Mary L. Bouxsein, PhDCenter for Advanced Orthopedic Studies

Department of Orthopedic Surgery, Harvard Medical School

MIT-Harvard Health Sciences and Technology Program

Boston, MA

16th Annual Osteoporosis Update Meeting

UCSF, July 2019

Denosumab Therapy for Osteoporosis

Disclosures

Consultant / Advisory board:

Agnovos Healthcare, Keros Therapeutics

Research funding:

Radius Health, Amgen

Outline

• Mechanism of action

• Effect on fracture risk

• Effect on bone turnover and BMD

• Long term treatment: BMD and fractures

• Safety & treatment cessation

Excess RANK Ligand Increases Bone Resorption

Bone Formation

Bone Resorption

Activated Osteoclast

CFU-GM PrefusionOsteoclast

MultinucleatedOsteoclast

Osteoblasts

Decreased Estrogen Leads to Increased RANK Ligand

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

RANKL

RANK

OPG

RANKL

RANK

OPG

Denosumab

Bone Formation Bone Resorption Inhibited

Osteoclast Formation, Function, and Survival Inhibited

Decreased Osteoclast Number and Function

CFU-GM PrefusionOsteoclast

Osteoblasts

HormonesGrowth FactorsCytokines

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

Denosumab Binds RANK Ligand PK and PD properties of Denosumab 60 mg Q 6

Serum denosumab

Serum CTX

Ser

um

co

nce

ntr

atio

n o

f d

eno

sum

ab n

g/m

l

McClung MR, et al. N Engl J Med. 2006;354:821-31 Vasikarin SD. Crit Rev Clin Lab Sci .2008;45:221-258

0

2

4

6

8

0 2 4 6 8 10 12Time (Month)

-80

-60

-40

-20

0

20

Seru

m C

TX

C

han

ge (%

) Fro

m B

aseline

Mean

S

E

Denosumab: fully human IgG2 antibody with very high affinity and specificity for RANK ligand

Denosumab Q 6 Month and Alendronate:

Serum C-telopeptide (Phase II Study)

-100

-80

-60

-40

-20

0

20

0 2 4 6 8 10 12Time (Month)

Placebo, N = 46

60 mg, N = 47

Alendronate 70 mg/wk, N = 45

Ch

ang

e (%

) F

rom

Bas

elin

eM

ean

S

E

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

Denosumab is a more potent but reversible inhibitor of bone

resorption than is alendronate

Outline

• Mechanism of action

• Effect on fracture risk

Denosumab FREEDOM Trial:Pivotal Phase III Study

Denosumab treatment reduces fracture risk over 3 years Phase 3: The FREEDOM Trial

40%(3%, 63%)P = 0.0362

20%(5%, 33%)P = 0.0106

68%(59%, 74%) P < 0.0001

7.2%

8.0%

1.2%

6.5%

0.7%

2.3%

0

1

2

3

4

5

6

7

8

9

New Vertebral* Nonvertebral† Hip†

Inc

ide

nc

e a

t M

on

th 3

6 (

%)

*Crude incidence†Kaplan-Meier estimate of incidence

(n = 3691)

(n = 3702)

(n = 3906)

(n = 3902)

(n = 3906) (n = 3902)

PlaceboDenosumab

Cummings SR, McClung M et al. New Engl J Med. 2009;361:756-765

ARR = 1.5% over 3 years

Denosumab effective in reducing hip fractures in high risk subgroups Phase 3: The FREEDOM Trial

Incidence represents Kaplan-Meier estimate at month 36

(n = 1406)2.8%

(n = 1384)

47%(8%, 70%)P = 0.0227

1.4%

(n = 1236)2.3%

62%(22%, 82%)P = 0.0065

(n = 1235)0.9%

40%(3%, 63%)P = 0.0362

(n = 3902)0.7%

(n = 3906)1.2%

Inci

den

ce a

t M

on

th 3

6 (%

)

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0% PlaceboDenosumab

Femoral Neck BMDT-score ≤ -2.5

Age ≥ 75Overall

Boonen S, McClung M et al. J Clin Endocrinol Metab. 2011 Jun;96(6):1727-36.

Outline

• Mechanism of action

• Effect on fracture risk

• Effect on bone turnover and BMD

BMD and bone turnover in Phase III study

Cummings SR, et al NEJM 2009; 361:756

LS BMD TH BMD

sCTX sP1NP

Outline

• Mechanism of action

• Effect on fracture risk

• Effect on bone turnover and BMD

• Long term treatment: BMD and fractures

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

RANDOMIZATION

Denosumab 60 mgSC Q6M

(N = 3902)

PlaceboSC Q6M

(N = 3906)

Long-termDenosumabTreatment

Cross-overDenosumabTreatment

Denosumab 60 mgSC Q6M

(N = 2343)

Denosumab 60 mgSC Q6M

(N = 2207)

Calcium and Vitamin D

FREEDOM Extension Study DesignInternational, multicenter, open-label, single-arm study

5

ExtensionFREEDOM

0

10

20

30

40

50

60

70

80

90

100ExtensionFREEDOM

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Effects of denosumab on bone turnover markers through 10 years

