Iron Deficiency Anemia in Hemodialysis-Dependent Chronic ... · Iron Deficiency Anemia in Hemodialysis-Dependent Chronic Kidney Disease (HDD-CKD) 1 US-TF-19-SPKR-00012 July 2019

Iron Deficiency Anemia in Hemodialysis-Dependent Chronic Kidney Disease (HDD-CKD)

1US-TF-19-SPKR-00012 July 2019

Prevalence of Anemia Increases With Worsening Kidney Function

2

(n=116) (n=2832) (n=1968) (n=298)

GFR (mL/min/1.73 m2)GFR=glomerular filtration rate; Hgb=hemoglobin.Data based on a large-scale, cross-sectional, US multicenter survey including 5222 patients (mean age, 68.2 years; 46.6% male) with CKD.McClellan W, et al. Curr Med Res Opin. 2004;20(9):1501-1510.

Causes of Anemia in CKD

3

ESA=erythropoiesis-stimulating agent.1. McCullough PA, Lepor NE. Rev Cardiovasc Med. 2005;6(1):1-10; 2. Ganz T. J Am Soc Nephrol. 2007;18(2):394-400; 3. Cobo G, et al. Nephrol Dial Transplant. 2018;33(suppl 3):iii35-iii40; 4. Macdougall IC, et al. Kidney Int. 2016;89(1):28-39; 5. Johnson DW, et al. Nephrology (Carlton). 2007;12(4):321-330.

Anemia

Hyper-parathyroidism

Concurrent illness

(malignancy)

Retained uremicsolutes Poor nutritionLoss of renal

parenchyma

Inflammation/infection2,3

Erythropoietin/ESA5

• Hyporesponsiveness• Resistance

Erythropoietindeficiency1

Blood loss

Iron deficiency4

4

Normal Iron Physiology: A Tightly Regulated System

Circulating RBCs(~1800 mg)25–30 mg/day

Bone marrow(~300 mg)

Muscle and other tissues

(~400 mg)

Reticuloendothelial macrophages

(~600 mg)

Iron loss(~1–2 mg/day)

Transferrin(~3 mg)

Liver parenchyma(~1000 mg)

Absorbed dietary ironDuodenum

(~1–2 mg/day)

RBCs=red blood cells.1. Wish JB, et al. Am J Nephrol. 2018;47(2):72-83; 2. Hentze MW, et al. Cell. 2004;117(3):285-297.

5

Absorbed dietary iron(<1 mg/day)

Iron Pathophysiology in Patients With CKD

Circulating RBCs(~1800 mg)25–30 mg/day

Bone marrow(~300 mg)

Reticuloendothelial macrophages

(~800 mg)

Transferrin(~3 mg)

Circulating RBCs(~1400 mg)(assumes 3 g/dL 🡫 in Hgb)

Iron loss(~5.5–8 mg/day)

(assumes 2–3 g/year)

HepcidinIron absorption

HepcidinIron export

Muscle and other tissues

(~400 mg)Liver parenchyma

(~1000 mg)

Wish JB, et al. Am J Nephrol. 2018;47(2):72-83.

6

KDIGO ERBP KDOQI Canadian Guidelines NICE

When to start

ESA-naive and ESA-treated• Ferritin

<500 ng/mL• TSAT <30%

ESA-naive• Ferritin <200 ng/mL

(ND) or <300 (5D)• TSAT <25%ESA therapy• Ferritin <300 ng/mL• TSAT <30%

All stages of CKD• Ferritin <500 ng/mL• TSAT <30%

All stages of CKD• Ferritin <500 ng/mL• TSAT <30%

All stages of CKD• Ferritin <100 ng/L • TSAT <20% (unless

ferritin >800 ng/mL)• Hypochromic red

cells <6% (unless ferritin >800 ng/mL)

When to stop

• Ferritin ≥500 ng/mL

• TSAT ≥30%

• Ferritin ≥500 ng/mL• TSAT ≥30%

• None • None • Ferritin 500–800 μg/L

Guidelines for Iron Therapy in Patients With CKD (2012+)

5D=stage 5D chronic kidney disease;ERBP=European Renal Best Practice; KDIGO=Kidney Disease: Improving Global Outcomes; KDOQI=Kidney Disease Outcomes Quality Initiative; ND=nondialysis; NICE=National Institute for Health and Care Excellence; TSAT=transferrin saturation. *If high ferritin, weigh potential risks and benefits of persistent anemia, ESA dosage, comorbid conditions, and health-related quality of life.Del Vecchio L, et al. Clin Kidney J. 2016;9(2):260-267.

