bilezikian, john - cdn.ymaws.com · amgen (consultant, advisory board) shire pharmaceuticals...
TRANSCRIPT
8/24/2017
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John P. Bilezikian, MD, PhD (hon) Silberberg Professor of Medicine
Vice-Chair, International Education and ResearchDepartment of Medicine
College of Physicians and Surgeons Columbia University New York, NY USA
The Therapeutics of Osteoporosis: Application of Bone Science to Clinical Practice
11th EFF-ASBMR Forum On Osteoporosis and Other Metabolic Bone Diseases
Denver, Colorado September 6-7, 2017
John P. Bilezikian, M.D.
Disclosures:
Amgen (Consultant, Advisory Board)Shire Pharmaceuticals (Advisory Board)
Radius Pharmaceuticals (Advisory Board)Ultragenyx (Advisory Board)
9-17
ADVANCES IN BASIC SCIENCE:New Knowledge
Regulatory Molecules
Hormone Action
New Therapeutic Concepts in Osteoporosis
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Antiresorptive Therapy
1. Bone turnover2. Architecture
3. Mineralization
4. Bone size and shape
5. Damage accumulation
6. Matrix quality
+ Bonestrength
How antiresorptive agents improve bone strength
=Bone
densityBone
quality
Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001): 785-95
Antiresorptive Agents:Efficacy Data Based upon Pivotal Clinical Trials
Agent Vertebral Nonvert Hip
Estrogen + + +Alendronate + + +Risedronate + + + Zoledronic acid + + +Ibandronate + - * -Denosumab + + +Raloxifene + - -Calcitonin + - -
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The birth of bisphosphonates Science Vol 165, 1969
Graham Russell, Herbie Fleisch, Dave Francis
dimethylallyl diphosphate isopentenyl diphosphate
MEVALONATE
farnesyl diphosphate squalene
HMG-CoA
CHOLESTEROL
phosphomevalonate
mevalonate diphosphate
geranylgeranyl diphosphate geranylgeranylatedRab proteins
squalene synthase
xx FPP synthase (main site of action of N-BPs)
xIPP isomerase
xRab GGTase
xGPP synthase
Mevalonate pathway. Multiple sites of inhibition by BPs
Statins inhibit here
CENTRAL MECHANISM OF ACTION OF THE BISPHOSPHONATES
Inhibition of bone resorptionby impairing osteoclast function
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Safety
Adverse Effects
• Randomized controlled trials: no increase in UGI issues
• “Class warning” regarding UGI symptoms
• “Class warning” regarding infrequent bone, joint and/or muscle pain
• Influenza-like symptoms may occur after first monthly oral dose or IV injection
• “Class warning” regarding jaw osteonecrosis
• “Class warning” regarding atypical fractures of subtrochanteric regions of the femur
Osteoporosis Therapy: Bisphosphonates
Prescribing information: http://online.factsandcomparisons.com.11 of 57
Perception has interfered with Reality
• Common perceptions about the bisphosphonates are that they…..
• “cause the stomach to hurt (UGI distress)”
• “cause the jaw to fall out (ONJ)”• “cause fractures (Atypical Femoral
Fractures)”• “cause cancer (esophageal)”
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Efficacy and Safety
• No drug is “safe”
• No action in life is “safe”(e.g. crossing the street in Denver!)
• All actions (and drugs) have to be considered along with the risks
The bisphosphonates: benefits and risks
• The benefits of the bisphosphonates are clear: ALN, RIS, and ZOL all reduce fracture risk at all sites
• ONJ and AFF are rare events
• Bisphosphonates cause more good than harm
“10-40 in 100,000 osteoporosis patients taking the drugs (including alendronate, ibandronate, risedronate and zoledronate) have sustained broken thigh bones. Fewer than one in 100,000 have had the jawbone problem.
• You only need to treat 50 people to prevent a fracture, but you need to treat 40,000 to see an atypical fracture”
•
New York TimesFront Page Story by
Gina KolataJune 2, 2016
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The bisphosphonates: public perception versus reality
OUR CHALLENGES To emphasize the importance of
osteoporosis
To place benefits front and center while properly and reasonably placing the matter of SAEs in the right perspective
New approaches based upon advances in bone cell biology
AntiresorptivesDenosumab
Growth Factors HormonesCytokines
RANK
RANKL
MatureOsteoclast
CFU-M
Pre-Fusion Osteoclast
MultinucleatedOsteoclast
RANKL Stimulates Osteoclast-mediated Bone Resorption
Adapted from Boyle WJ et al. Nature. 2003;423:337-42.
RANK Ligand Is Essential for Osteoclast Formation, Function, and Survival
CFU-M = colony forming unit macrophage
Bone
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Osteoprotegerin controls actions of RANKL on osteoclast function
Adapted from Boyle WJ et al. Nature. 2003;423:337-42.
