AACR 2025: Quintet of investigational oncological drugs puts Ascentage on positive ascent

Global biopharmaceutical company Ascentage Pharma, specialising in haematological malignancies, has presented results from five preclinical studies at the American Association of Cancer Research (AACR) 2025 annual meeting.

Ascentage – which is engaged in discovering, developing, and commercialising therapies to address global unmet medical needs, primarily for haematological malignancies – today announced details from its AACR 2025 poster presentations, featuring five of the company’s drug candidates: novel tyrosine kinase inhibitor (TKI) olverembatinib (HQP1351), Bcl-2 inhibitor lisaftoclax (APG-2575), FAK/ALK/ROS1 TKI APG-2449, embryonic ectoderm development (EED) inhibitor APG-5918, and IAP antagonist AS03157.

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1.

Abstract 5652, under the session ‘Novel Anti-tumour Agents 3’ showed that olverembatinib in combination with lisaftoclax overcomes venetoclax resistance in preclinical, venetoclax-resistant (VEN-R) models of acute myeloid leukaemia (AML).

While combining Bcl-2 inhibitor venetoclax with hypomethylating agents is the standard of care for patients with AML who are older or ineligible for intensive chemotherapy, resistance to venetoclax is a major clinical challenge, necessitating alternative therapeutic options.

Olverembatinib, a multikinase inhibitor, targets kinases associated with leukemogenesis and venetoclax resistance in AML, including FLT3, cKIT, PDGFR, Src family kinases, PI3K, and FGFR. Lisaftoclax, meanwhile, is an investigational, novel, selective Bcl-2 inhibitor currently being tested clinically for several haematologic malignancies, including relapsed/refractory AML.

In VEN-R AML cell lines, the combination of olverembatinib and lisaftoclax was found to synergistically inhibit cellular proliferation and induced cellular apoptosis.

2.

Abstract 5648, under the same session, looked at the effects of olverembatinib in combination with lisaftoclax in T-cell acute lymphoblastic leukemia (T-ALL), a high-risk haematologic cancer arising from malignant transformation of T-cell progenitors that affects approximately 15% of newly diagnosed paediatric and 25% of adult ALL cases.

Survival in patients with relapsed or refractory disease is poor, with limited treatment options, and some T-ALL subtypes depend on pre-TCR/Src signalling and antiapoptotic Bcl-2 family proteins for growth and survival.

Olverembatinib targets oncogenic Src-family kinases (Lck, Fyn, and YES1), which are essential for T-cell differentiation, survival, and activation. Combined with lisaftoclax, Ascentage Pharma evaluated anti-tumour effects in human T-ALL cell lines and xenograft models and explored potential mechanisms of action, finding the combination synergistically suppressed tumour growth in a MOLT4 xenograft model in vivo.

3.

Abstract 446, under the session ‘Experimental and Molecular Therapeutics’, showed that embryonic ectoderm development protein (EED) inhibitor APG-5918 exhibits potent anti-tumour activity and synergises with androgen receptor (AR) inhibitor enzalutamide in preclinical prostate cancer (PCa) models.

Castration-resistant prostate cancer (CRPC) remains incurable, due to resistance to therapies including the new generation of androgen receptor pathway inhibitors (ARPIs) such as enzalutamide. And dysregulation of polycomb repressive complex 2 (PRC2) is common in PCa, associated with poor prognosis and metastasis.

Targeting EED has emerged as a promising strategy to inhibit PRC2 function and APG-5918 alone demonstrated superior inhibitory effects on PCa cell proliferation in vitro, while in combination with enzalutamide it synergistically suppressed cell proliferation. APG-5918 alone induced dose-dependent cell cycle arrest in LNCaP and C4-2B cells, but combining enzalutamide with APG-5918 deepened G0/G1 cell cycle arrest. Additionally, the combination treatment showed enhanced downregulation of oncogenic drivers and DNA methylation factors.

4.

Abstract 1679, under the session ‘Drug Combination Strategies for Cancer Treatment’, showed that APG-2449, a novel focal adhesion kinase (FAK) inhibitor, enhances the anti-tumour activity of chemotherapy in preclinical models of small-cell lung cancer (SCLC) with activated FAK.

SCLC is a genetically heterogeneous disease with no standardised targeted therapy options. Despite the recent advancement of immune checkpoint inhibitors, improvements in overall survival (OS) have been modest, and platinum-based chemotherapy combined with topoisomerase inhibitors remains the standard of care in SCLC.

Meanwhile, FAK, a non-receptor tyrosine kinase, has been reported to regulate cellular proliferation, migration, invasion, and DNA-damage repair. Previous studies have shown that FAK is amplified and overexpressed in approximately 69% of SCLC tumours.

Novel FAK inhibitor APG-2449 was shown to demonstrate synergistic anti-tumour effects when combined with first- and second-line chemotherapies in SCLC.

5.

The final abstract under session ‘Novel Anti-tumour Agents 3’, abstract 5651, presented data on the discovery of AS03157 as a highly potent and orally active antagonist of inhibitor of apoptosis proteins (IAPs).

Overexpression of antiapoptotic proteins, such as cellular inhibitor of apoptosis protein 1 (cIAP1) and 2 (cIAP2) and X-linked IAP (XIAP), occurs in various haematologic and solid cancers, and is associated with drug resistance and a poor prognosis. IAP inhibitors bind to IAP proteins, displace and activate caspases, and induce degradation of cIAP1/2 and XIAP, thereby inhibiting pro-survival signalling and promoting apoptosis in cancer cells.

Investigational AS03157, a novel and structurally distinct IAP antagonist, was identified with enhanced specificity toward cIAP1 and XIAP, binding with high affinity and efficiently targeting cIAP1 for degradation, thereby generating potent antiproliferative activities (with IC50 values below 30 nM) in tested cancer cell lines – appearing to be a promising candidate for further clinical development.

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Dr Yifan Zhai, chief medical officer at Ascentage, said: “The encouraging data from our investigational assets […is] another testament to our strong and innovative pipeline. In particular, the combination of olverembatinib and lisaftoclax, two of our key drug candidates, has demonstrated strong synergistic effects in preclinical models of acute myeloid leukaemia and T-cell acute lymphoblastic leukaemia.”

Olverembatinib, lisaftoclax, APG-2449, APG-5918, and AS03157 are all investigational drugs and have not been approved by the US FDA. Olverembatinib is approved in China.

Ascentage Pharma has been listed on the Main Board of the Stock Exchange of Hong Kong Limited, with the stock code 6855.HK since October 2019 and has also been listed on the Nasdaq Global Market under the ticker symbol “AAPG” since January 2025. It is the only company in the world with active clinical programmes targeting all known key apoptosis regulators.

The Chinese biotech took the first US biotech initial public offering of 2025 over the finish line, raising $126 million for its pipeline of small-molecule cancer drugs.