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Mean Ferritin Levels Have Increased Over Time in Hemodialysis Patients1

Normal Hematocrit Study2

CHOIR3

CREATE4

TREAT5

2001990 1992 1994 1996 1998 2000 2000

Year2004 2006 2008 2010 2012 2014

300

400

500

600

700

800

900

1000

Mea

n Fe

rriti

n (n

g/m

L)

KDIGO Limit IV Iron to TSAT<30% and ferritin <500 ng/mL

Ferritin Goal200–500 ng/mL



ESAs and IV IronBundled by CMS

CHOIR=Correction of Hemoglobin and Outcomes in Renal Insufficiency; CMS=Centers for Medicare & Medicaid Services; CREATE=Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta; IV=intravenous; TREAT=Trial to Reduce Cardiovascular Events with Aranesp Therapy.1. Charytan DM, et al. J Am Soc Nephrol. 2015;26(6):1238-1247; 2. Besarab A, et al. N Engl J Med. 1998;339(9):584-590; 3. Singh AK, et al. N Engl J Med. 2006;355(20):2085-2098; 4. Drüeke TB, et al. N Engl J Med. 2006;355(20):2071-2084; 5. Pfeffer MA, et al. N Engl J Med. 2009;361(21):2019-2032.

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TransferrinCirculatingred blood

cells

RESMuscle,

other

Erythroidmarrow

Hepatocytes

GI

With Inflammation of CKD, Increased Hepcidin Blocks Recycling of Iron

GI=gastrointestinal; RES=reticuloendothelial system.Brittenham GM. Pathophysiology of iron homeostasis. In: Hoffman R, et al, eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Saunders; 2013;468-477.

HEPCIDINBLOCK

Dialysisand

uremic blood loss

9

Macromolecular IV Iron Is Sequestered Within the Reticuloendothelial System

IV IRON IV IRON

TransferrinDialysis

and uremic

blood loss

Circulatingred blood

cells

RESMuscle,

other

Hepatocytes

GI

Erythroidmarrow

Brittenham GM. Pathophysiology of iron homeostasis. In: Hoffman R, et al, eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Saunders; 2013;468-477.

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Macromolecular IV Iron May Increase Storage Iron in Functional Iron Deficiency

Cohen-Salal A, et al. Heart. 2014;100(18):1414-1420.

Absolute Iron Deficiency

Functional Iron Deficiency

Iron demand Normal HighFerritin Low Normal or highTSAT <20% <20%Hepcidin Low High

Storage iron

(ferritin)

Transport iron

(transferrin)

Bioavailable iron

(Hgb)

Storage iron

(ferritin)

Transport iron

(transferrin)

Bioavailable iron

(Hgb)

IV Iron

11

Hemodialysis Patients Have Excess Iron Loss

Average monthly iron losses:

30 mg per month

Gastrointestinal losses1

55 mg per month

Dialysis circuit and blood draws2

1. Rosenblatt SG, et al. Am J Kidney Dis. 1982;1(4):232-236; 2. Rao M, et al. Am J Kidney Dis. 2003;42(suppl 1):18-23; 3. Macdougall IC, et al. Kidney Int. 2016;89(1):28-39; 4. Gupta A, et al. Kidney Int. 2015;88(5):1187-1194.

