Abstract # 750
A Phase
P
Phase I/II Study of BHQ880, an Anti-
Anti DKK1
Antibody, in Patients With Relapsed or
Refractory Multiple Myeloma Treated With
At
An
A i
ti--mye
myelT
loma h
lT
Therapy
Th
d
an Z l
o edron
d
ic Ac
A id
id
Swaminathan Padmanabhan, Joseph Thaddeus Beck,
Kevin R. Kelly, Nikhil C. Munshi, Andy Dzik-Jurasz,
Esha Gangolli, Seth Ettenberg, Kelly Miner, Sanela Bilic,
Winston Whyte, Fazal Mehdi, Lu-May Chiang, Patricia Liz Rae,
A d
n rew Spencer, J ti
a n Shah, Kenneth C. A d
n erson,
Francis J. Giles, and A. Keith Stewart
Modulation of
o
of Bone
B
Bone Metabolism
M-CSF
M-CSF
Bone
Adapted by permission from Macmillan Publishers Ltd: Nature Med. 2007;13(2):133-4, Copyright (2007)
Bone Disease in Myeloma
3 | Presentation Title | Presenter Name | Date | Subject | Business Use Only
Adapted from Edwards CM, et al. Blood. 2008;112:216-217
Multiple Myeloma is Characterized by
Abnormally High Levels of
o
of DKK1
Of
Overexpression of DKK1 mRNA in a subset f
o multiple myeloma
patients with osteolytic lesions
Patients with lytic bone disease show higher DKK1 levels than patients
itho
w
t
u lytic lesions
lesions
Serum DKK1 levels correlate with number of bone lesions
Tian E, et al. N Engl J Med. 2003;349:24832494. Copyright © 2003 Massachusetts Medical Society. All rights reserved
Rationale for Targeting DKK1 in Multiple Myeloma:
Increasing Wnt Signaling
Signaling in
iin the
tthe Bone Microenvironment
Dkk-1
Dkk-1
Wnt
Frz
Dsh
Degradation
-
GSK3
Therapeutic hypothesis:
Neutralization of DKK1 activity will
+
attenuate cancer-induced bone loss
-
-
Degradation
catenin
Catenin-P
g
catenin
Catenin-P
Antibodies to DKK1 were generated
by phage display resulting in the
clinical candidate BHQ880
TCF
Target genes
Proliferation
Differentiation
BHQ880 Properties: Anti-
Anti DKK1 Antibody
BHQ880 is a fully human, neutralizing anti-DKK1
monoclonal
tib
an
ody
ith
w
the f l
o lll
i
ow ng properties:
· Binds to and blocks DKK1 binding to LRP5 and LRP6 with
hi h
g
ffi
a
it
n y
· Potently neutralizes DKK1 inhibition of canonical Wnt
signaling
· Has bone anabolic activity in vivo
· Demonstrates potent inhibition of tumor-induced osteolytic
lesions in several preclinical models
Phase I Study Design: Dose Finding With
BHQ880 in Patients With Multiple
M
Multiple Myeloma
M
Myeloma
Patients with relapsed or refractory multiple myeloma
· Pi
Prior sk l
e t
e l
a
ltd
-related
t
even requi d
re
BHQ880 administered monthly
®
· Zoledronic acid (Zometa ) administered in addition to BHQ880
Multiple myeloma therapy per investigator
· Therapy may be modified while receiving BHQ880
· Bortezomib (VELCADE®) excluded
Dose escalation following a Bayesian model
· 4 dose levels evaluated: 3, 10, 20, and 40 mg/kg
Phase I Study:
S
Study: Key
K
Key Objectives
Determine safety and tolerability of BHQ880 in patients
with multiple
multiple myeloma
myeloma
Assess DKK1 levels at baseline and following BHQ880
· BHQ880-bound DKK1 levels
Establish BHQ880 pharmacokinetics
Evaluate bone biomarkers
Assess effects on
on bone
· DXA scans
· Skeletal-related events
Phase I Study:
S
Study: Clinical
C
Clinical Summary
Patient demographics
Study status
· Age range:
range: 4174 y o
. .
