APG-1387 / Ascentage Pharma - LARVOL DELTA

Recent Advances and Challenges in the Treatment of Advanced Pancreatic Cancer: An Update on Completed and Ongoing Clinical Trials. (PubMed, Cancers (Basel)) - "This includes adagrasib (a KRAS inhibitor), olaparib (a PARP inhibitor for BRCA mutations), APG-1387 (an IAP antagonist), minnelide (an anti-stromal agent), arimastat (an MMP inhibitor), MK-0646 (an IGF1R inhibitor), sirolimus (an mTOR inhibitor), and metabolic inhibitors. Furthermore, we have summarized novel approaches such as cancer vaccines and ablation techniques as emerging strategies in the treatment of advanced pancreatic cancer. We have also examined the challenges in treating advanced pancreatic cancer and the factors contributing to therapeutic failure, which may offer valuable insights for developing more effective treatment strategies and innovative drug designs."

Journal • Review • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • BRCA • KRAS

APG-1387 Plus Chemotherapy in Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=44 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial primary completion date: Jun 2024 ➔ Dec 2024

Metastases • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Inhibitor of apoptosis proteins (IAP) inhibitor APG-1387 monotherapy or in combination with programmed cell death 1 (PD-1) inhibitor toripalimab in patients with advanced solid tumors: results from two phase I trials. (PubMed, ESMO Open) - "APG-1387 45 mg weekly plus toripalimab was well tolerated and is recommended for further study, with preliminary clinical activity observed in study participants with advanced solid tumors."

Combination therapy • Journal • Metastases • Monotherapy • P1 data • Oncology • Solid Tumor

Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer. (PubMed, Curr Med Chem) - "According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy."

Combination therapy • Journal • Head and Neck Cancer • Oncology • Solid Tumor

Synergistic effects of Smac mimetic APG-1387 with anti-PD-1 antibody are attributed to increased CD3 + NK1.1 + cell recruitment secondary to induction of cytokines from tumor cells. (PubMed, Cancer Cell Int) - P1 | "APG-1387 has the potential to turn "cold tumors" into hot ones by recruiting more CD3 + NK1.1 + cells into certain tumors. Based on these and other data, the safety and therapeutic effect of this combination will be investigated in a phase 1/2 trial in patients with advanced solid tumors or hematologic malignancies (NCT03386526)."

Journal • Tumor cell • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Hepatology • Liver Cancer • Melanoma • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • IL12A

APG-1387 Plus Chemotherapy in Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=44 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Jul 2024 ➔ Dec 2024 | Trial primary completion date: Feb 2024 ➔ Jun 2024

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

APG-1387 Plus Chemotherapy in Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=44 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Dec 2023 ➔ Jul 2024 | Trial primary completion date: Jul 2023 ➔ Feb 2024

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

APG-1387 in Patients With Advanced Solid Tumors or Hematologic Malignancies (clinicaltrials.gov) - P1 | N=90 | Completed | Sponsor: Ascentage Pharma Group Inc. | Recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Hematological Disorders • Hematological Malignancies • Immune Modulation • Oncology • Solid Tumor

FIRST-IN-HUMAN STUDY OF APG-1387, TARGETING INHIBITOR OF APOPTOSIS PROTEINS, FOR THE TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS B (AASLD 2022) - P1 | "APG-1387 at 12 and 30 mg showed significant anti-HBV potency and synergistic effect with sequential NA treatment. These preliminary safety and efficacy data support continued development of APG-1387 in combination with other agents towards a functional cure of chronic HBV infection."

Clinical • IO biomarker • P1 data • CNS Disorders • Hepatitis B • Hepatology • Immune Modulation • Infectious Disease • Inflammation • IFNG • IL10 • IL12A • TNFA

[VIRTUAL] Phase Ib study of a novel bivalent IAP antagonist APG-1387 in combination of pembrolizumab for patients with advanced solid tumors. (ASCO 2020) - P1 | "APG-1387 combined with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in patients with several tumor types. The ongoing study will further evaluate the efficacy of this combination."

