Renagel Health Economics Advisory Board Great Fosters, UK 28 th -29 th June 2006.

Renagel Health Economics Advisory Board

Great Fosters, UK28th -29th June 2006

Welcome and Meeting Objectives


David Goldsmith


Introduction

David Goldsmith

Aims and objectives 1

Strengths and gaps DCOR 2001-2004 CMS and RINDresults • Which data are compelling and why? What are the key conclusions

about Renagel? Which data are inconclusive?

• What are the remaining gaps and how can we explain these gaps using other existing evidence outside of DCOR (prospective trials, retrospective studies, epidemiologic data, etc)?

• What are the remaining gaps for future research?


Strengths and gaps of the DCOR/RIND costeffectiveness analysis• Is the overall framework of the model robust and supportable from

a clinical perspective?• Is the overall framework of the model robust, transparent and does

it meet the standards set by NICE?• Is the data used appropriately from DCOR and other sources, or

are there better sources of data • Are the assumptions of the model reasonable and accurate, or how

can we improve them further from a clinical perspective?


How best to communicate the evidence to NICE,reimbursement and guidelines authorities

• What are the key benefits of Renagel that should be communicated to reimbursement authorities and guidelines/listings?

• How should the Renagel clinical-economic story be told?• Is the evidence convincing enough and how simple/complex should

the story be made? What is the sequence of the critical messages and supporting data in that story?

• What targets (first-line, sub-groups, etc) should we be aiming for versus expect in the NICE CKD guidelines

What we know and what we don’t know

As we know, there are knownknowns. There are things we knowwe know. We also know there areknown unknowns. That is to say we know there are some things we donot know. But there are also unknown unknowns, the ones we don't know we don't know.

0

10000

20000

30000

40000

50000

60000

70000

2000 2005 2010 2015 2020 2025 2030

Transplant

PD

HD

Roderick et al 2004

No. of patients

Year

The CKD Forecast for England

Dialysis – TariffsFinancial envelope (a strait-jacket ?)

• Dialysis• Hospitalizations• Transport / outpatients• Drug costs

– EPO

– phosphate binders

– ACEI / ARB

– statins

DRUGS

FIXED DIALYSIS COSTS

DRUGS

ERYTHROPOIETINS £3000+

CINACALCET £3-9000

SEVELAMER / FOSRENOL £1500


DRUGS



DRUGS


CINACALCET £9000

SEVELAMER / FOSRENOL £3000

PARACALCITOL £2000


DCOR 2-year CMS data summary - Mortality

• Primary endpoint (all-cause mortality): No significant difference between sevelamer and calcium (22% vs 23%).

• All-cause mortality in patients aged ≥65 years: Significant difference in favour of sevelamer compared to calcium (28% vs 32%).

• Cardiovascular mortality: No significant difference between treatment groups (11.8% vs 11.7%).

DCOR 2 year summary - Hospitalization

• Trend towards fewer all-cause, CV and other hospitalizations with sevelamer vs calcium.

• Anderson-Gill regression models showed significantly lower relative risk of all-cause hospitalization with sevelamer vs calcium (RR 0.88, 95%, p=0.011) and for other hospitalization (RR 0.82, 95%, p=0.0045).

• Sevelamer patients had significantly fewer days hospitalized for other causes compared to calcium group and a trend toward fewer days hospitalized for all causes (p=0.0644) and CV causes (p=0.0582).

DCOR 2 year summary - Medicare expenditures and clinical events

• Sevelamer patients had lower mean total, inpatient, skilled nursing facility and other Medicare allowable expenditures vs calcium patients primarily due to a difference in inpatient costs ($1546 vs $1779 PMPM).

• Sevelamer patients used significantly more vitamin D.

• The incidence of clinical events was lower for sevelamer in 22/30 types of inpatient event and 17/19 types of outpatient event.

RIND Kidney International 2005

• Subjects with no evidence of coronary calcification at baseline showed little evidence of disease development over 18 months (independent of phosphate binder therapy), while subjects with at least mild calcification had significant progression at 6, 12 and 18 months.

• Subjects treated with calcium showed more rapid and more severe increases in coronary artery calcification score (CACS) compared to those on sevelamer (p=0.056 at 12 months; p=0.01 at 18 months).

RIND Mortality (Spiegel, Poster at NKF 2006)

• 114 patients from the primary RIND study were followed for up to 5 years to determine the relationship between phosphate binder and mortality in patients new to haemodialysis.

• Baseline CACS was a strong predictor of mortality.• Mortality was significantly lower in subjects randomized to

sevelamer vs calcium (p=0.0214).• There was a trend toward improved survival with sevelamer for all

levels of baseline CACS, even when adjusted for baseline CV risk using the Framingham Risk Index.

• Conclusion: The results provide strong evidence that phosphate binder selection and calcification are integrally linked with mortality in dialysis patients.

What we don’t know

• Where does new data take us?• Is the current model fit for purpose?• Is a new model needed and what should it be like? • Is DCOR strong enough alone or do other data need to

be combined with it (eg RIND) ? • Do DCOR and/or RIND change current clinical practice? • How can the rationale convince in the clinical setting, ie

can it support arguments of cost at the clinical level?

Deliverables

• What is the minimum/probable/best destination for sevelamer?

• What are the specific targets en route and how can they be reached?

• What specific actions are needed?

• What is a realistic timeframe?

Business Overview

Doug JermasekSenior Vice President,

Global Marketing & New Product Development

The Genzyme Commitment

• Genzyme’s mission is to: – Address serious diseases with unmet medical needs – Provide breakthrough therapies and services that significantly improve patients’ lives

• Kidney disease is an illness in need of new solutions – The complexity and severity of kidney disease has lead Genzyme to focus on many

aspects of renal care

• Genzyme has made a long-term commitment to renal care– Clinical research– Product development – Education– Access– Support

Our Global Corporation

• Founded in 1981 • From small start up to more than 8,000 employees • Headquarters in Cambridge, MA, and presence in over

30 countries• Helping patients in more than 80 countries• 14 manufacturing sites• 9 genetic testing lab sites

Our Focus: Seeking Frontiers

Breakthrough therapies and services

Significant improvement to patients’ lives

Serious diseases with unmet medical needs =+ Patient-focused

Variety of technology platforms

Life-changing standard of care products

Creating sustainable value

Our Technology Platforms

• Protein therapies• Polymer therapeutics• Small molecule therapeutics• Biomaterials• Cell therapy• Gene therapy• Diagnostics products and services• Pharmaceuticals

Our Products

Cerezyme® imiglucerase for injection

Fabrazyme®agalsidase beta

Aldurazyme®laronidase

Campath®

alemtuzumab for injection

Clolar®

clofarabine

Thyrogen®

thyrotropin alfa for injection

Renagel®

sevelamer hydrochloride

Hectorol®doxercalciferol

Thymoglobulin®

Anti-thymocyte Globulin [Rabbit]

LSDs Renal

Synvisc®

hylan G-F 20

Carticel®

autologous cultured

chondrocytes

OrthopaedicsOncology/

EndocrinologyTransplant &

Immune Disease

Diagnostic Products and Services

Our Late-Stage Pipeline

Research Pre-Clinical Phase 1 Phase 2 Phase 3 Phase 4

Myozyme - Pompe disease

Synvisc - for hip U.S.

Tolevamer - C. difficile

Hylastan - OA of knee

Sevelamer Carbonate - kidney disease

DX-88 - hereditary angioedema

Campath - multiple sclerosis

Tasidotin HCL - cancer

Gene therapy - peripheral arterial disease

Cell therapy - ventricular restoration

Iron Chelator - iron overload diseases

Thyrogen - goiter

DENSPM - liver cancer

Renal Disease is a growing concern

CURRENTLY THERE ARE OVER 1 MILLIONDIALYSIS PATIENTS WORLDWIDE. THIS ISEXPECTED TO DOUBLE IN THE NEXT DECADE.2

Majority of CKD patients die before reaching Stage 5

1. U.S. Renal Data System, USRDS 2004 Annual Data Report; Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2004.

2. Lysaght MJ. Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol. 2002;13:S37-40.

3. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1-12.