85 mg per month

In aggregate, iron losses in hemodialysis patients are considered to be of the order of 1000–2000 mg/year, but may be highly variable3

Patients lose on average ~5–7 mg of iron per dialysis session4

12

TRIFERIC® (ferric pyrophosphate citrate) The first and only FDA-approved product indicated to maintain hemoglobin in HDD-CKD patients

Please see full Important Safety Information included on slide 27.Please see the full Prescribing Information available at this presentation.

FDA=US Food and Drug Administration.

TRIFERIC® (ferric pyrophosphate citrate)Indication and Usage

INDICATION AND USAGE• TRIFERIC (ferric pyrophosphate citrate) is indicated for the replacement of iron

to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (HDD-CKD)

Limitations of use • TRIFERIC is not intended for use in patients receiving peritoneal dialysis • TRIFERIC has not been studied in patients receiving home hemodialysis

13Please see the full Prescribing Information available at this presentation.

1. Pratt R, et al. Biometals. 2018;31(6):1081-1089; 2. Gupta A, et al. Kidney Int. 2015;88(5):1187-1194.

TRIFERIC Formulation Overview

Iron (III) complexed with one pyrophosphate and two citrate

molecules in the solid state

• Water-soluble iron salt administered via dialysate1

• No complex carbohydrate shell1

• Tightly bound to pyrophosphate and citrate1

– Donates iron to transferrin immediately once in the blood

– No free iron or oxidative stress

• Mimics natural iron homeostasis1

• Restores the ~5–7 mg iron lost during each hemodialysis treatment2

Please see the full Prescribing Information available at this presentation.Please see full Important Safety Information included on slide 27.

14

15

TRIFERIC Bypasses Liver Sequestration by Hepcidin

Muscle,other

Hepatocytes

GITransferrinDialysis

and uremic

blood loss


cells

RES

dialysate

Erythroidmarrow

TRIFERIC

Brittenham GM. Chapter 35. Pathophysiology of Iron Homeostasis. In Hoffman R. and Furie B. eds. Hematology: Basic Principles and Practice. Saunders, 6th ed., 2013.


16

TransferrinCirculatingred blood

cells

RESMuscle,

other

Erythroidmarrow

Hepatocytes

GI

With Inflammation of CKD, Increased Hepcidin Blocks Recycling of Iron

GI=gastrointestinal; RES=reticuloendothelial system.Brittenham GM. Pathophysiology of iron homeostasis. In: Hoffman R, et al, eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Saunders; 2013;468-477.

HEPCIDINBLOCK

Dialysisand

uremic blood loss

17

Macromolecular IV Iron Is Sequestered Within the Reticuloendothelial System

IV IRON IV IRON

TransferrinDialysis

and uremic

blood loss


cells

RESMuscle,

other

Hepatocytes

GI

Erythroidmarrow

Brittenham GM. Pathophysiology of iron homeostasis. In: Hoffman R, et al, eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Saunders; 2013;468-477.

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TRIFERIC Donates Iron Directly and Completely to Transferrin

Negligible NTBI Even at the Highest Dose of TRIFERIC Administered to Healthy Volunteers

10 mg TRIFERIC NTBI 4 h10 mg TRIFERIC TBI 4 h10 mg TRIFERIC Total Serum Iron (BL Corr) 4 h

260

210

160

60

0

–40 0–4–8 4 8 12 16

μg/d

L ±

SD

110

BL Corr=baseline corrected; NTBI=non–transferrin-bound iron; SD=standard deviation; TBI=transferrin-bound iron.Pratt RD, et al. J Clin Pharmacol. 2017;57(3):312-320.

The study also showed that TRIFERIC is cleared from the circulation without increasing serum hepcidin levels or biomarkers of oxidative stress or inflammation

TBI nearly equals total serum iron


Overview of TRIFERIC Pivotal Clinical Trials

19

CRUISE 1 and CRUISE 2Two independent, identical Phase 3, multicenter, prospective, randomized, single-blind, placebo-controlled, parallel-group studies• Hypothesis: TRIFERIC can sustain iron delivery for erythropoiesis and is more

effective than placebo in maintaining hemoglobin concentration in hemodialysis• Iron-replete patients randomized to TRIFERIC or placebo

– No supplemental iron– ESA held constant while patients in randomized treatment phase– Randomized treatment continued until prespecified criteria were met

• Hgb concentrations across treatment arms limited to within predefined safe upper and lower limits

CRUISE=Continuous Replacement Using Iron Soluble Equivalents.Fishbane SN, et al. Nephrol Dial Transplant. 2015;30(12):2019-2026.


