ANEMIA IN CKD WEIGHING THE EVIDENCE FOR IRON

ANEMIA IN CKD: WEIGHING THE EVIDENCE FOR IRON DEFICIENCY MANAGEMENT OPTIONS Monday, April 24, 2017 Geoffrey A. Block, MD Director of Research Denver Nephrology Denver, Colorado

ANEMIA IN CKD: WEIGHING THE EVIDENCE FOR IRON DEFICIENCY MANAGEMENT OPTIONS Monday, April 24, 2017 Welcome and Introduction Geoffrey A. Block, MD Pathophysiology of Iron Deficiency in the Setting of Declining Renal Function in CKD Csaba P. Kovesdy, MD Treatment Options and Strategies for Addressing Iron Deficiency Pablo E. Pergola, MD, Ph. D Approaches and Challenges in Treating Iron Deficiency Anemia in Patients With CKD Geoffrey A. Block, MD Question and Answer Session All Faculty Concluding Remarks Geoffrey A. Block, MD

Disclosures Geoffrey Block, MD, has disclosed the following relevant financial relationships: • Served as an advisor or consultant for: Akebia Therapeutics; Astra. Zeneca Pharmaceuticals LP; Amgen Inc. ; Ardelyx; Keryx Biopharmaceuticals, Inc. • Served as a speaker or member of a speakers bureau for: OPKO Health Inc • Received grants for clinical research from: Ardelyx; Keryx Biopharmaceuticals, Inc. • Owns stock, stock options, or bonds from: Ardelyx Csaba P. Kovesdy, MD, has disclosed the following relevant financial relationships: • Served as an advisor or consultant for: Astra. Zeneca Pharmaceuticals LP; Fresenius Medical Care North America; Keryx Biopharmaceuticals, Inc. ; Relypsa, Inc. ; Sanofi • Received grants for clinical research from: Shire Pablo E. Pergola, MD, Ph. D, has disclosed the following relevant financial relationships: • Served as an advisor or consultant for: Abb. Vie Inc. ; Akebia Therapeutics; Gilead Sciences, Inc. ; Keryx Biopharmaceuticals, Inc. ; Vifor Pharma • Served as a speaker or member of a speaker bureau for: Keryx Biopharmaceuticals, Inc. 3

Answering Poll Questions 4

Polling Question Which of the following is the most common major barrier to using newly approved agents? 1. Ease of use (side effects, need for follow up labs) 2. Time after FDA approval (need for pre-authorization, letter of necessity) 3. Need for further data beyond registrational data (long term) 4. Not enough peers using the agent (don’t want to be an ‘early adopter’) 5. Not enough education on the agent (lack of familiarity) 5

Polling Question 2 With regard to iron therapy, which statement is MOST reflective of your practice pattern? 1. I typically give a trial of oral iron to my NDD-CKD patients prior to moving to IV iron 2. I typically go straight to IV iron therapy because oral iron simply isn’t effective 3. My use of oral iron depends on the level of Hb (how quickly I need to raise it) and the severity of iron deficiency 4. Theoretical concerns related to oxidative stress, iron overload and creating a permissive environment for infections strongly influences my use of IV iron 6

Polling Question 3 All of the following are investigational oral products which are being developed specifically for patients with anemia related to CKD and which affect iron metabolism: 1. 2. 3. 4. 5. 6. Ferric Citrate Ferric Maltol Vadadustat, Molidustat, and Roxidustat Etelcalcetide A and B A, B and C 7

Polling Question Results 8

Introduction • Iron deficiency anemia is a frequent and significant complication of CKD • Iron deficiency anemia develops in the early stages of CKD and increases in severity as renal disease progresses (absolute and functional) • It is associated with a high prevalence of cardiovascular disease in this patient population as well as other poor outcomes and reduced quality of life • There are currently several options available for treating anemia in this patient population, however there continue to be limitations with the current treatments and large gaps in knowledge about relationships between biomarkers, iron use and clinical outcomes. • Recent advances in understanding iron metabolism (hepcidin, eryrthroferrone, Hypoxia Inducible Factor) contribute to the complexity of medical decision making with regard to iron administration 9 Babitt JL, et al. J Am Soc Nephrol. 2012; 23: 1631 -1634.