4. U.S. Renal Data System, USRDS 1998 Annual Data Report. National Institutes of Health, Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1998. Cited by: National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification—Quick Reference Clinical Handbook. New York, NY: National Kidney Foundation; 2002.

1

Our Growing Focus on Renal Disease

RBRTRBRT PKDPKD

FSGSFSGS

Bone & Mineral Disease & Product Synergies

↓ ↓ Renal FunctionRenal Function

↑ ↑ Phosphate RetentionPhosphate Retention↓ ↓ 1,25 D Production1,25 D Production

↑ ↑ PTHPTH ↓ ↓ Ca+Ca+Decreased VDR Decreased VDR expressionexpression

Altered Parathyroid Gland Function Altered Parathyroid Gland Function Hyperplasia SHPT➙ ➙ Hyperplasia SHPT➙ ➙

CONSEQUENCESCONSEQUENCESRenal Osteodystrophy Fractures Calcification CV DiseaseRenal Osteodystrophy Fractures Calcification CV Disease

MORBIDITY & MORTALITYMORBIDITY & MORTALITY

↑ ↑ POPO44

HyperphosphatemiaHyperphosphatemia

Genzyme Renal Continuum of Care

HTN

CKD ESRD

DN

Fabry

APKD

FSGS

Un

der

lyin

g D

isea

se

CV Death

Infection

Transplant

Internal dvpt

GC-1008

RenaMed Collaboration

Tolevamer

Renagel ®

Fabrazyme ®Sevelamer carbonate

Alternate Phosphate Binder

Deferitrin

Renagel ®

ESRD

Thymoglobulin ®

ESRDCKDRenagel ®

Progression

Acute Renal Failure

SHPT

Hectorol ®

LR-103BCI-202

Renal Division Pipeline

Pre-Clinical

Phase 3Commercialized

ProductsPhase 2Phase 1

BCI 202BCI 202SHPTSHPT

Vials

1.0 mcg

HectorolHectorol

GC 1008GC 1008FSGSFSGS

CyclacelCyclacelPKDPKD

RenaMedRenaMedRBRTRBRT RenagelRenagel

AlternateAlternatePhosphatePhosphate

BinderBinder

SevelamerSevelamerCarbonateCarbonate

CKDCKD

Once-a-day Powder

TolevamerTolevamer

Renal Replacement Therapy for ESRD

• From a health economics standpoint, caring for ESRD patients is cost ineffective relative to other healthcare investments– yet most societies routinely provide dialysis

• Why are we so inconsistent in the way that we evaluate the economics of dialysis-related services?

• Dialyzers

• Vascular access

• Anemia management

• Binders

• In for a penny, in for a pound?

Lest we forget…

• Behind the products…

…there are economics

• Behind the economics…

…there is disease

• Behind the disease…

…there are patients

Thank You!

Renagel Clinical Overview


Robert Guiberteau

Clinical Overview

Health EconomicsAdvisory Board

Great Fosters June 28-29th 2006

Robert Guiberteau MD VP Global Medical Programs

consequences of hyperphosphatemiafrom the 60’s to the 90’s

PiPiCa **Ca **

PTH ResistancePTH ResistanceCalcitriolCalcitriol

Calcitriol ResistanceCalcitriol Resistance

PTH SecretionPTH Secretion

Parathyroid Cell GrowthParathyroid Cell GrowthIncreased Risk Increased Risk of Bone Diseaseof Bone Disease

Increased RiskIncreased Riskof Bone Diseaseof Bone Disease

consequences of hyperphosphatemiasince 1998

P

MortalityRisk of Calcification

Parathyroid Cell Growth

PTH Secretion

PTH Resistance

Ca++

Calcitriol Resistance

Calcitriol

the history of the paradigm shift

– 1996 Rapid progression of Coronary calcifications Braun

– 1997 Negative Calcium Balance??? Hsu

– 1998 Hyperphosphatemia as independant RRF Block

– 1999 Hyperphosphatemia, a silent killer? Amann

– 2000 Oral Calcium load is an independant RRF Goodman

– 2001 Calcifications predict outcome Blacher

– 2002 Calcifications, a modifiable risk factor Chertow

– 2004 Increased S.Calcium as independant RRF DOPPS

– 2004 Low PTH > High PTH as an increased RRF Stevens

High Serum Phosphorus Increases Mortality Risk

Serum phosphorus >6.5 mg/dL in 39% of patients

Block, et al. Am J Kidney Dis. 31:607-17. 1998

0.5

1

1.5

2

1.1 - 4.5 4.5 - 5.5 5.6 - 6.5 6.6 - 7.8 7.9 - 16.9

Serum Phosphorus Quintile (mg/dL)

Relative Mortality Risk (RR)

REFERENCE

1.00 1.00

1.02

1.18*

1.39**

*P = 0.03** P < 0.0001

association between mortality risk and serum phosphate in CKD patients

Block et al. JASN 2004 15: 2208–18

Serum phosphorus (mg/dL)

Rel

ativ

e ri

sk o

f d

eath

< 3 3–4 4–5 5–6 6–7 7–8 8–9 > 90

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2 Reference group

Multivariable-adjusted RR of death

n=40538

relationship between serum phosphate and morbi / mortality in patients with normal GFR

Tonelli M. Circulation 2005 112:2627-33

coronary calcifications in young adults

Goodman WG et al. N Engl J Med. 2000;342:1478-1483.

0.1

1

10

100

1000

10000

0 5 10 15 20 25 30 35

Age (years)

Cal

cifi

cati

on S

core

0.0

0.8

1.7

2.5

3.3

4.2

5.0

0 1 2 3 4

Arterial calcification score

CaC

O3

(g C

a el

emen

t/d

ay)

P<0.0001

arterial calcification score and daily dose of Ca containing PO4 binders

Guerin et al NDT 2002

calcification score

• Probality of all-cause survival according to calcification score. Comparison (log-rank test) between curves was highly significant ( Chi D =42.66 ; P<0.0001).

Calcification score : 0Calcification score : 0

0.250.25

0.500.50

0.750.75

11

00

00 2020 4040 6060 8080





Duration of follow-up (months)Duration of follow-up (months)

Pro

bal

ity

of s

urv

ival

Pro

bal

ity

of s

urv

ival

Blacher et al Hypertension 2001

smooth muscle cell matrix mineralization

Adapted from Yang Kidney Int 2004 66:2293-9

0.0

8.3

16.7

25.0

33.3

41.7

50.0

0 1 2 3 4Arterial calcification score

CR

P (

mg/

l)

arterial calcification score and CRP in ESRD patients

London et al NDT 2003

P<0.0001

absorption of phosphate binder

• Calcium : up to 20 %

• Aluminium : 0.06 – 0.10 %1

• Lanthanum : 0.00003 %2

1 De Broe ME et al. NDT 19:114-118, 20042 Joy MS Am J Kidn Dis 42:96-107, 2003

renagel a new phosphate binder

N H2

N H3C l

N H2

O

PO H

-OO

N H

N H3+

N H2

HH3P O4

+ HCl

H

Combination of anionic and hydrogen bonding.

4.5

5

5.5

6

6.5

7

7.5

8

8.5

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Weeks

Se

rum

P (

mg

/dl)

Ca (TTG)* Renagel (TTG)* Lanthanum** Ca (CARE)***

K/DOQI Limit

efficacy

* Chertow G. KI 2002 ** Hutchison A. WCN 2003Berlin*** Qunibi W. et al. KI 2004 65: 1914-1926

TTG: percentage change in coronarycalcification scores at 52 weeks

*Within treatment *Within treatment PP<0.0001; between treatment groups <0.0001; between treatment groups PP=0.02.=0.02.Patients with a baseline score >30.Patients with a baseline score >30.

