APG-5918 / Ascentage Pharma - LARVOL DELTA

HY809382, a PRC2 degrader with best-in-class properties, demonstrates efficacy across multiple tumors and overcomes EZH2 inhibitor clinical resistance caused by EZH2 genetic mutations (AACR 2026) - "Among various EZH2 inhibitors under development, Tazemetostat (Tazverik) was the first to received FDA approval for the treatment of follicular lymphoma (FL) and epithelioid sarcoma (ES)...Under identical experimental conditions, HY809382 exhibited greater potency than both PF-06821497 (an EZH2 inhibitor) and APG-5918 (an EED inhibitor)...Furthermore, HY809382 combined with enzalutamide synergistically suppressed tumor growth in a castration-resistant prostate cancer xenograft model. Clinically identified EZH2 mutations confer resistance to FDA-approved EZH2 inhibitors, whereas HY809382 remained effective in both cellular and in vivo xenograft models. Collectively, these data support HY809382 as a promising best-in-class PRC2 degrader candidate, warranting further development for the treatment of tumors exhibiting clinical resistance to EZH2 inhibitors."

Clinical • Castration-Resistant Prostate Cancer • Clear Cell Renal Cell Carcinoma • Endometrial Cancer • Follicular Lymphoma • Gastric Adenocarcinoma • Gastric Cancer • Genito-urinary Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • EZH2

Embryonic ectoderm development (EED) inhibitor APG-5918 synergizes with topoisomerase I inhibitors in preclinical small-cell lung cancer (SCLC) models through epigenetic priming of chemosensitivity (AACR 2026) - "Topoisomerase I inhibitors, such as topotecan and irinotecan, are used in relapsed SCLC, but efficacy is limited when SLFN11 is epigenetically suppressed. The combination further downregulated PRC2 components (EED, EZH1, EZH2, SUZ12), suppressed cell-cycle regulators (pRb, CDK4, CDK6), and induced DNA damage (γH2A.X) and apoptotic markers (cleaved PARP-1, cleaved caspase-3, BIM, Noxa), supporting a synergistic proapoptotic mechanism.APG-5918 synergistically enhances antitumor activity of topoisomerase I inhibitors in preclinical SCLC models by reversing PRC2-mediated epigenetic silencing of SLFN11 and amplifying DNA damage, cell-cycle arrest, and apoptosis. These findings support clinical investigation of APG-5918 combined with DNA-damaging agents as a promising strategy for SCLC."

Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ANXA5 • CASP3 • CDK4 • CDK6 • CDKN1A • EZH2 • SLFN11 • SUZ12

Embryonic ectoderm development (EED) inhibitor APG-5918 synergizes with topoisomerase I inhibitors in preclinical small-cell lung cancer (SCLC) models through epigenetic priming of chemosensitivity (GlobeNewswire) - "Ascentage Pharma to Present...at American Association for Cancer Research (AACR) 2026 Annual Meeting....In preclinical SCLC models, combination treatment with APG-5918 and topoisomerase I inhibitors synergistically inhibited cell proliferation and induced apoptosis. In vivo, APG-5918 combined with irinotecan demonstrated synergistic antitumor activity in the NCI-H446 SCLC cell-derived xenograft (CDX) model without significant body-weight loss, indicating favorable tolerability."

Preclinical • Lung Neuroendocrine Carcinoma • Small Cell Lung Cancer

Embryonic ectoderm development protein (EED) inhibitor APG-5918 exhibits potent antitumor activity and synergizes with androgen receptor (AR) inhibitor enzalutamide in preclinical prostate cancer (PCa) models (AACR 2025) - "APG-5918 appeared to be more potent than two EZH2 inhibitors (tazemetostat, PF-06821497) and EED inhibitor ORIC-944 under the same experimental condition. APG-5918 alone or in combination with enzalutamide exhibited antitumor activity in preclinical PCa models, supporting EED inhibition (± AR antagonists) as a therapeutic strategy for PCa."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CCND1 • CDK4 • DNMT1 • MCL1 • SUZ12 • UHRF1

Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumor growth in preclinical models of prostate cancer (PCa) (AACR 2024) - "Mechanistically, this combination likely modulated pathways related to DNA methylation, cell cycle, and apoptosis. The findings provide a scientific rationale for future clinical development of APG-5918 and alrizomadlin for PCa patients."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CDK6 • CDKN1A • DNMT1 • MCL1 • UHRF1

EED inhibitor APG-5918 renders vulnerability to immunotherapy by rewiring sphingolipid metabolism via nSMase2-ceramide pathway in pancreatic cancer (AACR 2025) - "Taken together, our results demonstrate that the novel EED inhibitor APG-5918 can reshape the tumor immune microenvironment by activating the nSMase2-ceramide pathway, overcoming immunotherapy resistance in pancreatic cancer. This promising approach, combining EED inhibition with PD-1 blockade, will be further explored in translational and clinical studies."

