Future directions for CKD anaemia · All ESAs have the same signalling pathway . Termination of...

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

  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

Pluripotent Stem Cell

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

Colony-Forming Unit-Erythroid Cells (CFU-E)

Reticulocytes RBCs Erythro- 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 intracellular signalling pathways

membrane

Jak2 Jak2

P

Jak2 Jak2 P P

P P

rHuEPO

Jak2 Jak2 P P

P P P

EPO receptor activation leads to activation of genes that promote erythropoiesis

membrane

nucleus

Jak2 Jak2 P

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

Gene Activation

P P

P

STAT

5 P


STAT

5

Gene Activation

P

PI-3-Kinase

Jak2 Jak2 P

SCH

MAPK

SOS GRB

P P

P

membrane

nucleus

EPO receptor activation leads to activation of genes that promote erythropoiesis

Jak2 Jak2 P P

P P

EPO, rHuEPO

EPO dimer EPO mimetic peptide

Darbepoetin alfa

membrane

C.E.R.A. Peg-rHuEPO

Signal Transduction


Gene Activation

Jak2 Jak2 P P

P P

Jak2 Jak2 P P

P P

Jak2 Jak2 P P

P P

Jak2 Jak2 P P

P P

Investigational

All ESAs have the same signalling pathway

Termination of EPO-receptor signalling

JAK 2 JAK 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

Lane Load(Units)

1 602 603 604 605 606 607 608 609 60

10 6011 6012 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 / HSAESPOGEN / KOREA / HSA

ZYROP / ARGENTINA / HSAHEMAX / 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

(Target Hb R

ange: 11 – 13 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 24 Week

Mea

n H

b C

hang

e Fr

om B

asel

ine

(g/d

L) Starting Dose:

Hematide in pre-dialysis CKD patients (Phase 2)

0.025 mg/kg SC 0.050 mg/kg SC 0.075 mg/kg SC 0.050 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

Perc

ent P

atie

nts

Rec

eivi

ng R

BC

Tra

nsfu

sion

s D

urin

g Ea

ch S

tudy

Mon

th

6

7

8

9

10

11

12

13

14

Hem

oglobin concentration (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

OH proteasomal degradation

OH

HRE

HIF-1α

HIF-2α

HIF β

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

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

  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

Chan

ge fr

om B

asel

ine

- Hem

oglo

bin

(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 CKD

260

88 wks

Hb 13 vs 9.5

QoL SF36 vit

EXTEND

Observ.

CKD pts

4000

q2wk vs q4wk DA

PREFERENCE

Prospective cohort

CKD 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 · All ESAs have the same signalling pathway . Termination of...

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