alrizomadlin (APG-115)

Analysis of five trajectories, including RMSD, RMSF, hydrogen bond, radius of gyration, coulomb short-range electrostatic spectra, and free binding energy, confirmed that Mol-126 exhibited the highest structural stability compared to the reference drug (Alrizomadlin). Notably, Mol-126 is a derivative of 3-phenoxypropionic acid, which shows promise for the development of alternative therapeutic treatments for non-responsive bladder cancer patients.Communicated by Ramaswamy H. Sarma.

P1/2, N=34, Suspended, University of Michigan Rogel Cancer Center | Recruiting --> Suspended

P1/2, N=69, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=224, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=36, Recruiting, Ascentage Pharma Group Inc. | Phase classification: P2a --> P2 | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2023 --> May 2024

When combined with inhibitors against mitogen-activated protein kinase kinase (MEK) [trametinib and selumetinib], mammalian target of rapamycin (mTOR) [rapamycin], focal adhesion kinase (FAK) [defactinib and Ascentage’s APG-2449, which targets FAK/ALK/ROS1], and MEK/rapidly accelerated fibrosarcoma [RAF] [VS-6766], alrizomadlin demonstrated enhanced antiproliferative activity. Combining MEK and FAK inhibitors also markedly augmented caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage (apoptosis hallmarks) and enhanced observed antitumor effects. In conclusion, our results demonstrate the potential utility of combining alrizomadlin with MAPK pathway inhibitors to treat patients with UM.

P1/2, N=224, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Oct 2023 --> Mar 2024 | Trial primary completion date: Dec 2022 --> Dec 2023

Internal study identifier: APG115-AU101. ClinicalTrials.gov identifier: NCT04358393.

Conclusions Preclinical research suggests that MDM2 inhibitor alrizomadlin in combination with pomalidomide has synergistic antitumor effects in MM tumors harboring TP53WT. These findings support further clinical evaluation of this novel combination for patients with relapsed/refractory MM.

Lisaftoclax in combination with alrizomadlin overcomes venetoclax resistance mediated by various mechanisms, including BCL-2 mutations. In addition, we posit further, putative molecular mechanisms. Our data rationalize clinical development of this treatment combination in patients with diseases that are insensitive or resistant to venetoclax.

In MM cell lines, APG-115 exhibited synergistic activity with anti-MM agents (e.g., carfilzomib, lenalidomide, melphalan, selinexor) and other targeted agents (e.g., panobinostat, bromodomain inhibitor OTX-015, tumor necrosis factor-related apoptotic-inducing ligand). In vivo studies showed that coadministration of alrizomadlin with proteasome inhibitor bortezomib or carfilzomib enhanced tumor regression (vs. single agents) in H929 xenograft models...In conclusion, our results demonstrate that the combination of MDM2 inhibitor APG-115 and proteasome inhibitors have synergistic antitumor effects on MM tumors harboring WT TP53. These data lay a foundation for clinical trials of a new and novel therapeutic option for patients with refractory MM.

The BCL-2 inhibitor venetoclax has shown impressive efficacy in patients with chronic lymphocytic leukemia, but its clinical benefits are limited by acquired BCL-2 gene mutations that confer drug resistance. Further, lisaftoclax plus alrizomadlin more effectively blocked cell cycle entry into the G2/M phase, resulting in accumulation of sub-G1 apoptotic cells. In summary, our study demonstrates, for the first time, that co-targeting BCL-2 and MDM2-p53 apoptosis pathways overcame resistance to BCL-2 inhibitors conferred by acquired BCL-2 gene mutations, potentially offering a viable strategy to overcome drug resistance and thus providing a rationale for clinical investigation.

In vivo efficacy of combination therapy was evaluated with CAL-51 and CAL-51 p53 CRISPR xenograft models. An MDM2 inhibitor (JNJ-26854165) was nominated as an effective drug in treatment for RT-resistant BC cell lines (R2 = 0.43, p value 10μm)... These results demonstrate the combination of RT and MDM2 inhibition may be an effective therapeutic strategy in patients with p53-wild type breast cancer, regardless of hormone receptor status.

P1/2, N=203, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Jan 2023 --> Aug 2023

We next treated NSG mice harboring PDX cells derived from an AML patient who relapsed on the VEN/decitabine therapy with APG2575 (50 mg/kg, p.o., daily), APG1387 (10 mg/kg, i.v., once/wk), APG115 (50 mg/kg, p.o., daily at wk 1 and 5), or combinations. Only in the triple combination group, cIAP1, cIAP2, and XIAP as well as MDM2 were largely diminished and p21 was marked decreased. In conclusion, our study demonstrates that co-targeting intrinsic and extrinsic apoptosis maximizes cell death induction in AML cells with acquired resistance to VEN or with TP53 deletion/mutations by antagonizing Bcl-2, eliminating cIAPs and XIAP, as well as MDM2 and p21, a finding that needs to be validated clinically.

No abstract available

P1/2, N=92, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting

P1/2, N=203, Recruiting, Ascentage Pharma Group Inc. | N=143 --> 203

P1/2, N=143, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Feb 2022 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Sep 2022

P1/2, N=73, Not yet recruiting, Ascentage Pharma Group Inc.

P1/2, N=143, Recruiting, Ascentage Pharma Group Inc. | N=67 --> 143 | Trial completion date: May 2021 --> Feb 2022 | Trial primary completion date: Sep 2020 --> Dec 2021

Further, antitumor activity of APG-115 in STK11-mutant tumors may be mediated through ferroptosis. Taken together, our data warrant clinical investigation of APG-115 in treating NSCLC tumors with STK11 mutations.

Our results demonstrate that p53 activation mediated by APG-115 promotes antitumor immunity in the tumor microenvironment (TME) regardless of the Trp53 status of tumors per se. Instead, such an effect depends on p53 activation in Trp53 wild-type immune cells in the TME. Based on the data, a phase 1b clinical trial has been launched for the evaluation of APG-115 in combination with pembrolizumab in solid tumor patients including those with TP53 tumors.

Mechanistically, the combined treatment synergistically downregulated p-FLT3, p-ERK, p-STAT5 and anti-apoptotic protein MCL-1, and thus enhanced antitumor effect. Taken together, our data provide scientific rationale for clinical development of the combination of HQP1351 and APG-115 in FLT3-ITD mutant and TP53 wild-type AML patients.

The phase I data have demonstrated that APG-115 monotherapy was well tolerated, with minimal toxicity at 100mg (RP2D), and conferred encouraging anti-tumor activities in patients with liposarcomas. Research Funding: Ascentage Pharma (Suzhou) Co., Ltd. Suzhou, China

APG-115 in combination with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in several tumor types. The phase II study is ongoing in the cancer patients with specific bio-marker profiling.