Growth Factors HormonesCytokines
RANK
RANKL
OPG
Bone
MatureOsteoclast
CFU-M
Pre-Fusion Osteoclast
MultinucleatedOsteoclast
Osteoclast Formation, Function and Survival Inhibited by OPG
Activated Osteoclast
CFU-M
Pre-Fusion Osteoclast
MultinucleatedOsteoclast
BONE
Growth Factors Hormones Cytokines
RANK
Denosumab
RANKL
Y
Osteoblast
Denosumab, a human IgG antibody to RANKL, controls osteoclast differentiation, activation and survival
The FREEDOM TrialStudy design:
• Randomized, placebo-controlled
• 60 mg denosumab or placebo subcutaneously every 6 months for 36 months– Plus 400-800 IU vitamin D and
1 g of calcium
Primary endpoint:
• New vertebral fracture (by X-ray over 36 months)
Secondary endpoints:
• Nonvertebral fracture and hip fracture
Cummings et al. N Engl J Med 2009; 361[8]:756-765
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The effect of Denosumab on “all” Fractures
The Freedom Trial
Fx
inci
denc
e at
36
mos
%
3-yr RCT 7808 postmenopausal women age 60-90 with osteoporosis (T-score -2.5)23% with vertebral fracture (severe fractures excluded)
Cummings et al. N Engl J Med 2009; 361[8]:756-765
↓68%
↓20%
↓40%
Key Inclusion Criteria for the Extension:• Completed the FREEDOM study (completed their 3-
year visit, did not discontinue investigational product, and did not miss > 1 dose)
• Not receiving any other osteoporosis medications
FREEDOM Extension
1
2
3Year 0 5 6 74 8 9 10
1 2 30 5 6 74Year
RANDOMIZATION
PlaceboSC Q6M
(N = 3906)
Long-termDenosumabTreatment
Cross-overDenosumabTreatment
Denosumab 60 mgSC Q6M
(N = 2343)
Denosumab 60 mgSC Q6M
(N = 2207)
Calcium and Vitamin D
Denosumab 60mgSC Q6M
(N = 3902)
Ferrari et al. Relationship Between Total Hip BMD T-Score and the Incidence of Non-Vertebral Fracture with up to 8 Years of Denosumab Treatment (ASBMR, 2015)
International, multicenter, open-label, single-arm study
FREEDOM Extension
-2
0
2
4
6
8
10
12
14
16
18
20
22
24
b
21.7%c
b
b
a
a
a
a
b
b
b
16.5%c
Lumbar Spine
Per
cen
tage
Cha
nge
Fro
m B
asel
ine b
b
BMD data are LS means and 95% confidence intervals. aP < 0.05 vs FREEDOM baseline. bP < 0.05 vs FREEDOM and Extension baselines. cPercentage change while on denosumab treatment. dAnnualized incidence: (2-year incidence) / 2. Lateral radiographs (lumbar and thoracic) were not obtained at years 4, 7, and 9 (years 1, 4,
and 6 of the Extension).
aa
b
b
Study Year
1 2 3 4 50 6 7 8 9 10
Placebo Cross-over DenosumabLong-term Denosumab
a
Bone et al. Ten Years of Denosumab Treatment in Postmenopausal Women with Osteoporosis: Results From the Freedom Extension Trial: LUMBAR SPINE AND HIP BMD (ASBMR, 2015)
FREEDOM Extension
-2
-1
0
1
2
3
4
5
6
7
8
9
10
b
b
b
b
b
b
b
b
a
a
a
a
a
a
a
a
9.2%c
7.4%c
b
b
Per
cen
tage
Cha
nge
Fro
m B
asel
ine
Study Year
1 2 3 4 50 6 7 8 9 10
Total Hip
a
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Long-term Denosumab Treatment Continuously Increases Total Hip BMD and Results in Reduced
Nonvertebral Fracture Incidence
Papapoulos S et al. Osteoporos Int 2015. DOI 10.1007/s00198-015-3234-7.LS Means and 95% confidence intervals. *P < 0.05 vs FREEDOM baseline; †P < 0.0001 vs FREEDOM baseline
and extension baseline. Percentages for nonvertebral fractures are Kaplan-Meier estimates.
Total Hip BMD
–2
0
2
4
6
8
10
* **
**
**
*
8.3%
††
†
†
†
†
4.9%
†
†
Study Year
Per
cent
age
Ch
ange
Fro
m B
asel
ine
1 2 3 4 50 6 7 8 1 2 3 4 865 7Years of Denosumab Treatment
Yea
rly
Inci
denc
e of
Non
vert
ebra
l Fra
ctur
es (
%)
FREEDOM EXTENSION FREEDOM EXTENSION
Nonvertebral Fractures
Placebo Denosumab
2626
Ferrari et al. Relationship Between Total Hip T-score and Nonvertebral Fracture (ASBMR, 2015)
Exp
ecte
d 1-
Ye
ar N
onve
rteb
ral
Fra
ctur
e In
cide
nce
(%)
–3.0 –2.5 –2.0 –1.5 –1.0 –0.5
Total Hip T-score
DMAb (N = 3612) 95% CI
1.0
1.5
2.0
2.5
3.0
3.5
4.04.55.0
5.5
6.06.5
On Dmab, the higher the BMD the lower
the non-vert fracture incidence
Revisiting the relationship between a therapeutic increase in BMD and
reduction in fracture Risk
0
5
10
15
20
25
30
35
-5 -4 -3 -2 -1 0
Relative Risk
ofFracture
Bone density (SD units)
-1SD
2 x
Adapted from Faulkner KG. J Bone Miner Res. 2000;15:183-187
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Bone Remodeling
Therapeutic Goals
Stabilize or increase BMD
Maintain trabecular architecture
Increase mineralization density of bone matrix
THE HOLY GRAIL?
