iron metabolism in...

Iron Metabolism in Hemoglobinopathies

Vip Viprakasit, MD, DPhil (Oxon)Professor of Pediatrics

Department of Pediatrics & Thalassaemia CenterFaculty of Medicine Siriraj Hospital

Mahidol University, Bangkok, THAILAND

International Conference Korean Society of hematology (ICKSH 2019)

대한혈액학회 Korean Society of Hematology

COI disclosureName of author ： Vip Viprakasit

I currently have, or I have had in the past two years, an affiliation or financial interest with business corporation(s):

(1) Consulting fees, patent royalties, licensing fees ： Yes, Novartis, Novartis,

La Jolla, Protagonist, Vifor, SEBIA, BioRad, Roche

(2) Research fundings： Yes, Celgene, Novartis,

La Jolla, Protagonist, Vifor, SEBIA, BioRad, Roche

Agenda

• Iron regulation: Normal vs. Hemoglobinopathy

• Monitoring and diagnosis

• Management: an Update

Balance between iron loss and acquisition

acquisitionloss

Fe-deficiencyAnaemia

Iron Overload

Nutrient ironRBC Transfusioni.v. iron

Driving Force:Mitochondria in erythroblasts

erythro-poiesis


Iron Overload

Driving Force:Mitochondria in erythroblasts

erythro-poiesis


Iron Def. AnemiaDriving Force:

Mitochondria in erythroblasts

erythro-poiesis

Normal pathway of iron exchange in human

Adapted from Fauci AS et al. http:// www.accessmedicine.com

How do we take iron from outside our body ?

Duodenal epithelial cell uptake of heme and nonheme iron: role of ferroportin-1

hepcidin

Ferroportin

HH

HH; Hereditary Hemochromatosis

How hepcidin is being controlled at cellular level ?

1° IOL: HH

IRIDA

GDF11/TWSG1

2° IOL: Chronic anemia

Erythropoiesis controls iron metabolism

BMP-SMAD pathway is required for ERFE-dependent hepcidin inhibition

DW Swinkels, MCH Janssen, J Bergmans, JJM Marx: Understanding and diagnosis of hereditary hemochromatosis since discovery of the HFE gene (Clinical Chemistry, 2006)

Erythroblast iron uptake

Erythroblast

Tf

Fe(III)

Ferritin

Fe(II)

Fe(III)

Fe(II)ROS

Prevalence of thalassemia and hemoglobinopathies in Southeast Asian countries

Thailandα thalassemia 5.5–30%β thalassemia 1–9% Hb E 5–50%

Myanmarα thalassemia 0.5%β thalassemia 4%HbE 1–26%

Malaysiaα thalassemia 1.8–7.5%β thalassemia 3–5% Hb E 5–46%

Indonesiaα thalassemia 0.5%β thalassemia 3%Hb E 1–25%

Philippinesα thalassemia 5.4%β thalassemia 1.2%Hb E 1%

Vietnamα thalassemia 5%β thalassemia 1.6–25% Hb E 1–73%

Laosα thalassemia 42%β thalassemia 9%Hb E 24–48%

Cambodiaα thalassemia 10%Β thalassemia 3%Hb E 31–63%

Viprakasit V et al. Expert Opinion on Orphan Drug 2014

A new classification of Thalassemia by Thalassemia International Federation (TIF)

Occasional transfusions required

Intermittent transfusions required

Regular, lifelong transfusions required

Non-deletional HbHβ-thalassemia major

Severe HbE/β-thalassemia

β-thalassemia intermediaHbC/β-thalassemia

Mild HbE/β-thalassemia Deletional HbHNondeletional HbH

Moderate HbE/β-thalassemia

1Muncie HL & Campbell JS. Am Fam Physician 2009;80:339–344; 2Galanello & Origa. Orphanet Journal of Rare Diseases 2010, 5:11; 3Harteveld & Higgs. Orphanet Journal of Rare Diseases 2010, 5:13; 4Cohen AR et al. Hematology Am Soc Hematol Educ Program 2004;14–34

Transfusions seldom required

α-thalassemia traitβ-thalassemia traitHomozygous Hb E

Non-transfusion-dependent thalassemias: NTDT (TI)

Transfusion-dependent thalassemias: TDT (TM)

Marrow expansion and bone disease

Extramedullary haemopoiesis and organomegaly

Ineffective erythropoiesis

α/β chain imbalance Peripheral haemolysis and gall stones

Anaemia

Organ damage(heart, liver. endocrine)

The introduction of transfusion therapy ameliorates ineffective erythropoiesis and anemia but exacerbates iron overload

Taner AT el al. Lancet 2017; Epub ahead of print.

