New evidence in the treatment of

hyperphosphatemia

Contempory issues in management

Mario Gennaro Cozzolino

University of Milan

Italy

THE LINK BETWEEN BONE AND CARDIOVASCULAR DISEASE: THE CENTRAL ROLE OF PHOSPHATE

PP

Mortality

XPO4 Vit.D

Ca CarbonateCa Acetate

+ CalcitriolCa CarbonateCa Acetate

+ Calcitriol

Ca x PO4

Ectopic Calcifications

“….unless all of the calcium which is absorbed is laid in bonethe calcium content of the soft tissues may rise and renalfunctional deterioration increase.”

XPO4 Vit.D

Al- and Ca-freeP-binders

+ VDRAsAl- and Ca-freeP-binders

+ VDRAs(Paricalcitol)

Ca x PO4

Ectopic Calcifications

Calcimimetics

April 8th, 2010

Avoid Calcium………..

� Older age

� Male Gender

� Female post-menopausality

Diabetes� Diabetes

� Low bone turnover

� Prevalent vascular/valvular calcification

� Inflammation

Cozzolino M, Mazzaferro S, Brandenburg V, NDT 2011

Optimizing the Treatment of Hyperphosphatemia in Experimental Uremia Experimental Uremia

↑↑↑↑Pi

Consequences of Hyperphosphatemiaon Parathyroid Function

↑↑↑↑ PTH Secretion

↑↑↑↑ Parathyroid Cell Growth

Pi

Silver et al, Am J Physiol Renal Physiol 2002

Regulation of PTH mRNA Stability by Lanthanum Carbonate in CKD

PiPO4

3-Na+

Pi Osf2/Cbfa-1?

Pit-1

Phosphate Regulation of Vascular SmoothPhosphate Regulation of Vascular SmoothMuscle Cell CalcificationMuscle Cell Calcification

Osteocalcin

?

Jono et al, Circul Res 2000Cozzolino et al, Kidney Int 2005Cozzolino et al, J Nephrol 2011

Effect of PFA on Ca deposition in VSMCs

Ciceri P et al. Nephrol. Dial. Transplant. 2012;27:122-127

Effect of Lanthanum on Ca deposition in VSMCs

Ciceri P et al. Biochem. Biophys. Res. Commun. (2012), in Press

Pi 5 mM LaCl 50 µµµµM LaCl 100 µµµµM

Calciphylaxis Responsive to Lanthanum Carbonate

Chan MR et al, Wisconsin Medical Journal 2008

Optimizing the Treatment of Hyperphosphatemia in CKD Hyperphosphatemia in CKD

Change in serum Pi from baseline during 8 weeks of treatment

Lanthanum carbonate reduces serum phosphate levels in CKD 3/4: Randomized multicentre trial

Weeks of treatment

0 1 2 3 4 6 8

PlaceboLanthanum

Ser

um P

i cha

nge

from

ba

selin

e (m

mol

/L)

0.0

-0.05

-0.10

Baseline: placebo 1.74 ± 0.04 mmol/L, lanthanum carbonate 1.71 ± 0.03 mmol/L. *p<0.05 between treatments, analysis of covariance (ANCOVA) model. Data are least square mean ± SE. To convert mmol to mg/dL, divide by 0.323

Lanthanum carbonate

Placebo (n)

Lanthanum carbonate (n)

34

56

32

55

31

46

32

45

30

44

28

43

28

42

Ser

um P

i cha

nge

from

ba

selin

e (m

mol

/L)

-0.15

-0.20

-0.25

-0.30

Sprague S, et al. C JASN 2009

25D and 1,25D Levels Are not Affected by Lanthanum Carbonate in CKD Patients

Objective� Evaluate the bioavailability of oral Vit D supplements in CKD 3 and 4 patients under lanthanum carbonate therapy

Methods� Randomized, double-blind, placebo-controlled, phase 2

25D

0 1 2 3 4 5 6 7 80

40

60

Mea

n (S

E)

25D

(nm

ol/L

)

Weeks of treatment

Lanthanum carbonatePlacebo

1314Lanthanum 7

Lanthanum carbonate

� Randomized, double-blind, placebo-controlled, phase 2

� Study population: subgroup of the former study who had received prior VDRAs

Conclusions� In this study, lanthanum carbonate did not interfere with the bioavailability of oral vit D supplements in patients with CKD 3-4

Finn W, et al. Nephrol Dial Transplant 2008;1(Suppl 2):59. #SP101

1,25D

13913Placebo (n)

1314Lanthanum carbonate (n)

0 1 2 3 4 5 6 7 80

60

90

Mea

n (S

E)

1,25

D (

nmol

/L)

Weeks of treatment

Placebo

121013Placebo (n)

1012Lanthanum carbonate (n)

70

80

50

15

7

Optimizing the Treatment of Hyperphosphatemia in DialysisHyperphosphatemia in Dialysis

Pro

port

ion

of p

atie

nts

cont

rolle

d (%

)

K/DOQI target serum phosphorus3.5–5.5 mg/dL1.13–1.78 mmol/L

n = 39n = 44 n = 42

n = 4850.060.070.080.0

Efficacy of Lanthanum in Patients Converting From Other Treatments

� Serum phosphorus control with LaCO3 monotherapy

41% receiving ≥2 binders

Pro

port

ion

of p

atie

nts

cont

rolle

d (%

)

n = 35

n = 8

n = 39n = 44 n = 42

0.010.020.030.040.050.0

Hutchison AJ, NDT 2009

K/DOQI, Kidney Disease Outcomes Quality Initiative LOCF, last observation carried forward