0

5

10

15

20

25

30

35

Calcium Sevelamer

Me

dia

n P

erc

en

tag

e C

ha

ng

e

0

5

10

15

20

25

30

35

Calcium Sevelamer

Me

dia

n P

erc

en

tag

e C

ha

ng

e

25%*

6%

Chertow KI 2002

TTG: percentage change in coronary calcification scores at 2 years

p*: Wilcoxon signed rank test p**: Wilcoxon rank sum test -20

0

20

40

60

80

100

p*=0.99 p*=0.40

p*=0.108

p*=0.020p*=0.004

p*=0.000

p**=0.129

p**=0.239

p**=0.040

(%)

week 26 week 52 final (1.8-2 yrs)

Sevelamer (n=17)Calcium (n=23)

Asmus Nephrol Dial Transplant 2005 20:1653-61

0

20

40

60

80

100

120

140

Sevelamer Ca Salts

Me

dia

n I

nc

rea

se

CA

CS

0

20

40

60

80

100

120

140

Sevelamer Ca Salts

Me

dia

n I

nc

rea

se

CA

CS

RIND: Effects of Sevelamer and Calcium on Coronary Artery Calcification

The Median Absolute Increase in CACS at 18 Months Was 11-Fold Greater in the Calcium Treated Group Compared to the Sevelamer-Treated Group The Median Absolute Increase in CACS at 18 Months Was 11-Fold Greater in the Calcium Treated Group Compared to the Sevelamer-Treated Group

P=0.01P=0.01

In Patients New to HemodialysisIn Patients New to Hemodialysis

Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005

*Wilcoxon signed rank test, within group P<0.05 **Wilcoxon rank sum test, between group P<0.05

Trabecular** Cortical

Sevelamer

Calcium

Per

cen

t ch

ang

e (m

edia

n)

*

*

TTG: sevelamer and bone density

3

2

1

0

-1

-2

-3

-4

-5

-6

-7

Raggi et al. J Bone Miner Res. 2005;20:764–772

100

80

60

40

20

20

Change in coronary calcium score

Ag

atson

score

Change in trabecular bone attenuation

40

5

5

10

10

15

20

Ho

un

sfie

ld u

nit

s

TTG: change in bone attenuation and coronary calcium score

Sevelamer

Calcium salts

Raggi et al. J Bone Miner Res. 2005;20:764–772

0.0

7.5

15.0

22.5

30.0

0 1 2 3 4

Arterial calcification score

Ost

eob

last

su

rfac

e (%

) (%

)

London et al JASN 2004

P<0.0001

bone histomorphometry and arterial calcifications in ESRD

sevelamer hydrochloride restores bone in osteopenic OVX rats

BV/TV, Tr.nOsteocalcinMAR, BFR

BMDBV/TV

Boneformation

Restorationof lost bone

Boneresorption sC-telopeptide

Vukicevic Abstract ASN 2005

Reversal of the Adynamic Bone Disorder and Established Vascular Calcification in Chronic Kidney Disease by Sevelamer Carbonate Therapy

• “The LDLR-/- high fat fed mouse exhibits an adynamic bone disorder in the presence of CKD characterized by decreased osteoblast surface, decreased bone formation rates and normal osteoclast surfaces similar to the excess representation of the ABD as the form of renal osteodystrophy observed in human diabetic nephropathy.

• Treatment with sevelamer significantly increased osteoblast surfaces and bone formation rates ameliorating the adynamic bone disorder of the LDLR-/- high fat fed animals with CKD.”

Hruska K. Submitted for publication

Sevelamer and bone: clinical data

Impact of phosphate binders on bone histomorphometry: results of a one-year bone biopsy study

A. Ferreira J. Frazao H.Malluche

A. Ferreira J. Frazao H.MallucheSubmitted for publication

Trends in Activation Frequency

RenagelN=33

Calcium

N=35

Away from normal

Towards normal

0 %

9 %

3 %

12 %

No change 67 % 54 %

Towards normal

Away from normal

21 %

3 %17 %

14 %

renagel a efficient phosphate binder with additional benefits……..

• Bioindicators– Lowering LDL C– Lowering biomarkers of inflammation– Lowering biomarkers of oxydative stress (animals)– Lowering uric acid– Lowering serum glucose– Binding to p cresol, indoxyl sulfate and indole (in vitro)– Increasing serum fetuin A

• Intermediate indicators– Preserving RRF (animals)– Halting progression of CV calcifications– Maintening / Improving bone health

• Improving patient outcomes

new terminologies and recommendationsfrom osteodystrophy to CKD-MBD

Moe, Drueke Am J Kidney Dis 2004 43:553

Outcomes Evidence:DCOR Trial and CMS 3-Year results

RIND Trial Results


Jose Menoyo

Patients New to Dialysis and Established PatientsPatients New to Dialysis and Established Patients

Prevalence of Vascular Calcification in CKD-IV

40%

57%

83%

0%

20%

40%

60%

80%

100%

Russo et al RIND TTG

40%

57%

83%

0%

20%

40%

60%

80%

100%

Russo et al RIND TTG

*Russo et al AJKD 2004 (CrCl =33 ml/min)**Spiegel D et al. Hemod Internat 2004: 8:265***Chertow et al KI 2002

*Russo et al AJKD 2004 (CrCl =33 ml/min)**Spiegel D et al. Hemod Internat 2004: 8:265***Chertow et al KI 2002

*

**

***

Effects of Sevelamer and Calcium on Coronary Artery Calcification in Patients New

to Hemodialysis

RIND TrialBlock, GA, Kidney Int; Vol68(4): 1815-1824, 2005Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005

Objective

• The primary aims of this study were to assess the degree of coronary artery calcification in a cohort of patients new to hemodialysis, and to compare the impact of sevelamer vs. calcium-based phosphate binders on the development and progression of coronary artery calcification

Study Design

Sevelamer Extended treatmentRANDOMIZEw/in 90 days

of HD

0 EBCT scan

Titrate doseP < 6.5 mg/dL

Ca2+ < 10.2 mg/dL

USUAL clinical practice

Calcium binder

Extended treatment

6 mo 12 mo 18 mo EBCT scans

Titrate doseP < 6.5 mg/dL

Ca2+ < 10.2 mg/dLPTH 150-300 pg/mL

Maintain dialysate Ca=2.5 mEq/L

•Renagel patients can receive Ca supplementation at night.•Dialysate Ca concentration was maintained at 2.5 mEq/l (1.25 mmol/l) throughout the study period.