ANEMIA IN CKD: WEIGHING THE EVIDENCE FOR IRON DEFICIENCY MANAGEMENT OPTIONS Pathophysiology of Iron Deficiency in the Setting of Declining Renal Function in CKD Csaba P. Kovesdy, MD Fred Hatch Professor of Medicine Director Clinical Outcomes and Clinical Trials Program Division of Nephrology University of Tennessee Health Science Center Nephrology Section Chief Memphis VA Medical Center Memphis, Tennessee

Objectives • Describe the physiology of normal iron metabolism • Review the role of inflammation in the development of iron-restricted anemias • Examine the pathophysiologic mechanisms underlying the abnormal iron homeostasis in CKD and ESRD 11

Iron: Why is it Important? • Most abundant element on Earth: 35% of Earth’s mass! • Essential trace element used by almost all living organisms – Catalyst of oxidative reactions – Transport of soluble gases • Essential component of hemoglobin Mertz W. Science. 1981; 213: 1332 -1338. 12

Erythropoiesis • 200 billion RBCs are produced every day – 20 m. L of blood being produced each day – 6 g of hemoglobin and 20 mg of iron • More than 2 × 1015 iron atoms are needed every second to maintain adequate erythropoiesis 13

Normal Erythropoiesis • EPO controls the rate of erythropoiesis • Inhibits hepcidin expression through ERFE • Adjusts iron efflux from macrophages and enterocytes Absorptive enterocyte Iron-recycling macrophage Tf-Fe 2 Erythroid cells Hepcidin EPO Bone ERFE Hepatocyte Kidney interstitial cell 14 Muckenthaler MU, et al. Cell. 2017; 168: 344 -361.

Physiologic Iron Trafficking Dietary iron (10 -15 mg/d) Absorbed iron (1 -2 mg/d) Iron losses Duodenum Bone marrow Iron Transferrin (300 mg iron) (3 mg Iron) Red blood cells (1800 mg iron) (1 -2 mg/d) Macrophage (600 mg iron) Liver and Spleen (1000 mg iron) 15 Panwar B, et al. Semin Nephrol. 2016; 36: 252 -261.

Serum Transferrin • Transferrin is a 90 Kd globulin that binds and transports iron in the plasma → transferrin receptors • The liver is the primary synthesis site 16 Kalantar-Zadeh K, et al. Clin J Am Soc Nephrol. 2006; 1(suppl 1): S 9 -S 18.

Ferritin: The Origin • A ubiquitous protein with a MW of 450, 000 • Originates from reticuloendothelial system (RES) and is produced mainly in the liver and erythroid cells • Functions as an iron binding protein for storage (represents body iron stores) • Ferritin is NOT a transport protein • "Hemosiderin" = condensed ferritin molecules Kalantar-Zadeh et al. CJASN. 2006 17 Kalantar-Zadeh K, et al. Clin J Am Soc Nephrol. 2006; 1(suppl 1): S 9 -S 18.

Ferritin: The Molecule • Spherical shell consisting of 24 subunits (peptide chains) folded into ellipsoids, connected through noncovalent bounds • Two types of subunits: – Heavy (H) subunits – Light (L) subunits • The subunits pack to form a hollow sphere approx 80 Å in diameter with walls that are approximately 10 Å thick • Two types of channels (3 -folds and 4 -folds) in the protein wall at the intersection of the subunits 18 Kalantar-Zadeh K, et al. Clin J Am Soc Nephrol. 2006; 1(suppl 1): S 9 -S 18.

Tissue Ferritin vs Serum Ferritin • Serum ferritin results from the leakage of tissue ferritin • While tissue ferritin clearly plays a role in intracellular iron handling, the role of serum ferritin is less clearly understood Serum ferritin contains little or no iron 19 Kalantar-Zadeh K, et al. Clin J Am Soc Nephrol. 2006; 1(suppl 1): S 9 -S 18.

Serum Ferritin • Serum ferritin is the result of balance between its secretion/leakage (related to intracellular iron synthesis or inflammation) and its clearance, mainly in liver • Liver dysfunction and inflammatory factors may interfere with the synthesis and clearance of ferritin, thereby increasing serum ferritin levels due to circumstances not related to iron metabolism 20 Kalantar-Zadeh K, et al. Clin J Am Soc Nephrol. 2006; 1(suppl 1): S 9 -S 18.

