Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for malignancies, today announced that it has released the latest clinical data of its novel Bcl-2 selective inhibitor, lisaftoclax (APG-2575), in patients with relapsed/refractory (R/R) multiple myeloma (MM) or immunoglobulin light-chain (AL) amyloidosis, in an Oral Report at the 66th American Society of Hematology (ASH) Annual Meeting, taking place in San Diego, CA, the United States. Prof. Sikander Ailawadhi, MD; and Prof. Asher A. Chanan-Khan, MD, from Mayo Clinic, Jacksonville, FL, are the principal investigators of this study.

The ASH 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, results from multiple clinical and preclinical studies on four of Ascentage Pharma's drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at this year's ASH Annual Meeting.

The data featured in this Oral Report on lisaftoclax in R/R MM further demonstrated compelling clinical benefit and favorable safety profile of the combination regimen. According to the results, in the 36 evaluable patients who were heavily pretreated, the overall response rate (ORR) was 63.9%; the very good partial remission (VGPR) rate was 30.6%; and more importantly, the median progression-free survival (PFS) reached up to 9.7 months. In terms of safety, lisaftoclax, at doses ranged from 800-1200 mg, in combination with other therapeutic agents showed favorable tolerability and no drug-drug interactions (DDIs). This is the first ever report on the long-term treatment with a Bcl-2 inhibitor at high doses.

Prof. Sikander Ailawadhi commented, "For previously heavily treated R/R MM, in combination with Pd, Lisaftoclax has shown improved response rates and extended duration of response, even in patients refractory to anti-CD38 antibodies. Lisaftoclax based treatments have demonstrated an impressive safety profile, even at a relatively high dose. Thus, lisaftoclax could be an effective target therapy for R/R MM patients."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "We are pleased that these data of lisaftoclax in R/R MM have been selected for Oral Report at the ASH Annual Meeting, which once again showcased the drug's favorable safety and impressive clinical benefit. Despite the considerable progress achieved in the therapeutic area of MM in recent years, there still remains urgent unmet clinical needs from patients with R/R MM, especially those who had failed on prior treatment with proteasome inhibitors and immune-modulating CD38 monoclonal antibodies. Lisaftoclax has broad therapeutic potential in hematologic malignancies and solid tumors. Very recently, a New Drug Application for lisaftoclax in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma has been accepted and granted the Priority Review designation in China. Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will expedite the global clinical development of our key drug candidates to bring more safe and effective therapies to patients as soon as possible."

Highlights of the data this study reported at ASH 2024 are as below:

Lisaftoclax (APG-2575) Combined with Novel Therapeutic Regimens in Patients (pts) with Relapsed or Refractory Multiple Myeloma (R/R MM) or Immunoglobulin Light-Chain (AL) Amyloidosis
Format: Oral Presentation
Abstract#: 1022
Session: 654. Multiple Myeloma: Pharmacologic Therapies: Into the Future: New Drugs and Combinations in Multiple Myeloma

Highlights:

Background:

• MM is characterized by the proliferation of abnormal clonal plasma cells, causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. The treatment of MM involves immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies to achieve disease remission.

• AL amyloidosis comprises disorders of abnormal extracellular deposition of misfolded proteins in various organs with resultant damage, and the key strategy of treatment is to prolong the time to or reverse organ dysfunction. However, many patients will relapse from the standard triplet or quadruplet therapies, necessitating additional treatments with novel mechanisms of action.

• Lisaftoclax is a novel investigational Bcl-2 inhibitor that has shown strong antitumor activity in earlier studies. This presentation reports clinical trial data on lisaftoclax combined with novel therapeutic regimens in patients with R/R MM or R/R AL amyloidosis.

Introduction: This is a multicenter, open-label Phase I/II study.

Enrolled Patients and Study Methods:

• Eligible patients had an ECOG performance status ≤ 2, ≥ 1 prior line of therapy, and adequate organ function. Patients with R/R AL amyloidosis had confirmed symptomatic organ involvement. Lisaftoclax was administered orally daily in repeated 28-day cycles. Pomalidomide, daratumumab, and lenalidomide were administered per label use. Dexamethasone 40 mg (20 mg, patients > 75 years old) was administered on days 1, 8, 15, and 22 of 28-day cycles.