Effects of Sevelamer and Calcium on Coronary Artery Calcification

Screened (N=385)Screened (N=385)Screened (N=385)Screened (N=385)

Declined/Screen Failures (N=237)Declined/Screen Failures (N=237)Declined/Screen Failures (N=237)Declined/Screen Failures (N=237) Randomized (N=148)Randomized (N=148)Randomized (N=148)Randomized (N=148)

Calcium (N=75)Calcium (N=75)Calcium (N=75)Calcium (N=75) Sevelamer (N=73)Sevelamer (N=73)Sevelamer (N=73)Sevelamer (N=73)

Adverse Event (N=1)Adverse Event (N=1)Transplanted (N=3)Transplanted (N=3)

Death (N=1)Death (N=1)Other (N=4)Other (N=4)

Lost to Follow-Up (N=1)Lost to Follow-Up (N=1)Transferred to PD (N=2)Transferred to PD (N=2)



Lost to Follow-Up (N=1)Lost to Follow-Up (N=1)Transferred to PD (N=2)Transferred to PD (N=2)



Transferred to PD (N=2)Transferred to PD (N=2)



Transferred to PD (N=2)Transferred to PD (N=2)

Available for Analysis (N=55)Available for Analysis (N=55)(at Least 1 Post Baseline EBCT)(at Least 1 Post Baseline EBCT)




Baseline EBCT (N=67)Baseline EBCT (N=67)Baseline EBCT (N=67)Baseline EBCT (N=67) Baseline EBCT (N=62)Baseline EBCT (N=62)Baseline EBCT (N=62)Baseline EBCT (N=62)

In Patients New to Hemodialysis In Patients New to Hemodialysis

RIND Baseline Demographics

• Age: 59• BP: 149/80• Hg: 11.8• Ca+: 9.3• Phos: 5.3• Albumin: 3.6• PTH: 363• Creatinine: 7.4• Days from

1st HD to EBT: 84.6

• 42% Caucasian• 32% African-American• 62% Male• 57% Diabetic• 96% HTN• 23% History of CAD• 30% History of ASVD• 16% History of CHF


SevelamerSevelamer CalciumCalcium

PhosphorusPhosphorus 5.2 (0.9)5.2 (0.9) 5.1 (0.8)5.1 (0.8)

Corrected CalciumCorrected Calcium 9.1 (0.5)9.1 (0.5) 9.6 (.5)9.6 (.5) PP<0.05<0.05

Ca x PCa x P 47 (7)47 (7) 49 (8)49 (8)

PTHPTH 298 (152)298 (152) 243 (136)243 (136) PP<0.05<0.05

LDLLDL 60 (34)60 (34) 81 (26)81 (26) PP<0.05<0.05

AlbuminAlbumin 3.8 (0.3)3.8 (0.3) 3.8 (0.4)3.8 (0.4)

CRPCRP 9.1 (9.7)9.1 (9.7) 10.5 (10.3)10.5 (10.3)

Hypercalcemia Hypercalcemia (Ca>10.2mg/dl)(Ca>10.2mg/dl) 22%22% 54%54% PP<0.0001<0.0001

Severe Severe HypercalcemiaHypercalcemia(Ca>11mg/dl)(Ca>11mg/dl)

5%5% 24%24% PP<0.02<0.02


Mean (SD)Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005Mean (SD)Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005

Average Phosphorus Control by Binder

4.4

4.6

4.8

5.0

5.2

5.4

5.6

5.8

6.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Study Month

Se

rum

Ph

os

ph

oru

s

Renagel Calcium

4.4

4.6

4.8

5.0

5.2

5.4

5.6

5.8

6.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Study Month

Se

rum

Ph

os

ph

oru

s

Renagel Calcium

Mean Serum Phosphorus by Study MonthMean Serum Phosphorus by Study Month


Mean Serum Calcium by Study MonthMean Serum Calcium by Study Month

Mean Serum Calcium Level by Binder

8.5

8.7

8.9

9.1

9.3

9.5

9.7

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Study Month

Se

rum

Ca

lciu

m (

Co

rre

cte

d)

Renagel Calcium

8.5

8.7

8.9

9.1

9.3

9.5

9.7

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Study Month

Se

rum

Ca

lciu

m (

Co

rre

cte

d)

Renagel Calcium



0

50

100

150

200

250

300

350

Baseline 6 months 12 months 18 months

Me

dia

n C

AC

S

Sevelamer Calcium

N=54N=54 N=55N=55 N=51N=51 N=53N=53 N=45N=45 N=47N=47 N=40N=40 N=45N=45



0

20

40

60

80

100

120

140

Sevelamer Ca Salts

Me

dia

n I

nc

rea

se

CA

CS

0

20

40

60

80

100

120

140

Sevelamer Ca Salts

Me

dia

n I

nc

rea

se

CA

CS


The Median Absolute Increase in CACS at 18 Months Was 11-Fold Greater in the Calcium Treated Group Compared to the

Sevelamer-Treated Group

The Median Absolute Increase in CACS at 18 Months Was 11-Fold Greater in the Calcium Treated Group Compared to the

Sevelamer-Treated Group

P=0.01P=0.01



Percentage Among Subjects with Baseline Coronary Artery Scores >30Percentage Among Subjects with Baseline Coronary Artery Scores >30

Subjects With or Without Progression of Coronary Artery Calcium Scores

60

44

38

40

56

626 Months

12 Months

18 Months

Progression Regression/Stable

93

86

63

7

14

326 Months

12 Months

18 Months93

86

63

7

14

326 Months

12 Months

18 Months

Sevelamer Sevelamer Sevelamer Sevelamer CalciumCalciumCalciumCalcium

Progression of CACS = Greater Than 15% Increase from BaselineFisher Exact Test P Value <0.05 for Between Group Differences at 12 and 18 MonthsBlock, GA, Kidney Int; Vol68(4): 1815-1824, 2005

Progression of CACS = Greater Than 15% Increase from BaselineFisher Exact Test P Value <0.05 for Between Group Differences at 12 and 18 MonthsBlock, GA, Kidney Int; Vol68(4): 1815-1824, 2005


• Substantially greater proportion of patients new to dialysis had no visible coronary calcification compared with previous reports of patients on chronic hemodialysis

• Subjects with no evidence of coronary artery calcification upon initiation of dialysis showed little evidence of coronary artery calcification development during follow-up

• While all subjects with evidence of baseline coronary calcification showed progression over time, patients randomized to calcium-based binders experienced significantly more rapid and severe progression of disease than sevelamer-treated patients

Block, GA et al. Kidney Int 2005; 68:1815-1824 Block, GA et al. Kidney Int 2005; 68:1815-1824

Calcium Containing Phosphate Binders are Associated with Increased Mortality Risk in

Hemodialysis Patients Compared to

Sevelamer

DM Spiegel, P Raggi, A Bellasi, L Kooienga, GA Block

NKF Spring Clinical Meeting 2006

Mortality Analysis Comparing Baseline Calcium Score

Months

0 6 12 18 24 30 36 42 48 54 60 66

Su

rviv

al D

istr

ibutio

n F

unctio

n

0.00

0.25

0.50

0.75

1.00

CCS=0 CCS< 400CCS >= 400

No. at RiskCCS = 0 43 41 41 38 32 18 4CCS < 400 35 34 33 29 25 14 1 CCS >= 400 36 34 32 28 23 15 4

Survival by Baseline Coronary Calcium Score

P = 0.0035

Mortality Analysis Comparing Calcium Versus Sevelamer

Months

0 6 12 18 24 30 36 42 48 54 60 66

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

0.00

0.25

0.50

0.75

1.00

No. at RiskCalcium 60 57 54 49 38 22 5Renagel 54 52 52 46 42 25 4

Calcium Renagel

10 Deaths

24 Deaths

P = 0.0214

Survival by Binder Randomization

Mortality by Baseline Calcification Score

Summary

• Sevelamer confers a survival benefit over calcium-based phosphate binders

• Within each strata of coronary artery calcification sevelamer demonstrated a improved survival

• Baseline CACS as measured by EBCT scan is a strong predictor of survival in patients new to dialysis

DCOR: Dialysis Clinical Outcomes

Revisited

Outcomes Studies in Hemodialysis

HEMO Study (n=1,846)– Standard or high dose of dialysis and a low or high flux dialyzer – Risk of death from any cause was same for both dialyzer doses

and both dialysis groups

U.S. Normal Hematocrit Trial (n=1,223)– Patients with clinical evidence of congestive heart failure or

ischemic heart disease– Study terminated after 29 months because the group targeted to

normal values had a higher mortality rate

4D (n=1,255)– Diabetic patients randomized to atorvastatin/day or matching

placebo– Atorvastatin had no statistically significant effect on

cardiovascular death, nonfatal myocardial infarction, and/or stroke in patients

• Largest prospective randomized clinical outcomes trial conducted in the hemodialysis population

