efficacy and safety of long-term denosumab therapy ... y seguridad del... · ooc • overall, no...

OOC

Michael R. McClung, MD, FACP

Professorial Fellow, Institute for Health and AgeingAustralian Catholic University, Melbourne, VIC

Director, Oregon Osteoporosis CenterPortland, Oregon, USA

[email protected]

Santiago de Chile

May 10, 2019

Efficacy and Safety of Long-term

Denosumab Therapy: FREEDOM Study

XXVII Congreso Chileno de Osteología

OOC

Conflict of Interest

I am disclosing financial relationships as follows:

Global Advisory Boards: Amgen, Radius Health

Honorarium for speaking: Amgen, Radius Health

Michael McClung, MD 2019

OOC

Osteoporosis

Definition:

A disorder due to bone loss that damages

skeletal architecture, weakens the skeleton

and predisposes a patient to fracture

• Several osteoporosis drugs effectively and quickly reduce fracture risk in patients with

osteoporosis

• Osteoporosis is a chronic disease requiring prolonged treatment

• It is important to develop a strategy for long-term management

Images Courtesy of

Drs. David Dempster & Roger Zambezi

Black DM and Rosen CJ. N Engl J Med 2016; 374:254-62

OOC

• To review

• the efficacy and safety of long-term denosumab therapy

• effects of discontinuing denosumab

• To discuss the role of denosumab in the long-term management of patients with osteoporosis

Objectives

OOC

RANK Ligand Is an Essential Mediator of

Osteoclast Formation, Function, and Survival

Osteoblasts

Activated

Osteoclast

CFU-GM Prefusion

Osteoclast

Multinucleated

Osteoclast

Hormones

Growth Factors

Cytokines

Bone Formation

Bone ResorptionAdapted from: Boyle WJ, et al. Nature. 2003;423:337-342.© 2009 Amgen. All rights reserved. Do not copy or distribute.

RANKL

RANK

OPG

OOC

RANKL

RANK

OPG

Denosumab

Bone Formation Bone Resorption

Inhibited

Osteoclast Formation, Function,

and Survival Inhibited

Decreases Osteoclast Number

and Activity

CFU-GM Prefusion

Osteoclast

Osteoblasts

Hormones

Growth Factors

Cytokines

© 2009 Amgen. All rights reserved. Do not copy or distribute.

Denosumab Binds RANK Ligand

OOC

Denosumab

• A fully human IgG2 monoclonal antibody that bonds RANK

ligand with very high specificity

• Administered subcutaneously Q 6 months

Serum denosumab

Serum CTX

Seru

m c

on

cen

trati

on

of

den

osu

mab

ng

/ml

0

2

4

6

8

0 2 4 6 8 10 12

Time (Month)

-80

-60

-40

-20

0

20

Seu

m C

TX

Ch

an

ge (%

) Fro

m B

aselin

e

Mean

S

E

1st dose 2nd dose

McClung MR, et al. N Engl J Med 2006;354:821-31

Vasikarin SD. Crit Rev Clin Lab Sci 2008;45:221-58

OOC

International, placebo-controlled study

Study population

▪ 7,808 postmenopausal women

▪ T-score < –2.5 at the lumbar

spine or total hip and

not < –4.0 at either site

▪ Exclusion any severe or > 2

moderate vertebral fractures

Primary endpoint

▪ New vertebral fracture over

36 months

Secondary endpoints

▪ Time to nonvertebral fracture

▪ Time to hip fracture

Study Month

241261Day 1Visit

SCREENING

36

END

OF

STUDY

RANDOMIZATION

Denosumab

60 mg SC Q6M

n = 3,902

Placebo

n = 3,906

Calcium and vitamin D

Denosumab FREEDOM Trial:Pivotal Phase III Study

SC = subcutaneously; Q6M = once every 6 months

Cummings SR, McClung MR et al. N Engl J Med 2009;361:756-65

OOC

Denosumab FREEDOM StudyIncidence of Vertebral and Hip Fracture

RRR 61%

P < 0.0001

2.2% 0.9%

0

1

2

3

4

5

6

7

8

9

0-12 Months

Inc

ide

nc

e a

t M

on

th 3

6 (

%)