CRUISE 1 and CRUISE 2Study Design

• Adults undergoing chronic HD• Hgb 9.5–11.5 g/dL• TSAT 15%–40%• Serum ferritin 200–800 μg/L• Stable ESA doses during the

4 weeks prior to randomization– Epoetin ≤45,000 U/week– Darbepoetin ≤200 μg/week

Primary EndpointMean change from baseline in Hgb at EoT during the last one-sixth of the randomized treatment period

R

Placebo

Patients completed randomized treatment if:• Hgb <9 or >12 g/dL for 2 weeks• Serum ferritin <100 μg/L for 2 weeks• Hgb ˃11.5 g/dL AND Hgb increases by ≥1.0 g/dL• 48 weeks of total randomized treatment

TRIFERIC 2 𝛍M (110 μg/L) Iron

‒4 0 12 24 36 48WeeksRun-In Randomization Open-Label

72

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EoT=end of treatment; HD=hemodialysis.Fishbane SN, et al. Nephrol Dial Transplant. 2015;30(12):2019-2026.


21

Patient Demographics

TRIFERIC(n=290)

Placebo(n=295)

Age (years) Mean (SD) 57.1 (12.5) 59.6 (13.7)

Sex, n (%) Male 177 (61.0) 195 (66.1)

Race, n (%) Black or African American 111 (38.3) 99 (33.6)White 153 (52.8) 165 (55.9)

Undergoing hemodialysis >1 year, n (%) 253 (87.2) 259 (87.7)History of heart failure 90 (31.0) 71 (24.1)History of diabetes 183 (63.1) 180 (61.0)Whole blood hemoglobin, g/dL (SD) 11.0 (0.6) 10.9 (0.6)Ferritin, µg/L (SD) 511.5 (197.4) 495.9 (206.0)

Fishbane SN, et al. Nephrol Dial Transplant. 2015;30(12):2019-2026.


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TRIFERIC Maintains Hemoglobin Concentration

CRUISE 1 CRUISE 2

TRIFERIC (n=148)

Placebo (n=151)

TRIFERIC(n=142)

Placebo (n=144)

Baseline Hgb, mean g/dL (SD) 10.96 (0.591)

10.90 (0.636)

10.96 (0.609)

10.93 (0.625)

EoT Hgb mean g/dL 10.9(1.25)

10.5(1.35)

10.9(1.38)

10.5(1.33)

Mean change from baseline g/dL (SE) 0.06 (0.115)

–0.30 (0.114)

–0.05(0.108)

–0.40 (0.109)

Mean difference g/dL (SE) 0.36 (0.140)

0.36(0.139)

P value (95% CI)

0.011(0.08, 0.63)

0.011(0.08, 0.63)

CI=confidence interval; SE=standard error.Data on file. Wixom, MI; Rockwell Medical, Inc.


23

9.0

9.2

9.4

9.6

9.8

10.0

10.2

10.4

10.6

10.8

11.0

11.2H

gb g

/dL

(SE

M)

TRIFERIC HgbTRIFERIC Ferritin

Placebo HgbPlacebo Ferritin

EoT

P<0.001

P<0.001

TRIFERIC Maintains Hemoglobin Without Increasing Ferritin*

LOCF=last observation carried forward; SEM=standard error of the mean.*LOCF analysis.Data on file. Wixom, MI; Rockwell Medical, Inc.


24

Summary of TRIFERIC Effect on Serum Iron, UIBC, and TSAT%

Pre-HD

Par

amet

er

250

225

200

175

150

125

100

75

50

25

0

TRIFERIC (CRUISE 1)TRIFERIC (CRUISE 2)Placebo (CRUISE 1)Placebo (CRUISE 2)

Serum Iron, µg/dL UIBC, µg/dL TSAT, %Post-HD Pre-HD Post-HD Pre-HD Post-HD

UIBC=unsaturated iron-binding capacity.Data on file. Wixom, MI; Rockwell Medical, Inc.