• First large scale head-to-head trial comparing clinical outcomes in patients randomized to alternative phosphate binder therapies

• Real-world study design– Broadly applicable across clinical practice settings– Health economic outcomes data allow for

analysis of cost-effectiveness

The DCOR Trial

DCOR Study Objectives

• Primary Objective– To compare the association of sevelamer use versus

calcium-based phosphate binder use on all-cause mortality in hemodialysis patients

• Secondary Objectives– To compare the association of sevelamer use and

calcium-based phosphate binder use with:• Cause-specific mortality (cardiovascular, infection, other)• All-cause and cause-specific hospitalization and morbidity• Medicare expenditures

Study Design

• Multi-center, open-label, parallel design trial

• Patients randomized to receive sevelamer or a calcium-based phosphate binder in a 1:1 fashion

• Randomization stratified by age, race, gender and diabetic status

• 1,000 patients per arm

• Patients enrolled from March 2001 through January 2002

• The treatment period was scheduled to go through December, 2004 for a total duration of at least 3 years

Patient Enrollment

• Inclusion criteria– > 18 years– On dialysis for > 3 months– Required phosphate binder therapy– Had Medicare as their primary insurance

• Exclusion criteria– Current dysphagia, swallowing disorders, severe

gastrointestinal motility disorders, or bowel obstruction

– Hypersensitivity to sevelamer

Statistical Methods

• Sample Size Calculation:

– Assuming a mortality rate of 200 per 1000 patient years in the control group, a two sided test, and a preserved overall significant level of 0.05

– A total of 1000 patients per treatment arm would provide 80% power to detect a 22% decrease in all-cause mortality

Statistical Methods

• Survival probabilities (Kaplan-Meier curves) were calculated for time to death by treatment group overall

• Cox regression models were run to determine relative risks and 95% confidence intervals adjusting for the following pre-specified prognostic factors (age, race, gender, diabetes, cause of ESRD, and vintage)

• Treatment interactions with each of the prognostic factors were assessed

• A statistically significant interaction was required as a gating step prior to subset analysis

Results

* Completers either died or followed through the end of the study. All patients dispensed study medication were included in the data analysis.

Patient DispositionRandomized

N = 2,103

Renagel N = 1,053

Calcium N = 1,050

Never DispensedN = 20

DispensedN = 1,033

Never DispensedN = 43

DispensedN = 1,007

Terminated Early (N=491)• Consent Withdrawn (N=61)• Investigator Decision (N=141)• Lost to Follow-up (N=98)• Adverse Event (N=50)• Renal Transplant (N=46)• Changed Dialysis Modality (N=25)• Other (N=70)

Completed Study*N = 516

Terminated Early (N=484)• Consent Withdrawn (N=62)• Investigator Decision (N=90)• Lost to Follow-up (N=107)• Adverse Event (N=81)• Renal Transplant (N=59)• Changed Dialysis Modality (N=22)• Other (N=63)

Completed Study*N = 549

Demographics

VariableSevelamer(N=1033)

Calcium(N=1007)

p-value*

Race [N (%)]

Caucasian Black Asian Other

508 (49)482 (47)

6 (1)37 (4)

479 (48)470 (47)

11 (1)47 (5)

0.36

Age

[Mean ± SD, (years)]

[Median (years)]

60 ± 14

62

60 ± 15

62

0.69

Gender [N (%)] Male Female

562 (54)471 (46)

546 (54)461 (46)

0.96

Diabetes Status [N (%)]

No Yes

509 (49)524 (51)

499 (50)508 (50)

0.93

* Fisher’s exact test for categorical variables and Wilcoxon rank sum test for continuous variables

Renal History

VariableSevelamer(N=1033)

Calcium(N=1007)

p-value*

Primary Cause of CKD [N (%)]

Diabetes Hypertension/Large Vessel Disease Glomerulonephritis Secondary GN/Vasculitis Interstitial Nephritis/Pyelonephritis Neoplasms/Tumors Miscellaneous Conditions Cystic/Hereditary/Congenital Disease

440 (43)342 (33)108 (10)

16 (2)24 (2)10 (1)66 (6)27 (3)

432 (43)338 (34)97 (10)22 (2)29 (3)8 (1)

47 (5)34 (3)

0.54

Dialysis Vintage [Mean ± SD, (months)]

[Median (months)]38 ± 39

24

38 ± 40

24

0.58


Laboratories (Mean + SD)

0.11

< 0.0001

< 0.0001

< 0.0001

0.60

< 0.0001

< 0.01

p-value*

1.6 ± 0.31.6 ± 0.3Kt/V

84.9 ± 31.069.0 ± 25.9LDL Cholesterol

160.8 ± 34.7145.6 ± 33.8Total Cholesterol

226278iPTH ^

53.6 ± 12.953.7 ± 12.0Calcium x Phosphorus Product

9.5 ± 0.79.2 ± 0.7Calcium

5.7 ± 1.35.8 ± 1.3Phosphorus

Calcium(N=843)

Sevelamer(N=843)

Parameter

* Wilcoxon Rank Sum Test ^ Presented as median

Results

All-Cause Mortality

Time on Study (Years)

Cu

mu

lati

ve I

nci

de

nce

of

All

-Cau

se M

ort

alit

y

CalciumSevelamer

1007 640 430 161 1033 656 449 195

No. at Risk

1 2 3 40

0.0

0.1

0.2

0.3

0.4

0.5

0.6

SevelamerCalcium

Primary endpoint results inconclusive across entire

study population

Primary endpoint results inconclusive across entire

study population

p = 0.30

Pre-Specified Subset Analysis

Variable

Gender[male/female]

Race[black/non-black]

Age[< 65 or ≥ 65 years]

Diabetes[yes/no]

Dialysis vintage≤ or > 2 years

Cause ESRDdiabetes, hypertension, other

Co

x R

egre

ssio

n M

od

el

p-value

0.67

0.84

0.03

0.35

0.83

0.82

Of the pre-specified variables, only age

demonstrated a statistically significant treatment interaction

Subset analysis of patients < or ≥ 65 years

was undertaken in accordance with pre-

specified statistical plan


Cu

mu

lati

ve I

nci

de

nce

of

All

-Cau

se M

ort

alit

y

No. at RiskCalciumSevelamer

556 366 245 98 585 381 253 99

0 1 2 3 4

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

SevelamerCalcium

Sevelamer therapy resulted in

a statistically significant reduction in the relative risk

for all-cause mortality in pre-specified subset[RR 0.78 (0.62-0.97)]

Sevelamer therapy resulted in

a statistically significant reduction in the relative risk

for all-cause mortality in pre-specified subset[RR 0.78 (0.62-0.97)]

↓ 22% p = 0.03

All-Cause Mortalityin Patients ≥ 65 years

All-Cause Mortality Patients < 65 years


Cu

mu

lati

ve I

nci

de

nce

of

All

-Cau

se M

ort

alit

y

No. at RiskCalciumSevelamer

451 274 185 62 448 275 196 97

1 2 3 400.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

SevelamerCalcium

p = 0.31

Results inconclusive for patients <65 years

Results inconclusive for patients <65 years

All-Cause Mortality for Patients Other Than the Pre-specified Age Cut-point (< or ≥ 65

years)

Age Cut point (years)

All 25 30 35 40 45 50 55 60 65 70

Rel

ativ

e R

isk

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Statistically significant reduction of relative risk for all-cause mortality was observed for patients >45 years of age

treated with Sevelamer

Statistically significant reduction of relative risk for all-cause mortality was observed for patients >45 years of age

treated with Sevelamer

Cause specific Mortality

• Results for CV and infection mortality were similar to all-cause mortality

• With only 53% of deaths due to CV causes, the study is not powered to detect differences in CV death

All-Cause Hospitalizations

0.0917 ± 32 5.8

15 ± 285.0

Number of Days Hospitalized[per patient year] Mean ± SD Median

0.062.3 ± 4.91.3

2.1 ± 4.41.0

Number of Hospitalizations[per patient year] Mean ± SD Median

p-value*Calcium(N=1007)

Sevelamer(N=1033)

Variable

* Wilcoxon rank sum test

Conclusions

• Results of the DCOR trial failed to reach statistical significance for the primary end-point of all-cause mortality (RR 0.91; p = 0.3)

• Statistically significant reduction in all-cause mortality was observed for patients receiving sevelamer in a pre-specified subset analysis of patients ≥ 65 years of age (RR 0.78, p = 0.03)

• A strong trend toward reduced hospitalizations in sevelamer-treated patients was observed (p = 0.06)

QUESTIONS?