Placebo

Denosumab

0-24 Months 0-36 Months

5.0% 1.4% 7.2% 2.3%

RRR 71%

P < 0.0001

RRR 68%

P < 0.0001

Cummings SR, McClung MR et al. N Engl J Med 2009;361:756-65

Hip FractureVertebral Fracture

Cu

mu

lati

ve

in

cid

en

ce

-%

Month

Effect of fracture protection seen with in first 12 months of therapy

OOC

• Increased trabecular bone score in lumber spine

• Increased volumetric BMD of cortical and trabecular bone

• Increased cortical thickness, especially at sites of loading in the hip

• Decreased cortical porosity

• Increased estimated bone strength in hip and spine by finite element analysis (FEA) of CT scans

• No abnormalities observed on bone biopsies

Denosumab: Improved Bone QualityPhase 3: The FREEDOM Trial

OOC

• Overall, no increased risk of adverse events or serious adverse events in clinical trials (1)

• In FREEDOM: increased incidence of

• skin rash (3.0% vs 1.7%)

• cellulitis (12/3808 vs 1/3805)

• Numerically more neoplasms and “infections”-- no signal of opportunistic infections

• No renal or cardiovascular effects noted

• Deaths: 90 in placebo group; 70 with DMab (p=0.06)

• No immunological resistance

• No impact on fracture healing (2)

Denosumab: Safety and TolerabilityPhase 3: The FREEDOM Trial

1. Cummings SR, McClung MR et al. N Engl J Med 2009;361:756-65

2. Adami S, et al. J Bone Joint Surg Am 2012;94:2113-9

Usually mild and resolved with

ongoing treatment

Unrelated to site or time of injection

OOC

Key Inclusion Criteria for the Extension:

• Completed the FREEDOM study (completed the 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 6 74Year

R

A

N

D

O

M

I

Z

A

T

I

O

N

Denosumab 60 mg

SC Q6M

(N = 3902)

Placebo

SC Q6M

(N = 3906)

Long-term

Denosumab

Treatment

Cross-over

Denosumab

Treatment

Denosumab 60 mg

SC Q6M

(N = 2343)

Denosumab 60 mg

SC Q6M

(N = 2207)

Calcium and Vitamin D

FREEDOM Extension Study Design

5

OOC

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 SpineP

erc

en

tag

e C

ha

ng

e F

rom

Ba

se

lin

e

b

b

aa

Long-term Denosumab TherapyLumbar Spine and Total Hip BMD

b

b

Study Year

1 2 3 4 50 6 7 8 9 10

Placebo Cross-over DenosumabLong-term Denosumab

a

FREEDOM Extension

-2

-1

0

1

2

3

4

5

6

7

8

9

10

b

bb

b

b

b

b

b

a

a

a

a

a

a

a

a

9.2%c

7.4%c

b

b

Pe

rce

nta

ge

Ch

an

ge

Fro

m B

ase

lin

e

Study Year

1 2 3 4 50 6 7 8 9 10

Total Hip

a

Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23

OOC

Long-term Denosumab TherapyVertebral and Non-vertebral Fractures

Persistent or improved reduction in fracture risk


OOC

FREEDOM Years 1–3 Extension Years 1–7

Rates per 100 subject-yearsPlacebo

(N = 3883)

Cross-over Denosumab (N = 2206)

Long-term Denosumab(N = 2343)

All AEs 156.1 96.8 97.0

Infections 30.7 20.7 19.9

Malignancies 1.6 2.0 2.0

Eczema 0.6 0.9 0.9

Hypocalcemia < 0.1 < 0.1 < 0.1

Pancreatitis < 0.1 < 0.1 < 0.1

Serious AEs 10.4 10.1 10.3

Infections 1.3 1.4 1.5

Cellulitis or erysipelas < 0.1 < 0.1 < 0.1

Fatal AEs 0.8 0.8 0.8

Osteonecrosis of the jaw 0 < 0.1 < 0.1

Atypical femoral fracture 0 < 0.1 < 0.1

N = number of subjects who received ≥ 1 dose of investigational product. AE = adverse event.