Pathophysiology in the absence of treatment

Hypercoagulability and vascular disease

Iron overload

Questions to answer when there is suspicion for iron overload (IOL)

1. Does iron overload exist?

2. How serious is the iron overload; signs of organ damage?

3. What is the cause of iron overload?

Primary vs. Secondary

Ineffective erythropoiesis leads to primary iron overload in NTDT

Musallam KM et al. Curr Opin Hematol 2013;20:187.Iron overload

Ineffective erythropoiesisChronic anemia/hypoxia

↓ Hepcidin↑ Erythropoietin

↑ Ferroportin↑ Intestinal iron absorption

↑ Release of recycled iron from reticuloendothelial system

GDF-11TWGF-1HIFsTmprss6

TransfusionsMinor role

Globin imbalance

Without treatment iron overload is cumulative in NTDT

Adapted from Fauci AS et al. http:// www.accessmedicine.com

Increase hemecatabolism

By transfusion

Transferriniron

Secondary Iron Overload in TDT- Due to blood transfusion- Chronic anemia and compensatory process

Iron overload leads to formation of NTBI and organ iron loading

100%

30%

Normal: no NTBI produced Iron overload

Subsequent formation of NTBI in

plasma

Fe

FeFe

FeFe

FeFe

Uncontrolled iron loading of organs

Pituitary

ParathyroidThyroid

HeartLiverPancreas

Gonads

Tran

sfer

rin s

atur

atio

n %

NTBI, non-transferrin-bound iron. LPI; labile plasma iron

Agenda

● Iron regulation: Normal vs. Hemoglobinopathy

● Monitoring and diagnosis

● Management: an Update

Iron distribution in TDT (due to Tx) vsNTDT (due to absorption)

Origa R et al. Haematology 2007;92:583-88: Taher AT et al. Br J Haematol 2011;152:512-23.

Küpffer cells = macrophages of the liver

Preferential periportal and hepatocyte iron loading (with rare Küpffer cells, arrow)

Remember: low hepcidiniron release from macrophages

NTDT TDT

RE system distribution(mainly in Küpffer cells, arrow)

Iron monitoring in TDT: TIF Guidelines

MRI for the Diagnosis of Cardiac and Liver Iron Overload in Patients with Transfusion-Dependent Thalassaemia: An

Algorithm to Guide Clinical Use When Availability Is Limited

Viprakasit V. et al. Am J Hematol 2018; 93(6):E135-E137

Agenda

• Iron regulation: Normal vs. Hemoglobinopathy

• Monitoring and diagnosis

• Management: an Update

Novel targeted therapies in thalassemia

Taher AT et al. Lancet. 2018;391 (10116):155-167.

LJPC-401 (Synthetic Human Hepcidin) in Healthy Subjects and Patients with Iron

Overload: Results of Three Phase 1 Dose Escalation Studies

Vip Viprakasit,1 Yesim Aydinok,2 Maria Dominica Cappellini,3 AntonisKattamis,4 Kris Kowdley,5 Ashutosh Lal,6 Rafaella Origa,7 Antonio Piga,8 Ali T. Taher,9 Jeff Vacirca,10 Dan Yaeger,11 Brian Byrnes,11

Zancong Shen,11 George Tidmarsh,11 John Porter,12

1Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 2Department of Pediatric Hematology, Ege University Hospital, Izmir, Turkey; 3Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy; 4Division of Pediatric

Hematology-Oncology, University of Athens, Athens, Greece; 5Swedish Medical Center, Seattle, WA, USA; 6Northern California Comprehensive Thalassemia Center, UCSF Benioff Children’s Hospital Oakland, Oakland, CA, USA; 7Ospedale Microcitemico “Antonia

Cao”, Cagliari, Italy; 8Università di Torino, Turin, Italy; 9Emory School of Medicine, Atlanta, GA, USA; 10New York Cancer & Blood Specialists, Setauket-East Setauket, NY, USA; 11La Jolla Pharmaceutical Company, San Diego, CA, USA; 12University College

Hospital, London, UK;

Presented at EHA 2018 and manuscript under preparation 2019

Potential effects of hepcidin agonists or activators on iron absorption under normal and β-thalassemic conditions

Gardenghi S et al. J Clin Invest. 2010;120(12):4466-4477

Normal condition

β thalassemia (NTDT)

Drug treatment

• LJPC-401, a synthetic human hepcidin, is being developed as a therapeutic intervention for iron overload