The chronology of the development of therapies for osteoporosis: irony #2
The attempt to improve skeletal microstructure as a treatment for
osteoporosis began with the development of a drug that was
thought to do the opposite!
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Parathyroid Hormone?
“Parathyroid hormone is bad for bones”
PHPT IN THE EARLY YEARS, 1929-1970
The captain (1929-1933) and The lady (1970)
70
80
90
100
Lumbar Spine Femoral Neck Radius
The densitometric signature of primary hyperparathyroidism in the modern era
Bon
e M
iner
al D
ensi
ty:
% o
f Exp
ecte
d
*
** Differs from radius,p<.05
Silverberg, Bilezikian et al.JBMR, 1989
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The conceptual ‘leap’ from PTH as a bad actor when present in excess to PTH as
a therapeutic for Osteoporosis
Parathyroid Hormone Excess
Rats will gain enormous amounts of bone
In human subjects with Primary Hyperparathyroidism, the differential changes in bone mass at trabecular versus cortical bone led initially to the idea that PTH might be advantageous to bone under certain circumstances
Bolstered by work by Parsons et al. in the early ‘70s
Background by Parsons, Reeve, Potts, Slovik, Neer, Hodsman, Dobnig, Fujita, et al.
(circa 1969-1997)
All demonstrated an anabolic effect of PTH under certain circumstances
A common cautionary note: PTH alone might serve an anabolic function on trabecular bone but a catabolic function at cortical bone (“borrowing from Peter to pay Paul”)
Use of either an active Vitamin D analogue or an antiresorptive was thought to be important in demonstrating a true anabolic effect of PTH, namely an increase in total bone mass (subsequently shown not to be the case- Neer et al. N Eng J Med 2001)
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0
10
20
30
40
Osteoblast Osteoclast
Vehicle1 hour/dayContinuous
PTH Mode of Administration, Timing and Dose Determine whether PTH is anabolic or catabolic
in the rat skeleton
*p<.01 vs vehicle**p<.001 vs vehicle*
Dobnig H, Turner RT. Endocrinology. 1997;138(11):4607-4612.
Cel
l Abu
ndan
ce(%
Tra
becu
lar B
one
Perim
eter
)
**
AnabolicDaily
(low dose)
CatabolicContinuous (high dose)
EFFECTMODE
PTH dose and timing determine its effect on bone
Dobnig H, et al. Endocrinology 1997;138:4607-12.
Three keys to the anabolic potential of PTH
• Low dose• Intermittent administration• Pulsatility with rapid “on” and “off”
kinetics
Under these conditions…..
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0
10
20
30
40
50
60
70
80
0 1 2 3 4 5 6
Osteocalcinn-telopeptide
PTH is anabolic:
Lindsay R, et al. Lancet. 1997;350(9077):550-555.
Time (Months)
Mea
n %
Cha
nge
in
Turn
over
Mar
ker
Bone Formation Markers increase beforeBone Resorption Markers
Teriparatide Control
Quadruple Labels in Teriparatide-treated and Control Subjects
Dempster et al. 2003
Initial Cellular Mechanisms of PTH
PTH stimulates bone formation directly first and then stimulates the remodeling process PTH stimulates bone formation directly first and then stimulates the remodeling process
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PTH as an Anabolic Agent for Bone:A Kinetic Model
Months
Inde
x of
Bon
e Tu
rnov
er
Peak
Bone formation markers
Early increase in bone formation alsoseen in dynamic histomorphometicindices by transiliac bone biopsy
PTH as an Anabolic Agent for Bone:A Kinetic Model
Months
Inde
x of
Bon
e Tu
rnov
er
Peak
Bone formation markers
Bone resorptionmarkers
“Anabolic Window”
Believed to limitthe osteoanabolic potential of PTH
Teriparatide
Abaloparatide
Romosozumab
Osteoanabolics
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HisGluSer
Gly
Human Parathyroid Hormone
1 10
20
30
Ser Val Ile Gln Leu Met AsnLeu
LysHisLeuAsnSerMetGluArgValGlu
Trp
LeuArg Lys Lys Leu Gln Asp Val His Asn Phe
-COOH
H2N
GlyTeriparatide
Inta
ct P
TH
(1-
84)
Neer RM, et al. N Engl J Med 2001;344:1434-41.
Teriparatidein Postmenopausal Women
• Prospective, randomized, double-blind trial
• Multinational:17 countries; 99 sites
• 1637 enrolled;1239 completed
• 3 arms: placebo, 20 µg or 40 µg rhPTH (1-34)
• Endpoints
– Vertebral and nonvertebral fractures
– Bone density
– Bone markers
• Median treatment: 21 months
Effect of Teriparatide on Incidence of Vertebraland Non-Vertebral Fractures in Postmenopausal Women with Osteoporosis
Neer RM, et al. N Engl J Med. 2001;344:1434-41
0
2
4
6
8
10
12
14
16
18
20
Non-vertebral fractures
Pa
tie
nts
(%
) w
ith
fra
ctu
re
P< 0.01
53%
20 g PTH0
2
4
6
8
10
12
14
16
18
20
New vertebral fracture
Pat
ien
ts (
%)
wit
h f
ract
ure
P< 0.01
65%
20 g PTH PlaceboPlacebo
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Major Clinical Trials With Teriparatide
• Reduction in vertebral (65%) and non-vertebral (53%) fractures (Neer et al. N Eng J Med. 2001)
• As effective in women with mild or severe previous fragility fractures (Gallagher et al. 2004)
• As effective in women with 1, 2 or more previous fragility fractures (Gallagher et al. 2004)
• Effective in Glucocorticoid-induced osteoporosis (Saag et al. N Eng J Med 2007; Arthritis Rhem, 2009)
• Effective in Male Osteoporosis (Kurland et al, 2002; Orwoll et al. N Eng J Med, 2003)
Improved Trabecular ConnectivityAfter hPTH (1-34) Therapy
Dempster DW, et al. J Bone Miner Res. 2001;16(10):1846-1853.