Cumulative osteonecrosis of the jaw cases: 6 cross-over, 7 long-term. Cumulative atypical femoral fracture cases: 1 cross-over, 1 long-term.

Long-term Denosumab TherapySafety (Exposure-adjusted Subject Incidence of Adverse Events)

Bone HG et al. Lancet Diabetes Endocrinol 2017;5:513-23

Watts NB, et al. J Bone Miner Res 2017;32:1481-5

No increase in incidence of adverse events with long-term therapy

OOC

• In FREEDOM and its Extension, all oral adverse events were adjudicated by a committee of experts to identify cases consistent with ONJ

• 13 cases in FREEDOM Extension study (5.2 per 10,000 subject-years)

• 45% of responders to questionnaire during Extension reported at least one invasive oral procedures or event (OPE)

• ONJ incidence was higher in those reporting an OPE (0.68%) than not (0.05%)

• 212 patients had dental implants – no ONJ

• 6 of the 13 patients with ONJ had ill-fitting dentures

• Most cases resolved with conservative therapy or surgery while denosumab therapy was continued

• No literature found exploring use of denosumab after ONJ has healed

Denosumab and Osteonecrosis of the Jaw

Bone HG et al. Lancet Diabetes Endocrinol 2017;5:513-23

Watts NB et al. J Clin Endocrinol Metab 2019 Feb 13. doi: 10.1210/jc.2018-01965. [Epub ahead of print]

OOC

• RANK ligand is expressed in some lymphocytes

• What roles RANKL play in the immune system is unknown

• Adults with genetic syndromes of RANKL deficiency do not have immune dysfunction

• No laboratory signal of immune dysfunction on Phase 2 or 3 denosumab studies

• In FREEDOM study, numerically more serious adverse events related to infection in the denosumab arm (4.12%) vs the placebo group (3.45%)

• No imbalance in rates of opportunistic infections

Denosumab and Immune Dysfunction

Watts NB et al. Osteoporos Int 2012;23:327-37

OOC

FREEDOM Extension StudySafety

• In neither the long-term treatment group or the cross-over group

was there an increase in rate of infection

Watts NB et al. J Bone Miner Res 2017;32:1481-5

OOC

• No evidence of increased risk of infection in the studies with denosumab treatment (120 mg/month) in patients with skeletal

metastases (1, 2)

• Denosumab was well tolerated in 63 patients with solid organ transplant (3)

• No studies about the use of denosumab in patients with HIV


1. Xgeva prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf.

Accessed April 2, 2019

2. 2. Sun L et al. Am J Clin Oncol 2013;36:399-403

3. Brunova J et al. Front Endocrinol (Lausanne). 2018;17;9:162. doi: 10.3389/fendo.2018.00162. eCollection 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf

OOC

• The rate of hospitalized infection among patients (average age 72 years) with rheumatoid arthritis (RA) receiving denosumab for

osteoporosis (n=1340) concurrently with biologic agents for RA was

not increased compared to matched patients those receiving

zoledronic acid (n=4460).

• After adjustment, the HR of hospitalized infection for denosumab users was noninferior to that for ZA users (HR 0.89 [95% CI 0.69-1.15])


Curtis JR et al. Arthritis Rheumatol 2015;67:1456-64

OOC

• Summary: No effect of denosumab on immune function has been demonstrated – and no adverse effect has been observed with

denosumab therapy in patients with immune dysfunction

• But caution should be exercised when considering denosumab use in patients with known immune-related diseases


McClung MR. Personal opinion. 2019

OOC

Long-term Denosumab TherapyTotal Hip BMD

Perc

en

tag

e C

han

ge F

rom

Baselin

e


-2

-1

0

1

2

3

4

5

6

7

8

9

10

Study Year

1 2 3 4 50 6 7 8 9 10

Filling remodeling space

Secondary mineralization

Gradual decrease in cortical porosity

Persistent periosteal apposition

OOCOminsky MS et al. J Bone Miner Res 2015;30:1280-9

Effects of Denosumab on Remodeling and

Modeling in Cynomolgus Monkeys

OVX + Veh OVX + DMab

Remodeling was decreased but modeling-based formation

on perisoteum was maintained at the rib cortical bone in

cynomolgus monkeys treated with denosumab

Drugs may have

different effects on

different skeletal

surfaces

intracortical bone formation

(remodeling)

periosteal bone formation

(modeling)

