Bilezikian, John - cdn.ymaws.com · Amgen (Consultant, Advisory Board) Shire Pharmaceuticals (Advisory Board) Radius Pharmaceuticals (Advisory Board) Ultragenyx (Advisory Board) 9-17

8/24/2017

1

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

8/24/2017

2

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 + - -

8/24/2017

3

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

8/24/2017

4

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)”

8/24/2017

5

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

8/24/2017

6

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

8/24/2017

7

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



Osteoclast Formation, Function and Survival Inhibited by OPG

Activated Osteoclast

CFU-M



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

8/24/2017

8

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

8/24/2017

9

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

8/24/2017

10

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!

8/24/2017

11

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

8/24/2017

12

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)

8/24/2017

13

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…..

8/24/2017

14

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

8/24/2017

15

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

8/24/2017

16

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

8/24/2017

17

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

8/24/2017

18

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

8/24/2017

19

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

8/24/2017

20

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

8/24/2017

21

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

8/24/2017

22

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

8/24/2017

23

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.

8/24/2017

24

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.

8/24/2017

25

*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.

8/24/2017

26

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.

8/24/2017

27

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

8/24/2017

28

Safety and Adverse EventsSafety Population N=2460

Placebon=820


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


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)

8/24/2017

29

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)


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


*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


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


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


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


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


10

8

6

4

2

0

Oc S/BS


5

4

3

2

1

0

Perio MS/BS


60

50

40

30

20

10


40

30

20

10

0

Intracort MS/BS

100

75

50

25

0

Endocort MS/BS


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


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


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%


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

Documents

Bilezikian, John - cdn.ymaws.com · Amgen (Consultant, Advisory Board) Shire Pharmaceuticals (Advisory Board) Radius Pharmaceuticals (Advisory Board) Ultragenyx (Advisory Board) 9-17