Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Phase 1 Study of ACE-041, a First-in-Class Inhibitor of Vascular Development in Patients with Advanced Solid and Hematologic Tumors N. G. Borgstein1, S. Sharma2, J. C. Bendell3, M. S. Gordon4, H. Hurwitz5, N. Solban1, D. Mitchell1, A. Mulivor1, S. Pearsall1, C. H. Condon1, J. Seehra1 , M. L. Sherman1 1Acceleron Pharma, Cambridge, MA; 2Huntsman Cancer Institute ,Salt Lake City, UT; 3Sarah Cannon Research Institute, Nashville, TN; 4Premiere Oncology of Arizona, Scottsdale, AZ; 5Duke University Medical Center, Durham, NC The Role of ALK1 Signaling in Angiogenesis ACE-041 is a First-in-Class Angiogenesis Inhibitor ALK1 a Novel Target for Angiogenesis Inhibition BMP9 BMP10 ALK1 Type I ACE-041 is a first-in-class angiogenesis inhibitor that works by inhibiting ALK1 signaling Type II P ACE-041 is a fully-human, recombinant fusion protein produced by ACE-041 joining the extracellular domain of the human ALK1 to the Fc ALK1-Fc fusion protein portion of a human antibody SMAD1/5/8 ALK1 receptor is expressed exclusively on arterial endothelium, and only during active angiogenesis. SMAD4 − In contrast, VEGF receptors are constitutively expressed on numerous tissues − Expression of ALK1 is activated during embryogenesis, wound healing and tumor angiogenesis ACE-041 is a Fully Human ALK1-Fc Fusion Protein ALK1 Activin Receptor-Like Kinase 1 (ALK1) is a Type 1 receptor that binds to BMP9 and BMP10, which are members of the TGF-β protein superfamily ALK1 signaling is required to complete development of functional vasculature, during normal and pathologic angiogenesis ACE-041 Prevents Signaling Through ALK1 Receptor Extracellular Domain of ALK1 The TGF-β superfamily of proteins regulates growth, differentiation, and development of tissue systems, including vasculature SRE Activin Receptor-Like Kinase (ALK1) Involves a Unique Signaling Pathway for Angiogenesis ALK1 is a Type 1 receptor that binds with high affinity to BMP9 and BMP10, proteins in the TGF-β protein superfamily. Signals transduced through R-Smads, including Smad1, Smad5, Smad8. Phase 1 Study of ACE-041 in Advanced Cancer This creates a ligand “trap”, which intercepts BMP9 and BMP10 before these proteins can activate ALK1 signaling IgG1 Antibody ACE-041 binds with high affinity to BMP9 and BMP10, but does not bind to VEGF, FGF, or TGF-β Study Overview Study Objectives Evaluate the safety, tolerability, and pharmacokinetics of ACE-041 Identify a maximum tolerated dose (MTD) of ACE-041 to advance into phase 2 studies Assess for pharmacodynamic and anti-tumor activity of ACE-041 Study Design Open-label, multiple-dose, 3+3 dose-escalation study in patients with advanced cancer ACE-041 administered q3w SC for 4 injections; patients with SD or better allowed to continue therapy Patients with advanced solid tumors or relapsed / refractory multiple myeloma Pharmacodynamic Measures Fc Domain of IgG1 Antibody ACE-041 Inhibits Multiple Pro-Angiogenic Growth Factors Basement Membrane Plug Assay Chick Chorioallantoic Membrane (CAM) Assay RECIST 1.1 imaging criteria to assess tumor response DCE-MRI scans to assess changes in blood flow and vascular permeability PET-CT scans to assess metabolic activity Panel of exploratory, serum biomarkers of angiogenesis and TGF-β protein superfamily ALK1 Regulates Development of Functional Vasculature Study Status - currently ongoing − Regulates proliferation, migration, differentiation, maturation, tube formation, and several other functions of endothelial cells 0.8 mg/kg • In adult humans, Hereditary Hemorrhagic Telangiectasia (HHT2) patients develop sporadic arteriovenous malformations, recurrent epistaxis, and telangiectasias, which manifest later in life MCF-7 Orthotopic Breast Cancer Model CD31 ALK1 is a Novel Therapeutic Target for Cancer ACE-041 is a potent inhibitor of tumor angiogenesis Treatment with ACE-041 inhibits tumor growth and progression in numerous animal models of cancer CONTROL • In animal studies, crossing HHT2 mice with RIP1-Tag2 mice (an animal model of pancreatic islet cell tumors) suppresses tumor growth and progression by inhibiting angiogenesis RAP-041 − Breast cancer − Pancreatic islet cell cancer − Lung cancer (not shown) RIP1-Tag2 Pancreatic Islet Cell Tumor Model 0.4 mg/kg − Hemizygous deletion of ALK1 results in a similar but milder phenotype 0.2 mg/kg − Homozygous deletion of ALK1 is embryonic lethal due to severe vascular malformations ACE-041 Inhibits Tumor Growth by Inhibiting Angiogenesis 0.1 mg/kg Complete or partial loss-of-function mutation of ALK1 impairs angiogenesis and results in structural abnormalities, which form during development of new vasculature 1.6 mg/kg 3.2 mg/kg ALK1 signaling is essential to guide development of endothelial cells into a functional vessel system ACE-041 represents a unique approach to therapeutic angiogenesis, and has potential as a novel treatment for cancer + still on treatment Conclusions References: Cunha et al. (2010) J Exp Med. 207:85-100 Mitchell et al. (2010) MCT 9:379-88 Park et al. (2009) JCI 119:3487 Oh et al. (2000) PNAS 97:2626-31 Seki et al. (2003) Circ Res 93:683-89 Suzuki et al. (2010) J Cell Sci. 123:1684-1692 CONTROL RAP-041 + + + + + 0 − Multiple myeloma (not shown) Characteristic structural abnormalities are arteriovenous shunts, abnormal looping, and the absence of intervening capillary beds, which produce new vasculature that is incapable of oxygen delivery + + + + Osteosarcoma Hemangiopericytoma Met synovial sarcoma Unknown primary Angiosarcoma NSCLC Angiosarcoma Esophageal Head and Neck Pancreatic Head and Neck NSCLC Cervix Carcinoid Head and Neck Colon/Rectal NSCLC Ovarian Pancreatic 1 2 3 4 5 6 7 8 Cycles ACE-041 is a novel inhibitor of vascular maturation targeting ALK1 Preclinical evidence of antitumor activity observed with ACE-041 in numerous animal tumor models