AfterCD: 4.6/mm3Before
CD: 2.9/mm3
SAFETY
• Animal toxicity data (osteosarcoma), still a concern to some prescribers and patients
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Safety of PTH
• No oncogenic signals after 15 years of human use, worldwide
• The likelihood that osteosarcoma is a human toxicity when used in the way it is being used would appear to be remote.
• Surveillance (and the black box) continues
Teriparatide: Contraindications and Cautions
Teriparatide should not be used in patients with:
• history of skeletal malignancies
• increased baseline risk of osteosarcoma:─ Paget's disease of bone
─ Pediatric populations and young adults with open epiphyses
─ Prior external beam or implant radiation therapy
• hypercalcemia
Use with caution if pre-existing hypercalciuria and active or recent urolithiasis
COMBINATION ANABOLIC AND
ANTIRESORPTIVE THERAPY
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Antiresorptive
PTH
PTH and ALN: Monotherapy with PTH gives a better BMD response than combination therapy---(ALN “too potent?”}-Black et al, 2003, Finkelstein et al, 2003, 2010
PTH and Raloxifene (Deal et al., 2006)
PTH and Zoledronic Acid (Cosman et al., 2011)
PTH and Denosumab (Tsai, Leder et al. 2013- )
SOST WntWnt
CtBPTcf
-catenin
CtBPTcf
-catenin
BMPBMP
Smad
4 P
TFs
R-S
mad
s
PTHRunx2-expressing
osteoblast progenitor
cAMP/PKA
P
CREB
P
CREB
RANKL OPG
CatabolismAnabolism
Denosumab
Combination Denosumab and PTH Therapy
Teriparatide and Denosumab(Tsai JN et al. Lancet May 15, 2013)
• Design: Randomized, open label, 1 year• Study Population: postmenopausal women (>
45 yrs) at high risk for fracture• Endpoint: Change in BMD• 3 arms: Teriparatide (20 ug daily) or
Denosumab (60 mg q 6 mos) alone or in combination
• Numbers of subjects in each group:29-33
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CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: COMBINATION THERAPY WITH DENOSUMAB AND TERIPARATIDE
(Leder et al, JCEM, 2014)
N=100 divided equally among Teriparatide (20 ug daily); Denosumab (60 mg q 6mos); and combination. 83 completed the study
Tsai et al., J Bone Miner Res, 2015
Total vBMD
Cort vBMD
Cort Th
Trab vBMD
Limitations to simultaneous combination regimens and
their variations
Bone density and bone markers are only end points No long term data Limited data on bone quality No fracture data
Bisphosphonate
PTH
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The search for another osteoanabolic treatment for osteoporosis
An analogue of PTHrP
Taking advantage of basic mechanisms to develop a PTHrP analogue that has
greater osteoanabolic activity
Premise:
2 states of PTH/PTRrP receptor binding to its ligand R0: leads to prolonged signaling
RG: associated with more transient signaling
Taking advantage of basic mechanisms to develop a PTHrP analogue that has
greater osteoanabolic activity
Hypothesis:
Abaloparatide will bind more selectively bind to the transient RG configuration of the PTH/PTRrP receptor
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Emergence of a new osteoanabolicAbaloparatide, an analogue of PTHrP
Hattersley G, Bilezikian JP, Kumar P et al. The Endocrine Society 94th Annual Mtg Houston, 2012
64
22 30 34100% hPTHrP
38% hPTHrP
Teriparatide
hPTHrP1-34
Abaloparatide
100% hPTHrP 38% hPTHrP
22 34
based on amino acid replacements between residues 22-34
The binding of ABL, PTH (1–34), PTHrP (1–36) and LA-PTH to two distinct PTHR1 conformations RG (A) and R0 (B)was assessed by competition methods in membranes prepared from GP-2.3 cells stably expressing the PTHR1.
RG reactions used 125I-M-PTH (1–15) as tracer radioligand, which binds selectively to the G protein–coupled receptor conformation (RG). R0 reactions used 25I-PTH (1–34) as tracer radioligand and contained an excess concentration
(1 × 10−5 M) of GTPγS, which enriches for the G protein–uncoupled receptor conformation (R0). Data are means (± SEM) of six experiments, each performed in duplicate. Curve fitting parameters are reported in Table 1.
Published in: Gary Hattersley; Thomas Dean; Braden A. Corbin; Hila Bahar; Thomas J. Gardella; Endocrinology 2016, 157, 141-149.DOI: 10.1210/en.2015-1726
Copyright © 2016
Hattersley, Dean, Corgin, Bahar and Gardella. Endocrinology 2016:157:141-149
Transient State Prolonged response
GP-2.3 cells preloaded with luciferin were treated with a near-EC50 concentration of PTH (1–34) (0.3nM), PTHrP (1–36) (1nM), ABL (0.1nM), or LA-PTH (0.3nM) and luminescence was assessed at 2-min intervals for 14 min (A).
