(ASCO2020) Ascentage Pharma Presents Latest Clinical Data of Apoptosis Targeting Drug Candidates, Showing Promising Clinical Effects with Combination Therapies

SUZHOU, China and ROCKVILLE, Md., May 31, 2020 /PRNewswire/ -- Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, today announced that the company presented four posters of the latest clinical data on three of its drug candidates, including the MDM2-p53 inhibitor APG-115, novel Bcl-2/Bcl-xL dual inhibitor palcitoclax or APG-1252, and IAP inhibitor APG-1387, at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting (ASCO20).

As a globally focused biotech company, Ascentage Pharma showcased the research advances of its drug candidates at ASCO for the third consecutive year and attracted global attention.

"In this Phase Ib study, the novel IAP antagonist APG-1387 was combined safely with pembrolizumab with a manageable adverse event profile. This represents an important milestone in the continued development of APG-1387," said Drew W. Rasco, MD, Associate Director of Clinical Research at the START Center for Cancer Care in San Antonio. "Furthermore, we observed some encouraging signs of clinical activity, which warrants further evaluation in specific patient populations, including microsatellite-stable colorectal cancer [CRC] and non-small-cell lung cancer [NSCLC]."

"Palcitoclax [APG-1252] is a novel and potent inhibitor of the Bcl-2 family of proteins and induces apoptosis in tumor cells. In the first-in-human Phase I trial in the U.S., palcitoclax has demonstrated safety and tolerability as well as preliminary evidence of efficacy in patients with solid tumors," said Nehal Lakhani, MD, PhD, START Center for Cancer Care（START Midwest）. "It also demonstrates predictable pharmacokinetics ideal for a new molecular entity. Given the promising evidence of safety and efficacy in the Phase I trial, further evaluation of efficacy in select solid tumors is warranted."

"Advanced liposarcoma is a common histological type of malignant soft-tissue sarcoma with poor prognosis and high recurrence rate, and there is lack of effective treatment options currently. APG-115 is a highly potent MDM2-p53 inhibitor, and our data on liposarcoma presented in last year's ASCO report were promising," said Prof. Xing Zhang, Chief Physician of Melanoma and Sarcoma Medical Oncology Unit of Sun Yat-sen University Cancer Center. "In the updated data, a safety expansion at the 100-mg dose level was performed, and the recommended phase II dose [RP2D] was determined as 100 mg. These results support our previous findings that wild-type TP53 is a predictive biomarker of response to APG-115, and liposarcoma may be one of its potential target tumor types. We also look forward to more clinical studies and molecular biological evidence of APG-115."

"Through the showcase at ASCO, Ascentage Pharma is demonstrating its capabilities of global clinical development in apoptosis. The initial data with our drug candidates, including MDM2-p53 inhibitor APG-115, novel Bcl-2/Bcl-xL dual inhibitor palcitoclax or APG-1252, and IAP inhibitor APG-1387, support further study with great potential in combination therapies," said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma. "We will accelerate our clinical development programs, hoping to offer more treatment options for cancer patients with unmet medical needs."

Phase Ib study of a novel, small-molecule MDM2 inhibitor
APG-115 combined with pembrolizumab in U.S. patients with metastatic solid tumors
Abstract：#3512

• APG-115-US-002 is an open-label, multi-center, Phase Ib/II study in U.S. , which was designed to assess safety, toxicity, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of APG-115 in combination with pembrolizumab in patients with advanced solid tumors. The Phase Ib dose-escalation study has been completed, and the Phase II is ongoing. The poster only reports the Phase Ib results.
• As of April 1, 2020, in the Phase Ib study, 19 patients were treated with
  APG-115 in 4 alternate-day (QOD) dose cohorts (50 mg, 100 mg, 150 mg, and 200 mg) in combination with pembrolizumab. No dose-limiting toxicities (DLTs) were observed. The maximum tolerated dose (MTD) was not reached, and the recommended Phase II dose (RP2D) of APG-115 combined with pembrolizumab was determined as 150 mg QOD according to safety data.
• APG-115 in combination with pembrolizumab was generally tolerated. The most common treatment related adverse events (TRAEs) (>10%) included: nausea, fatigue, platelet count decreased, appetite decreased, vomiting, neutrophil count decreased, diarrhea, hypothyroidism, etc.
• Antitumor effects were observed among 18 efficacy evaluable patients, including one patient with a confirmed complete response (CR) lasting for 20 months (still ongoing). Two patients had confirmed partial response (PR) for 8 to 9 months: of these, one patient with NSCLC failed 3 months, nivolumab therapy and the other had immunotherapy-naïve appendix cancer; seven patients had stable disease (SD) for 1.5 to 7 months. The objective response rate (ORR) was 16.7%, and the disease control rate (DCR) was 55.5%. Details of the patient with CR follows:
• White female, age 55 years, diagnosed with stage IIIc serous-cell ovarian carcinoma in 2014, which recurred (as stage IV) within 6 months after surgery and platinum-containing adjuvant chemotherapy and then progressed on doxorubicin, topotecan + bevacizumab, and XMT1536 (ADC targeting NaPi2b) multiple lines of antitumor therapy, but still progressed. However, the patient had a PR after receiving APG-115 and pembrolizumab for 4 cycles, CR after 8 cycles, then maintain CR, now in 25th cycle of treatment. This patient has a family history of malignancy, with blood genetic tests showing wild-type TP53, ATM germline mutation.
• PK analyses showed that AUC and Cmax generally increased dose proportionally over the dose range of 50 to 200 mg. Combining APG-115 with pembrolizumab did not appear to affect the PK of APG-115. PD analyses showed an increase in serum MIC-1 (biomarker of TP53 activation) that was dose dependent within the APG-115 dose ranges (50-200 mg).