OOC

Effects of Long-term Therapy on Total Hip BMD

1. Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23

2. Bone HG et al. New Engl J Med 2004; 350:1189-1199

3. Black DM et al. J Bone Miner Res 2015;30:934-44

Long-term Denosumab

FREEDOM Extension

-2

-1

0

1

2

3

4

5

6

7

8

9

10 9.2%P

erc

en

tag

e C

ha

ng

e F

rom

Baseli

ne

Study Year

1 2 3 4 50 6 7 8 9 10

4.6%

Zoledronic acid 5 mg/y3

Denosumab1

Progressive increase with

denosumab vs plateau

after 5 years with

bisphosphonates

OOC

BMD: Denosumab vs AlendronateTotal Hip BMD; Phase 2 Study

McClung MR, et al. N Engl J Med 2006;354:821-31

Placebo, N=46

Denosumab 60 mg Q6M, N=46

Alendronate 70 mg/wk, N=46

Time (Month)

-2

-1

0

1

2

3

0 2 4 6 8 10 12

% C

han

ge f

rom

Baselin

em

ea

n

SE

OOC

Switching From Bisphosphonates to Denosumab

Data are least-squares means and 95% confidence intervals. *p < 0.0001 denosumab vs BP.

(1) Roux C et al. Bone. 2014;58:48-54. (2) Recknor C et al. Obstet Gynec 2013;121:1291-9. (3) Kendler DL et

al. J Bone Miner Res. 2010;25:72-81. (4) Miller PD et al. J Clin Endo Metab. 2016;101:3163-70.

IBN

ALN

ZOL

RIS

1.6%*1.4%*

0.9%* 1.3%*

To

tal

Hip

Perc

en

t C

ha

ng

e F

rom

Baseli

ne

0.5% 0.9% 1.1% 0.6%2.0% 2.2% 1.9% 1.9%0.0%

1.0%

2.0%

3.0%

4.0%

vs RIS (1) vs IBN (2) vs ALN (3) vs ZOL (4)

Patients who had previously been treated with bisphosphonates

randomly assigned to a bisphosphonate or denosumab.

OOC

Denosumab Following Teriparatide

After 2 years of teriparatide, therapy was switched to denosumab

for 2 additional years

Progressive increases in BMD at spine and hip

Leder BZ et al. Lancet. 2015. pii: S0140-6736_61120-5

Shown in BLUE

Teriparatide Denosumab

Teriparatide Denosumab

Total HIP BMDLumbar Spine BMD

OOC

FNIH Meta-regressionChange in Total Hip BMD vs Reduction in Hip Fracture

MORE (RAL)

FIT II(ALN)

FIT I(ALN)

HORIZON(ZOL)

HIP(RIS)

FREEDOM (DMAB)

WHI

Clodronate

*Bubble size ~ to n fractures in study

R2=0.52

Bouxsein M et al. J Bone Miner Res 2019 Jan23. doi: 10.1002/jbmr.3641

OOC

Relationship Between On-Treatment Total Hip

BMD T-score and Non-vertebral Fracture Risk

Inc

ide

nc

e o

f n

on

-ve

rteb

ral

fra

ctu

re a

t 1

ye

ar

(%)

-3.0 -2.5 -2.0 -1.5 -1.0 -0.5

1.0

2.0

3.0

4.0

5.0

6.0

Total Hip T-score

Treating to a BMD target

may now be feasible

Ferrari S et al. J Bone Miner Res 2019 Mar 28

Current NV fracture risk

was strongly correlated

with on target hip BMD

Similar findings have been

reported with romosozumab and

alendronate (Cosman F. ASBMR

2018)