Placebo Cross-over DenosumabLong-term Denosumab

sCTX P1NP

Concentrations of the predose bone turnover markers sCTX and P1NP in subjects included in the BTM substudy. Dashed lines represent the premenopausal reference ranges: 0.20–0.90 ng/mL for sCTX and 17.4–61.6 µg/L for P1NP. Data are medians and interquartile ranges. Time points: baseline, month 1, and years 0.5, 1, 2, 3, 3 (day 10), 3.5, 4, 5, 6, 7, 8, 9, and 10.

ng

/mL

0 1 2 3 4 5 6 7 8 9 10Study Year Study Year

0 1 2 3 4 5 6 7 8 9 10

μg

/L

Bone HG et al. Lancet Diabetes Endocrinol. 2017;27:1677-82

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).

Placebo Cross-over DenosumabLong-term Denosumab

FREEDOM Extension

-2

-1

0

1

2

3

4

5

6

7

8

9

10

b

bb

b

b

b

b

b

a

a

aa

a

a

a

a

9.2%c

7.4%c

b

b

Per

cen

tag

e C

han

ge

Fro

m B

asel

ine

Study Year

1 2 3 4 50 6 7 8 9 10

Total Hip

a

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

tag

e C

han

ge

Fro

m B

asel

ine

b

b

aa

b

b

Study Year

1 2 3 4 50 6 7 8 9 10

a

Bone HG et al. Lancet Diabetes Endocrinol. 2017;27:1677-82

Effects of denosumab on BMD through 10 yearsEffects of therapy on total hip BMD through 10 years (not head to head studies!)

Long-term Denosumab

FREEDOM Extension

-2-10123456789

109.2%

6.8%Percentage

Change From Baseline

Study Year1 2 3 4 50 6 7 8 9 10

Total Hip BMD

4.6%

1. Bone HG et al. New Engl J Med. 2004; 350:1189-11992. Black DM et al. New Engl J Med, 2007; 2016

ZOL (5 mg/y)2

ALN (10 mg/d)1

Dmab

FREEDOM Extension

-2

-1

0

1

2

3

4

5

6

7

8

9

10

Effects of denosumab on total hip BMD andnonvertebral fractures through 10 years

b

bb

b

b

b

b

b

a

a

aa

a

a

a

a

9.2%c

7.4%c

b

b

Per

cen

tag

e C

han

ge

Fro

m B

asel

ine

Study Year

1 2 3 4 50 6 7 8 9 10

Total HipFREEDOM Extension

FREEDOM Extension

Yea

rly

Inci

de

nce

of

No

nve

rteb

ral F

ract

ure

s (%

)Y

earl

y In

cid

en

ce o

fN

on

vert

ebra

l Fra

ctu

res

(%)

1 532 4

1 2 3 4 865 7 9 10

6 7

Years of Denosumab Treatment

Years of Denosumab Treatment

Placebo Cross-over DenosumabLong-term Denosumab

a

Bone HG et al. Lancet Diabetes Endocrinol. 2017;27:1677-82

Non-vertebral fracture rate significantly lower with longer-term treatmentNon-vertebral fracture rate significantly lower with longer-term treatment

Ferrari et al, JCEM (online May 24, 2019)

Incidence of specific non-vertebral fractures with long-term denosumab treatmentIncidence of specific non-vertebral fractures with long-term denosumab treatment

Ferrari et al, JCEM (online May 24, 2019)

Both Lumbar Spine and Total Hip Only Total Hip

Denosumab treatment over 10 years enables asubstantial proportion of women with osteoporosis toachieve non-osteoporotic T-scores

Denosumab treatment over 10 years enables asubstantial proportion of women with osteoporosis toachieve non-osteoporotic T-scores

Years of Denosumab Treatment

0

20

40

60

80

100

Years of Denosumab Treatment

Pe

rce

nta

ge

of

Su

bje

cts

0

20

40

60

80

100

Ferrari et al JBMR (online March 19, 2019)

Relationship between total hip T-score and non-vertebralfracture risk

Inci

den

ce o

f n

on

-ver

teb

ral

frac

ture

at

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

DMAb (N = 3612)

Age ≥ 75 (N = 1118)

Age < 75 (N = 2494)

Total Hip T-score

Ferrari et al JBMR (online March 19, 2019)

Outline

• Mechanism of action

• Effect on fracture risk

• Effect on bone turnover and BMD

• Long term treatment: BMD and fractures

• Safety & treatment cessation

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

• Increased incidence of • skin rash (3.0% vs 1.7%)• cellulitis (12/3808 vs 1/3805)

• No renal or cardiovascular effects noted

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

• Less than 1% of patients developed binding antibodies over 2-8 years; none have developed neutralizing antibodies

Denosumab Ph III study: Safety and Tolerability

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

• Very few cases of ONJ (13) and AFF (2) were reportedin the FREEDOM Extension trial to 10 years (>50,000patient-years exposure)

