lisaftoclax (APG-2575)

P3, N=464, Not yet recruiting, Ascentage Pharma Group Inc.

P1/2, N=284, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Aug 2025 --> Aug 2026 | Trial primary completion date: Aug 2024 --> Aug 2025

P1/2, N=40, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting

P1, N=30, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P1/2, N=65, Suspended, Ascentage Pharma Group Inc. | Recruiting --> Suspended

P2, N=78, Recruiting, Ascentage Pharma Group Inc. | N=36 --> 78 | Trial completion date: May 2025 --> May 2027 | Trial primary completion date: May 2024 --> May 2026

P1, N=46, Completed, Ascentage Pharma Group Inc. | Recruiting --> Completed | N=123 --> 46 | Trial completion date: Dec 2025 --> Feb 2024 | Trial primary completion date: Dec 2024 --> Feb 2024

P1/2, N=40, Not yet recruiting, Ascentage Pharma Group Inc. | Initiation date: Dec 2023 --> Oct 2024

P3, N=486, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting

P1, N=30, Not yet recruiting, M.D. Anderson Cancer Center

P3, N=486, Not yet recruiting, Ascentage Pharma Group Inc.

P3, N=344, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting

P3, N=344, Not yet recruiting, Ascentage Pharma Group Inc.

P1, N=35, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Jan 2023 --> Jun 2026 | Trial primary completion date: Dec 2022 --> Mar 2025

P3, N=400, Recruiting, Ascentage Pharma Group Inc. | Not yet recruiting --> Recruiting

P2, N=75, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Jan 2024 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Sep 2024

P1, N=74, Active, not recruiting, Ascentage Pharma Group Inc. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=40, Not yet recruiting, Ascentage Pharma Group Inc.

Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

P1/2, N=65, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Jul 2023 --> Jul 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

P1, N=90, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Feb 2023 --> Feb 2025 | Trial primary completion date: Sep 2022 --> Sep 2024

P3, N=400, Not yet recruiting, Ascentage Pharma Group Inc.

P1, N=123, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Dec 2024 --> Dec 2025

P1/2, N=108, Recruiting, Ascentage Pharma Group Inc. | Trial primary completion date: Sep 2023 --> Sep 2024

P1/2, N=24, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Jul 2023 --> Jul 2024

Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.

Among 52 patients with hematological malignancies the maximum tolerated dose (MTD) was not reached and no clinical TLS was observed.20 In this study of 22 evaluable patients with RR CLL there was an overall response rate (ORR) of 63.6% (14/22).20 A larger study of 114 patients with RR CLL evaluated lisaftoclax in combination with either the Bruton's tyrosine kinase inhibitor (BTKi) acalabrutinib or the anti CD20 monoclonal antibody rituximab (NCT04215809)...In CLL an overall response rate (ORR) to BGB-1147 of 100% as monotherapy was observed among 8 patients with RR disease.25 In 12 patients with RR MM, the ORR to BGB-1147 in combination with dexamethasone varied from 0–68% depending on the dose cohort.26 In combination with azacytidine in AML the ORR to BGB-11417 was 74% among those with treatment naïve (TN) disease (n=20/27) and 65% (n=13/20) in the cohort with RR disease.27 BGB-11417 monotherapy in 23 patients with RR NHL demonstrated responses in 2 patients with diffuse large B cell lymphoma (DLBCL) and one patient with marginal zone lymphoma (MZL).28 In 11 patients with RR MCL treated with BGB-11417 in combination with zanubrutinib there was a 55% (6/11) ORR.28 S55746 is a potent BAX/BAK dependent BCL2 inhibitor administered orally.18,29 Developed by Servier, it has been tested in phase I studies in CLL, NHL and AML. In a study of S55746 among 37 patients with RR NHL, no dose limiting toxicities (DLT) or TLS was observed after a medium duration of treatment of 42 days.30 FCN-338 is another orally available selective BCL2 inhibitor developed by Fochon currently undergoing phase I testing in RR CLL.18,31 Clinical outcomes with this drug are yet to be publicly reported...More recently navitoclax has been tested in RR myelofibrosis (MF) in combination with ruxolinitib with evidence of clinical response to the combination.35 AZD0466 by Astrazeneca is a nanomedicine potent dual BCL2/ BCLxL inhibitor that mediates BAX/BAK induced apoptosis36,37 and is administered intravenously...Among 9 patients reported undergoing testing for RR hematological malignancy the DLT had not yet been reached.38 Pelcitoclax or APG1252 by Ascentage is a more recent BAX/BAK dependent dual BCL2 and BCLxL inhibitor18,39,40 currently in phase I trials in RR NHL (NCT05186012)...There are multiple emerging BCL2 inhibitors currently undergoing clinical trial testing in hematological malignancies, and it remains too early to appreciate the differential efficacy and toxicity profiles that these agents may carry compared with venetoclax. It is hoped that the results seen with venetoclax can be improved upon across a raft of disease groups over the coming years.

