FDA Clears Phase 3 Trial of Lisaftoclax in CLL/SLL


Lisaftoclax is a novel, orally administered small-molecule BCL-2 selective inhibitor. A study of the agent in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma will commence in the second half of 2023.

The FDA has cleared a global phase 3 trial to evaluate lisaftoclax (APG-2575), a novel BCL-2 inhibitor, for the treatment of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were previously treated with a Bruton’s tyrosine kinase inhibitor (BTKi).1

This clearance of lisaftoclax follows its approval by the Center for Drug Evaluation in China for the registrational phase 2 study of the agent in patients with relapsed/refractory CLL/SLL in December 2021. With this clearance, lisaftoclax has potential to become the second BCL-2 inhibitor approved anywhere globally.

The global, multi-center, randomized-controlled, registrational phase 3 study (APG2575CG301) will evaluate the safety and efficacy of lisaftoclax plus a BTKi in patients with CLL/SLL who were previously treated with a BTKi. Commencement of the trial is expected in the second half of 2023.

“Lisaftoclax [is] a BCL2 inhibitor, which may differentiate this class of drugs in ramp-up safety and tolerability, ease of use, and potential effectiveness. Those drugs are very early in development, but that’s something to keep an eye out for,” John N. Allan, MD, assistant professor of medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, told Targeted OncologyTM.

John N. Allan, MD

John N. Allan, MD

"With progress in the research and development of targeted therapies, we have seen considerable improvement to the survival of patients with CLL/SLL. However, there remain major clinical challenges and urgent unmet medical needs for novel therapies that are safe and effective," said Yifan Zhai, MD, chief medical officer of Ascentage Pharma, in a press release. "Lisaftoclax, a key drug candidate of our apoptosis-targeted pipeline with global best-in-class potential, has shown promising efficacy and favorable safety in earlier studies.”

Lisaftoclax is a novel, orally administered small-molecule BCL-2 selective inhibitor designed for the treatment of a wide range of malignancies through selectively blocking BCL-2. In turn, this will restore the normal apoptosis process in cancer cells. Lisaftoclax is the first BCL-2 inhibitor in China and the second globally to have shown compelling clinical activity and entered a pivotal study.

A total of 19 clinical trials assessing lisaftoclax have been initiated in over 600 patients, including more than 300 patients with CLL/SLL. Studies have shown that when used as a monotherapy as well as in combination regimens, lisaftoclax elicited clear therapeutic potential, was safe and effective, and was easy-to-use, specifically for patients with CLL/SLL.

Initial results from a global phase 2 study of lisaftoclax combined with the next-generation BTKi acalabrutinib were announced at the American Society of Hematology 2022 Annual Meeting.2 In the study, 141 patients with R/R CLL/SLL were enrolled with a median age of 62 (range, 18-80 years), 70% of patients were male, 89% had an ECOG performance status of 0-1, and 2 in 11%. The median number of prior therapies was 2 (range, 1-15), and 12% of patients had progressed on BTKi and/or after venetoclax (n = 3) therapy.

The combination achieved encouraging objective response rates (ORRs), including a total of 43 (65%) ORRs in the monotherapy group, and 53 (98%) and 23 (87%) among patients in the acalabrutinib and rituximab cohorts, respectively.

Regarding safety, the combination regimens showed a safety profile that was similar to lisaftoclax alone. There was also an extremely low incidence of tumor lysis syndrome.

“We are very encouraged by the FDA's clearance for the global registrational phase 3 study as it marks a major milestone in the development of lisaftoclax. Fulfilling the mission of addressing unmet clinical needs in China and around the world, we will press ahead with the global registrational phase 3 study of lisaftoclax to allow patients around the world to benefit from this novel therapeutic as soon as possible," said Zhai, in the press release.1

  1. Ascentage Pharma received clearance from U.S. FDA to proceed with global registrational phase III clinical trial for lisaftoclax (APG-2575) in previously treated patients with CLL/SLL. News release. Ascentage Pharma. August 6, 2023. Accessed August 8, 2023. https://tinyurl.com/2fsu9ak7
  2. Davids M, Chanan-Khan A, Mudenda B, et al. Lisaftoclax (APG-2575) safety and activity as monotherapy or combined with acalabrutinib or rituximab in patients (pts) with treatment-naïve, relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL): Initial data from a phase 2 global study. Blood. 2022;140(1): 2326–2328.
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