[PPT] - We need drugs that New treatments, new mechanisms of action PowerPoint Presentation

SLIDE 1

7/25/2014 1 New Osteoporosis Treatments

Mary L. Bouxsein, PhD Department of Orthopedic Surgery Harvard Medical School, Boston, MA

Advisory Board: Merck, Amgen, Eli Lilly Research funding: Merck, Amgen

What we have today

Treatments that reduce the risk of vertebral

fractures by 50 to 80%

Treatments that reduce the risk of non-vertebral

fractures by 20-25%

– Non-vertebral fracture remain major source of disability % of days of disability due to different types of fractures

Results from FIT II Cummings et al, JAMA 2006

We need drugs that…

Maintain or promote bone formation
Strengthen cortical bone —> reduce NVFx
Are convenient for patient
Are cost-effective

New treatments, new mechanisms of action

Cathepsin K inhibitors

Odanacatib (ODN)

Anti-sclerostin antibodies

Romozosumab Blozosumab

Novel PTH Analogs

Abaloparitide (BA-058)

SLIDE 2

7/25/2014 2

Cathepsin K and Bone Resorption

CatK is a lysosomal protease highly expressed in osteoclasts, where it is

released during bone resorption.

CatK is the major protease responsible for degradation of type I collagen

Rodan SB et al. IBMS BoneKey. 2008;5:16–24.

Pennypacker B. et al., Bone, 2009

Global deletion of Cathepsin K in mice decreases bone resorption but increases bone formation

WT KO

WT KO WT KO

Serum CTx BFR/BS

Distal femur

How can cathepsin K inhibition lead to increased bone formation? Revisiting the ‘ ‘ ‘ ‘coupled’ ’ ’ ’ process of bone remodeling

MDGFs (IGF1, TGFß) “ “ “ “Clastokines” ” ” ”

Coupling of bone formation & resorption

Direct effects on osteoblasts?
Indirect effects via the osteoclasts and coupling?

Image courtesy of R. Baron

RANKL OPG

SLIDE 3

7/25/2014 3

CON OC CatK KO

WT KO

*

N.Oc/TA (/mm2)

# Oc

KO

BFR/TV (%/year)

* BFR

WT Lotinun, et al. J Clin Invest, Feb 2013

Genetic deletion of CatK in osteoclasts ↑Bone mass ↓Bone resorption ↑Bone formation ↑Osteoclast #

Bone Formation Bone Resorption

Osteoclasts have a dual function

Pharmacologic inhibition of CathepsinK Odanacatib

Odanacatib is a selective, and reversible nonbasic inhibitor of Cat K with minimal metabolism, which supports once weekly dosing in humans. Cat K 0.2 Cat B 1,034 Cat L 2,995 Cat S 60 IC50 (nM)

N H O H N N CF3 MeO2S F

IC50 = 50% inhibitory concentration; Cat = cathepsin.

Duong LT. BoneKey Reports. 2012;1. Article no. 67. Gauthier JY et al. Bioorg Med Chem Lett. 2008;18:923–928.

Leung et al. Bone, 2011

Human Osteoclasts

CON ODN-treated

Effects of reducing activity of CatK in the osteoclast

Same or increased

number of

steoclasts
Shallow resorption

pits

SLIDE 4

7/25/2014 4 ODN treatment increases avg. cortical thickness in femur of OVX monkeys

Cortical Thickness, mm

Central Femur

† p = 0.08 vs VEH

4.0 3.6 3.2 Veh ODN, mg/kg 6 30 #

Proximal Femur

1.6 1.4 1.2 † Veh ODN, mg/kg 6 30

Cortical Thickness, mm

Femoral Neck

# p<0.05 vs VEH Cusick et al. J Bone Miner Res. 2012;27:524–537.

VEH ODN

ODN increases periosteal bone formation in proximal femur of OVX monkeys

Proximal Femoral Periosteum (Rhesus monkeys @ 21-mo Tx)

Cusick T et al. J Bone Miner Res. 2012;27:524–537.