• Tested in 3 clinical studies to date 2 single-dose studies NHV01 in healthy volunteers (poster presentation PF470) TPP01 in patients at risk for iron overload

1 multidose study NHV02 in healthy volunteers

Background (cont’d)

Viprakasit V. et al. MS under preparation 2019

• Eligible patients were adults with 1 of the following: Transfusion-dependent anemia Iron chelation therapy in the past 6 months Serum ferritin level >1000 ng/mL, or hemochromatosis*

TPP01 Study Design and Objectives

PRIMARY ENDPOINT Safety and tolerability TEAEs, laboratory values, ECGs, vital signs, and physical examination data

SECONDARY ENDPOINTSerum iron level

• Population: Adult patients at risk of iron overload

• Design: Phase 1, open-label, dose-escalation study

• Study Duration: Single SC dose, 7-day observation

LJPC-401 dosing at 1, 5, 10, 20, or 30 mg

*Patients with hemochromatosis that required phlebotomy at least once every 2 months or had received iron chelation therapy in the past 6 months.

ECG, electrocardiogram; SC, subcutaneous; TEAE, treatment-emergent adverse event.


Safety assessments • TEAEs

• Physical examinations

• Laboratory evaluations

• Immunogenicity

• Visits/sampling on day 1 predose, day 8, and day 22

Study Assessments

PK assessments • Parameters of baseline-

corrected serum LJPC-401 obtained by noncompartmental analysis

• Blood samples collected at predose and 0.5, 2, 4, 8, 24, 48, and 168 hours postdose

PD assessments • Effects on

Serum iron level Transferrin level Transferrin saturation Ferritin level

• Samples collected at screening, day 1 predose, 24, 48, and 168 hours postdose

PD, pharmacodynamics; PK, pharmacokinetics; TEAE, treatment-emergent adverse event.


Patient Baseline Characteristics

Parameter, n (%)

LJPC-401 doseTotal

(N = 18)1 mg

(n = 3)5 mg

(n = 3)10 mg (n = 3)

20 mg (n = 6)

30 mg (n = 3)

Age<65 years≥65 years

3 (100)0

1 (33.3)2 (66.7)

3 (100)0

6 (100)0

3 (100)0

16 (88.9)2 (11.1)

GenderMaleFemale

2 (66.7)1 (33.3)

03 (100)

3 (100)0

2 (33.3)4 (66.7)

1 (33.3)2 (66.7)

8 (44.4)10 (55.6)

Iron overload diseaseHemochromatosisBL serum ferritin, mean (SD), 248 (592) ng/mL

Sickle cell diseaseBL serum ferritin, mean (SD), 10151 (7375)

ng/mL

TD β-ThalassemiaBL serum ferritin, mean (SD), 1599.7 (2040)

ng/mL

1 (33.3)

2 (66.7)

0

3 (100)

0

0

3 (100)

0

0

3 (50.0)

1 (16.7)

2 (33.3)

1 (33.3)

1 (33.3)

1 (33.3)

11 (61.1)

4 (22.2)

3 (16.7)

BL, baseline; SD, standard deviation.


Summary of Safety

ALT, alanine aminotransferase; PD, pharmacodynamics; PK, pharmacokinetics; SAE, severe adverse event; TEAE, treatment-emergent adverse event.a34 mild and 4 moderate in severity; bPossibly, probably, or definitely related to study drug administration; cSickle cell pain crisis, not considered treatment-related, fully recovered.

Parameter, n (%)

LJPC-401 dose

Total (N = 18)

1 mg (n = 3)

5 mg (n = 3)

10 mg (n = 3)

20 mg (n = 6)

30 mg (n = 3)

Number of TEAEs 7 6 3 14 8 38a

Patients with ≥1 TEAEs 2 (66.7) 3 (100) 2 (66.7) 6 (100) 3 (100) 16 (88.9)

Number of treatment-relatedb TEAEs 0 3 2 10 5 20

Patients with ≥1 treatment-relatedb TEAEs 0 3 (100) 1 (33.3) 6 (100) 3 (100) 13 (72.2)

Number of SAEs 1c 0 0 0 0 1

Most frequently occurring TEAEs (≥2 patients)

Injection site reactions 0 3 (100) 0 6 (100) 3 (100) 12 (66.7)

Nausea 2 (66.7) 0 0 0 0 2 (11.1)

ALT increased 0 0 1 (33.3) 0 1 (33.3) 2 (11.1)

Decreased appetite 1 (33.3) 0 0 1 (16.7) 0 2 (11.1)

Hypoesthesia 1 (33.3) 1 (33.3) 0 0 0 2 (11.1)

• No severe (grade ≥3) TEAEs, TEAEs leading to discontinuation, or deaths.