• This study evaluated the safety and efficacy of lisaftoclax combined with pomalidomide and dexamethasone (Pd; Arm A) or daratumumab, lenalidomide, and dexamethasone (DRd; Arm B) in R/R MM, and lisaftoclax combined with the Pd regimen in R/R AL amyloidosis (Arm C).

• As of November 5, 2024, 58 patients were enrolled, including 48 with R/R MM and 10 with AL amyloidosis.

• In Arm A (n=41), lisaftoclax was administered orally at dose assigned: 400 mg (n=3); 600 mg (n=4); 800 mg (n=15); 1,000 mg (n=13); and 1,200 mg (n=6). In Arm B (n=7), all patients were treated with lisaftoclax 600 mg. In Arm C (n=10), lisaftoclax was administered at 400 mg (n=1); 600 mg (n=4); 800 mg (n=3); and 1,000 mg (n=2).

Efficacy Results:

• In Arm A, out of 36 evaluable patients, 3 (8.3%) achieved complete remission (CR), 8 (22.2%) reached VGPR, and 12 (33.3%) achieved partial response (PR). The ORR was 63.9% (n=23), and 11 (30.6%) achieved≥VGPR.

• In Arm B, of 5 evaluable patients, 2 (40%) achieved CR.

• In Arm C, of 9 assessed patients, 1 (11.1%) achieved CR, 6 (66.7%) achieved VGPR, for an ORR of 88.9% (n=8); 2 patients had cardiac responses.

Safety Results: Among all 58 patients in the safety population, 39 (67.2%) reported any-grade lisaftoclax treatment-related AEs (TRAEs; ≥ 5% incidence), including neutropenia (25.9%), thrombocytopenia (6.9%), leukopenia (13.8%), nausea (15.5%), abdominal distension (8.6%), diarrhea (12.1%), and constipation (8.6%). A total of 14 patients experienced grade ≥ 3 TRAEs, including neutropenia (13.8%) and febrile neutropenia (1.7%), and 4 patients experienced lisaftoclax-related serious AEs (1 each): febrile neutropenia, acute kidney injury, bacterial infection, and diarrhea with electrolyte imbalance. In Arm B, 1 pt experienced a dose-limiting toxicity (prolonged QT interval). Pharmacokinetic analyses showed no DDIs in all patients treated with lisaftoclax at all doses in combination with other therapeutic agents used in 3 arms.

Conclusions: These findings suggest that lisaftoclax improves the depth of response in patients with R/R MM or AL amyloidosis when combined with Pd or DRd. These combination therapies demonstrated a favorable safety profile with no DDIs, particularly in hematologic side effects.

*Lisaftoclax is an investigational drug that has not been approved in any country or region.

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a global, integrated biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily in malignancies. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code 6855.HK.

The company has built a rich pipeline of innovative drug candidates that includes novel, highly potent Bcl-2 and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation TKIs. Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company has conducted more than 40 clinical trials in the US, Australia, Europe, and China, including 13 registrational studies (completed/ ongoing/planned).

Olverembatinib, the company's first lead asset developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product in China, has been granted Priority Review Designations and Breakthrough Therapy Designations by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). To date, the drug had been included into the China National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted Orphan Drug Designations (ODDs) and a Fast Track Designation (FTD) by the US FDA, and an Orphan Designation by the EMA of the EU.

To date, Ascentage Pharma has obtained a total of 16 ODDs from the US FDA and 1 Orphan Designation from the EMA of the EU for 4 of the company's investigational drug candidates. Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships and other relationships with numerous leading biotechnology and pharmaceutical companies such as Takeda, AstraZeneca, Merck, Pfizer and Innovent; and research and development relationships with leading research institutions such as Dana-Farber Cancer Institute, Mayo Clinic, National Cancer Institute and the University of Michigan.

The company has built a talented team with a wealth of global experience in the discovery and development of innovative drugs and fully functional commercial manufacturing and Sales & Marketing teams. One pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs, in order to fulfil its mission of addressing unmet clinical needs in China and around the world for the benefit of more patients.

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