OOC

Treat to Target: An Evolving Concept

OOC

Long-term Denosumab TherapySummary

Over 10 years of denosumab therapy

• BMD at spine and hip increases progressively

• Improved mechanical strength in cortical and trabecular bone

• Fracture protection occurs early and persists

• No increasing incidence of adverse events

• The level of total hip BMD achieved on denosumab therapy correlates with current fracture risk

• Switching from bisphosphonates to denosumab produces progressive gains in BMD

OOC

Denosumab

Fracture protection

• begins within months of starting therapy

• persists with long-term therapy

• wanes when treatment is stopped

OOC

Discontinuing Denosumab: Phase 2 Study in Women With Low BMD

Adapted from Miller PD, McClung M et al. Bone 2008;43:222-29

PlaceboDmab 210 mg Q6MOpen-label alendronate

Discontinued

TreatmentLumbar Spine BMD

Perc

en

t C

ha

ng

e

(LS

Mean

±S

E)

Months

−4

−2

0

2

4

6

8

10

12

14

0 6 12 18 24 36 48

Serum CTx

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

0 6 12 18 24 30 36 42 48

Med

ian

ng

/mL

(Q1,

Q3)

Months

Discontinued

Treatment

Rapid loss of BMD to baseline due to

rebound in bone remodeling

OOC

*P < 0.001 at month 36 and = 0.05 at month 48 vs placebo.†P = 0.008 at month 36 vs placebo.

Adapted from Miller PD, et al. Bone. 2008;43:222-229.

Serum CTx BSAP

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

0 6 12 18 24 30 36 42 48

Me

dia

n n

g/m

L (

Q1

, Q

3)

0

5

10

15

20

25

0 6 12 18 24 30 36 42 48

Months Months

Med

ian

mcg

/L (

Q1,

Q3)

*

*

†

Adapted from Miller PD, McClung M et al. Bone. 2008;43:222-229.

Discontinuing Denosumab: BMDPhase 2 Study in Women With Low BMD

Discontinued

Treatment

Discontinued

Treatment

Placebo210 mg Q6MOpen-label alendronate

OOC

–6.7%

–5.1%

N = 10

N = 52

Discontinuing Denosumab After 8 YearsLumbar Spine BMD

Extension StudyParent Study

All on DMAb Treatment

–7

–5

–3

–1

1

3

5

7

9

11

13

15

17

19

21

01 3 6 12 18 24 36 48 60 72 84 961 108

16.8%

8.1%

N = 52

N = 10

McClung M et al. Osteoporos Int 2017;28:1723-32.

Observation

Study Month

Perc

en

tag

e C

ha

ng

e F

rom

Baseli

ne

Placebo Denosumab 60 mg Q6M Off-treatment

OOC

Vertebral Fractures After Discontinuing

Denosumab Therapy

• Several case series of patients have been reported who

experienced multiple and/or severe vertebral fractures within

3-18 months after discontinuing denosumab therapy. (1)

• Raised concern about “rebound” risk of fracture

Anastasilakis AD et al. J Bone Miner Res 2017;32:1291-6

OOC

Fracture Risk after Stopping Denosumab

• Subgroup of 797 subjects (470 placebo, 327 denosumab), who discontinued

study drug in FREEDOM after 2-5 doses.

• During the off-treatment period (median 0.8 years per subject), 42% versus

28% of placebo- and denosumab-treated subjects, respectively, initiated other

therapy.

Brown J.P et al. J Bone Miner Res 2013;28:746-52

Following discontinuation, similar percentages of

subjects in both groups sustained a new fracture

(9% placebo, 7% denosumab)

Fracture rate per 100 subject-years of 13.5 for

placebo and 9.7 for denosumab

Hazard ratio [HR] 0.82; 95% confidence interval

[CI], 0.49–1.38, adjusted for age and total hip BMD

T-score at baseline.

There was no apparent difference in fracture

occurrence pattern between the groups during

the off-treatment period.