• Individual patient clinical labs reviewed by the study investigator suggested no clinically significant shifts.


Mean Baseline-Corrected Serum LJPC-401

• Dose-dependent increase in exposure (except 30 mg)

• Peak concentrations occurred at 2-4 h

• Half-life ~6-13 h

150

125

100

75

50

25

0

0 4 8 12 16 20 24 28 32 36Time, h

Mea

n (S

E) c

once

ntra

tion,

ng/

mL

40 44 48

Dose, mg

1

5

10

2030

SE, standard error.


Mean Serum Iron Concentration at 8 Hours Post-dose Post Hoc Analysis

LJPC-401 dosing cohorts

-80

-60

-40

-20

0

1 mg(n=3)

5 mg(n=3)

10 mg(n=3)

20 mg(n=6)

30 mg(n=2)

Mea

n Se

rum

Iron

Cha

nge

From

Bas

elin

e (S

D),

%

Dose ResponseP=0.0102

SD, standard deviation. Excluding 1 Subject Outlier


Sustained Iron-Lowering Effect With Comparable PK Exposures Between Healthy Subjects and Patients

Healthy Subjects (NHV01) Patients (TPP01)

Iron-Lowering EffectHepcidin Exposures

• PK exposures (AUC and Cmax) are generally comparable between healthy subjects and patients• Longer and sustained iron-lowering effect observed in patients returning toward baseline after 1 week• PD effect likely due to difference in iron hemostasis and regulation between the 2 populations

AUC (ng.h/mL)400

300

200

100

010

Dose, mg20

Cmax, ng/mL

1500

1000

500

010 20

AUC, ng·h/mL

Mea

n (S

E) v

alue

Healthy Subjects

Patients

0 24 48 72 96 120 144 168

Time, h

Mea

n (S

E) ir

on %

chan

ge

806040200

-20-40-60-80

80604020

0-20-40-60-80

0 24 48 72 96 120 144 168

Mea

n (S

E) ir

on %

chan

ge

Time, h

Dose, mg10

20

Heathy subjects (10 mg: n=6; 20 mg: n=6)Patients (10 mg: n=3; 20 mg: n=6)

AUC, Area under the curve; Cmax, maximum drug concentration.


Improved Formulation-Enhanced Iron-Lowering Effect

Enhanced bioavailability resulted in greater iron reduction at the same dose.

Formulation Improved (NHV02) Original (NHV01)

–25

0

–75

–50

0 5 10 15 20 25 30Dose, mg

Mea

n (S

E) Ir

on %

Cha

nge

at H

our 8

Original (TPP01)


• LJPC-401 was well tolerated at doses between 1 mg and 30 mg, with the maximum iron-lowering effect observed at 20 mg

• LJPC-401 showed significant decreases in serum iron levels compared with baseline, which were sustained in most patients for up to 8 days

• In comparison to healthy adults, in whom LJPC-401 caused a decrease in serum iron levels that returned to baseline levels within 48 hours,1 the iron-lowering effect in iron overload patients was more sustained

Conclusions

1. Yaeger D et al. Presented at the 23rd Congress of the European Hematology Association; June 14-17, 2018; Stockholm, Sweden; poster PF470.

• New formulation has improved PK exposure and PD effect with no corresponding increase of injection site reaction severity or duration

• Additional studies are planned to further explore the iron-regulating effects of LJPC-401 in patients with iron-overload disorders

1. Pivotal study in patients with transfusion-dependent beta thalassemia (HELIOS)

– 100 patient, 12 mo., parallel group study, evaluating the effects of LJPC-401 on myocardial iron

2. Phase 2 study in patients with hereditary hemochromatosis (HERCULES Study)

– 60 patient, 4 mo., single-blind, placebo-controlled study evaluating the effects of LJPC-401 on TSAT and phlebotomy requirements

Conclusions (cont’d)

Take home message

• Normal iron regulation is under control of hepcidin ferroportin pathway

• Hepcidin works through BMD signaling and modulating this key receptor can alter hepcidin expression

• In thalassemia and hemoglobinopathy, hepcidin expression is low leading to increased iron absorption and ineffective erythropoiesis

• Exogeneous hepcidin provides a novel treatment modality to enhance iron mobilization and probably improve erythropoiesis

iron metabolism in...

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