The cells were then removed from the plate reader, rinsed twice with media to remove unbound ligand, and then fresh media containing luciferin but lacking ligand was added and luminescence was assessed for additional 150 min (B).
Data are means (± SEM) of six experiments, each performed in triplicate. Curve fitting parameters are reported in Table 3.
Hattersley, Dean, Corgin, Bahar and Gardella. Endocrinology 2016:157:141-149
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Relative ligand binding states
Transient/prolonged state of the PTH/PTHrP receptor:
Abaloparatide>> Teriparatide
Update on Abaloparatide
• International Phase 3 trial ended, Sept, 2014
• Results made available, December, 2014
• Presented by Miller et al, Endocrine Society, 2015-2016
• Clinical Trial Results: Miller et al. JAMA 2016
• FDA approval: April 28, 2017
Abaloparatide Study: Background
• ACTIVE (Abaloparatide Comparator Trial In Vertebral Endpoints)1
– 18 months of abaloparatide-SC compared with placebo and open-label teriparatide
– Multicenter, multinational, double-blind, placebo-controlled
– 2463 postmenopausal women aged 49 to 86 were enrolled
• With prior radiographic vertebral or recent (< 5 yrs prior) nonvertebral fracture
– T-score ≤ -2.5 at spine or femoral neck and age ≤ 65
– T-score ≤ -2.0 if age >65
• No prior fracture required if age >65 and T-score ≤ -3.0 and > -5.0
1Miller et al. JAMA. 2016;316:722-733.
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Phase 3 Trial Design of Abaloparatide Clinical Trial
Placebo
Abaloparatide 80 mcg Daily SC
Teriparatide 20 mcg Daily SC (Open Label)
Ra
nd
om
iza
tion
Months 6 12 18
N = 2463
Miller et al. JAMA. 2016;316:722-733.
ITT population N=2463Placebo(n=821)
Abaloparatide-SC (n=824)
Teriparatide (n=818)
Age (years) 68.7 68.9 68.8
Race, %
White 79.8 80.5 78.9
Asian 16.0 15.5 16.7
Black or African American 2.8 3.2 2.9
Other 1.5 0.8 1.5
Baseline prevalent vertebral fracture (%)
22.9 21.5 26.9
Prior nonvertebral fracture history (% within 5 years)
32.4 30.1 29.3
Patients with no history of prior fracture, %
37.4 37.0 37.7
Lumbar spine BMD T-score -2.9 -2.9 -2.9
Total hip BMD T-score -1.9 -1.9 -1.9
Femoral neck BMD T-score -2.2 -2.2 -2.1
ACTIVE: Baseline Characteristics
Miller et al. JAMA. 2016;316:722-733.
ITT population N=2463Placebo(n=821)
Abaloparatide-SC (n=824)
Teriparatide (n=818)
Age (years) 68.7 68.9 68.8
Race, %
White 79.8 80.5 78.9
Asian 16.0 15.5 16.7
Black or African American 2.8 3.2 2.9
Other 1.5 0.8 1.5
Baseline prevalent vertebral fracture (%)
22.9 21.5 26.9
Prior nonvertebral fracture history (% within 5 years)
32.4 30.1 29.3
Patients with no history of prior fracture, %
37.4 37.0 37.7
Lumbar spine BMD T-score -2.9 -2.9 -2.9
Total hip BMD T-score -1.9 -1.9 -1.9
Femoral neck BMD T-score -2.2 -2.2 -2.1
ACTIVE: Baseline Characteristics
Miller et al. JAMA. 2016;316:722-733.
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*P < 0.01 vs. placebo; †P 0< 0.05 abaloparatide vs. teriparatide.Error bars indicate median interquartile ranges.
Serum Biomarkers of Bone Turnover
Adapted from Miller et al. JAMA. 2016; 316:722-733.
“Anabolic window”
PTH/PTHrP analogues that stimulate bone formation to a greater extent than bone
resorption: a time dependent model
Months
Inde
x of
Bon
e T
urno
ver
Peak
Bone Formation Markers
Bone ResorptionMarkers
PlaceboAbaloparatideTeriparatide
0
1
2
3
4
5
6
7
8
9
10
0 6 12 18
Lumbar Spine BMD
% C
hang
e fr
om B
asel
ine
Months
#p < 0.01 vs TP
#
#
Changes in BMD at the Spine and Reduction in New Vertebral Fractures: All 3 Groups
Miller et al. JAMA. 2016;316:722-733.
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Changes in BMD at Non-Vertebral Sites and NVF Risk Reduction: All 3 Groups
‐0.5
0
0.5
1
1.5
2
2.5
3
3.5
4
0 6 12 18
Total Hip BMD
% C
hang
e fr
om B
asel
ine
Months
#
#^#p < 0.0001 vs TP
p̂ = 0.0003 vs TP
‐1
‐0.5
0
0.5
1
1.5
2
2.5
3
3.5
0 6 12 18
Femoral Neck BMD
% C
hang
e fr
om B
asel
ine
Months
#
#
@#p < 0.0001 vs TP@p = 0.0016 vs TP
Miller et al. JAMA. 2016;316:722-733.