• Rare cases of AFF in patients receiving denosumab inclinical practice have been described: most hadreceived previous bisphosphonate therapy

• There are too few cases of ONJ and AFF to knowwhether these events are related to denosumabtherapy or the duration of therapy

• Very few cases of ONJ (13) and AFF (2) were reportedin the FREEDOM Extension trial to 10 years (>50,000patient-years exposure)

• Rare cases of AFF in patients receiving denosumab inclinical practice have been described: most hadreceived previous bisphosphonate therapy

• There are too few cases of ONJ and AFF to knowwhether these events are related to denosumabtherapy or the duration of therapy

Osteonecrosis of the jaw and atypical femur fractures with denosumabOsteonecrosis of the jaw and atypical femur fractures with denosumab

Discontinuing denosumab: BMD changesPhase 2 Study in Women With Low BMD

Discontinuing denosumab: BMD changesPhase 2 Study in Women With Low BMD

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

Discontinued Treatment

Discontinued Treatment

Lumbar Spine Total Hip

Per

cen

t C

han

ge

(LS

Mea

n ±

SE

)

Months

6

4

2

0

2

4

6

8

Months

0 6 12 18 24 36 484

2

0

2

4

6

8

10

12

14

0 6 12 18 24 36 48

Placebo210 mg dmab Q6MOpen-label alendronate

*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

Med

ian

ng

/mL

(Q

1, Q

3)

0

5

10

15

20

25

0 6 12 18 24 30 36 42 48

Months Months

Me

dia

n m

cg

/L (

Q1

, Q

3)

*

*

†

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

Discontinuing denosumab: Bone Turnover MarkersPhase 2 Study in Women With Low BMD

Discontinued Treatment

Discontinued Treatment

Placebo210 mg Q6MOpen-label alendronate

–6.7%

–5.1%

N = 10

N = 52

Discontinuing denosumab after 8 yearsLumbar Spine BMD 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

Pe

rce

nta

ge

Ch

an

ge

Fro

m B

as

elin

e

Placebo Denosumab 210 mg Q6M Off-treatment

BMD declines after long-term denosumabcessation

BMD declines after long-term denosumabcessation

• 10 yrs dmab (n=9)

• 3 yrs PBO -> 7 yrs dmab (n=3)

• BMD measured 12 mo later

Popp et al, Osteop Int, 2018

Vertebral fractures after discontinuing denosumab therapyVertebral fractures after discontinuing denosumab therapy

• Many case studies and case series report vertebral fractures within 3-18 months after discontinuing denosumab therapy.1

• Many or most have had multiple and/or severe VFx

• Raised concern about risk of “rebound” VFx

• Similar to rapid loss of fracture protection when estrogen therapy is discontinued2

1) Anastasilakis et al, Osteop Int 2016; Aubry-Rozier et al, Osteop Int 2016; Popp et al, Osteop Int 2016; Lamy et al, JCEM 2017; Anastasilakis et al. JBMR 2017; Polyzos et al, Endocrin 2016; Tripto-Schkolnik et al Calcif Tissue Int 20182) Heiss G et al. JAMA 299:1036–45; McClung MR. Osteoporos Int. 2016;27:1677-82

Vertebral fractures increase after discontinuing denosumab or placebo in FREEDOM studyVertebral fractures increase after discontinuing denosumab or placebo in FREEDOM study

• Fracture risk increased upon stopping denosumab but not to levels greater than seen in those who stopped placebo

Vertebral Fracture Multiple Vertebral Fractures

Cummings et al, JBMR 2018

• Treat forever.

• Stop denosumab, follow with other anti-resorptivetherapy to consolidate BMD gains

-- Which therapy?-- When to give it?

Zoledronate after denosumab cessation Zoledronate after denosumab cessation

• 6 postmenopausal women with 7 years denosumab rx

• ZOL given 6 months after last dmab injection -> BMD measured 18-23 mo later

Reid et al, Osteop Int 2017

Denosumab discontinuation: known & unknown

KNOWN UNKNOWN

Persistence with Rx ~50% at 36 mo1 True incidence of VFx after discontinuation

Fast reversal of BMD gain & rapid increase in BTM’s

Whether treatment duration influences BMD loss, BTM risk and

risk of VFx after cessation

Increased risk of VFx after discontinuation, higher in those with

prevalent VFx

Optimal “consolidation” therapy: what, when & for how long?

10 yrs of treatment associated with continued BMD gain, low BTM, low fracture incidence and acceptable

safety profile

Whether prior rx with bisphosphonates attenuates

response to dmab discontinuation

1) Borek et al, Osteop Int 2019

ConclusionsConclusions• Mechanism of action

• Rapid and potent effect

• Effect on fracture risk• Reduction in fracture risk at all sites

• Effect on bone turnover and density• Greater than oral alendronate

• Long-term effect on bone density and non-vert fractures• Continued effects to 10 years

• Safety• Cellulitis; a few cases of ONJ, AFF; transient hypocalcaemia

(avoided by administration of calcium and vitamin D supplements), and if discontinuing denosumab- strongly consider treatment with another anti-resorptive agent for a few years.