BEIJING – Suzhou, China-based Ascentage Pharma Group Inc. said on Monday that it is working with Astrazeneca plc’s hematology R&D unit, Acerta Pharma, to develop a combination therapy of its Bcl-2 inhibitor, APG-2575, with Acerta's BTK inhibitor, Calquence (acalabrutinib). The first patient has been dosed in the U.S.

The clinical partnership will take aim at relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Ascentage will sponsor the clinical trial to evaluate the efficacy and safety of the combination therapy. Further financial terms were not disclosed.

This latest trial follows studies that investigated BTK inhibitor ibrutinib in combination with Bcl-2 inhibitor venetoclax for CLL, which have showed encouraging results. Ibrutinib is a first-in-class BTK inhibitor that won FDA approval for CLL in 2014, while acalabrutinib is a more selective BTK inhibitor that was approved for the same indication in 2019. Venetoclax was approved in the U.S. in 2016.

APG-2575, a key drug candidate in Ascentage’s pipeline, is designed to target apoptosis. Following IND approval from the FDA in March, the company is conducting a global, multicenter, open-label phase Ib/II dose-escalation and dose-expansion study to evaluate the safety, tolerability and anticancer activity of APG-2575 as a single agent or in combination in patients with r/r CLL/SLL. The trial has dosed the first patient in the U.S. and is also expected to take place in Europe and Australia.

Ascentage did not respond to BioWorld’s request for comment on the details of the clinical trial and the collaboration as of press time.

According to public information, the first half of the trial will study APG-2575 at different dose levels as a monotherapy using a 3+3 dose-escalation design with dose expansion at the recommended phase II dose. The second half will be a 3+3 dose-escalation design combining APG-2575 plus rituximab or acalabrutinib or voruciclib. Ascentage expects the trial to be completed in January 2022.

The company is now recruiting patients who are on anticoagulants or patients who discontinued the acalabrutinib and APG-2575 cohort due to acalabrutinib toxicity.

“This combination therapy has the potential to partially cure CLL or achieve the effect of discontinuing treatment,” said Ascentage CEO Dajun Yang. He added that that there have been substantial clinical data on its mechanism of action to support that combination therapy, and the rationale of the combination is sound. Results from recent studies combining ibrutinib with venetoclax showed the combination can deepen responses and even shorten cyclic treatment for CLL patients, which may enable patients to achieve complete remission and discontinue treatment.

In May 2019, researchers from The University of Texas MD Anderson Cancer Center said in The New England Journal of Medicine that “preclinical investigations have indicated potential synergistic interaction of their combination.”

The study enrolled 80 patients with a median age of 65. Researchers saw more patients reach complete remission, with or without normal blood count recovery, and remission with undetectable minimal residual disease (MRD) over time with combined treatment. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable MRD.

The results led to the researchers’ conclusion that “combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL.”

Janssen’s phase II CAPTIVATE trial studying ibrutinib plus venetoclax also achieved encouraging results. Partial results presented at the 61st American Society of Hematology (ASH) Annual Meeting last year showed that most patients with previously untreated CLL achieved undetectable MRD with that combination therapy. Undetectable MRD was achieved in 75% of patients in peripheral blood and 72% of patients in bone marrow.

Meanwhile, acalabrutinib is being investigated in combination with anti-CD20 monoclonal antibody obinutuzumab (marketed as Gazyva by Genentech Inc.) for CLL in the phase III ELEVATE-TN study.

Interim results presented at the American Society of Hematology meeting last year showed that acalabrutinib in combination with obinutuzumab led to significantly longer progression-free survival compared with obinutuzumab combined with chlorambucil, with a 90% reduction in the risk of disease progression or death. Obinutuzumab combined with chlorambucil was a standard front-line option for CLL before ibrutinib came along.

It remains to be seen whether acalabrutinib will create synergistic effects with Ascentage’s Bcl-2 inhibitor.

APG-2575 is designed to treat hematologic malignancies with Bcl-2 overexpression, including leukemia, lymphoma and multiple myeloma. Ascentage said it has demonstrated antitumor activity in combination with MDM2-p53 inhibitors, BTK inhibitors, anti-CD20 monoclonal antibodies and PI3K inhibitors in various types of B-cell malignancies.

Ascentage received trial approvals from the FDA and the NMPA in March and April, respectively, to conduct phase Ib/II studies of APG-2575 as a single agent or in combination therapies for r/r CLL/SLL. The drug candidate is also in a global phase Ib/II study for Waldenström macroglobulinemia and a phase Ib/II study for r/r acute myeloid leukemia in China.

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