Ascentage Pharma Group International , a global, commercial stage, integrated biopharmaceutical company engaged in the discovery, development and commercialization of novel, differentiated therapies to address unmet medical needs in cancer, announced that its novel next-generation Bruton's tyrosine kinase (BTK)-targeted protein degrader, APG-3288, has received investigational new drug (IND) application clearance from the China Center for Drug Evaluation (CDE) and is poised to enter a clinical study in patients with relapsed/refractory hematologic malignancies. This IND clearance from the China CDE, which came shortly after the IND was cleared by the U.S. Food and Drug Administration (FDA), ushers in a new phase in the multicenter clinical development of APG-3288 and highlights Ascentage Pharma’s robust global development capabilities in the field of targeted protein degradation.

Ascentage Pharma will be conducting a multicenter, open-label Phase I study designed to evaluate the safety, tolerability, pharmacokinetic (PK) profile, and preliminary efficacy of APG-3288 in patients with relapsed/refractory hematologic malignancies.

BTK is a key kinase in the B-cell receptor (BCR) signaling pathway and plays a central role in the activation, proliferation, and survival of B-cells. Aberrant BTK activation is closely associated with the initiation and progression of multiple B-cell malignancies such as B-cell lymphoma (including diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma), chronic lymphocytic leukemia (CLL), and Waldenström’s macroglobulinemia (WM)¹. BTK inhibitors have drastically improved treatment outcomes for patients with B-cell malignancies. However, BTK mutations and remodeling of signaling pathways often lead to acquired resistance during prolonged treatment. There remains an urgent clinical need for new drugs promising novel mechanisms of action².

APG-3288 is a highly potent and selective BTK degrader developed utilizing Ascentage Pharma’s proprietary proteolysis-targeting chimera (PROTAC) technology platform. This candidate induces the formation of a ternary complex consisting of the BTK target, the PROTAC, and the Cereblon E3 ubiquitin ligase, leading to proteasome-mediated degradation of the BTK target. Unlike conventional BTK inhibitors, APG-3288 is designed to act through degradation rather than inhibition, inducing rapid, potent, highly selective, and sustained degradation of both wild-type BTK and multiple BTK mutants associated with resistance to existing BTK inhibitors. Critically, this approach blocks the BCR-BTK signaling axis at its source, thereby overcoming resistance to BTK inhibitors and potentially providing a novel and differentiated therapeutic strategy for BTK-targeted treatment³.

As a company focused on developing innovative drugs for cancer treatment, Ascentage Pharma has dedicated many years building a strong presence in the field of hematologic malignancies with a portfolio that includes Olverembatinib and Lisaftoclax, two products that have already been approved in China. This IND clearance for APG-3288 in China will further strengthen the Company’s pipeline in hematologic malignancies and lay a strong foundation for potential combinations with other key assets within the pipeline.

Yifan Zhai, M.D., Ph.D., Chief Medical Officer of Ascentage Pharma, said, “After receiving IND clearances for APG-3288 from the U.S. FDA and then the China CDE, we have reached a significant milestone in the field of targeted protein degradation, taking another major step forward with our global innovation strategy. There is considerable unmet clinical need in patients with hematologic malignancies, particularly those drug-resistant patients who desperately lack treatment options. We will expeditiously advance this global clinical development program for APG-3288 and actively explore its combinatory potential in efforts to bring this innovative therapeutic to patients in China and around the world as soon as possible.”

*APG-3288 is currently under investigation and has not been approved by the U.S. FDA

References:
[1]. Pal Singh, S., F. Dammeijer, and R.W. Hendriks, Role of Bruton’s tyrosine kinase in B cells and malignancies. Molecular Cancer, 2018. 17(1).
[2]. Wang, E., et al., Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors. New England Journal of Medicine, 2022. 386(8): p. 735-743.
[3]. Zhang, D., et al., NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts. Blood, 2023. 141(13): p. 1584-1596.