IO biomarker • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • GLI2

Ascentage Pharma to Present Data From Four Preclinical Studies In Its Innovative Pipeline at American Association of Cancer Research (AACR) Annual Meeting 2026 (GlobeNewswire) - "The data to be presented encompasses three of the Company’s novel drug candidates: BCR-ABL tyrosine kinase inhibitor Olverembatinib (HQP1351), FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, and PRC2/EED inhibitor APG-5918."

Preclinical • Colorectal Cancer • Endometrial Cancer • Mantle Cell Lymphoma • Small Cell Lung Cancer

Embryonic ectoderm development (EED) inhibitor APG-5918 overcomes immunomodulatory drug (IMiD) resistance as monotherapy and synergizes with IMiDs/cereblon E3 ligase modulators (CELMoDs) in preclinical models of multiple myeloma (MM) (ASH 2025) - "Introduction IMiDs (eg, lenalidomide, pomalidomide) are approved for the treatment of patients with MM and otherhematologic malignancies...We assessed antitumor activity and mechanisms of APG-5918 (± IMiDs orCELMoDs) in preclinical MM models.MethodsA genetically diverse panel of MM cell lines, including IMiD-resistant (KMS11, MOLP-8, U266, RPMI-8226)and -sensitive (AMO-1, OPM-2, MM.1S) lines, were used to assess in vitro antiproliferative activity of APG-5918 (± pomalidomide or CELMoD CC-92480)...APG-5918 showed potent antiproliferativeactivity across most IMiD-sensitive and -resistant cell lines, with low nanomolar to submicromolar IC50values, indicating efficacy regardless of IMiD sensitivity and superior antiproliferative effects vs. EZH2inhibitor tazemetostat...Combined withpomalidomide, it restores IMiD signaling via IRF4 suppression and reinforces cell cycle arrest bydownregulating CDK4/pRb, resulting in synergistic antitumor activity. These findings..."

Immunomodulating • Monotherapy • Preclinical • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • ANXA5 • CASP3 • CDK4 • CRBN • IKZF1 • IKZF3 • SUZ12

A Study to Investigate the Safety, Pharmacokinetics and Efficacy of APG-5918 in Healthy Subjects or Anemic Patients (clinicaltrials.gov) - P1 | N=105 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Mar 2026 ➔ Jul 2028 | Trial primary completion date: Aug 2025 ➔ Dec 2027

Trial completion date • Trial primary completion date • Anemia • Hematological Disorders

Embryonic Ectoderm Development (EED) Inhibitor APG-5918 Demonstrates Robust Antitumor Activity in Preclinical Models of T-Cell Lymphomas (TCLs) (ASH 2024) - "The antiproliferative activity of APG-5918 was superior to that of dual EZH1/2 inhibitor valemetostat and EZH2-selective inhibitor tazemetostat under the same experimental conditions. Mechanistically, APG-5918 likely exerts its antitumor activity by modulating the PRC2 complex, leading to apoptosis induction and cell cycle arrest. These findings provide a strong scientific rationale for the future clinical development of APG-5918 for TCLs."

IO biomarker • Preclinical • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • ANXA5 • BCL2L11 • CASP3 • CDK6 • EZH2

Embryonic Ectoderm Development (EED) Inhibitor APG5918 Improves Chronic Kidney Disease- (CKD)-Induced Hemoglobin Insufficiency in Preclinical Models of Anemia (ASH 2023) - "76-fold of the control group, respectively, which was pharmacologically superior to effects observed with hydroxyurea at 33 µM (~6. APG-5918 also showed synergistic antianemia effects when combined with EPO. These findings support APG-5918 as a novel treatment option for CKD-induced anemia."

Preclinical • Anemia • Chronic Kidney Disease • Hematological Disorders • Infectious Disease • Nephrology • Renal Disease • CD34 • HBB • SUZ12

EMBRYONIC ECTODERM DEVELOPMENT (EED) INHIBITOR APG-5918 EXHIBITS POTENT ANTITUMOR ACTIVITY AND SYNERGIZES WITH HISTONE DEACETYLASE INHIBITOR TUCIDINOSTAT IN PRECLINICAL T-CELL LYMPHOMA (TCL) MODELS (EHA 2025) - "A subcutaneous HuT102 cell line-derived xenograft (CDX) model was established to assess in vivo antitumor efficacy.APG-5918 exhibited potent antiproliferative activity in vitro, with IC50 values ranging from 0.1 to 7.2 μM, outperforming dual EZH1/2i valemetostat and EZH2i tazemetostat. APG-5918 exhibited potent antitumor activity alone and synergized with tucidinostat in preclinical TCL models. Mechanistically, it modulated PRC2 complex and induced apoptosis and cell cycle arrest. Combination with tucidinostat further enhanced these effects."

