ASH 2022 | Ascentage Pharma to Present Initial Data of Bcl-2 Inhibitor Lisaftoclax (APG-2575) in Combination with BTK Inhibitors for the Treatment of R/R CLL/SLL, Including an ORR of 98%, in an Oral Report at the ASH Annual Meeting

SUZHOU,China,and ROCKVILLE,Md.,Nov. 4,2022 --Ascentage Pharma (6855.HK),a global biopharmaceutical company engaged in developing novel therapies for cancers,chronic hepatitis B (CHB),and age-related diseases,today announced that the initial results from a global Phase II study of the company's Bcl-2-selective inhibitor,lisaftoclax (APG-2575),as a monotherapy or in combination regimens for the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL),have been selected for an oral presentation at the 64th American Society of Hematology (ASH) Annual Meeting. In this presentation,Ascentage Pharma will release the first data of lisaftoclax in combination with acalabrutinib (CALQUENCE® ),a Bruton tyrosine kinase inhibitor (BTKi),or rituximab in patients with R/R CLL/SLL.This year,five studies of Ascentage Pharma's three drug candidates (olverembatinib,lisaftoclax,alrizomadlin),have been selected for presentations,including four oral presentations.

This study of lisaftoclax,to be reported in an oral presentation at the ASH Annual Meeting,showed the promising therapeutic potential of lisaftoclax either as a monotherapy or in combinations in patients with R/R CLL/SLL,demonstrating an interim objective response rate (ORR) of 98% with lisaftoclax plus acalabrutinib and 87% with lisaftoclax plus rituximab. In addition,results from the monotherapy cohort are comparable to prior studies,suggesting favorable safety and promising efficacy of lisaftoclax. The combination therapies,especially lisaftoclax plus acalabrutinib,showed high response rates. In terms of safety profiles,the combination therapies maintained low incidence of tumor lysis syndrome (TLS) and hematologic adverse events.

The ASH Annual Meeting is one of the largest gatherings of the international hematology field,bringing together cutting-edge scientific and clinical research in hematology. The 64th ASH Annual Meeting & Exposition will take place on December 11-14,2022,both online and in-person in New Orleans,LA,the United States.

"Lisaftoclax is the first China-developed Bcl-2 inhibitor entering clinical development in China. It is also the world's second and China's first Bcl-2 inhibitor with clear clinical activity to have entered pivotal studies. Previously,we released multiple encouraging results of lisaftoclax monotherapy in patients with R/R CLL/SLL,drawing widespread interest and recognition from the field," said Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma.

Dr. Zhai continued,"The combined use of Bcl-2 inhibitors and BTKis has been a therapeutic approach of particular interest for the hematology community. This year,our presentation will feature the initial results from the first study evaluating the efficacy and safety of lisaftoclax plus acalabrutinib or rituximab in patients with R/R CLL/SLL. We are very encouraged by these results,as they signal the significant therapeutic potential of the combination regimens."

"Moving forward,we will continue to accelerate the global clinical development of lisaftoclax and the drug's journey to market. We hope our efforts will soon allow patients to benefit from this novel therapeutic."

Drug Candidate

Abstract Title

Abstract#

Format

Olverembatinib

Olverembatinib (HQP1351) Overcomes

Ponatinib Resistance in Patients with Heavily

Pretreated/Refractory Chronic Myeloid

Leukemia (CML) and Philadelphia

Chromosome-Positive Acute Lymphoblastic

Leukemia (Ph+ ALL)

162387

Oral

Presentation

Updated Results of Pivotal Phase 2 Trials of

Olverembatinib (HQP1351) in Patients (Pts)

with Tyrosine Kinase Inhibitor (TKI) -Resistant

Chronic- and Accelerated-Phase Chronic

Myeloid Leukemia (CML-CP and

CML-AP) with T315I Mutation

170698

Oral

Presentation

A Five-Year Follow-up on Safety and Efficacy of

Olverembatinib (HQP1351),a Novel Third-

Generation BCR-ABL Tyrosine Kinase Inhibitor

(TKI),in Patients with TKI-Resistant Chronic

Myeloid Leukemia (CML) in China

170868

Oral

Presentation

APG-2575

Lisaftoclax

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

160386

Oral

Presentation

APG-115

Alrizomadlin

MDM2-p53 Inhibitor Alrizomadlin (APG-115)

Enhances Antitumor Activity of Pomalidomide

in Multiple Myeloma (MM)

162666

Poster

Presentation

These data of lisaftoclax to be reported in an oral presentation at this year's ASH Annual Meeting are as follows (for details of those oral presentations on olverembatinib,please refer to a parallel press release):

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

Format: Oral Presentation

Abstract: 160386

Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Drugs in Development and COVID-19

Time: Monday,December 12,5:15 PM,Eastern Time / Tuesday,December 13,6:15 AM,Beijing Time

Highlights

Lisaftoclax,a specific Bcl-2 inhibitor,is active in patients with R/R CLL/SLL,including patients whose disease harbored del(17p) and had progressive disease (PD) after BTKi therapies. This is the first report of lisaftoclax combined with acalabrutinib or rituximab in patients with CLL/SLL.