Kaplan-Meier Time to First Event
Per
cent
of
Pat
ient
s w
ith
Fra
ctur
e
Time to Event (Days)
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
0 100 200 300 400 500
PlaceboAbaloparatide
Teriparatide
Non-Vertebral Fractures
Per
cent
of
Pat
ient
s w
ith ≥
1 N
ew N
on-V
erte
bral
Fra
ctur
e
Abaloparatide
Miller et al. JAMA. 2016;316:722-733.
Effects of Abaloparatide on Major Osteoporotic Fracture Incidence in Postmenopausal Women with Osteoporosis- Results of the Phase 3 ACTIVE Trial
Objective: Effect of Abaloparatide or Teriparatide on Major Osteoporotic Fractures (high or low trauma clinical fxs; upper arm, forearm, hip, shoulder, and/or spine)
Results: Abaloparatide vs PBO (70% reduction: p=0004 )Teriparatide vs PBO (no significant reduction)Abaloparatide vs Teriparatide (P < 0.05)
Miller et al. JAMA. 2016;316:722-733.
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Risk Reduction of Major Osteoporotic Fractures
ITT Population N=2463
*P < 0.001, abaloparatide-SC vs placebo; †P = 0.03, abaloparatide-SC vs teriparatide; NS, teriparatide vs placebo.Based on cumulative Kaplan-Meier estimates ITT at 19 months.
Placebon=821
Abaloparatide-SCn=824
Pro
port
ion
of P
atie
nts
with
M
ajor
Ost
eopo
rotic
Fra
ctur
es, %
Teriparatiden=818
-70%* -55%†
6.2%(n=34)
1.5%(n=10)
3.1%(n=23)
Miller et al. JAMA. 2016;316:722-733.
Early Risk Reduction of Major Osteoporotic
Fractures
0
1
2
3
4
5
6
0 100 200 300 400 500
Time to event (days)
AbaloparatideP=0.0004 vs placebo
P=0.031 vs teriparatide
Placebo
TeriparatideP=0.1350 vs
placebo
Pro
po
rtio
n (
%)
of
pat
ien
ts
wit
hm
ajo
r o
steo
po
roti
c fr
actu
re
Effects of Abaloparatide on Major Osteoporotic Fracture Incidence in Postmenopausal Women with Osteoporosis- Results of the Phase 3 ACTIVE Trial
Miller et al. JAMA. 2016;316:722-733.
Changes in Wrist BMD and Wrist Fracture Reduction: Abaloparatide vs. Teriparatide vs. Placebo
(Miller et al. Endo Soc 3-15)
K-M Estimated Incidence RateWrist Fracture (ITT Population)
-1.5
-1
-0.5
0
0.5
1
1.5
2
0 6 12 18
% C
hang
e fr
om B
asel
ine
*
Months
*p < 0.001 vs placebo#p = 0.0013 vs TP
#* *NS
NS
NS
Ultra-Distal Radius BMD
Abaloparatide
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Safety and Adverse EventsSafety Population N=2460
Placebon=820
Abaloparatide-SCn=822
Teriparatiden=818
All treatment-emergent adverse events
87.6% 89.4% 88.9%
Serious treatment-emergent adverse events
11.0% 9.7% 10.0%
Deaths 0.6% 0.4% 0.4%
Adverse events leading to discontinuation
6.1% 9.9% 6.8%
Discontinuation due to >7.0% BMD decrease
6.5% 0.5% 0.6%
Hypercalcemia (prespecified)* 0.4% 3.4%†‡ 6.4%‡
Adverse events of special interest
Orthostatic hypotension 16.4% 17.1% 15.5%
Neoplasms 3.5% 2.4% 3.8%
Fall 0.2% 0.5% 0.5%
Drug hypersensitivity 0.2% 0.2% 0.0%
Renal impairment 0.5% 0.2% 0.4%
Myocardial infarction 0.2% 0.1% 0.2%
Miller et al. JAMA. 2016;316:722-733.
*Serum albumin-corrected calcium value ≥10.7 mg/dL at any time point, prespecified safety endpoint.†P = 0.006 abaloparatide-SC vs teriparatide; ‡P < 0.001 vs placebo.
Most Frequently Observed Adverse Events (≥5%)
Safety Population N=2460
Most common AEs reported by ≥5% in any treatment group
Placebon=820
Abaloparatide-SCn=822
Teriparatiden=818
Hypercalciuria 9.0% 11.3% 12.5%
Dizziness 6.1% 10.0% 7.3%
Arthralgia 9.8% 8.6% 8.6%
Back Pain 10.0% 8.5% 7.2%
Nausea 3.0% 8.3% 5.1%
Upper respiratory tract infection 7.7% 8.3% 8.9%
Headache 6.0% 7.5% 6.2%
Hypertension 6.6% 7.2% 5.0%
Influenza 4.8% 6.3% 4.2%
Nasopharyngitis 8.0% 5.8% 6.5%
Urinary tract infection 4.6% 5.2% 5.0%
Palpitations 0.4% 5.1% 1.6%
Pain in extremity 6.0% 4.9% 5.1%
Constipation 5.1% 4.5% 4.2%
Miller et al. JAMA. 2016;316:722-733.