Clinical • P1 data • Breast Cancer • Cardiovascular • Fatigue • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immune Modulation • Immunology • Inflammation • Lung Cancer • Mucositis • Non Small Cell Lung Cancer • Oncology • Pain • Pneumonia • Solid Tumor • Thoracic Cancer • HER-2 • IL10 • IL12A • PD-L1

APG-1387 in Patients With Advanced Solid Tumors or Hematologic Malignancies (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Jun 2021 ➔ Dec 2022 | Trial primary completion date: Mar 2021 ➔ Oct 2022

Combination therapy • Trial completion date • Trial primary completion date • Hematological Disorders • Hematological Malignancies • Immune Modulation • Oncology • Solid Tumor

Co-Targeting Intrinsic and Extrinsic Apoptosis to Maximize Cell Death Induction in Venetoclax-Resistant AML Cells (ASH 2021) - "We next treated NSG mice harboring PDX cells derived from an AML patient who relapsed on the VEN/decitabine therapy with APG2575 (50 mg/kg, p.o., daily), APG1387 (10 mg/kg, i.v., once/wk), APG115 (50 mg/kg, p.o., daily at wk 1 and 5), or combinations. Only in the triple combination group, cIAP1, cIAP2, and XIAP as well as MDM2 were largely diminished and p21 was marked decreased. In conclusion, our study demonstrates that co-targeting intrinsic and extrinsic apoptosis maximizes cell death induction in AML cells with acquired resistance to VEN or with TP53 deletion/mutations by antagonizing Bcl-2, eliminating cIAPs and XIAP, as well as MDM2 and p21, a finding that needs to be validated clinically."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BIRC3 • CDKN1A • MDM2 • PTPRC • XIAP

Targeting cIAPs attenuates CCl-induced liver fibrosis by increasing MMP9 expression derived from neutrophils. (PubMed, Life Sci) - "These results suggested that IAPs, especially cIAP2, might play a novel role in the pathogenesis of liver fibrosis, and targeting IAPs represented a promising therapeutic strategy for liver fibrosis by increasing MMP9 expression induced by CCL5 chemotactic neutrophils."

Journal • Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases • BIRC3 • MMP9

Clover and Ascentage Pharma Announce Clinical Collaboration to Evaluate Recombinant Human TRAIL-Trimer Fusion Protein, SCB-313, in Combination with IAP Antagonist, APG-1387 for the Treatment of Peritoneal Carcinomatosis (GlobeNewswire) - "Clover Biopharmaceuticals, Ltd...and Ascentage Pharma....announced that they have entered into a clinical collaboration to evaluate Clover’s SCB-313, a recombinant human TRAIL-Trimer fusion protein and Ascentage Pharma’s APG-1387....Based on positive Phase 1 interim analyses, Clover plans to advance SCB-313 into a Phase 2 clinical trial for malignant ascities in the first half of 2022....Clover also plans to initiate new Phase 1 trials for SCB-313 in new indications, such as bladder cancer, in 2022."

Licensing / partnership • New P1 trial • New P2 trial • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

APG-1387 Study of Safety, Tolerability ,PK/PD in Patients With Chronic Hepatitis B (clinicaltrials.gov) - P1; N=49; Completed; Sponsor: Ascentage Pharma Group Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Phase I study of a novel IAP inhibitor APG-1387 as a monotherapy or in combination with pembrolizumab in treatments of patients with advanced solid tumors. (ASCO 2019) - P1/2; "APG-1387 was well tolerated and had manageable adverse events. The potential effects of APG-1387 alone or in combination with pembrolizumab deserve further exploration in patients with advanced solid tumors, especially in the mPC patients. Clinical trial information: NCT03386526"