· 11 patients have completed
completed cycle 1 for
for
· ECOG status 02
safety analysis
· Patient disease status:
· Up to 8 cycles completed
- 7 relapsed and refractory
· 9t
9 pa i
tients ongoing
- 4 refractory
· Data from 8 patients available for PK
and PD analysis
- 4t
4 pa i
ti
t
en s t
a 10
10
/
mg k
/kg
- 4 patients at 20 mg/kg
Safety summary
yy
· No treatment-related adverse effects associated with BHQ880
· BHQ880 is well tolerated over multiple cycles of administration
Pharmacokinetics of BHQ880:
Mean BHQ880 Concentration Profiles
P
Profiles
Mean BHQ880 Conc (ng/mL) - 10 mg/kg
800
Mean BHQ880 Conc (n
Q( g/mL
g
) - 20 mg/k
g g
*
*Sample collected
600
(ng/mL)
from infusion arm
400
ncentrationo
C
200
BHQ880
0
Cycle 1
Cycle 2
Mean
0
200
400
600
800
1000
1200
1400
1600
Infusion
Time (hr)
Preliminary Analysis of BHQ880 Pharmacokinetics:
Key Points
P
Points
BHQ880 exhibits pharmacokinetics consistent with a
human IgG1 antibody in humans
C
is reached between 5 minutes
minutes and 2 hours after
after
max
the infusion
Mean calc lated
u
T ranges from 19 to 25 da s
y across
across
½
dose levels tested to date (multiple dosing)
Ol
Overa lll exposure is
h
roug l
hly dose
t
propor i
ti
l
ona
BHQ880: Overview of Clinical Biomarkers
BHQ880
Target Engagement
DKK1
Plasma cell
· Increase in total DKK1
MSC
Wnt
Osteoclast
Early Detection of Response
· Bone: Bone formation and
resorption markers
Pre-
Bone resorption
osteoblast
ff
E ect on Tissue
· Imaging: Change in bone
Mature
Bone formation
mineral density (DXA) and
osteoblast
bone quality (qCT)
MSC: Mesenchymal stem cells.
Bone Biomarker Panel
Bone formation
Bone homeostasis
· PINP
· Osteoprotegerin
· Osteocalcin
· Parathyroid hormone
· Bone-specific alkaline
· Calcitonin
phosphatase
· 25-OH Vitamin D
Bone resorption
· IL-6
· Trap5b
· TGF
· Trap5b
· CTx
· NTx
· ICTP
PINP: N-terminal propeptide of type-I procollagen .
PD and Bone Biomarker Data
10 mg cohort
Prior Z
No prior Z
Prior Z
Prior Z
Prior Rx
Dex
M+Pred+Thal
Rev Dex
Rev Dex
[Dkk1]
DKK1
Log2
from
PINP
ange
aseline
Z=Zoledronic acid
PINP
a
h
B
C
M=Melphalan
%
m
fro
OC
Baseline
Change%
PD and Bone Biomarker Data
20 mg cohort
Prior P
Prior Z
Prior P
No prior Z
Prior Rx
Rev Pred
Rev
Dex
Rev Pred
[Dkk1]
DKK1
Log2
efrom
PINP
g
line
Z=Zoledronic acid
PINP
g
an
P=Pamidronate
h
Base
C%
OC
from
aseline
hange
B
C%
DXA Findings: Analysis and Interpretation of
Bone Mineral Density
Changes in bone mineral density measured by DXA
· Lumbar spine Range: + 6.10 % to - 1.95 % (n = 4)
· Femur Range: + 5.80 % to - 0.20 % (n = 5)
Small sample size limits statistical interpretation
Effects on bone mi
l
nera density
ill
w
i
requ re longer times f
o
assessment and a larger sample size
Summary
BHQ880 is safe and well tolerated in patients with
multiple myeloma
BHQ880 exposure is dose proportional
DKK1 binding to BHQ880 occurs rapidly and is
sustained through multiple cycles of treatment
Bone anabolic markers, osteocalcin and PINP, are
elevated following BHQ880 treatment
Acknowledgements
The Institute for Drug Development, CTRC at the University of Texas
Health Science Center at San Antonio, San Antonio, TX
Highland Oncology Group, P.A., Fayetteville, AR
Dana-Farber Cancer Institute, Boston, MA
The Alfred Hospital, Melbourne, Australia
University of Texas M.D. Anderson Cancer Center, Houston, TX
Mayo Clinic, Scottsdale, AZ
Novartis Pharmaceuticals Corporation, East Hanover, NJ
Nt
Novar i
tis Instit
tit t
u es for Bid
Biome i
dical Research Inc, C
b
am i
r d
idge, MA
MA
Douglas Robinson PhD
Lilli Petruzzelli MD, PhD