Summary
• In postmenopausal women with osteoporosis, 18 months of subcutaneous abaloparatide compared with placebo significantly
– Increased BMD at the lumbar spine, total hip and femoral neck
– Reduced the risk of vertebral and nonvertebral fractures
– Reduced the risk of clinical and major osteoporotic fractures (exploratory endpoints)
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Summary -2-
• Abaloparatide-SC had an acceptable safety profile
– No differences were evident between the placebo, abaloparatide and teriparatide groups in treatment-emergent adverse events, serious adverse events, or deaths
– A lower incidence of hypercalcemia was observed with abaloparatide-SC compared with teriparatide (3.4% vs 6.4%)
ACTIVExtend Trial Patient Population
ACTIVExtend (extension trial of ACTIVE)
• Patients from abaloparatide and placebo groups who completed ACTIVE were invited to participate (92% of eligible ACTIVE patients were enrolled)
• After conclusion of ACTIVE, patients were given alendronate 70 mg/wk for 6 months
• Study personnel and participants remained blinded to the initial treatment group assignment in ACTIVE while they received open-label alendronate 70 mg weekly during the first 6 months of therapy
Cosman et al. Mayo Clin Proc. Feb 2017; 92(2):200-210.
ACTIVExtend Study Objectives
• Primary Endpoint:
Percentage of participants who sustained 1
or more new morphometric vertebral
fractures between ACTIVE baseline and 6
months after starting alendronate between
the two groups (Abaloparatide-
SC/Alendronate vs Placebo/Alendronate)
Cosman et al. Mayo Clin Proc. Feb 2017; 92(2):200-210.
8/24/2017
30
Teriparatide 20 mcg daily SC (n=818)
Abaloparatide 80 mcg daily SC (n=824)
Ran
dom
izat
ion Placebo (n=821)
Months 6 12 18 25
ACTIVEN=2463
ACTIVExtendN=11396 months planned
interim analysis
19* 43*1-month gap in treatment was allowed for rollover from ACTIVE to ACTIVExtend.
Alendronate
Alendronate
Eighteen Months of Treatment with Abaloparatide Followed by Six Months of Treatment with Alendronate in Postmenopausal Women with Osteoporosis- Results of the ACTIVExtend Trial
Cosman et al. Mayo Clin Proc. Feb 2017; 92(2):200-210.
*P<0.0001 vs placebo.
0
1
2
3
4
5
6
PlaceboN=711
AbaloparatideN=690
Pro
po
rtio
n (
%)
of
pat
ien
ts w
ith
n
ew v
erte
bra
l fra
ctu
res
4.22% (n=30)
0.58%
(n=4)
0.84%
(n=6)Teriparatide
N=717
ACTIVExtend Trial with Abaloparatide: Risk Reduction of Vertebral Fractures
Placebo/alendronate
N=568
Abaloparatide/alendronate
N=544
ACTIVExtend, 6 months
1.23% (n=7)
0% (n=0)
-86%* -80%*
ACTIVE, 18 months
Cosman et al. Mayo Clin Proc. Feb 2017; 92(2):200-210.
0
1
2
3
4
5
6
ACTIVExtend Trial with Abaloparatide: Risk Reduction of Non-Vertebral Fractures
*P= 0.0489 vs placebo ; †P=0.2157 vs placebo.
PlaceboN=821
AbaloparatideN=824
Pro
po
rtio
n (
%)
of
pat
ien
ts w
ith
n
on
vert
ebra
lfra
ctu
res
TeriparatideN=818
4.0%(n=33)
2.2%(n=18)
2.9%(n=24)
-43%* NS†
ACTIVE, 18 months
Placebo/alendronate
N=581
Abaloparatide/alendronate
N=558
1.2%(n=7)
0.5%(n=3)
ACTIVExtend, 6 months
Cosman et al. Mayo Clin Proc. Feb 2017; 92(2):200-210.
8/24/2017
31
Summary
• ACTIVExtend: 18 months of abaloparatidefollowed by 6 months of alendronate
– No vertebral fractures during 6-month extension in Abaloparatide-SC/Alendronate group
– 52% reduced risk of nonvertebral fractures in Abaloparatide-SC/Alendronate vs Placebo/Alendronate group
– Continued BMD gains at vertebral and hip sites
Cosman et al. Mayo Clin Proc. Feb 2017; 92(2):200-210.
Teriparatide 20 mcg daily SC (n=818)
Abaloparatide 80 mcg daily SC (n=824)
Ran
dom
izat
ion Placebo (n=821)
Months 6 12 18 25
ACTIVEN=2463
ACTIVExtendN=11396 months planned
interim analysis
19* 43*1-month gap in treatment was allowed for rollover from ACTIVE to ACTIVExtend.
Alendronate
Alendronate
Bone et al: Eighteen Months of Treatment with Abaloparatide Followed by 24 Months of Treatment with Alendronate in Postmenopausal Women with Osteoporosis- Results of the ACTIVExtend Trial
Cosman et al. Mayo Clin Proc. Feb 2017; 92(2):200-210.
RESULTS TO BE PRESENTED AT ASBMR ANNUAL MEETING,
SEPTEMBER 10, 2017 @ 10:45 AM
THE FUTURE OF OSTEOANABOLIC THERAPY
8/24/2017
32
• increased bone mass throughout skeleton.
• very low fracture risk
• due to absence of sclerostin (SOST) - an inhibitor of Wnt signaling and bone formation
Clues to a new therapeutic approach:Sclerosteosis & van Buchem’s Disease
Janssens and Van Hul. Hum Mol Genet. 2002;11:2385-93.