DCOR study: CMS-based data analysis

Jeremy Heaton

Outline

• CMS data used in analysis• Study rules

• Randomized versus dosed population

• 90-day versus study completion follow-up

• Baseline data• Mortality• Hospitalization• Morbidity• Costs

CMS data background

• Medicare tracks vital status (mortality)• Medicare pays for:

– Dialysis procedures– Hospitalizations– Physician visits, outpatient procedures– Some IV medications (EPO, iron, vitamin D, antibiotics

administered in dialysis unit)– Other treatments, excluding most oral medications

• All payments occur following adjudication by Medicare• Payments finalized over time• Data presented reflect up to December 31, 2004

What are CMS data?

CMS = Centers for Medicare and Medicaid Services

USRDS 2004 Annual Data Report

Structure of the CMS database

Methods – patient matching

• 2101 patients in CMS database were matched to patients in the Case Report Form (CRF) database ITT population

• Patients were matched based on:– SSN

– first/last name initial

– date of birth

– dialysis initiation date

– gender

– race

– primary cause ESRD

Data used in CDRG data analysis

CRF• Baseline age, race, gender,

diabetes, vintage, ESRD cause• Randomization date, drug

dispensed date, stop date, study completion date

CMS• Pre-study comorbidities (CHF,

ASHD, other cardiac, PVD, CVA/TIA; diabetes-by CRF)

• CVD history (0, 1, ≥1)• Baseline Hb, URR, Vit D use• Death date and cause• Hospitalization date and cause• Morbidity (inpatient and

outpatient) and cause• Costs (total, inpatient,

outpatient, skilled nursing facility, other)

Randomized versus Dosed populations

• Analyses were conducted for both randomized and dosed populations (majority):– Randomized population – followed from date of randomization

– Dosed population – followed from date of first dose of study medication

Four rules used

Randomizationor first dose date

Study completion12/31/0312/31/04

+90 days

Early termination: withdrawal pt consent, renal transplant, modalitychange; investigator decision, lost-to-follow-up, adverse event, other

EventDeath (mortality analysis only)

HospitalizationMorbidity

Cost

Early termination

Importance of data captured by CMS

• Support results from prospective DCOR trial

• Provide additional details otherwise impossible without great expense– Hospitalization dates, causes, costs

– Morbidity (inpatient, outpatient), dates, causes, costs

– Cost breakdown

• Follow more early termination patients– More death, hospitalization events

Risk factors adjusted for in analyses

• Clinical trial– Age – Race– Gender– Diabetes status (2 categories)– Vintage– ESRD Cause

• CMS analysis– Age – Race– Gender– Vintage– Pre-study comorbidities

• Diabetes (per CRF-3 categories)• CHF• ASHD• CVA/TIA• PVD• Other cardiac

CMS 3-year results

• New data– Haemoglobin– URR– Vitamin D use– Baseline co-morbidities

• CHF• PVD• ASHD• CVA/TIA• Other cardiac

• 90-day (mainly) and SC follow-up data

Baseline characteristics

VariableTotal

(n=2038)Sevelamer(n=1031)

Calcium(n=1007)

p value*

Haemoglobin, g/dL

Mean ± SD Median

11.9 ± 1.311.9

11.9 ± 1.411.9

11.8 ± 1.311.8

0.9289

URR, n (%) < 60 % 60- < 64 % 65- < 70 % 70- < 75 % ≥ 75% Unknown %

99 (5)123 (6)

371 (18)612 (30)706 (35)127 (6)

54 (5)61 (6)

198 (19)308 (30)343 (33)

67 (7)

45 (5)62 (6)

173 (17)304 (30)363 (36)

60 (6)

0.6696

Vitamin D use, n (%) No Yes

687 (34)1351 (66)

339 (33)692 (67)

348 (35)659 (65)

0.4261


Baseline characteristics: Dosed populationHb, URR, vitamin D use

VariableTotal

(n=2038)Sevelamer (n=1031)

Calcium(n=1007)

p value*

Cardiovascular History #

[N (%)]

0.9269

0 co-morbidities 686 (33.7) 351 (34.0) 335 (33.3)

1 co-morbidity 491 (24.1) 248 (24.1) 243 (24.1)

> 1 co-morbidity 861 (42.2) 432 (41.9) 429 (42.6)


Baseline characteristics: Dosed populationCardiovascular comorbidities

Mortality

All-cause mortalityKaplan-Meier survival curves of time to all-cause mortality, by treatment (90-day follow-up rule, ITT population)

p = 0.5332

Hospitalization

Multiple hospitalizations (per 100 patient-years)

Sevelamer Calcium p value

All-cause 170 191 0.02

CV 55 60 0.05

Infection 25 30 0.11

Vascular Access 33 34 0.94

Fracture 3 3 0.21

Other 55 64 0.10

Hospital days (mean per patient-year)Dosed population, SC rule

12.1

3.7

2 2

0.38

3.9

13.9

4

2.72.2

0.48

4.6

0

2

4

6

8

10

12

14

All-cause CV Infection VA Fracture Other

Me

an

ho

sp

ita

l da

ys

pe

r p

ati

en

t y

ea

r

Sevelamer Calcium

p=0.052

p=0.06

p=0.1 p=0.85

p=0.21

p=0.155

p value: Wilcoxon rank sum test was usedFollow-up time calculated as total number of patient-years at risk of hospital admission including time in hospitalUnadjusted analyses

Relative Risk for Multiple Hospitalization

Adjusted for demographics and pre-study comorbidities, dosed population

0.4 0.6 0.8 1.0 1.2 1.4 1.6

All-cause

Fracture

Other

Sevelamer (Referent: Calcium)

Cardiovascular

Infection

Vascular access

p < 0.05Relative Risk

10.2.1.1Genzyme Corporation Protocol GTC-68-401Centers for Medicare and Medicaid Services Data Analysis

Multiple Hospitalizations (Anderson-Gill Regression Model)

Relative Risk for Days Hospitalized Per 100 Patient Years

Adjusted for demographics and pre-study comorbidities, dosed population

10.2.1.1

0.4 0.6 0.8 1.0 1.2 1.4 1.6

Sevelamer (Referent: Calcium)

All-cause

Cardiovascular

Infection

Vascular access

Fracture

Other

p < 0.05Relative Risk

Genzyme Corporation Protocol GTC-68-401Centers for Medicare and Medicaid Services Data Analysis

Hospitalization days per patient (Poisson Main-Effects Regression Model)

Morbidity

Morbidity analyses

• Categories– Cardiovascular (CV)

– Vascular access (VA)

– Infection

– Fracture

• Included both inpatient and outpatient events

• Rules were created to avoid counting same event twice

Morbidity results (adjusted analyses)

• First morbidity (Cox regression analysis)– Final Model: All RR (when no interactions) favour sevelamer, but all

are NS• CV: interaction with CVA/TIA (SC only)• VA: interaction with diabetes (90 d, SC)• Infect: interaction with dialysis duration (90 d only)

• Multiple morbidity (Anderson-Gill model)– Final model: All RR favour sevelamer, but all are NS