Conclusion: Safety and efficacy data from this Phase Ib study demonstrated that APG-115 in combination with pembrolizumab is promising. The Phase II study is ongoing in the cancer patients with specific biomarker profiling.

Phase Ib study of a novel bivalent IAP antagonist APG-1387 in combination of pembrolizumab for patients with advanced solid tumors
Abstract：#3508

• APG-1387-US-001 is an open-label, two-part, Phase I (APG-1387 monotherapy) and Phase Ib (APG-1387 in combination with pembrolizumab) study in U.S. Previous Phase I study showed that the MTD of APG-1387 single agent was 45 mg IV once weekly, and DLTs included elevated lipase and facial nerve disorder. This poster reports only Phase Ib results, including the safety, tolerability and preliminary efficacy of APG-1387 + pembrolizumab in patients with advanced solid tumors.
• Through April 1, 2020, 41 patients with various advanced solid tumors had been treated with APG-1387 in combination with pembrolizumab, including 10 patients in dose escalation: 20 mg (n=4), 30 mg (n=3), and 45 mg (n=3); and 31 patients in MTD dose expansion. No DLT was observed during dose escalation, and the MTD of APG-1387 was determined as 45 mg.
• APG-1387 was generally well tolerated with manageable adverse events when used in combination with pembrolizumab. Most common TRAEs (≥10%) included fatigue, headache, nausea, and maculopapular rash. Facial nerve disorder was seen in 2 patients (4.9%), which was not higher than in the single-agent study.
• Antitumor effects: among 37 efficacy evaluable patients, 4 patients had PR (2 NSCLC, 1 CRC, and 1 breast cancer) and 12 patients had SD; the overall ORR was 10.8%, and the DCR was 43.2%. The NSCLC cohort achieved 50% ORR and 100% DCR. The CRC cohort achieved 50% DCR with 1 PR and 3 durable SD.
• Preliminary PK data of APG-1387 showed dose proportionality in exposure (Cmax and AUC) over the dose range of 20 to 45 mg.
• APG-1387 treatment induced rapid and significant cIAP-1/XIAP suppression, suggesting a potential PD effect.

Conclusion：The efficacy and safety data demonstrated that APG-1387 in combination with pembrolizumab is a promising approach and deserves further study in patients with advanced NSCLC and CRC.

First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors
Abstract：#3509

• The study of palcitoclax (APG-1252) is a Phase I trial to characterize the safety, tolerability, PK, PD and preliminary anti-tumor effects of palcitoclax, and to determine the MTD/RP2D as well. Palcitoclax is intravenously administered twice per week (BIW) or once per week (QW) to patients with small-cell lung cancer (SCLC) and other solid tumors in a 28-day cycle, the standard "3+3" design was applied to dose-escalation stage. More patients will be included in the MTD expansion cohort after MTD/RP2D is determined.
• As of December 21, 2019, 42 patients (31 on BIW and 11 on QW) with metastatic solid tumors had received APG-1252 treatment ranging from 10 to 400 mg in a 28-day cycle.
• Four DLTs (Grade 4 thrombocytopenia) were judged by investigators at 400 mg and 320 mg. APG-1252 was well tolerated up to 240mg. MTD/RP2D was determined as 240mg QW.
• Most adverse events (AEs) were G1 or G2, and 26.2% patients had ≥ G3 TRAEs. The most common TRAEs were platelet count decreased (14.3%), aspartate aminotransferase increased (9.5%), and alanine aminotransferase increased (7.1%).
• Of 36 efficacy-evaluable patients, 3 patients with PR had relapsed SCLC, poorly differentiated neuroendocrine tumor of the prostate, or high-grade serous ovarian cancer. The patient with SCLC had PR that lasted for >18 cycles (dose level: 40 mg BIW). A total of 7 patients achieved SD, including 2 patients with SD lasting ≥ 6 cycles and 3 lasting ≥4 cycles. Another 26 patients had progressive disease at their first tumor assessment. The overall DCR was 27.8%.
• APG-1252 displayed linear PK, which were approximately dose proportional over the dose range of 10 to 400 mg.

