1. Phase 1 Study of ACE-041, a First-in-Class Inhibitor of Vascular Development in Patients with Advanced Solid and Hematologic Tumors N. G. Borgstein 1, S. Sharma 2, J. C. Bendell 3, M. S. Gordon 4, H. Hurwitz 5, N. Solban 1, D. Mitchell 1, A. Mulivor 1, S. Pearsall 1, C. H. Condon 1, J. Seehra 1, M. L. Sherman 1 1 Acceleron Pharma, Cambridge, MA; 2 Huntsman Cancer Institute,Salt Lake City, UT; 3 Sarah Cannon Research Institute, Nashville, TN; 4 Premiere Oncology of Arizona, Scottsdale, AZ; 5 Duke University Medical Center, Durham, NC ALK1 a Novel Target for Angiogenesis Inhibition SMAD1/5/8 SRE ALK1 Type I Type II P SMAD4 BMP9 BMP10 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. The Role of ALK1 Signaling in Angiogenesis ACE-041 is a First-in-Class Angiogenesis Inhibitor Basement Membrane Plug Assay ALK1 Regulates Development of Functional Vasculature  The TGF-β superfamily of proteins regulates growth, differentiation, and development of tissue systems, including vasculature  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 receptor is expressed exclusively on arterial endothelium, and only during active angiogenesis. −In contrast, VEGF receptors are constitutively expressed on numerous tissues  ALK1 signaling is required to complete development of functional vasculature, during normal and pathologic angiogenesis −Expression of ALK1 is activated during embryogenesis, wound healing and tumor angiogenesis Phase 1 Study of ACE-041 in Advanced Cancer ACE-041 Inhibits Multiple Pro-Angiogenic Growth Factors ACE-041 Inhibits Tumor Growth by Inhibiting Angiogenesis ACE-041 Prevents Signaling Through ALK1 Receptor  ALK1 signaling is essential to guide development of endothelial cells into a functional vessel system −Regulates proliferation, migration, differentiation, maturation, tube formation, and several other functions of endothelial cells  Complete or partial loss-of-function mutation of ALK1 impairs angiogenesis and results in structural abnormalities, which form during development of new vasculature −Homozygous deletion of ALK1 is embryonic lethal due to severe vascular malformations −Hemizygous deletion of ALK1 results in a similar but milder phenotype In adult humans, Hereditary Hemorrhagic Telangiectasia (HHT2) patients develop sporadic arteriovenous malformations, recurrent epistaxis, and telangiectasias, which manifest later in life 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  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 ACE-041 is a Fully Human ALK1-Fc Fusion Protein  ACE-041 is a first-in-class angiogenesis inhibitor that works by inhibiting ALK1 signaling  ACE-041 is a fully-human, recombinant fusion protein produced by joining the extracellular domain of the human ALK1 to the Fc portion of a human antibody  This creates a ligand “trap”, which intercepts BMP9 and BMP10 before these proteins can activate ALK1 signaling  ACE-041 binds with high affinity to BMP9 and BMP10, but does not bind to VEGF, FGF, or TGF-β Chick Chorioallantoic Membrane (CAM) Assay Study Status - currently ongoing 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 Study Overview Pharmacodynamic Measures  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 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 −Breast cancer −Pancreatic islet cell cancer −Lung cancer (not shown) −Multiple myeloma (not shown)  ACE-041 represents a unique approach to therapeutic angiogenesis, and has potential as a novel treatment for cancer MCF-7 Orthotopic Breast Cancer Model RIP1-Tag2 Pancreatic Islet Cell Tumor Model CONTROLRAP-041 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 Conclusions  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 CONTROLRAP-041 CD31 ALK1 IgG1 Antibody Extracellular Domain of ALK1 Fc Domain of IgG1 Antibody ACE-041 ALK1-Fc fusion protein + + + + + + + + still on treatment + +