50 40 30 20 10 Mineralized Surface, % Veh ODN, mg/kg 6 30 0.8 Mineral Apposition Rate, µm/d Veh 0.6 0.4 0.2 120 Bone Formation Rate, µm3/µm2/y Veh 90 60 30

#

ODN, mg/kg 6 30 ODN, mg/kg 6 30

A B C #

Veh. ODN

TCY TCY

MS/BS MAR BFR

# P<0.05 vs Veh.

Human trials

Randomized trial (phase 2b)

Original: 2 year dose-ranging study
Postmenopausal women 45-85 years (N=399)
BMD T-score < -2.0 but not < -3.5
50 mg odanacatib vs. placebo (once weekly, oral)
After 2 years, randomly assigned to stop or continue

to 5 years

Langdahl et al. JBMR 2012

SLIDE 5

7/25/2014 5 Study design

PBO 3 mg 50 mg

PBO 50 mg 50 mg 50 mg PBO 50 mg 50 mg 50 mg PBO PBO 50 mg 50 mg PBO PBO 50 mg 50 mg PBO PBO 50 mg 50 mg

Years 1 & 2

(N=399)

Year 3

(N=189)

Years 4 & 5a

(N=141)

n=13 n=15 n=14 n=14 n=13 n=12 n=14 n=16 n=14 n=16 Women who entered the Year 4 to 5 extension

PBO = placebo.

aYear 6 to 10 extension in planning.

Langdahl B et al. J Bone Miner Res. Nov 2012

10 mg 25 mg

Lumbar spine BMD

PBO/PBO (n=14) ODN 50 mg/PBO/PBO (n=14) ODN 50 mg/50 mg/50 mg (n=13)

11.9% 0.8% –0.4%

Mean % change from baseline (SE)

15 0 3 1 6 12 18 24 36 48 60 54 42 30 14 13 12 11 10 9 8 7 6 5 4 3 2 1 –1 –2

Month

Langdahl et al. JBMR 2012 50 mg 50 mg Placebo Placebo

Femoral neck BMD

9.8% –1.6%

–0.5%

15 3 1 6 12 18 24 36 48 60 54 42 30 14 13 12 11 10 9 8 7 6 5 4 3 2 1 –1 –2

Month

PBO/PBO (n=14) ODN 50 mg/PBO/PBO (n=14) ODN 50 mg/50 mg/50 mg (n=13)

Mean % change from baseline (SE)

Langdahl et al. JBMR 2012 50 mg 50 mg Placebo Placebo

Effect of ODN on bone resorption markers

% change rom baseline (geometric mean ± ± ± ± SE) Month

100
75
50
25

25 50 75 100 18 36 54 6 12 24 30 42 48 60

uNTx/Cr ratio

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

Langdahl et al. JBMR 2012

SLIDE 6

7/25/2014 6 ODN: Bone turnover markers

Per-Protocol Population

* P<0.001 vs PBO 3.03

42.56

* * *

CTX

Geometric LS Mean Percent Change from Baseline (± ± ± ±SEM)

60
50
40
30
20
10

6 12 24

Month

10 20 18

*

1.99

Month Geometric LS Mean Percent Change from Baseline (± ± ± ±SEM)

50
40
30
20
10

10 6 12 24 18

11.06

* *

P1NP

ODN 50 mg OW N=74-76 Placebo OW N=78-80

Brixen et al, JCEM 2013 98:571-80

Iliac crest bone biopsies at 24 mo

(Ph III imaging study)

ODN 50 mg OW (n=5) Placebo OW (n=5) Osteoid Thickness, micron 5.06 (1.07) 5.60 (0.85) Mineral Apposition Rate, micron/day 0.58 (0.05)* 0.56 (0.10) Mineralizing Surface, % 5.52 (5.88) 6.32 (4.22) Mineralization Lag Time, day 21.03 (23.88)* 31.96 (36.63) Bone Formation Rate, Total Volume Referent, %/yr 18.72 (16.29)* 23.14 (13.94) Bone Formation Rate, Total Surface Referent, micron3/ micron2/ day 0.04 (0.03)* 0.03 (0.02) Eroded Bone Surface, % 1.90 (1.32) 1.66 (1.13) Activation Frequency /yr 0.47 (0.38)* 0.50 (0.30) Osteoclast bone surface, % trab surface covered by OC 0.93 (0.92) 0.35 (0.23)

*n=4

Brixen et al, JCEM 2013 98(2):571-80

Phase 3 Fracture Trial

Randomized, placebo-controlled
ODN (50 mg/wk) vs PBO
>16,000 subjects enrolled

– Age > 65 yrs – Low hip BMD, with or without prior vertebral fx

Phase 3 Fracture Trial: Updates

July 2012: study stopped early

“The study met its primary efficacy outcomes … and is being concluded early… Robust efficacy and a favorable benefit-risk profile… safety issues remain in certain selected areas”

