Ascentage Pharma Secures FDA IND Clearance For BTK Degrader APG-3288 In B-Cell Malignancies

Ascentage Pharma Group International, a global commercial-stage biopharmaceutical company focused on the discovery, development, and commercialization of innovative therapies for cancer, announced that its next-generation BTK-targeted protein degrader, APG-3288, has received Investigational New Drug (IND) clearance from the U.S. Food and Drug Administration (FDA). The clearance enables the initiation of a clinical study in patients with relapsed or refractory B-cell malignancies.

The FDA IND clearance marks Ascentage Pharma’s first clinical-stage program in targeted protein degradation, representing a significant expansion of the company’s global innovation pipeline. APG-3288 will be evaluated in a global, multicenter, open-label Phase 1 study designed to assess safety, tolerability, pharmacokinetics (PK), and preliminary efficacy in patients with relapsed or refractory hematologic malignancies.

Bruton’s tyrosine kinase (BTK) is a critical component of the B-cell receptor (BCR) signaling pathway, playing a central role in B-cell activation, proliferation, and survival. Dysregulated BTK signaling is implicated in the development and progression of several B-cell malignancies, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia (CLL), and Waldenström’s macroglobulinemia. While BTK inhibitors have significantly improved outcomes in these diseases, acquired resistance driven by BTK mutations and signaling pathway reprogramming remains a major clinical challenge, underscoring the need for therapies with novel mechanisms of action.

Yifan Zhai, M.D., Ph.D., Chief Medical Officer of Ascentage Pharma, said, “Compared to existing conventional BTK inhibitors, Ascentage Pharma’s BTK degraders developed with our PROTAC technology can achieve complete degradation of target protein and are enabled by a molecular mechanism that can induce stronger efficacy. APG-3288 represents a strategic clinical stage candidate in the field of BTK-targeted therapies. Its high selectivity, potency, and consistent PK/PD profiles across multiple BTK-resistant models fully validate our differentiated design capabilities of PROTAC-based therapeutic candidates. This FDA clearance marks a significant milestone in the development of APG-3288 and strategic pipeline expansion, underscoring our commitment to innovation in the field of hematologic malignancies. It also lays a strong foundation for our future exploration of the combinatory potential between APG-3288 and our existing proprietary small-molecule agents. We plan to accelerate the global clinical development of APG-3288 and actively explore the therapeutic potential of protein degraders in hematologic malignancies and other BTK-driven diseases, with the goal of bringing more new treatment options to patients as soon as possible.”

APG-3288 is a first-in-class, highly potent and selective BTK degrader developed using Ascentage Pharma’s proprietary PROTAC (proteolysis-targeting chimera) technology platform. The molecule promotes the formation of a ternary complex between BTK, the PROTAC compound, and the Cereblon E3 ubiquitin ligase, leading to the proteasome-mediated degradation of BTK.

Unlike traditional BTK inhibitors, APG-3288 is designed to eliminate BTK protein rather than inhibit its activity, enabling rapid, sustained, and highly selective degradation of both wild-type BTK and multiple mutant forms associated with resistance to existing BTK inhibitors. By targeting BTK at its source, APG-3288 has the potential to overcome resistance mechanisms and deliver a novel, differentiated therapeutic approach for BTK-driven diseases.

In preclinical studies, APG-3288 demonstrated superior BTK degradation potency, enhanced selectivity, and favorable pharmacokinetic properties compared with other BTK degraders currently in development, supporting its advancement into clinical evaluation.