Conclusion: A sustainable antitumor effect was observed in this first-in-human study, which supports further development of palcitoclax (APG-1252) in combination with other therapies for solid tumors and hematological malignancies.

Phase I study results of APG-115, a MDM2-p53 antagonist, in Chinese patients with advanced liposarcoma and other solid tumors
Abstract：#11542

• As of January 9, 2020, 21 eligible patients with advanced solid tumors were treated with APG-115 at 3 dose levels: 100 mg, 150 mg, and 200 mg. Liposarcoma comprised two-thirds of all tumors. Most of the 21 patients had completed ≥ 2 cycles of APG-115 treatment, and 1 patient had completed 6 cycles.
• Efficacy assessment was performed in 19 patients (4 patients were still on treatment), including 13 with liposarcoma. Among these patients, 1 had a PR, and 12 had SD. The ORR was 5.3%, and the DCR was 68.4%. In patients with LPS and wild-type TP53 (n=9), the ORR was higher, reaching 11.1%, with a DCR of 77.8%.
• Common treatment-emergent adverse events (TEAEs) included anemia and decreases in leukocyte and platelet counts. However, most AEs were G1 or G2, and the incidence of TEAEs was much lower at the 100-mg dose level.
• This study found that, using a 21 day-on/7 day-off dosing schedule, APG-115 was generally safe and well tolerated especially at the 100-mg dose level. The RP2D was determined as 100 mg QOD.

Conclusion:

• Evidence of single-agent clinical efficacy of APG-115 was observed in patients with LPS, as well as in patients with expression of wild-type TP53. Updated results of this study continue to support our previous interpretation that wild-type TP53 is a predictive biomarker of response to APG-115 in patients with LPS and other cancers.
• The over 10 months' duration of response observed in a patient with PR after treatment discontinuation suggests host immunomodulatory effects of APG-115 and also provides impetus for further evaluation of APG-115 as monotherapy or in combination with immunotherapy.

About APG-115
APG-115 is an orally administered, selective, small-molecule inhibitor of the MDM2-p53 protein-protein interaction (PPI). APG-115 has strong binding affinity to MDM2 and is designed to activate p53 tumor suppression activity by blocking the MDM2-p53 PPI. Ascentage Pharma has previously commenced three clinical trials of APG-115 in the U.S., including a Phase I study as single agent, a Phase Ib/II study in combination with pembrolizumab for treatment of metastatic melanoma or advanced solid tumors, and a Phase I/II study as single agent or in combination with chemotherapy for treatment of salivary gland cancer. APG-115 is the first MDM2-p53 inhibitor to enter clinical studies in China. A Phase I study as single agent and a Phase Ib study as single agent or in combination with chemotherapy for treatment of AML (acute myelogenous leukemia) or MDS (myelodysplastic syndromes) are ongoing in China.

About APG-1387
APG-1387 is a novel small molecule inhibitor of apoptosis protein (IAP) antagonist that was discovered and is being developed by Ascentage Pharma. Ascentage is developing APG-1387 globally and has completed dose-escalation Phase I trials in solid tumors in China and Australia, and a Phase Ib/II clinical trial of APG-1387 and pembrolizumab combination is currently ongoing in the U.S. In addition, APG-1387 is being investigated in a Phase Ib trial for treatment of patients with CHB in China. In February 2020, APG-1387 was approved for a Phase Ib/II clinical trial in combination with chemotherapy for treatment of advanced pancreatic cancer.

About Palcitoclax or APG-1252
APG-1252 is a novel, highly potent, small-molecule drug that was discovered and is being developed by Ascentage Pharma. APG-1252 is designed to treat SCLC, NSCLC, lymphoma, and other solid tumors by selectively blocking Bcl-2 and Bcl-xL to restore the apoptosis process. Two Phase I dose-escalation trials in patients with advanced cancers are currently ongoing in the U.S. and Australia, and a Phase I dose-escalation/expansion trial as monotherapy in patients with SCLC is ongoing in China.

About Ascentage Pharma
Ascentage Pharma (6855.HK) is a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, CHB, and age-related diseases. The Company focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited.

Ascentage Pharma has built a pipeline of eight 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. The Company is conducting more than 30 Phase I/II clinical trials to evaluate the eight drug candidates in the U.S., Australia, and China.

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