25

Adverse EventTRIFERIC(n=292)

Placebo(n=296)

Any 78% 75%Peripheral edema 7% 4%Pyrexia 5% 3%Asthenia 4% 3%Fatigue 4% 2%Urinary tract infection 5% 10%Procedural hypotension 22% 19%Arteriovenous (AV) fistula thrombosis 3% 2%AV fistula site hemorrhage 3% 2%Muscle spasms 10% 8%Pain in extremity 7% 6%Back pain 5% 3%Headache 9% 5%Dyspnea 6% 4%

Adverse Reactions (≥3% Incidence) Were Similar Between TRIFERIC and Placebo

TRIFERIC Prescribing Information. Wixom, MI: Rockwell Medical, Inc.; 2018.


Overall Safety Profile Similar to Placebo• 780 patient-years of exposure in the pivotal clinical trials1

– Hypersensitivity reactions were reported in 1 (0.3%) patient who received TRIFERIC

– No serious adverse events considered related to the study drug

• Overall, in controlled clinical trials, there were no differences in serious cardiovascular events between TRIFERIC and placebo, including2:– Serious cardiovascular ischemic events

– Composite cardiovascular events or other special safety events

– No incidence of serious arrhythmia

• No cases of anaphylaxis in >675,000 doses administered1,2

26

1. Fishbane SN, et al. Nephrol Dial Transplant. 2015;30(12):2019-2026; 2. Data on file. Wixom, MI; Rockwell Medical, Inc.


IMPORTANT SAFETY INFORMATIONWarnings and Precautions• Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have

been life-threatening and fatal, have been reported in patients receiving parenteral iron products. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after hemodialysis until clinically stable. Personnel and therapies should be immediately available for the treatment of serious hypersensitivity reactions. Hypersensitivity reactions have been reported in 1 (0.3%) of 292 patients receiving TRIFERIC in two randomized clinical trials

• Iron status should be determined on pre-dialysis blood samples. Post dialysis serum iron parameters may overestimate serum iron and transferrin saturation

Adverse Reactions • Most common adverse reactions (incidence ≥3% and at least 1% greater than placebo) in

controlled clinical studies include: headache, peripheral edema, asthenia, AV fistula thrombosis, urinary tract infection, AV fistula site hemorrhage, pyrexia, fatigue, procedural hypotension, muscle spasms, pain in extremity, back pain, and dyspnea

27Please see the full Prescribing Information available at this presentation.

28

Easy, Convenient Delivery of TRIFERIC Via Bicarbonate Concentrate

TRIFERIC 272 mg Powder Packet

Add one packet to every 25 gallons of bicarb solution in the bicarb mixer

TRIFERIC works in any central feed system

TRIFERIC Is Simply Added to Liquid Bicarbonate

TRIFERIC 5 mL Ampule

Add one ampule to every 2.5 gallons of bicarb solution


TRIFERIC Summary

• First and only treatment indicated for the replacement of iron as maintenance therapy in adult patients with HDD-CKD– Donates iron directly and completely to transferrin, bypassing liver

sequestration– Restores the ~5 to 7 mg of iron lost during each hemodialysis

procedure, mimicking natural iron homeostasis– Maintains hemoglobin with no increase in iron stores (ferritin) – Generally well tolerated, with few serious adverse events

•Safety profile similar to placebo, with greater than 780 patient-years exposure

29

Please see full Important Safety Information included on slide 27.Please see the full Prescribing Information available at this presentation. US-TF-19-SPKR-00012 July 2019

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Iron Deficiency Anemia in Hemodialysis-Dependent Chronic ... · Iron Deficiency Anemia in Hemodialysis-Dependent Chronic Kidney Disease (HDD-CKD) 1 US-TF-19-SPKR-00012 July 2019