Future directions for CKD anaemia Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and...

Future directions for CKD anaemia

Iain C Macdougall BSc, MD, FRCP

Consultant Nephrologist and Honorary Senior Lecturer

Renal Unit, King’s College Hospital, London, UK

Honoraria, lecture fees, grants from:-

Disclosure

Amgen

Ortho Biotech

Roche

Affymax

Shire

Lancet, 9th September 2006

Overview of erythropoiesis in CKD in 2007

Cellular and molecular mechanisms relevant to anaemia

Future therapies for stimulating erythropoiesis

Future developments in the management of CKD anaemia

Outline of presentation

Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4th ed. 2005;267-288.

SCF, GM-CSF, IL-3

SCF, IL-1, IL-3, IL-6, IL-11

PluripotentStem Cell

Burst-Forming Unit-Erythroid Cells (BFU-E)

Colony-FormingUnit-ErythroidCells (CFU-E)

Reticulocytes RBCsErythro-blasts

Proerythro-blasts

About 8 Days

Iron

Erythropoietin

Erythropoiesis in CKD

Pro-inflammatory cytokines (IL-1, TNFα, IL-6, IFNγ)

EPO production

EPO

+ +

Iron

Fas Ag

Apoptosis

─

hepcidin Fe absorption Fe transport Fe availability(EPO-R, Tf, TfR, Ferriportin, DMT-1)

─

Erythropoiesis in CKD

rHuEPO stimulates erythropoiesis by activating EPO receptors

membrane

Activation

EPO Receptor

rHuEPO

Signal Transduction

Growth and Differentiation

Activation of EPO receptors results in initiation of intracellular signalling pathways

Conformational change

Phosphorylation of JAK2,

a tyrosine kinase

Phosphorylation of EPO receptor

Initiation of intracellularsignalling pathways

membrane

Jak2Jak2

P

Jak2Jak2Jak2 Jak2

P P

P P

rHuEPO

Jak2Jak2P P

P PP

EPO receptor activation leads to activation of genes that promote erythropoiesis

membrane

nucleus

Jak2Jak2P

Survival, differentiation, proliferation, and maturation of RBC progenitors and precursors

Gene Activation

P

P

P

ST

AT

5

P


ST

AT

5

Gene Activation

P

PI-3-Kinase

Jak2Jak2P

SCH

MAPK

SOS

GRB

P

P

P

membrane

nucleus

EPO receptor activation leads to activation of genes that promote erythropoiesis

Jak2Jak2P P

P P

EPO,rHuEPO

EPO dimer EPO mimetic peptide

Darbepoetinalfa

membrane

C.E.R.A.Peg-rHuEPO

Signal Transduction


Gene Activation

Jak2Jak2P P

P P

Jak2Jak2P P

P P

Jak2Jak2P P

P P

Jak2Jak2P P

P P

Investigational

All ESAs have the same signalling pathway

Termination of EPO-receptor signalling

JAK 2JAK 2

S S

P P

P

P

EPO

P

Haemopoietic cell phosphatase

Internalisation and degradation

All ESAs have the same mechanism of action

Activation of the EPO receptor is the common mechanism by which all ESAs stimulate erythropoiesis

However, ESAs may differ from one another in:– Biophysical characteristics (e.g. molecular weight)– EPO receptor binding affinity– Pharmacokinetic properties (e.g. serum half-life,

clearance)

Weiss & Goodnough, NEJM, March 2005

Lancet 9th September 2006

I. EPO-receptor agonists

Protein-based ESA therapy

Epoetin (alfa, beta, delta, omega)

Biosimilar EPOs (epoetin zeta)

Darbepoetin alfa

C.E.R.A. (methoxy polyethylene glycol epoetin beta)

Synthetic erythropoiesis protein (SEP)

EPO fusion proteins

~ EPO–EPO

~ GM–CSF–EPO

~ Fc–EPO

~ CTNO 528

Small molecule ESAs

Peptide-based (e.g. Hematide)

Non-peptide based

II. Other mechanisms

Prolyl hydroxylase inhibitors (HIF stabilisers)

GATA inhibitors

Haemopoietic cell phosphatase (HCP) inhibitors

EPO gene therapy

I. EPO-receptor agonists

Protein-based ESA therapy

Epoetin (alfa, beta, delta, omega)

Biosimilar EPOs (epoetin alfa, epoetin zeta)

Darbepoetin alfa

C.E.R.A. (methoxy polyethylene glycol epoetin beta)

Synthetic erythropoiesis protein (SEP)

EPO fusion proteins

~ EPO–EPO

~ GM–CSF–EPO

~ Fc–EPO

~ CTNO 528

Small molecule ESAs

Peptide-based (e.g. Hematide)

Non-peptide based

II. Other mechanisms

Prolyl hydroxylase inhibitors (HIF stabilisers)

GATA inhibitors

Haemopoietic cell phosphatase (HCP) inhibitors

EPO gene therapy

Multiple generic epoetin alfas are being marketed worldwide

– variable quality– variable biological activity– inaccurate labelling– ? immunogenicity

PERU

China

LaneLoad

(Units)

1 60

2 60

3 60

4 60

5 60

6 60

7 60

8 60

9 60

10 60

11 60

12 60

13 60

14 60

EPO F.P. STD

HEMAX / INDIA / HSA

EPO P.B. STD

EPO F.P. STD

WEPOX / INDIA / HSA FREE

Condition/TimePoint

NINGHONGXIN / CHINA / HSA

EMCURE / CHINA / HSA

ESPOGEN / KOREA / HSA

ZYROP / ARGENTINA / HSA

HEMAX / ARGENTINA / HSA

Candidate EPO Ph. Eur. BRP Batch 2 (BRP2)

EPO Ph. Eur. BRP Batch 1 (BRP 1)

EPO P.B. STD

ISOFORM 6

The “generic” epoetin alfas differ from approved epoetin alfas

Isoelectric Focusing*

The first biosimilar epoetin alfa was approved in Europe in June 2007 (Sandoz) – others pending

C.E.R.A.

