clinical activity of HH2853 were assessed in ES pts from the Ph I part.

From Dec 2, 2021 to Nov 7, 2022, 32 pts with pre-treated ES were enrolled into three dose levels (400, 600, and 800 mg BID) at 4 sites in China. Median lines of prior treatment was two. 10 (31.3%) pts received ≥3 lines of prior therapies. 31 (96.9%) pts had recorded loss of INI1 by local immunohistochemical analysis. There were 20 (62.5%) pts with proximal subtype. As of February 28, 2023, median treatment duration was 173 days. The most common treatment-related adverse events (TRAE) were diarrhea (68.8%), blood bilirubin increased (46.9%), rash (37.5%), white blood cell count (WBC) decreased (34.4%), anemia (34.4%), urine bilirubin increased (28.1%), aspartate aminotransferase increased (25.0%), hypokalemia (25.0%), hyperuricemia (21.9%), alanine aminotransferase increased (21.9%), alopecia (21.9%), and platelet count (PLT) decreased (21.9%). TRAEs of ≥Grade 3 included diarrhea (12.5%), anemia (9.4%), and WBC decreased, hypokalemia, and neutrophil count decreased (6.2%, each), and blood bilirubin increased, PLT decreased, blood creatine phosphokinase increased, and hyperglycemia (3.1%, each). No TRAE led to death. TRAEs leading to dose discontinuation was only reported in 1 (3.3%) pt. TRAEs leading to dose interruption or reduction were reported in 25.0% and 15.6% of pts, respectively. 400 mg BID dose group has superior safety to the whole group.

Patient response to HH2853 was observed from 400 to 800 mg BID. Overall response rate (ORR) was 28.1% per investigator assessment according to RECIST 1.1. Median time to response was 1.9 months. One patient with complete response (CR) has lasted273 days from the initial response. Disease control rate (DCR) (DCR= CR + partial response + stable disease for 6 weeks) was 78.1% (95% CI: 60, 90.7). The investigator-assessed ORR and DCR of HH2853 at 400mg BID were 36.4% (95%CI: 10.9, 69.2) and 81.8% (95%CI: 48.2, 97.7), respectively, which were numerically higher than the overall population.

HH2853 showed an acceptable safety profile and promising anti-tumor activity in heavily pretreated ES pts with a wide therapeutic window, which laid foundation for further investigation.

The American Society of Clinical Oncology (ASCO) is the world's leading academic organization for the specialty of oncology. The organization has nearly 40,000 members in more than 100 countries. ASCO annual meeting is the highest level meeting in the field of clinical oncology. Many important research findings and clinical trial results are presented at ASCO's annual meeting.

Enhancer of zeste homolog 1/2 (EZH1/2) are the catalytic subunits of the polycomb repressive complex 2 (PRC2) complex, which can catalyze the trimethylation of histone H3 at lysine 27 (H3K27me3) to regulate the expression of multiple genes. EZH2 overexpression or gain-of-function mutations were reported in multiple tumor types and are closely related to tumor growth and metastasis as well as poor prognosis. Furthermore, there is an evolutionarily conserved antagonistic relationship between PRC2 and the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex. Deficiencies or mutations in the core subunits of SWI/SNF complex may weaken its resistance to PRC2 and promote tumor development. Consequently, targeting EZH1/2 is a potential therapeutic strategy for various types of hematological and solid tumors. EZH1 is the homologous protein of EZH2, with compensatory effects to the function of EZH2. As a result, EZH1/2 dual inhibitors may have better therapeutic potential. To date, no EZH2 or EZH1/2 inhibitors have been approved in China.

HH2853 is a potent and selective small molecule inhibitor targeting EZH1/2. In preclinical studies, HH2853 significantly reduced overall H3K27me3 level in cells, and exhibited potent anti-tumor activity against peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL) harboring EZH2 mutation, and various solid tumor models harboring mutations in the subunits of SWI/SNF complex both in vitro and in vivo. Phase I clinical data show that HH2853 has good safety and pharmacokinetic characteristics, and has demonstrated preliminary efficacy in multiple doses of multiple tumor types.

Haihe Biopharma Co., Ltd is a global, values-based, R&D driven biopharmaceutical leader headquartered in China with operation centers in the US and Japan, focusing on the research, development, manufacturing and commercialization of innovative anti-tumor therapies. The Company aims to discover and deliver life-saving therapies to cancer patients world widely. As an R&D focused company led by an academician of the Chinese Academy of Engineering, Haihe Biopharma is committed to in-house innovation. The Company has a full R&D and management team with global perspectives and is proactively mapping out its global drug development strategy. The Company currently has one approved product (INN:Gumarontinib) in China and twelve drug candidates. As of today, Haihe Biopharma has received total 33 clinical trial approvals and has been conducting clinical trials in four major countries.