Our results demonstrate that olverembatinib and BCL-2 inhibitor lisaftoclax have additive antitumor effects in imatinib-resistant GIST. This novel dual approach may have the potential for treating patients with GISTs whose disease has progressed after treatment with TKIs.

P1, N=22, Recruiting, Institute of Hematology & Blood Diseases Hospital | Not yet recruiting --> Recruiting

Seventeen (12%) pts had progressed on BTKi (n = 15) and/or after venetoclax (n = 3) therapy. Conclusions The RP2D of lisaftoclax was 600 mg daily. Initiated with a daily dose ramp-up, lisaftoclax alone or combined with acalabrutinib or rituximab had a manageable safety profile and was active in pts with treatment-naïve or R/R CLL/SLL.

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.

These findings demonstrate that lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2-selective inhibitor with considerable potential for the treatment of certain hematologic malignancies.

P1/2, N=65, Recruiting, Ascentage Pharma Group Inc. | Trial primary completion date: Jul 2022 --> Jul 2023

P1, N=22, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital

Our results provide an effective AML treatment strategy through combination of APG-2575 and HHT, which is worthy of further clinical research.

Although indicated for the management of certain hematological malignances (HMs), BCL-2 inhibitor (BCL-2i) venetoclax requires a slow dose ramp-up to reduce the risk of tumor lysis syndrome (TLS) and is associated with severe neutropenia. Lisaftoclax may offer a more convenient treatment alternative, with a daily ramp-up schedule that may be more pt friendly. ClinicalTrials.gov: NCT03913949.

Investigational agent lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor, while palbociclib inhibits cyclin-dependent kinases (CDK) 4 and 6. The primary objective for phase II is to determine clinical benefit response, and secondary efficacy endpoints include overall response rate, duration of response, time to response, and progression-free survival. Lisaftoclax is being administered orally once daily in a 28-day cycle at the assigned dose.

As a result, APG-2575-mediated macrophages transition could improve tumor immunosuppression, thus skewing the cytokines profiles into immunostimulatory one in the TME and further enhancing antitumor T cell immunity. These results provided a novel promising strategy for NSCLC treatment and warranted future clinical evaluation of combination therapy of APG-2575 and ICIs.Key words: BCL-2, APG-2575, ICIs, macrophages, non-small cell lung cancer.

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.

Studies of the BCL-2i venetoclax have demonstrated activity in certain HMs but show that venetoclax requires a slow dose ramp-up over several weeks to reduce the risk of tumor lysis syndrome (TLS), which may warrant frequent or intensive laboratory monitoring. The BCL-2i lisaftoclax offers a treatment alternative for pts with R/R HMs, with a daily ramp-up schedule that may be more pt friendly with a favorable preliminary safety profile. Internal study identifier APG-2575-CN-001; ClinicalTrials.gov identifier: NCT03913949.

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.