• VA: interaction with diabetes (90 d, SC), • Fracture: interaction with ASHD (SC only); too few events to

evaluate

Cost analysis

Mean Annual Medicare costsDosed population, 90-day follow-up

$66,348 $68,688

$18,528 $20,748

$44,760 $44,532

$960 $1,320 $2,088 $2,100

$0

$10,000

$20,000

$30,000

$40,000

$50,000

$60,000

$70,000

Total Inpatient Outpatient Skilled nursingfacility

Other

Sevelamer

Calcium

($2,340) ($2,220) $228 ($360) ($12)

(3.5%) (12.0%) 0.5% (37.5%) (0.6%)

Difference:

Inpatient actual annual cause-specific costsDosed population, 90-day follow-up

$6,240

$4,176

$5,316

$6,432

$5,916

$4,128

$2,592$3,372

$0

$5,000

$10,000

$15,000

$20,000

$25,000

Sevelamer Calcium

Other

Infection

Fracture

VA

CVD

Annual Medicare allowable expenditures: selected sub-groupsDosed population, 90-day follow-up

p = 0.034

$50,000

$55,000

$60,000

$65,000

$70,000

$75,000

$80,000

Total >=65 Diabetic Dialysis<2 yrs

Me

an

pa

tie

nt co

st p

er

ye

ar

Calcium

Sevelamer

p = 0.030

p = 0.028

p = 0.063

N 934 961 428 415 468 484 454 473

Total cost per patient shown

Summary – mortality

• All-cause and cause-specific mortality NS at 3 yrs

• Trend for sevelamer benefit is seen for all-cause and other cause mortality

• CRF and CMS results are consistent using 90-day rule, even though more deaths captured by CMS data

• Significant age interaction seen with all-cause mortality

Summary – hospitalization

Multiple hospitalization (Anderson-Gill)• Dosed population, 90-day rule

– Positive sevelamer effect on all-cause (RR=0.9, p=0.05) and ‘other’ (RR=0.85, p=0.02), but not CV hospitalization

• Dosed population, SC rule– Positive sevelamer effect on all-cause (RR=0.89, p=0.01), infection (RR=0.03) and

“other” (RR=0.86, p=0.02), but not CV hospitalization

• Diabetes: significant interaction in multiple analyses

Hospital days (Poisson regression)• All-cause: Positive sevelamer effect seen with both 90-d (RR=0.84, p=0.01) and

SC (RR=0.86, p=0.02)• Infection: Positive trend with 90-d (RR=0.78, p=0.06), positive effect with SC

(RR=0.76, p=0.02)• ‘Other’: Positive effect with 90-d (RR=0.81, p=0.04) only, trend with SC

(RR=0.86, p=0.11)

Summary – morbidity

• First morbidity (adjusted, Cox regression): – All RR (when no interactions) <1 favouring sevelamer, but all are NS

– Scattered interactions; not consistent

• Multiple morbidity (adjusted, Anderson-Gill model):– All HR < 1 favoring sevelamer, but all are NS

– Scattered interactions; not consistent

Conclusions

• There was no statistically significant difference for all-cause mortality overall.

– All-cause mortality was significantly reduced by 19% in patients over 65 years.

• All-cause hospitalisation was significantly reduced by 10 %.

• Overall, sevelamer resulted in less Medicare expenditure, reducing inpatient expenditure by 12.0% annually.

• Expenditures were consistently less for sevelamer in sub-groups, including:

– older patients

– diabetic patients

– patients on dialysis for at least 2 years.

DCOR study: CMS-based data analysis

Principal Investigator Wendy L. St. Peter, Pharm.D., FCCP, BCPS

Principal BiostatisticianJiannong Liu, Ph.D.

BiostatisticiansQiao Fan, M.S. and Eric Weinhandl, M.S.

Company Chronic Disease Research Group

Discussion and Conclusions


Debrief Day OneWorkshop One: Weighing the Evidence


Group A: Orangery Group B: Mowbray

Share Discussion from Workshop One


What Price Health?What Price Health?The case for sevelamerThe case for sevelamer

Heba Elgazzar MScHeba Elgazzar MSc

Global Health Outcomes GenzymeGlobal Health Outcomes Genzyme

OverviewOverview

ContextContext

Health Economic AnalysisHealth Economic Analysis

Conclusions and QuestionsConclusions and Questions

ContextContext

Health Care in CKDHealth Care in CKD


WHO Goal by 2015: Reduce mortality in chronic

diseases by 2% annually

Number of dialysis patients:

1.45 millionSource: WHO ‘Preventing chronic diseases: a vital investment’, 2006; Fresenius Annual Report, 2005.


Dialysis is the only treatment in the world for which all

governments pay.

Source: Jonssen, Pharmacoeconomics 2005.

Annual Resources Per Annual Resources Per CapitaCapita

WHO, 2003; Romão Jr, 2005; USRDS, 2003; IGES 2006; Grun et al, 2004.

$0

$10,000

$20,000

$30,000

$40,000

$50,000

$60,000

$70,000

Brazil USA Germany UK

General

Hemodialysis

Resources per patientResources per patient

Ploth et al, 2003; Romão Jr 2005; Grun et al, 2003.

1. Perceived Medical and Clinical Need: “Is it needed?”

2. Effectiveness: “Does it work?”

3. Budgetary impact and cost effectiveness: “Can we afford it and is it worth it?”

Key Questions asked by Key Questions asked by Health AuthoritiesHealth Authorities

Budgetary impact and cost effectiveness:

Health Economic Health Economic Analysis - AimsAnalysis - Aims

1.1. Demonstrate value-for-moneyDemonstrate value-for-money

2.2. Support reimbursement and Support reimbursement and patient access to health care patient access to health care coveragecoverage

Comparative evidence in Comparative evidence in ESRDESRD

Risk FactorRisk Factor Relative Relative Risk on Risk on

Mortality*Mortality*

InterventionIntervention

Kt/VKt/VVascular accessVascular access

1.161.161.231.23

Dialysis modeDialysis mode

Hg levelsHg levels 1.141.14 ErythropoeitinErythropoeitin

CholesterolCholesterol ---- StatinsStatins

Parathyroid Parathyroid hormonehormone

1.011.01 Vitamin D Vitamin D Cinacalcet Cinacalcet

PhosphatePhosphate 1.11 / 1/041.11 / 1/04 CalciumCalcium

LanthanumLanthanum

SevelamerSevelamer

*Port et al, 2004 DOPPS

Comparative evidence in Comparative evidence in ESRDESRD

Risk FactorRisk Factor Relative Relative Risk on Risk on

Mortality*Mortality*

InterventionIntervention MortalityMortality MorbidityMorbidity Quality Quality of Lifeof Life

Kt/VKt/VVascular accessVascular access

1.161.161.231.23

Dialysis modeDialysis mode ++++ ++++ ++

Hg levelsHg levels 1.141.14 ErythropoeitinErythropoeitin ---- ---- ++

CholesterolCholesterol ----

StatinsStatins ---- ---- ----

Parathyroid Parathyroid hormonehormone

1.011.01 Vitamin D Vitamin D Cinacalcet Cinacalcet

--------

+ + ----

--------

PhosphatePhosphate 1.11 / 1/041.11 / 1/04 CalciumCalcium ---- ---- ----

LanthanumLanthanum ---- ---- ----

SevelamerSevelamer ++ ++ ----

*Port et al, 2004 DOPPS

Health economics of Health economics of Sevelamer —Sevelamer —

Treat-to-Goal Predictive Treat-to-Goal Predictive modelmodelCVD events predicted per 100 patients in long-term:CVD events predicted per 100 patients in long-term:

Huybrechts et al. Value in Health 2005.