Epigenetic controller • Preclinical • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CASP3 • CDK6 • EZH2

Embryonic Ectoderm Development (EED) Inhibitor APG-5918 Exhibits Potent Antitumor Activity and Synergizes with Histone Deacetylase Inhibitor Tucidinostat in Preclinical T-Cell Lymphoma (TCL) Models (GlobeNewswire) - "Highlights of select abstracts presented at EHA 2025 are as follows....APG-5918 demonstrated potent inhibitory effects on the proliferation of TCL cell lines in vitro, showing superior activity compared to other EZH and EED inhibitors. Its combination with tucidinostat synergistically suppressed cell proliferation. APG-5918 induced dose-dependent apoptosis and cell cycle arrest in TCL cells. In a HuT102 cell line-derived xenograft (CDX) model, APG-5918 exhibited significant, dose-dependent antitumor activity, achieving complete tumor regression at 30 mg/kg with a 100% ORR. Its combination with tucidinostat synergistically enhanced antitumor activity."

Preclinical • Lymphoma

Thirteen Studies of Ascentage Pharma’s Assets Including Olverembatinib and Lisaftoclax Selected for Presentations at 2025 European Hematology Association Annual Congress (GlobeNewswire) - "Ascentage Pharma...announced that 13 studies of its core assets - including the novel drug olverembatinib (HQP1351), the investigational Bcl-2 inhibitor lisaftoclax (APG-2575), and the investigational EED inhibitor APG-5918 - will be featured in an oral presentation, multiple poster presentations and multiple online publications at the 2025 European Hematology Association (EHA) Annual Congress taking place in Milan, Italy, from June 12-15, 2025."

Clinical data • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Lymphoma

Embryonic ectoderm development protein (EED) inhibitor APG-5918 exhibits potent antitumor activity and synergizes with androgen receptor (AR) inhibitor enzalutamide in preclinical prostate cancer (PCa) models (GlobeNewswire) - "APG-5918 demonstrated superior inhibitory effects on PCa cell proliferation in vitro. APG-5918 in combination with enzalutamide synergistically suppressed cell proliferation. APG-5918 induced dose-dependent cell cycle arrest in LNCaP and C4-2B cells. Combining enzalutamide with APG-5918 deepened G0/G1 cell cycle arrest. APG-5918 showed significant antitumor activity in human LNCaP and enzalutamide-resistant 22Rv1 xenograft models in castrated nude mice. Mechanistically, APG-5918 downregulated key on-target PD markers (e.g., H3K27me3, EED, EZH2, SUZ12) and AR pathway proteins. APG-5918 also suppressed oncogenic driver ERG, DNA methylation factors (UHRF1, DNMT1), and antiapoptotic protein MCL-1, and reduced pRb, CDK4, cyclin B1 and cyclin D1—crucial mediators of cell cycle regulation."

Preclinical • Prostate Cancer

Ascentage Pharma to Present Five Preclinical Studies from Innovative Pipeline at American Association of Cancer Research (AACR) Annual Meeting 2025 (GlobeNewswire) - "Ascentage Pharma...announced that five abstracts highlighting the latest preclinical results from its pipeline programs have been selected for presentations at the 2025 American Association of Cancer Research Annual Meeting (AACR)....The data to be presented encompasses five of the company’s novel drug candidates: BCR-ABL tyrosine kinase inhibitor olverembatinib (HQP1351), Bcl-2 inhibitor lisaftoclax (APG-2575), FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, EED inhibitor APG-5918, and IAP antagonist AS03157."

Preclinical • Acute Myelogenous Leukemia • Prostate Cancer • Small Cell Lung Cancer • T Acute Lymphoblastic Leukemia

ASH 2024 | Results From Three Clinical Studies of Ascentage Pharma’s Bcl-2 Inhibitor Lisaftoclax Selected for Presentations, Including an Oral Report (PRNewswire) - "Ascentage Pharma...today announced that the latest results from three clinical studies of one of the company's key drug candidate, lisaftoclax (APG-2575), have been selected for presentations, including an Oral Report, at the 66th American Society of Hematology (ASH) Annual Meeting. This is the third consecutive year in which clinical results on lisaftoclax have been selected by the ASH Annual Meeting. In 2024, results from multiple clinical and preclinical studies on four of the company's investigational drug candidates...have been selected for presentations...At this year's ASH Annual Meeting, Ascentage Pharma will present an Oral Report featuring the latest results from a Phase I/II study of lisaftoclax in patients with relapsed/refractory multiple myeloma (R/R MM) or immunoglobulin light-chain (AL) amyloidosis. Furthermore, the latest data of lisaftoclax combinations in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and myelodysplastic..."

