0 1 2 3 4 5 6 7 8

PancreaticOvarianNSCLC

Colon/Rectal Head and Neck

CarcinoidCervix

NSCLCHead and Neck

PancreaticHead and Neck

EsophagealAngiosarcoma

NSCLCAngiosarcoma

Unknown primaryMet synovial sarcomaHemangiopericytoma

Osteosarcoma

0.1

mg/k

g

0.2

mg/k

g

0.4

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0.8

mg/k

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1.6

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g3.2

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Cycles

Phase 1 Study of ACE-041, a First-in-Class Inhibitor of Vascular Development in Patients with Advanced Solid and Hematologic TumorsN. 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

ALK1 a Novel Target for Angiogenesis Inhibition

SMAD1/5/8

SRE

ALK1Type I

Type II

P

SMAD4

BMP9 BMP10

Activin Receptor-Like Kinase (ALK1) Involves a Unique Signaling Pathway for AngiogenesisALK1 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

CONTROL RAP-041References: Cunha et al. (2010) J Exp Med. 207:85-100Mitchell et al. (2010) MCT 9:379-88Park et al. (2009) JCI 119:3487

Oh et al. (2000) PNAS 97:2626-31Seki et al. (2003) Circ Res 93:683-89Suzuki 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

CONTROL RAP-041

CD31

ALK1

IgG1Antibody

Extracellular Domain of ALK1

Fc Domain of IgG1 Antibody

ACE-041ALK1-Fc

fusion protein

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