May 2014: press release

“ODN reduced the risk of osteoporotic fractures vs. placebo, including vertebral, non-vertebral and hip fractures, … Among adjudicated adverse effects associated with odanacatib, morphea was reported uncommonly (<0.2%), with improvement after discontinuation of treatment, and femoral shaft fractures of an atypical type were rare (<0.1%). Both were higher than placebo. There were no reported cases of osteonecrosis of the jaw. “

Plan to file for FDA approval in second half of 2014

SLIDE 7

7/25/2014 7 New treatments, new mechanisms of action

Cathepsin K inhibition

Odanacatib (ODN)

Anti-sclerostin antibodies

Romozosumab Blozosumb

Sclerostin: Osteocyte-derived cytokine that inhibits bone formation

Sclerosteosis, van Buchem’

’ ’ ’s disease

- Due to mutations in gene SOST

Courtesy of C Lowik/W Van Hul Li et al, JBMR 2008

Sclerostin: protein encoded by gene SOST

– Potent inhibitor of Wnt signaling & bone formation – Deletion of SOST in mice: ↑bone mass – Sclerostin expression localized to

steocytes

Treatment of rats & monkeys with Sclerostin Antibody

SHAM OVX + VEH OVX + SclAb Li et al, JBMR 2009

VEH SclAb

Vertebral Strength

Ominsky et al, JBMR 2011

Phase 2 Study of Sclerostin Antibody (Romozosumab) in Postmenopausal Women with Low BMD

SLIDE 8

7/25/2014 8 Phase 2 Study Design

McClung et al, NEJM 2014

Phase 2 Study Design

McClung et al, NEJM 2014 McClung et al, NEJM 2014

Romosozumab TPTD ALN PBO

Lumbar spine BMD Total hip and femoral neck BMD

SLIDE 9

7/25/2014 9 % Change in serum bone turnover markers: P1NP and CTX

P1NP CTX

New treatments, new mechanisms of action

Cathepsin K inhibition

Odanacatib (ODN)

Anti-sclerostin antibodies

Romozosumab Blozosumb

Novel PTH Analogs

Abaloparitide (BA-058)

Abaloparatide was selected to achieve

Potent and rapid bone anabolic activity
Limited effect on bone resorption
Room temperature stability

22 34

ABL hPTHrP hPTH

100% hPTHrP 38% hPTHrP

1

34

1

Abaloparatide is a novel analog of hPTHrP (1-34) Abaloparatide (BA058): Introduction

2 4 6 8 10 12 14 16

Week 12 Week 24 Week 48

Phase 2 Clinical Study: Spine BMD at 48 Weeks

% Change in BMD

Mean (SE) % Change in Lumbar Spine BMD from Baseline (Ext. pop, N=55)

Placebo Teriparatide ABL 20 µg ABL 40 µg ABL 80 µg

+0.7% +5.1% +9.8% +12.9% +8.6%

SLIDE 10

7/25/2014 10

0.5 1 1.5 2 2.5 3 3.5

Week 12 Week 24

Phase 2 Clinical Study: Hip BMD

% Change in BMD

Mean (SE) % Change in Total Hip BMD from Baseline (ITT, N=221)

Placebo Teriparatide ABL 20 µg ABL 40 µg ABL 80 µg

+0.4% +1.4% +2.0% +2.6% +0.5%

Weeks % Change from Baseline

Percent Change in PINP from Baseline

Bone Formation Markers

* * * * * * * * * * * * * * *

*p-value < 0.05 vs. baseline

TPTD

Bone Resorption Markers

Weeks % Change from Baseline

Percent Change in CTX from Baseline

Lower rise in CTX with BA058 compared with teriparatide

*p-value < 0.05 vs. baseline

* * * * *

TPTD

Summary

Cathepsin K inhibition (odanacatib)

– Bone formation sparing anti-resorptive, weekly oral – Persistent gains in BMD over 5 yrs – Decreases hip and vertebral fracture risk

Sclerostin inhibition (romozosumab, blozosumab)

– Potent anabolic with mild anti-resorptive effect, monthy SC – Effect on bone formation marker CTX gone by 6 mo

PTH Analog (abaloparatide)