Ferroportin -- The Iron Exporter • The only cellular iron exporter known in vertebrates • Member of the major facilitator superfamily (MFS) • Mechanism: alternating access, anion symporter? Extracellular Cytoplasmic 21 Taniguchi R, et al. Nat Commun. 2015; 6: 8545.

Systemic Iron Homeostasis • Enterocytes take up elemental Fe from the gut via DMT 1 • Fe passage is stimulated by HIF 2α and inhibited through Fe sequestration in ferritin • Fe utilization by the erythroid marrow and its recycling by RES macrophages account for the major iron fluxes • Peritubular fibroblasts of the kidney sense Fe and O 2 deficiency and release EPO • Low Fe and/or O 2 inactivate PHD 2, leading to HIF 2α accumulation and stimulation of EPO transcription 22 Muckenthaler MU, et al. Cell. 2017; 168: 344 -361.

Intestinal Iron Transport 23 Panwar B, et al. Semin Nephrol. 2016; 36: 252 -61.

Iron Metabolism in Erythroid Cells • Iron acquisition in erythroid cells is dependent on endocytosis of Fe 2+ transferrin via the transferrin receptor • In mitochondria, iron is inserted into protoporphyrin IX to produce heme – Heme is transported outside of mitochondria for incorporation into hemoglobin • In the cytosol, excess iron is sequestered within ferritin • Cellular iron efflux is mediated by ferroportin and requires iron oxidation on the extracellular side 24 Muckenthaler MU, et al. Cell. 2017; 168: 344 -361.

Systemic Iron Homeostasis Under Pathologic Conditions Response to hemorrhage, iron deficiency: – Dietary absorption of iron increased – Stored iron released from macrophages and hepatocytes Response to iron overload: – Dietary absorption of iron decreased Response to infection or inflammation: – Iron release from macrophages and hepatocytes decreased – Dietary iron absorption decreased – Hypoferremia 25

Estimated Annual Iron Loss in Patients With HD Average annual iron loss due to 3 0. 5 Repeated laboratory tests ~ 0. 5 g 1 Accidental losses during HD and other bleeding events ~ 1. 0 g 1 Blood retention in dialyzer and tubing ~ 1. 0 g Normal iron losses ~ 0. 5 g Total annual iron loss ~ 3. 0 g Iron Loss, g 2. 5 2 1. 5 1 0. 5 0 HD Patients a. Sakiewicz P, et al. J Nephrol. 1998; 11: 5 -15. b. Cook JD, et al. Iron Metabolism and Its Disorders. 1975; 190 -198. c. Eschbach JW. Semin Dialysis. 1999; 12: 212 -218. d. Kalantar-Zadeh K, et al. Adv Chronic Kidney Dis. 2009; 16: 143 -151. 26

Hepcidin • An iron-regulatory peptide hormone – Made in the liver as 84 aa preprohepcidin – Cleaved to 25 aa bioactive hepcidin by furin – Circulates in blood plasma 27 Ganz T. Blood. 2003; 102: 783 -788.

Hepcidin-Mediated Inhibition of Ferroportin • Hepcidin binds to the h. FPN C lobe, inhibiting its state transition toward the inwardfacing state • Hepcidin binding may also change the conformation of the intracellular side of h. FPN – Triggers the ubiquitination and subsequent internalization 28 Taniguchi R, et al. Nat Commun. 2015; 6: 8545.

Regulation of Intestinal Iron Absorption Dietary iron uptake Food Ferritin Dietary iron uptake Duodenal enterocytes Ferritin Fpn Intestinal lumen H Iron release into plasma H Fe Fe Low hepcidin High hepcidin © Medscape, LLC Hepcidin Blood 29

Serum Hepcidin Is Very High in CKD 2009[a] 2010[b] Median Hepcidin, mg/m. L a. b. Median Hepcidin, mg/m. L Pediatric Controls (n = 20) 25. 3 Adult Controls (n = 24) 72. 9 PCKD 2 -4 (n = 48) 127. 3 Pediatric HD (n = 30) 240. 5 ACKD 2 -4 (n = 32) 269. 9 Adult HD (n = 33) 690. 2 PCKD 5 D (n = 26) 652. 4 Zaritsky J, et al. Clin J Am Soc Nephrol. 2009; 4: 1051 -1056. Zaritsky J, et al. Clin J Am Soc Nephrol. 2010; 5: 1010 -1014. 30

Pathways Involved in Hepcidin Regulation • Hepcidin expression is regulated by iron signals (middle), erythropoiesis (left), and inflammation (right) 31 Muckenthaler MU, et al. Cell. 2017; 168: 344 -361.