Lanthanum Carbonate vs SevelamerDifferential Effects on Renal Osteodystrophy

Ferreira A et al. JASN 2008

D’Haese Kidney International, 2003 (63)S85:S73–S78

� Clinical study conducted in CKD 5 dialysis patients

� Directly compares the efficacy of Lanthanum vs SevelamerDirectly compares the efficacy of Lanthanum vs Sevelamer� Serum phosphate reduction

� Doses commonly used in clinical practice

� Compared serum phosphate reduction in terms of:� Magnitude at end of treatment

� Magnitude at 1 week

Trial design

� Prospective, multicenter, open-label, randomized cross-over study conducted in the US, Germany and the UK

� Subjects randomized to receive Lanthanum or Sevelamer for the first 4-week treatment period

� Subjects then received alternative binder for the second 4-week treatment periodweek treatment period

0−3 −1

Lanthanum

Sevelamer

4 10−2

Screening (1 week)

Washout (2–3 weeks)

Washout (2 weeks)

6

Week

R 1:1

Sevelamer

Lanthanum

Doseincrease after 1 week

Sprague SM, et al Clin Nephrol 2009

Fixed dose titration

� Subjects received predefined fixed doses for each treatment period

� Week 2 - 4 fixed dose based on that typically used in previous clinical trials1,2 and clinical practice3

Week 1 daily Week 2−4

1. Hutchison et al. Nephrol Clin Pract. 2008;110:15–23. 2. Chertow et al. Kidney Int. 2002;62:245–52 3. US DACON IMS Custom Basic Data Report, March 2006

Week 1 daily dose

Tablets/day Week 2−4 daily dose

Tablets/day

Lanthanum 2250mg 3 3000mg 3

Sevelamer 4800mg 6 6400mg 8

Sprague SM, et al Clin Nephrol 2009

Change in serum phosphate from baseline during treatment periods

-1

-0,8

-0,6

-0,4

-0,2

0

Lanthanum

Sevelamer

p=0.024

Leas

t squ

are

mea

n ch

ange

from

bas

elin

e se

rum

pho

spha

te le

vels

(m

g/dL

)

-2

-1,8

-1,6

-1,4

-1,2

Baseline Week 1 Week 2 Week 3 Week 4

p=0.438 p=0.599

p=0.028

Observed Case

Leas

t squ

are

mea

n ch

ange

from

bas

elin

e se

rum

pho

spha

te le

vels

(m

g/dL

)

Sprague SM, et al Clin Nephrol 2009

Treatment-emergent adverse events (safety populatio n)

Lanthanum Sevelamer

Any TEAE 44.7% 50.9%

Gastrointestinal Disorders 18.2% 23.3%Gastrointestinal Disorders 18.2% 23.3%

Diarrhoea 7.1% 7.4%

Nausea 8.8% 5.5%

Vomiting 5.3% 3.7%

Cardiac Disorders 4.1% 4.9%

Vascular Disorders 4.7% 3.7%

Sprague SM, et al Clin Nephrol 2009

The results from this study demonstrate interesting trends that support the suggestion from preclinical studies that

Sprague SM, et al Clin Nephrol 2009

suggestion from preclinical studies that Lanthanum Carbonate may be a more effective phosphate binder than Sevelamer Hydrochloride. These observations warrant further investigations in long-term studies.

Calcitriol + Lantanum (B)

Calcitriol

(A)Difference B-A

(95% CI) p-value

AUC0-48 (pg.h/mL) 429 318 111 (-48.9, 270) 0.171

AUC0-t (pg.h/mL) 429 318 111 (-48.9, 270) 0.171

Cmax (pg/mL) 47.0 49.7 -2.74 (-8.12, 2.63) 0.313Cmax (pg/mL) 47.0 49.7 -2.74 (-8.12, 2.63) 0.313

tmax (h) 4.00 2.00 1.27 (0.00, 2.48) 0.039

Calcitriol + Sevelamer(C)

Calcitriol(A)

Difference C-A (95% CI) p-value

AUC0-48 (pg.h/mL) 137 318 -181 (-338, -24.0) 0.024

AUC0-t (pg.h/mL) 137 318 -181 (-338, -24.0) 0.024

Cmax (pg/mL) 40.1 49.7 -9.62 (-14.9, -4.34) <0.001

tmax (h) 2.50 2.00 0.500 (-0.50, 1.46) 0.305

Pierce D, Nephrol Dial Transplant 2010

MAIN REMARKS

… Sevelamer carbonate significantly reduces serum concentrations ofexogenous calcitriol when co-administered with oral calcitriol…whereas lanthanum carbonate has no clinical relevant effects onwhereas lanthanum carbonate has no clinical relevant effects onexogenous calcitriol

… The most likely explanation for the effect of sevelamer is areduction in bioavailability through sequestering the fat-solublecalcitriol

… These findings may represent an important consideration inpatients with CKD who often require vitamin D supplementation

Avoid Calcium!

Cozzolino M, Mazzaferro S, Brandenburg V, NDT 2011

Avoid Calcium!

Cozzolino M, Mazzaferro S, Brandenburg V, NDT 2011

Avoid Calcium!

Cozzolino M, Mazzaferro S, Brandenburg V, NDT 2011

Avoid Calcium!

Cozzolino M, Mazzaferro S, Brandenburg V, NDT 2011

P

BONE-VASCULAR AXIS: THE ROLE OF PHOSPHATE

P

Mortality