0

10

20

30

40

50

60

70

80

All CVD events Fatal CVD events

Ev

en

ts p

er

10

0 p

ati

en

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Sevelamer Calcium acetate

12%RR

12%RR

Treat-To-Goal Predictive ModelTreat-To-Goal Predictive Model

Huybrechts et al, 2005, Kidney International; Value-in-Health

Less CVD morbidity

Sevelamer predicted cost-effective

Predicted cost-effectivenessPredicted cost-effectiveness

Source: National Institute for Health and Clinical Excellence, 2002.

Sevelamer

DCOR: Economic DCOR: Economic ImplicationsImplications

Cause-specific hospitalizationsCause-specific hospitalizations ExpenditureExpenditure

DCOR All-cause DCOR All-cause HospitalizationsHospitalizations

0.090.0917 ± 32 17 ± 32 5.85.8

15 ± 2815 ± 285.05.0

Number of Days HospitalizedNumber of Days Hospitalized[per patient year][per patient year] Mean ± SD Mean ± SD Median Median

0.060.062.3 ± 4.92.3 ± 4.91.31.3

2.1 ± 4.42.1 ± 4.41.01.0

Number of HospitalizationsNumber of Hospitalizations[per patient year][per patient year] Mean ± SD Mean ± SD Median Median

p-value*p-value*CalciumCalcium

(N=1007)(N=1007)SevelamerSevelamer(N=1033)(N=1033)VariableVariable

* Wilcoxon rank sum testSuki et al, ASN 2005

Outcomes Benefit and ValueOutcomes Benefit and ValueConclusionsConclusions

50% less mortality over 5 years in incident patients

10% less hospitalisation in prevalent patients over 3 years

22% less mortality in patients over 65 years

34% less mortality in patients treated for at least 2 years

Net cost: - 4.0% to + 1.0% relative to calcium

Economic Evaluation Economic Evaluation QuestionsQuestions

Which treatment effects?Which treatment effects? Follow-up time?Follow-up time? Binder costs – compliance?Binder costs – compliance? Sub-groups?Sub-groups? Quality of life gains (due to less Quality of life gains (due to less

hospitalisation)?hospitalisation)? Sensitivity analysis parameters?Sensitivity analysis parameters?

Cost-Effectiveness Analysis (CEA)


Jörgen Möller and Paul Trueman

Sevelamer (Renagel) in the Management of CKD: A NICE

Perspective

Paul Trueman29th June 2006

Items for Discussion

Overview Sevelamer and NICE DCOR & RIND for the UK setting Key issues Summary

Overview

Aims To demonstrate the cost-effectiveness of

sevelamer (Renagel) in the management of chronic kidney disease in a UK setting

To incorporate data emerging from the DCOR and/or RIND trials

To ensure that the revised economic model is tailored for use in submission to NICE

Overview

Key Issues for today Comparison of Sevelamer with similar technology

appraisals from NICE; Application of emerging evidence (DCOR/RIND); Utility measurement; Model parameters (population and horizon); Costs.

Case Study: Cinacalcet NICE Review

“Cinacalcet hydrochloride is not recommended for the routine treatment of secondary hyperparathyroidism in patients with ESRD on maintenance dialysis therapy”

Implications for sevelamer Similar patient group, so can we expect a similar decision?

Case Study: Cinacalcet Incremental cost-effectiveness ratio

Manufacturer’s submission = £35,600 Assessment Group’s model:

Base case = £61,900 Inclusion of dialysis costs = £72,000 Alternative assumption = £43,000 Best case = £38,900 Treatment discontinuation = £57,400

“The committee concluded that cinacalcet hydrochloride was unlikely to be a cost-effective use of NHS resources”

Case Study: Cinacalcet Key differences between sevalamer and cinacalcet

Incremental cost-effectiveness ratio Comparator (‘cinacalcet + standard care’ versus ‘standard care

alone’)

“…it did not replace the need for dietary restrictions and the use of other medications such as phosphate binders and vitamin D sterols”

Sevelamer positioned as an alternative calcium containing phosphate binders

Cinacalcet positioned as an adjuvant to other therapies – less potential for cost offsets

Case Study: Cinacalcet Implications for sevelamer

“…there was a lack of data relating to long-term treatment”

“…there was considerable uncertainty in the extent to which intervening to correct derangements in the levels of PTH, calcium and phosphate (in particular by lowering PTH levels) was effective in reducing the risk of adverse events”

“…people on dialysis have many other factors that contribute to their risk of serious adverse events, and these add to the uncertainty in predicting clinical benefits from changes in surrogate markers”

Case Study: Cinacalcet Implications for sevelamer

Reviewing HTA report to determine how utilities, costs and mortality were addressed.

Patient Demographics Applying the DCOR and RIND results to the UK

population

UK (Renal Registry)

DCOR RIND

Age (years)

64.7 60.5 58.0

Male 62.0% 54.4% 63.0%

Patient Demographics

EthnicityUK (Renal Registry)

DCOR RIND

Caucasian 84% 48% 42%

Black 4% 47% 31%

Asian 10% 1% -

Other 3% 4% 27%

Patient DemographicsPrimary cause of ESRD

UK (Renal Registry)

DCOR RIND

Glomerulonephritis 10.4% 10.1% 7.0%

Pyelonephritis 7.0% 2.6% -

Diabetes 18.0% 42.7% 53.0%

Reno-vascular disease

7.5% - -

Hypertension 5.5% 33.3% 20.0%

Polycystic kidney disease

5.4% - -

Patient Demographics

Median vintage (prevalent patients)

UK (Renal Registry)

DCOR RIND

Vintage (years) 2.70 3.16 -

Discussion Point – Outcomes

Key outcomes from DCOR & RINDOutcome Suitable for model?

All-cause mortality Yes, but modelled to specify cause

CV mortality Yes, see above

Hospitalisations Only for costing purposes

Time to 1st hospitalisation No – only use overall rate

Medicare costs No, not representative of ‘real world’

Non-fatal CV events Yes, for quality of life and costing

Non-fatal other events Yes, for quality of life and costing

Change in calcification Not as main outcome (use as marker)

Discussion Point – Outcomes

Currently no utility data for patients with ESRD and adverse events (i.e. myocardial infarction)

Options: Elicit utility scores

Ideal, but insufficient time Obtain utility scores from literature

Search already undertaken Additional search from York, but no positive findings

Based on assumptions i.e. multiplicative (or additive) effect of AEs + ESRD, with

extensive discussion No use of utility (i.e. use life years only)

Discussion of likely impact (i.e. overestimation of benefits)

Discussion Point - Scenarios

Subgroup analysis Incident / prevalent patients Vintage Age Pre-end stage renal disease

Time horizon Lifetime (captures long-term benefits) Five-year analysis (to address issues relating to

lack of long-term data)

Discussion Point - Costing Should we include the cost of dialysis?

This will apply to both treatment arms (i.e. calcium binders and sevelamer)

However, increased life expectancy will be associated with increased costs

Are ‘background costs’ important when considering the cost-effectiveness of sevelamer?

NICE tend to account for all costs We should accommodate an alternative analysis

which includes dialysis costs in order to anticipate the Assessment Group’s approach.

Summary Sevelamer differs from cinacalcet submission

Improved ICER ‘Treatment versus treatment’ analysis, rather than ‘treatment

versus do nothing’

Are DCOR and/or RIND applicable to the UK setting? Approach towards cost-utility analysis Time horizon Subgroup analysis Inclusion of dialysis costs

Workshop Two: CEA Critique


Group A: Orangery Group B: Mowbray

Share Discussion from Workshop Two


NICE Discussion


Assessment and Recommendations:Presenting the Evidence to Health

Authorities Country by Country


Meeting Wrap-up


David Goldsmith

Renagel Health Economics Advisory Board Great Fosters, UK 28 th -29 th June 2006.

Documents

Transcript of Renagel Health Economics Advisory Board Great Fosters, UK 28 th -29 th June 2006.