Patients with R/R CLL/SLL were treated daily with oral lisaftoclax (400,600,and 800 mg) alone or combined with continuous acalabrutinib or rituximab for six 28-day cycles. Primary objectives were to determine the recommended Phase II dose (RP2D),safety,and efficacy,including ORRs of lisaftoclax alone and combined with acalabrutinib or rituximab. Patients underwent lisaftoclax daily ramp-up over 4 to 6 days,with the monitoring of TLS as follows: Day 1 (D1) 20 mg; D2 50 mg; D3 100 mg; D4 200 mg; and D5 400 mg. Dose ramp-up was followed by Cycle 1 Day 1 (C1D1) of lisaftoclax target doses of 400,or 800 mg. Patients in the combination groups completed ramp-up,as well as an additional 7 days of lead-in of lisaftoclax at the target dose,before acalabrutinib or rituximab was added on C1D8,and then treated until PD or unacceptable toxicity was observed.

As of July 4,141 patients had been enrolled. The median age was 62 (range,18-80) years; 98 (70%) were male; and the Eastern Cooperative Oncology Group (ECOG) score was 0-1 in 125 (89%) and 2 in 15 (11%). The median number of prior therapies was 2 (range,1-15). A total of 17 (12%) patients had progressed on BTKi (n = 15) and/or after venetoclax (n = 3) therapy. In the combination cohorts (n = 95),39 (41%) patients had the TP53 mutation or del(17p),27 (28%) had del(11q),36 (38%) had unmutated IGHV,14 (15%) had mutated IGHV,and 47% were unknown. Median exposure to lisaftoclax was 10.0 (range,0-30) cycles,including 16.5 in the lisaftoclax monotherapy group,9.0 (1-15) in the rituximab,and 7.0 (0-18) in the acalabrutinib combination cohorts. 3 (2%) patients with bulky disease met the criteria for TLS (2 clinical/1 laboratory),and 2 of them fully recovered. No TLS was observed when acalabrutinib or rituximab was added to lisaftoclax on C1D8.

Safety: Common (> 5%) adverse events (AEs) of any grade in all cohorts were: neutropenia (30% [26% grade 3/4]); COVID-19 infection (26%); anemia (24% [12% grade 3/4]),diarrhea (20%); thrombocytopenia (17% [5% grade 3/4]),hyperuricemia or pyrexia (9% each); nausea,headache,or fatigue (8% each); increased aspartate aminotransferase (AST) levels (7%); hyperphosphatemia (6%); and increased creatinine (6%). First onset of grade ≥ 3 cytopenias occurred during ramp-up or C1 and rarely after C2 (n = 3[2%]). Grade ≥ 3 neutropenia was manageable with growth factor support in 13% of patients. No discontinuations were due to lisaftoclax alone or combined with the other agents. No dose-limiting toxicities were observed. No drug-drug interactions were observed in either combination group.

Preliminary efficacy: Rapid normalization of absolute lymphocyte counts occurred in 56% of patients at the end of daily ramp-up. ORRs were 65% (n = 43) in the monotherapy group and 98% (n = 53) and 87% (n = 23) in the acalabrutinib and rituximab cohorts,respectively.

Conclusions: Initiated with a daily dose ramp-up,lisaftoclax alone or combined with acalabrutinib or rituximab had a manageable safety profile and favorable clinical activity in patients with treatment-naïve or R/R CLL/SLL.

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a globally focused biopharmaceutical company engaged in developing novel therapies for cancers,chronic hepatitis B,and age-related diseases. 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.

Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis,or programmed cell death. The company has built a pipeline of nine clinical drug candidates,including 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 tyrosine kinase inhibitors (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 is conducting more than 50 Phase I/II clinical trials in the US,Australia,Europe,and China. Olverembatinib,the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML),was granted Priority Review status and a Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) and is already approved for the indication. In addition,olverembatinib was also granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA,and an Orphan Designation by the EU. To date,Ascentage Pharma has obtained a total of 15 ODDs,2 FTDs,and 2 Rare Pediatric Disease (RPD) designations from the FDA and 1 ODD from the EU for four of the company's investigational drug candidates. Ascentage Pharma has been designated for multiple Major National R&D Projects,including 5 National Major New Drug Discovery and Manufacturing projects,1 New Drug Incubator status,4 Innovative Drug Programs,and 1 Major Project for the Prevention and Treatment of Infectious Diseases.

Leveraging its robust R&D capabilities,Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships with numerous renowned biotechnology and pharmaceutical companies and research institutes such as UNITY Biotechnology,MD Anderson Cancer Center,Mayo Clinic,Dana-Farber Cancer Institute,Merck,AstraZeneca,and Pfizer. The company has built a talented team with global experience in discovering,developing,launching,and commercializing innovative drugs and is setting up world-class 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.

Forward-Looking Statements

The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law,Ascentage Pharma undertakes no obligation to update or revise publicly any forward-looking statements,whether as a result of new information,future events,or otherwise,after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article,statements of,or references to,our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development.

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