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Extracellular Domain of ALK1. ALK1. IgG1 Antibody. BMP9. BMP10. Type II. ALK1 Type I. Fc Domain of IgG1 Antibody. P. SMAD1/5/8. SMAD4. ACE-041 ALK1-Fc fusion protein. SRE. CD31. CONTROL. RAP-041.

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Extracellular Domain of ALK1






Type II


Type I

Fc Domain of IgG1 Antibody






fusion protein





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

Phase 1 Study of ACE-041 in Advanced Cancer

The Role of ALK1 Signaling in Angiogenesis

ACE-041 is a First-in-Class Angiogenesis Inhibitor

Study Overview

ALK1 a Novel Target for Angiogenesis Inhibition

ACE-041 Prevents Signaling Through ALK1 Receptor

  • 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

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

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

Pharmacodynamic Measures

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.

  • 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

ACE-041 Inhibits Multiple Pro-Angiogenic Growth Factors

Basement Membrane Plug Assay

Chick Chorioallantoic Membrane (CAM) Assay

ALK1 Regulates Development of Functional Vasculature

Study Status - currently ongoing

  • 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 Inhibits Tumor Growth by Inhibiting Angiogenesis



MCF-7 Orthotopic Breast Cancer Model


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



RIP1-Tag2 Pancreatic Islet Cell Tumor Model

+ still on treatment


  • 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


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