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Cathepsin K Inhibitors for the Treatment of Bone Metastasis
E. Lindström1, L. Vrang 1, S. Sedig1, Y. Terelius
B.-L. 1, K. Sahlberg1, Wikström 1, B. Samuelsson 1, T.J.
Chambers 2, U. Grabowska1
1Medivir AB, Huddinge, Sweden; 2St George’s, University of London, London, UK
Abstract Potency and Selectivity in vitro MV076159
Vehicle (n=12)
Bone metastasis is characterised by excessive bone turnover 30 mol/kg (n=7) 3 mol/kg (n=4)
Human enzyme level 10 mol/kg (n=9) 3.5
10 mol/kg (n=9)
Plasma level (mol/L)
by osteoclasts. Cathepsin K is a lysosomal cysteine protease 1
3 mol/kg (n=4) 3.0 30 mol/kg (n=7)
CTX-I (ng/ml)
expressed abundantly in osteoclast cells. Numerous lines of Assay MV074942 MV076159 0.1
2.5
2.0
evidence support a pivotal role for cathepsin K in bone Cathepsin K 1.6 0.75 0.01 1.5
degradation and the development of cathepsin K inhibitors is 1.0
0.001
being pursued by many companies. Recently cathepsin K Cathepsin S 14000 19000 0.5
inhibitors have demonstrated efficacy in phase II trials, as 0.0001 0.0
measured by increased bone mineral density (BMD), in a dose Cathepsin L 1600 1800 0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time after dose (h) Time after dose (h)
dependent manner. Studies also show that inhibition of
Cathepsin B 1200 1300
cathepsin K can decrease bone degradation without negatively
impacting bone formation, differentiating this treatment from Cathepsin H >10000 >10000
currently available anti-resorptives such as bisphosphonates. A In vivo efficacy summary:
rationale for this augmentation of bone formation may arise Cathepsin V 1700 4000
Treatment Dose Max Inhibition Inhibition
from a new mechanism of action wherein cathepsin K inhibitors (μmol/kg) inhibition (%) at 24h (%) at 48h (%)
Cathepsin F 1700 2800
lead to the intact release of matrix-derived growth factors
Vehicle ~50 0 0
and/or PTH spikes. Additionally, cathepsin K is produced by All values are given as mean Ki in nM
cancer cells to promote cancer cell invasion and cathepsin K MV074942 28 78 53 3
inhibitors have been shown to reduce breast cancer-induced MV074942 and MV076159 display more than
osteolysis and skeletal tumour burden in such diseases as 1000-fold selectivity vs related cysteine MV076159 30 88 62 16
bone metastasis and osteoporosis. proteases
Medivir has now developed a series of novel, highly potent, • The inhibitors bind reversibly to cathepsin K • Significant reductions of CTX-I are present 24h
specific and non-nitrile warhead cathepsin K inhibitors. These enzyme with fast Koff after dose of cathepsin K inhibitor, despite minimal
inhibitors were additionally selected for their high potency in plasma exposure at this time point
inhibiting bone resorption by human osteoclasts in-vitro. The
pharmacodynamic effect of these inhibitors on attenuating bone • Effects of inhibitors are fully reversible
resorption was evaluated in vivo in young male cynomolgus Cellular level
monkeys. Plasma levels of the C-terminal telopeptides of Type
I collagen (CTX-I) was used as a collagenous bone resorption Assay MV074942 MV076159
marker. Oral administration of compounds (3, 10 and 30 μmol Human
/kg) to the animals resulted in a rapid reduction in CTX-I levels osteoclasts
44 34 Exposure vs Effect
within 2 h to a maximum of 75-95% after 4-8 hours. This Iip10
suppression of CTX-I was reversible with bone resorption 48000 23000
accumulation
marker returning to pre-treatment levels within 48 h.
All values are given as mean IC50 in nM 100
(corrected for vehicle)
AUC CTX-I inhibition
MV074942
MV074942 and MV076159 display approx 1000- 75
MV076159
Introduction fold selectivity at cellular level 50
25
Bone metastases comprise cancer cells that separate from 0
primary tumors and migrate to bone tissue where they settle
time-response: 300 nM -25
and grow. The presence of cancer cells in bone disrupts the
tight coupling between bone formation and bone resorption. A 160 -50
vicious cycle occurs where tumor growth triggers more bone 140
-10 -9 -8 -7 -6 -5 -4
(% of control)
resorption while more bone resorption liberates growth factors 120
100 log AUC exposure (molxh)
from bone which stimulate tumor growth. Cathepsin K inhibitors # #
not only prevent bone resorption but also allow bone 80
** ##
reformation to continue in contrast to approved and widely used 60
bisphosphonates and other anti-resorptives such as 40 *** ## * Degree of efficacy over 24h is significantly related to
denosumab which suppress bone formation. 20
** odanacatib compound plasma exposure over 24h
Besides the beneficial effects on the bone re-modelling 0 *** *** MV076159
cathepsin K inhibitors may assist in preventing the spread of MV074942: r2: 0.71, p<0.001
0 2 4 6 8 10 20
cancer to bone. The current summary describes the Time after washout (h) MV076159: r2: 0.64, p<0.001
pharmacology of two potent and highly selective cathepsin K
inhibitors on markers of bone resorption in cynomolgus
monkeys. After washout, MV076159 pre-treated osteoclasts
take a longer time to recover than odanacatib pre-
treated. This is likely due to the lysosomotropic nature
Methods of MV076159 and would predict enhanced efficacy Summary and Conclusions
• The potency and selectivity of the inhibitors were determined using • The two inhibitors described are potent and highly
recombinant human cathepsins K, S, L, H, F, V and B
• Functional reversibility of the inhibitors against cathepsin K was
PK and Efficacy in vivo selective inhibitors of human cathepsin K in vitro
assessed • Advantageous lysosomotropic properties of these
• Cellular inhibition of cathepsin K was monitored using a human compounds lead to no loss of selectivity at the cellular
MV074942 level coupled with prolonged efficacy in an osteoclast
osteoclast system as previously described
• Iip10 Accumulation, which reflects inhibition of cellular cathepsin S cell-based assay
Vehicle (n=10)
activity, was measured in a human EBV-B-cell line 28 mol/kg (n=7)
4 3 umol/kg (n=3) • The compounds are well-tolerated and inhibit
Plasma level (mol/L)
• Conscious cynomolgus monkeys were dosed p.o. with cathepsin K 0.1 10 mol/kg (n=7) 10 umol/kg (n=7)
circulating CTX-I levels by up to 88% in cynomolgus
28 umol/kg (n=7)
CTX-I (ng/ml)
3
inhibitor or corresponding vehicle between 7.00 a.m. and 9.00 a.m. 3 mol/kg (n=3)
monkey in vivo
Blood samples were drawn at various time points after dosing. 0.01
2
compound levels and CTX-I. • Efficacy duration exceeds plasma exposure, likely due
• The C-terminal degradation product of collagen Plasma samples
0.001 1 to a prolonged residence time in osteoclasts – the
were collected for analysis of type I (CTX-I) in plasma was measured 0
intended site of action
0.0001
using a commercially available kit (CrossLaps, IDS Nordic A/S, Herlev,
0 4 8 12 16 20 24 0 4 8 12 16 20 24
• The high potency and prolonged efficacy duration in
Denmark) Time after dose (h) Time after dose (h) vivo together with excellent selectivity renders these
• Compound levels in plasma were determined using reverse–phase compounds attractive candidates for clinical
liquid chromatography and electrospray tandem mass spectrometry development
(LC-MS-MS)