Continuous Erythropoietin Receptor Activator Methoxy polyethylene glycol epoetin beta

long-acting ESA IV half-life = SC half-life = 130 hrs ?once–monthly dosing

C.E.R.A. EPO

EPO mimetic peptides

Family of peptides discovered with erythropoietin-mimetic activity Amino acid sequences completely unrelated to native EPO Same functional / biological properties as EPO First one described was EMP-1 A similar EMP pegylated and dimerised to produce HematideTM

HematideTM is about to begin Phase III of clinical development– stable at room temperature– antibodies do not cross-react with EPO, x1/month, ?cheaper

Injection 1 Injection 2 Injection 3 Injection 4 Injection 5 Injection 6

(Targ

et H

b R

an

ge: 1

1 – 1

3 g

/dL

)

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 4 8 12 16 20 24Week

Me

an

Hb

Ch

an

ge

Fro

m B

as

eli

ne

(g

/dL

)

Starting Dose:

Hematide in pre-dialysis CKD patients (Phase 2)

0.025 mg/kg SC0.050 mg/kg SC0.075 mg/kg SC0.050 mg/kg IV

Macdougall et al., ASN, San Diego, Nov. 2006.

0

20

40

60

80

100

-3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Months

Pe

rce

nt

Pa

tie

nts

Re

ce

ivin

g R

BC

Tra

ns

fus

ion

s

Du

rin

g E

ac

h S

tud

y M

on

th

6

7

8

9

10

11

12

13

14

He

mo

glo

bin

co

nc

en

tratio

n (g

/dL

)

0

0 0 0 0 0 0 0 0 0 0 0

Hematide™ Injections

0

n= 9 9 9 10 10 10 9* 9 8 6** 5*** 5 5 5 5 5 5 5 4 3 2

*Subject 39-003, **Subject 39-004, and ***Subject 14-032 were censored due to kidney transplantation.

10 CKD patients with Ab+PRCA (Germany, France, UK) Treated with once-monthly SC Hematide 0.05mg/kg End-point – Hb > 11 g/dL without RBC transfusions

O2

OHproteasomaldegradation

OH

HRE

HIF-1

HIF-2

HIF

HIF-2 HIF-1

PHD

1

3

2

HIF target genes- EPO, etc.

HIF stabilizers (Prolyl hydroxylase inhibitors)

Macdougall & Eckardt, Lancet, 2006

HIF stabilizers

FDA has suspended further development of FG-2216 following the death of a female patient from fulminant hepatic necrosis

BUT

FG-2216 was in phase II of its clinical trial programme

Orally-active inhibitors of HIF prolyl hydroxylase have been synthesized (FG-2216; FG-4592 - FibroGen)

They cause an increase in EPO levels, even in CKD patients

Urquilla P et al.: J Am Soc Nephrol 2004; 15: 546A.

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42

Day

Ch

ang

e fr

om

Bas

elin

e -

Hem

og

lob

in (

gm

/dL

)

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42

Day

FG-2216 Patients Placebo Patients

Wiecek A. et al. XLII ERA-EDTA Congress, Istanbul 2005.

FG-2216 Patients Placebo Patients

New iron preparations – ferrumoxytol, Ferrinject, etc.

New trials

Further initiatives

Study design

Study pop. n

Follow-up

Goals End-points

RCT-db Type 2 DM

CKD 4000 4 years Hb 13

vs 9 CVS

RCT-sb > 70 yrs

CKD260 88 wks Hb 13

vs 9.5QoL

SF36 vit

EXTEND Observ. CKD pts 4000 q2wk vs q4wk DA

PREFERENCE Prospective

cohortCKD pts Several

hundred

Compare diff.mode of admin.

ESA mode of admin.

MIRCERA in Renal Tx

Open-label

Renal Tx Several hundred

1 year Hb QoL

New trials

TREAT1

CHOIR2

CREATE3

Besarab4

1000 2000 3000 4000

Number of patients

3896*

* IVRS 12 October 2007

TREAT vs. CHOIR

No. of centres

Median (pt-mths)

Total follow-up (pt-yrs)

Events (n)

CHOIR 130 14 1900 222

TREAT vs. CHOIR

No. of centres

Median (pt-mths)

Total follow-up (pt-yrs)

Events (n)

CHOIR 130 14 1900 222

TREAT 700 16 (already) 5182.9 (already)

> double that of CHOIR

Questions we don’t have answers to

Are high doses of EPO bad or is it just that “being hyporesponsive” is bad?

Is giving EPO to “hyporesponsive” patients bad?

Is a Hb of 11–12 g/dl appropriate for all CKD patients?

Does Hb variability/instability/cycling impact on mortality/morbidity, or is it just a marker of outcome?

Future directions for CKD anaemia Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and...

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