Heterozygous carriers of Sclerosteosis and van Buchem’s disease do not appear to have
complications as seen in the homozygous subjects
• Higher bone density
• Increased markers of bone formation
• Levels of sclerostin are intermediate
• No long-term or progressive sequellae
Wnt Wnt
Sclerostin
DSHFrat1
GSK3ββcatenin
DSH
AXIN
βcatenin P
Proteosomal Degradation
βcatenin
Osteoblast differentiation,
proliferation, and mineralization
activity
Osteoblast:Reduced activity
βcatenin
Sclerostin
DKK1 DKK1
8/24/2017
33
Wnt
DSH
Frat1
βcateninβcatenin
Sclerostin
Sclerostin Antibody
βcatenin
DKK1
Antisclerostin Antibody Rx (Li et al, JBMR, 2009)
12
8
4
0Sham Ovx Ovx + Scl-Ab
Periosteal BFR
Sham Ovx Ovx + Scl-Ab
5
4
3
2
1
0
Ob S/BS
Sham Ovx Ovx + Scl-Ab
10
8
6
4
2
0
Oc S/BS
Sham Ovx Ovx + Scl-Ab
5
4
3
2
1
0
Perio MS/BS
Sham Ovx Ovx + Scl-Ab
60
50
40
30
20
10
Sham Ovx Ovx + Scl-Ab
40
30
20
10
0
Intracort MS/BS
100
75
50
25
0
Endocort MS/BS
Sham Ovx Ovx + Scl-Ab
Cortical
Endocortical BFR
Li et al, JBMR 2009
CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: ANTISCLEROSTIN ANTIBODY
• Romosozumab (osteoporosis)
• Blosozumab (osteoporosis)*
*Development stopped 7-16
Human Studies
8/24/2017
34
Cosman F, Crittenden B, Adachi JD et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N
Eng J Med 2016;375: 1532-1543 (October 20, 2016)
Design: Double-blinded, placebo-controlled, multinational study
Number: 7180
Inclusion: T-score, -2.5 to -3.5 TH or FN
Drug: Romo 210 mg sc or placebo monthly x 12 months; Followed by denosumab 60 mg sc x 12 months
Co-primary endpoints: cumulative incidence of new vertebral fractures 14 12 and 24 months
Secondary endpoints: clinical (nonvertebral and symptomatic vertebral fractures) and nonvertebral fractures
Cosman F et al. N Engl J Med 2016;375:1532-1543.
Percentage Change from Baseline in Bone Mineral Density and Levels of Bone-Turnover Markers.
P1NP
CTX
Cosman F, Crittenden B, Adachi JD et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N
Eng J Med 2016;375: 1532-1543 (October 20, 2016)
RESULTS: VERTEBRAL and CLINICAL FRACTURES
At 12 months: New vertebral fractures: 1.8% (PLB) vs 0.5% (Romo): 73% RR
reduction (P <0.001)
Clinical fractures: 2.5% (PLB) vs 1.6% (Romo): 36% RR reduction (P=0.008)
At 24 months: New vertebral fractures: 2.5% (PLB to Dmab) vs 0.6% (Romo to
Dmab): 75% RR reduction
8/24/2017
35
Cosman F et al. N Engl J Med 2016;375:1532-1543.
Incidence of New Vertebral, Clinical, and Nonvertebral Fractures
NewVertebralFractures
NewNon-Vertebral
Fractures
Cosman F, Crittenden B, Adachi JD et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N
Eng J Med 2016;375: 1532-1543 (October 20, 2016)
RESULTS: Non-vertebral fractures.
No significant reduction vs placebo
Site to site heterogeneity: detected
Post-Hoc Analysis Latin America vs the rest of the world
Latin America: 1.2% (PLB) vs 1.5% (Romo) P NS
Rest of World: 2.7% (PLB) vs 1.6% (Romo) P =0.04
FRAX for MOF by region:
Latin America: 8.7%
Rest of World: 17.0%
Cosman F, Crittenden B, Adachi JD et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N
Eng J Med 2016;375: 1532-1543 (October 20, 2016)*
Adverse Events:
Hypersensitivity Reactions: 7 patients
Injection site reactions: 2.9% (PLB) vs 5.2% (Romo)
ONJ: 2 (12 months after Romo ill-fitting dentures; 12 months after Romo and 1 dose of Dmab: following tooth extraction and osteomyelitis of the jaw.
AFF: 1 (prodromal pain prior to enrollment)
8/24/2017
36
Update on FDA Review of Romosozumab
FDA review has been delayed due to an imbalance in cardiovascular and
cerebrovascular safety end pointsin the “ARCH” study
(Romosozumab vs Alendonate)
• Late-breaking abstract #1162 (Saag et al. )to be presented at ASBMR, September 11, 2017
CATEGORY RESORPTION FORMATION
Anti-remodeling agents- bisphosphonates, RANKL inhibitor
Osteoanabolics- Teriparatide
- Abaloparatide
- Romosozumab
Osteoporosis Rx and Mechanisms
Summary
New insights into bone biology have led to new osteoanabolic approaches to the treatment of osteoporosis
Emphasis on pathways that directly effect bone resorption or bone formation (or both) have enhanced our therapeutic options
Further advances may well lead to even more definitive therapy of osteoporosis!
8/24/2017
37
THANK YOU