Clinical • Combination therapy • Monotherapy • P1 data

APG-1387 Study of Safety, Tolerability ,PK/PD in Patients With Chronic Hepatitis B (clinicaltrials.gov) - P1; N=49; Active, not recruiting; Sponsor: Ascentage Pharma Group Inc.; Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatitis B • Hepatology • Infectious Disease • Inflammation

[VIRTUAL] Therapeutic potential of inhibitor of apoptosis protein (IAP) inhibitor APG-1387 combined with DR5 agonist monoclonal antibody (mAb) CTB-006 in preclinical models of solid tumors (AACR 2021) - "Addition of APG-1387 potentiated this effect, with the combination treatment leading to T/C values of 3% to 15%, and complete regression, PR, or stable disease in all treated tumors. In summary, our results suggest great potential of combination therapy with APG-1387 and CTB-006 for solid tumor therapy and deserves further clinical investigation."

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CASP8

APG-1387 Plus Chemotherapy in Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2; N=44; Recruiting; Sponsor: Ascentage Pharma Group Inc.; Not yet recruiting ➔ Recruiting; Initiation date: Dec 2020 ➔ Mar 2021

Clinical • Enrollment open • Trial initiation date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Ascentage Pharma Releases Preclinical Data of Its Core Drug Candidates at AACR Annual Meeting 2021, with Results Signifying the Potential of Multiple Combination Therapies in Cancer (PRNewswire) - "Ascentage Pharma...today presented the preclinical results of five of the company's novel drug candidates at the American Association for Cancer Research (AACR) Annual Meeting 2021. These studies are from seven preclinical studies in various tumor types and have signified the therapeutic potential of multiple combination therapies in cancer."

Preclinical • Acute Myelogenous Leukemia • Breast Cancer • Gynecologic Cancers • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Ovarian Cancer • Solid Tumor

Ascentage Pharma to Present the Latest Results from Six Preclinical Studies at AACR Annual Meeting 2021 (PRNewswire) - "Ascentage Pharma...announced that the latest preclinical research results of the company's five novel drug candidates have been selected for presentations at the American Association for Cancer Research (AACR) Annual Meeting 2021, and have already been published in the meeting's official website. This year's AACR annual meeting will be held in a virtual format on April 27-28 and June 22-24."

Preclinical • Acute Myelogenous Leukemia • Breast Cancer • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Myelodysplastic Syndrome • Neuroendocrine Tumor • Oncology • Ovarian Cancer • Solid Tumor

APG-1387 Plus Chemotherapy in Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2; N=44; Not yet recruiting; Sponsor: Ascentage Pharma Group Inc.

Clinical • New P1/2 trial • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

A Clinical Study of APG-1387 in Combination With Entecavir in Patients With Chronic Hepatitis B (clinicaltrials.gov) - P2; N=122; Recruiting; Sponsor: Ascentage Pharma Group Inc.; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Hepatitis B • Hepatology • Infectious Disease

A Clinical Study of APG-1387 in Combination With Entecavir in Patients With Chronic Hepatitis B (clinicaltrials.gov) - P2; N=122; Not yet recruiting; Sponsor: Ascentage Pharma Group Inc.

Clinical • Combination therapy • New P2 trial • Hepatitis B • Hepatology • Infectious Disease

[VIRTUAL] Targeting inhibitor of apoptosis proteins (IAPs) enhances intrahepatic antiviral immunity to clear hepatitis B virus infection in vivo (EASL-ILC-I 2020) - "However, pan-caspase inhibitor Emricasan or Z-VAD-FMK treatment could not block the antiviral effect of APG-1387. These findings indicated that APG-1387 was able to clear chronic HBV infection in various mouse models with a unique induction of apoptosis and immunoregulation mechanism. Application of IAP antagonist might represent a novel immunotherapeutic strategy for HBV functional cure."

IO Biomarker • Preclinical • Hepatitis B • Hepatology • Infectious Disease • Oncology • CASP3 • CD8 • TNFA