New Treatments for Osteoporosis

No Conflicts of Interest

Clifford Rosen MD [email protected]

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OTHER WAYS TO TARGET THE OSTEOCLAST Cathepsin K is highly expressed in the osteoclast, where it is localized in the lysosomes and released during bone resorption.

Biological Roles of Mammalian Cysteine Cathepsins Epidermal Homeostasis L

Pro-enzyme Activation B, C

Rodan & Duong. BoneKey 2008

Apoptosis S, B

Cysteine Cathepsins

Cancer growth, metastases B, L, S, H

Antigen Presentation L, S, V

Bone Resorption K

Odanacatib is a selective, non-basic inhibitor of Cathepsin K with minimal metabolism and an excellent pharmacokinetic profile

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Cathepsin K Deficiency
Pycnodysostosis is a genetic disease

Frontal bossing

associated with cathepsin K deficiency (Gelb,et al.,1996; Schilling et al 2007)


Rare autosomal recessive skeletal dysplasia
~150 cases of pycnodysostosis reported worldwide


Short stature, acrosteolysis of distal phalanges and large fontanelles


High bone mass and increased fragility associated with high risk of fracture


Normal intelligence, sexual development and lifespan


Cat K null mice have osteopetrotic phenotype, but otherwise healthy

Schilling et al 2007

Proteolytic Pathways of Bone Collagen Degradation ICTP/CTx

NTx






1-CTP is C-terminal peptide of Col I generated by MMPs 1-CTP is cleaved by Cat K to generated CTX-I Inhibition of Cathepsin K leads to accumulation of serum 1-CTP Garnero et al., J. Biol.Chem. 2003. 7

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2

Dose Ranging Phase I/II

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10

11

12

3

Bone Resorption

Bone Formation

60 40

80

20

60

0

40

-20

20

-40

0

-60

-20

u-NTx

Odanacatib 50 mg + Vitamin D3 5600 IU OW

• Postmenopausal women age 45-85

• No previous hip fx at any time

Screening period

• No previous non-hip clinical fragility fx within 24 months • Not >1 prior clinical vertebral fx

-40 s-BSAP

s-CTx

Odanacatib Protocol 031 Study Design

R

Placebo + Vitamin D3 5600 IU OW

T-Score -3.5 at hip or spine, confirmed by DXA

Month 24

s-P1NP 1. 7 clinic visits (Screening & Months 0, 6, 12, 18, 23, 24) + follow up phone call

Placebo

ODN 3 mg

ODN 25 mg

ODN 50 mg

ODN 10 mg

2. Efficacy measurements [aBMD by DXA, vBMD by QCT (hip and spine) and HRpQCT (radius and tibia), FEA, BMx of bone turnover, subset of bone biopsies]

3. Safety measurements (AEs, safety labs, physical exam)

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Odanacatib: 4 Year Data Primary Endpoint: Lumbar Spine BMD (L1 to L4)

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10.7%

10

Lumbar Spine BMD (gm/cm2) % Change from Baseline (Mean ± SE)

Geometric Mean Percent Change from Baseline at Month 18

Biochemical Markers at 18 Months

8 6

4.8%

50 mg/50 mg/50 mg 50 mg/PBO/PBO PBO/PBO/50 mg

4 2

0.4%

0 -2 0 3 1 6

12

18

24

30

Month

36

42

48

Data for all women who entered year 4 extension. Last Observation Carried Forward

Binkley N et al ASBMR 2010

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PN 031- Change in s-CTx (pg/mL): Bone Resorption

Geometric LS Mean Percent Change (±SE)

Per-Protocol Population 20 10

3.03

0.70

-1.96

-1.44

0 -10

∆ = - 45.59 P 1000 IU Vitamin D daily, anabolic steroids, glucocorticoids within 6 months; nor bisphosphonates or fluoride within 12 months; T score < - 2.5 0.1 to 10 mg/kg SC Scl-MAb Safety, pharmacokinetics, bone turnover markers, BMD

Dose groups: Endpoints:

Spine Mean % Change from Baseline

Objective:

Total Hip

7 6 5 4 3 2 1 0 -1 -2 -3 28

56

84

Time (day)

Follow-up:

Up to 85 days Amgen Confidential. Do not copy or distribute.

Percent Change from Baseline (Mean ± SEM)

Percent Change from Baseline (Mean ± SEM)

100 50 0 -50

250 200

0

7

14

21

28

35

100 50 0 -50

42

49

56

63

70

77

84

Time (day)

0

7

14

21

28

35

42

49

56

63

70

77

84

Time (day)

I would skip this –except to say very strong analbolic effects Padhi D, et al. J Bone Miner Res. 2007;22(suppl 1):S37. Abstract 1129 and oral presentation. © 2007 Amgen. All rights reserved.

Amgen Confidential. Do not copy or distribute.

• There may be less inhibition of bone formation

150

-100

-100

© 2007 Amgen. All rights reserved.

• There are newer approaches to treating osteoporosis besides the bisphosphonates • CatK inhibitors suppress bone resorption, increase BMD, and may reduce fracture risk

10 mg/kg (N = 6)

5 mg/kg (N = 6)

150

84

Summary: New treatments

Phase 1 Study of Sclerostin Antibody in Healthy Postmenopausal Women: Anabolic Window Following Single SC Doses of 5 and 10 mg/kg

P1NP CTX

56

Time (day)

I would skip this – saying only that there are Phase 1 results

© 2007 Amgen. All rights reserved.

200

28

Padhi D, et al. J Bone Miner Res. 2007;22(suppl 1):S37. Abstract 1129 and oral presentation.

Padhi D, et al. J Bone Miner Res. 2007;22(suppl 1):S37. Abstract 1129 and oral presentation.

250

Placebo (N=7) 1 mg/kg (N=6) 3 mg/kg N=6) 5 mg/kg (N=6) Placebo (N = 7) 10 mg/kg 1 mg/kg (N =(N=6) 6) 3 mg/kg (N = 6) 5 mg/kg (N = 6) 10 mg/kg (N = 6)

Amgen Confidential. Do not copy or distribute.

• Monoclonal antibodies to sclerostin increase bone mass by enhancing bone formation • This biologic therapy has the potential to be the second anabolic approach for osteoporosis; however safety has not been established yet

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