Clinical data • Preclinical • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Small Lymphocytic Lymphoma

EED inhibition renders vulnerability to immunotherapy by rewiring ceramide metabolism in pancreatic cancer (ESMO 2024) - "Our results indicate the promising roles of the novel EED inhibitor APG-5918 in reshaping the tumor immune microenvironment, mechanistically through upregulating nSMase2-ceramide pathway, and overcoming the immunotherapy resistance in pancreatic cancer. The new therapeutic strategy of EED inhibitor combining with PD-1 antibody will be tested in further translational and clinical studies."

IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • GLI2

EMBRYONIC ECTODERM DEVELOPMENT (EED) INHIBITOR APG-5918 IMPROVES CHRONIC KIDNEY DISEASE- (CKD)-INDUCED HEMOGLOBIN (HB) INSUFFICIENCY IN PRECLINICAL MODELS OF ANEMIA (EHA 2024) - "76-fold of the control group, respectively, which was pharmacologically superior to the effects observed withhydroxyurea at 33 µM (~6. APG-5918 treatment led to inhibition of H3K27me3 and induction of HbF and Hb mRNA and protein in CD34⁺HSCs. APG-5918 improved hematologic parameters and renal function in a CKD-induced anemia model, eitheras a single agent or in combination with EPO. Figure 1."

Preclinical • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Oncology • Renal Disease • CD34 • HBB

EHA 2024 | Results from Five Studies of Ascentage Pharma's Key Drug Candidates Selected for Presentations at 2024 European Hematology Association Hybrid Congress (PRNewswire) - "Ascentage Pharma...announced today that the latest results from five studies have been selected for Poster Presentations at the 2024 European Hematology Association Hybrid Congress (EHA 2024). These posters will feature olverembatinib (HQP1351), the first and only China-approved third-generation BCL-ABL1 inhibitor; investigational lisaftoclax (APG-2575), a Bcl-2 selective inhibitor; and investigational APG-5918, an EED selective inhibitor."

Clinical data • Preclinical • Acute Lymphocytic Leukemia • Anemia • Chronic Myeloid Leukemia • Multiple Myeloma

AACR 2024 | Ascentage Pharma Presents Results from Three Studies at 2024 American Association of Cancer Research Annual Meeting (PRNewswire) - "In PCa preclinical models, the combination of APG-5918 and alrizomadlin synergistically inhibited cellular proliferation and induced cellular apoptosis. APG-5918 in combination with alrizomadlin synergistically enhanced antitumor activity in PCa xenograft models in vivo. Mechanistically, PD analysis revealed that APG-5918 downregulated the oncogenic DNA methylation factors (UHRF1, DNMT1) and histone methylation marker H3K27me3. Alrizomadlin markedly downregulated UHRF1 and DNMT1, and upregulated p53 and p21 expression. Combined treatment further enhanced downregulation of DNMT1, UHRF1, cell cycle pathway proteins (pRb, CDK6), antiapoptotic protein MCL-1, and synergistically increased cleavage of PARP-1, a marker of apoptosis."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

AACR 2024 | Ascentage Pharma to Present Three Preclinical Studies at 2024 American Association of Cancer Research Annual Meeting (PRNewswire) - "Abstract#: 3223:...Results from this preclinical study show that in preclinical models of PCa, targeting both EED and MDM2 can synergistically enhance antitumor activities by modulating pathways related to DNA methylation, cell cycle, and apoptosis. These findings provide a scientific rationale for the future clinical development of APG-5918 in combination with alrizomadlin for the treatment of PCa."

Preclinical • Prostate Cancer

A Study to Investigate the Safety, Pharmacokinetics and Efficacy of APG-5918 in Healthy Subjects or Anemic Patients (clinicaltrials.gov) - P1 | N=115 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Anemia • Hematological Disorders

A Study to Investigate the Safety, Pharmacokinetics and Efficacy of APG-5918 in Healthy Subjects or Anemic Patients (clinicaltrials.gov) - P1 | N=115 | Not yet recruiting | Sponsor: Ascentage Pharma Group Inc.

New P1 trial • Anemia • Hematological Disorders

Study of Safety, Pharmacokinetic and Efficacy of APG-5918 in Advanced Solid Tumors or Lymphomas (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Diffuse Large B Cell Lymphoma • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Lung Cancer • Lymphoma • Mesothelioma • Nasopharyngeal Carcinoma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Prostate Cancer • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CAST • SMARCB1