On December 10, 2023 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, reported that it has released the clinical data of lisaftoclax (APG-2575), one of the company’s key drug candidates, combined with various novel therapies in patients with relapsed/refractory (R/R) multiple myeloma (MM) or immunoglobulin light-chain (amyloid light-chain [AL]) amyloidosis, in a Poster Presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in San Diego, CA, the United States (Press release, Ascentage Pharma, DEC 10, 2023, View Source;ascentage-pharma-releases-the-first-dataset-of-bcl-2-inhibitor-lisaftoclax-in-patients-with-rr-mm-demonstrating-encouraging-orr-and-vgpr-302010980.html [SID1234638389]). This is the first data readout of lisaftoclax for the treatment of patients with R/R MM.

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The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, multiple studies of Ascentage Pharma’s key drug candidates (lisaftoclax and olverembatinib) have been selected for presentations at this year’s ASH (Free ASH Whitepaper) Annual Meeting, including two Oral Presentations.

These data signalled the favorable therapeutic potential and tolerability of lisaftoclax combination regimens in patients with hematologic malignancies such as R/R MM. Results showed an overall response rate (ORR) of 66.7% and a very good partial response (VGPR) rate of 28.6% in patients with R/R MM who received lisaftoclax combined with pomalidomide and dexamethasone; and an ORR of 100% and a VGPR rate of 50% in patients with R/R MM who received lisaftoclax combined with daratumumab, lenalidomide, and dexamethasone. Lisaftoclax was well tolerated at doses up to the maximum of 1,200 mg.

Prof. Sikander Ailawadhi, MD, from Mayo Clinic and the principal investigator of this study, commented, "It was the first time to issue efficacy of lisaftoclax in patients with R/R MM, with an outstanding overall response rate. Lisaftoclax was well tolerated even when the combination dose was escalated up to 1200 mg. At the same time, the efficacy of lisaftoclax for patients with AL amyloidosis is also showing up."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "At this year’s ASH (Free ASH Whitepaper) Annual Meeting, we presented data of lisaftoclax combinations in patients with malignant plasmocyte diseases such as R/R MM that demonstrated promising ORR, VGPR; and favorable tolerability at doses up to 1,200 mg. These results reaffirmed the global best-in-class potential and unique therapeutic utility of lisaftoclax. Remaining committed to the mission of addressing unmet clinical needs in China and around the world, we will expedite our clinical development programs to bring safe and effective therapies to patients in need."

Highlights of the study presented at ASH (Free ASH Whitepaper) 2023:

First Report on the Effects of Lisaftoclax (APG-2575) in Combination with Novel Therapeutic Regimens in Patients with Relapsed or Refractory Multiple Myeloma (R/R MM) or Immunoglobulin Light-Chain (Amyloid Light-Chain [AL]) Amyloidosis

Format: Poster Presentation
Abstract: #2016
Session: 653. Multiple Myeloma: Prospective Therapeutic Trials: Poster I
Time: December 9, 2023, Saturday, 5:30 PM – 7:30 PM (Pacific Time) / December 10, 2023, Sunday, 9:30 AM – 11:30 AM (Beijing Time)
Highlights
Background: Lisaftoclax is an investigational, novel, potent, selective Bcl-2 inhibitor under clinical development for treatment of patients with hematologic malignancies or solid tumors and has shown clinical antitumor benefits. In a previous study on chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other hematologic malignancies, lisaftoclax was shown to require only a short dose ramp-up to mitigate tumor lysis syndrome (TLS) and was associated with a low incidence of adverse events (AEs). This multicenter study was designed to evaluate the safety and efficacy of lisaftoclax combination regimens in patients with R/R MM or R/R AL amyloidosis.

Methods:

This study has three treatment arms that included Arm A: lisaftoclax combined with pomalidomide and dexamethasone in patients with R/R MM; Arm B: lisaftoclax combined with daratumumab, lenalidomide, and dexamethasone in patients with R/R MM; and Arm C: lisaftoclax combined with pomalidomide and dexamethasone in patients with R/R AL amyloidosis.
Lisaftoclax was administered orally once daily (QD) at 5 dose levels (400 mg, 600 mg, 800 mg, 1,000 mg, and 1,200 mg) without ramp-up in 28-day cycles. Pomalidomide, daratumumab, and lenalidomide were administered per label use. Dexamethasone 40 mg (20 mg for patients aged >75 years) was administered on Days 1, 8, 15, and 22 of 28-day cycles.
Patients: As of July 3, 2023, a total of 30 patients were enrolled. Among them, 22, 3, and 5 patients were enrolled into Arms A, B, and C, respectively. 66.7% of patients were male, and the median (range) age was 70.5 (24-88) years. All patients were previously exposed to multiple lines of treatment. 18 (60%) patients were triple-class-exposed, 7 (35%) had received pomalidomide and 3 (10%) harbored the t(11;14) chromosomal abnormality.

Efficacy results:

In Arm A, 21 patients with R/R MM were efficacy evaluable, including 6 (28.6%) who have reached VGPRs and 8 (38.1%) who have reached partial responses (PRs), resulting in an ORR (PR + VGPR) of 66.7%.
In Arm B, 1 patient with R/R MM achieved PR and another achieved VGPR, resulting in an ORR of 100%.
In Arm C, 3 patients with R/R amyloidosis achieved a hematologic VGPR, resulting in an ORR of 60%; 1 patient achieved improvement in organ functions.
Conclusions: Lisaftoclax combination regimens were well tolerated and demonstrated potent antitumor activity (especially VGPRs and PRs) in patients with R/R MM and R/R AL amyloidosis.

* Lisaftoclax (APG-2575) is an investigational drug that has not been approved in any country and region.