Transcript ASCO_2010_files/Borgstein ACE

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
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+
+
+
+
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
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+
+
+
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
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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