OOC

Vertebral Fractures After Discontinuing

Denosumab or Placebo in FREEDOM Study

• Vertebral fracture risk was assessed in patients who discontinued either

placebo or denosumab in the FREEDOM study or who stopped

denosumab in the FREEDOM Extension study and who had a follow-up at

least 7 months after their last dose

• Fracture risk increased upon stopping denosumab but not to levels

greater than seen in those who stopped placebo

Vertebral fractures Multiple vertebral fractures

Cummings SR et al. J Bone Miner Res 2018;33:190-8

OOC

Fracture Risk after Stopping Denosumab

• Protection from vertebral fractures is quickly lost upon stopping denosumab

BUT

• There is no apparent excess or rebound in vertebral fracture risk upon stopping

therapy

McClung M. Personal opinion, 2019

OOC

0

2

4

6

8

0 12 24

Denosumab and Alendronate (DAPS Trial)Cross-over Treatment after 12 Months

Freemantle N et al. Osteoporos Int. 2012;23:317-26

Perc

en

t C

ha

ng

e F

rom

Baseli

ne

Months

Denosumab Alendronate

Switching from denosumab to alendronate, bone loss did not occur

Lumbar spine

Total hip

OOC

Discontinuing DenosumabChange in Prescribing Information

• A new caution has been added to Prolia label in USA and

several other countries

• Multiple vertebral fractures have been

reported following Prolia discontinuation.

• Consider transitioning to another

antiresorptive agent if Prolia is discontinued.

OOC

• There are very few reasons to consider stopping denosumab therapy

• If therapy is stopped after a year or more, consider options to prevent rapid bone loss and fracture risk

• At present, the most appealing strategy would be to treat with a bisphosphonate for 2 years and to then re-evaluate the patient. (1)

1. McClung MR. Cancel the denosumab holiday. Osteoporos Int. 2016;27:1677-82

OOCCamacho PM et al. Endocr Pract. 2016;22(Suppl 4):1-42

AACE Osteoporosis Treatment Guidelines - 2016

No prior fragility fractures or

moderate fracture risk

Alendronate, denosumab,

risedronate, zoledronic acid

Alternative: raloxifene

Prior fragility fractures or indicators of

higher fracture risk

Denosumab, teriparatide, zoledronic acid

Alternatives: alendronate, risedronate

OOC

Osteoporosis: Long-term Treatment Plan

Raloxifene

Bisphosphonate

Teriparatide

Denosumab

When concerned

about hip fracture

After 18-24 months

After 18-24 months

3-5 years

Low risk

High risk

Consider drug holiday

Re-treat

Denosumab Bisphosphonate1 dose ZOL

2 years ALNIf “target”

is met

OOC

Denosumab TherapyOther Indications

• Treatment to increase bone mass in men with osteoporosis at high

risk of fracture

• Treatment to increase bone mass in men and women at high risk of

fracture who are receiving hormone deprivation therapy for non-

metastatic prostate or breast cancer

• Treatment of glucocorticoid-induced osteoporosis in men and

women at high risk of fracture

PROLIA Prescribing Information, 2019

OOC

Denosumab TherapySummary

• Therapy with denosumab rapidly and effectively reduces the risk of

serious fragility fractures in women with postmenopausal

osteoporosis at risk of fracture

• effectiveness continues through at least 10 years of therapy

• No increase in incidence of adverse events with long-term therapy

• BMD increases progressively over at least 10 years of therapy

• Total hip BMD achieved on therapy correlates with current fracture

risk

• Switching from bisphosphonates or teriparatide to denosumab

results in progressive gain in BMD

• Upon discontinuing therapy, protection from vertebral fracture is

quickly lost


OOC


• Contraindications

• hypocalcemia

• pregnancy

• hypersenstivity

• as with other potent inhibitors of bone resorption, ensuring

adequate intakes of calcium and vitamin D is important

• Not contraindicated in patients with impaired renal function

• extra care to optimize calcium and vitamin D status is required in

these patients to avoid hypocalcemia


OOC


• Denosumab is

• an attractive first line agent for treating postmenopausal

osteoporosis

• the best current choice for long-term management of

osteoporosis


OOC

Thank you

Michael R. McClung, MD, FACP, FASBMR

Oregon Osteoporosis CenterPortland, Oregon, USA

[email protected]

Mt Hood, Oregon
mailto:[email protected]

efficacy and safety of long-term denosumab therapy ... y seguridad del... · ooc • overall, no...

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