Dysregulated Iron Homeostasis in CKD • Iron homeostasis is dysregulated in CKD • Reduced GFR • Iron supplementation • Inflammation • Vitamin D deficiency – Several factors lead to upregulation of hepcidin production • Hepcidin reduces iron bioavailability: – Blocks absorption in gut – Blocks iron release from the cells of the RES ↑Hepcidin Reduced iron release from cells of RES Reduced gut iron absorption Iron-restricted erythropoiesis 32 Panwar B, et al. Semin Nephrol. 2016; 36: 252 -261.

Iron-Restricted Anemias Inflammation IL-6 Liver Hepcidin Spleen Kidneys Hepcidin clearance Duodenum Ganz T. Blood. 2003; 102: 783 -788; Atanasiu V, et al. Eur J Haematol. 2007; 78: 1 -10; Basseri RJ, et al. J Crohns Colitis 2013; 7: e 286 -e 291. Plasma Fe-Tf Red blood cells Bone marrow 33

Anemia of CKD Causes and effects • ↓ EPO production • ↑ hepcidin (2° to ↓ renal clearance and ↑ IL-6) – Iron sequestration in macrophages – Iron-restricted erythropoiesis, resistance to EPO • True iron deficiency (2° to increased blood loss and hepcidin-mediated decrease in intestinal iron absorption) • Suppression of erythropoiesis by inflammatory cytokines (important in acute inflammation) • Shortened erythrocyte lifespan (2° to inflammation and uremia) Treatments and modulators • Exogenous EPO – Causes pulsatile erythropoiesis and transient high demand for iron – High doses ↓ hepcidin but at the cost of AEs • Iron treatment – Overcomes hepcidin-induced blockade of iron release from macrophages – Decreases resistance to EPO 34 Babitt JL, et al. J Am Soc Nephrol. 2012; 23: 1631 -1634.

Overview of Iron Metabolism in CKD and ESRD • Iron stores decreased by blood losses • Hepcidin levels increased by inflammation and decreased renal clearance, despite counter effects from EPO-stimulated erythroferrone – High hepcidin blocks iron efflux from macrophages and hepatocytes – High hepcidin decreases absorption of dietary iron • Iron availability for erythropoiesis is restricted • Intermittent stimulation by EPO therapy requires intermittently high iron flows into the marrow • Iron may be limiting for erythropoiesis • Ferritin is an unreliable marker of iron stores 35 Babitt JL, et al. J Am Soc Nephrol. 2012; 23: 1631 -1634.

ANEMIA IN CKD: WEIGHING THE EVIDENCE FOR IRON DEFICIENCY MANAGEMENT OPTIONS Treatment Options and Strategies for Addressing Iron Deficiency Pablo E. Pergola, MD, Ph. D Clinical Associate Professor Division of Nephrology UT Health, San Antonio Director Research Division Renal Associates PA San Antonio, Texas

Anemia Associated With CKD Available Treatments Erythropoietin Deficiency ("Absolute or functional") ERYTHROPOIETIN ANALOGUES (ESA) Absolute Iron Deficiency Less Iron Available for Erythropoiesis Functional Iron Deficiency (Iron sequestration due to inflammation) Improved Hemoglobin PO IRON IV IRON DIALYSATE IRON 38 Yilmaz MI, et al. Blood Purif. 2011; 32: 220 -225; Auerbach M, et al. Best Pract Res Clin Anaesthesiol. 2013; 27: 31 -140.

Iron Deficiency Anemia in CKD KDIGO Anemia Guidelines • Initial evaluation: CBC, absolute reticulocyte count, serum ferritin levels and transferrin saturation, B 12 and folate levels • Give iron supplementation when TSAT ≤ 30% and ferritin ≤ 500 ng/m. L Aim is to: • Raise Hb without use of ESA • Make sufficient iron available for erythropoiesis and other iron-dependent functions 41 KDIGO Anemia Guidelines. Kidney Int. 2009; 2(suppl): 283 -287.

Treatment Options PO and IV Iron Treatment Potential Benefits Potential Risks Challenges • Improved Hb levels • Delayed need for transfusion or ESA use IV Iron[a] • Accumulation in tissue • Reduce ESA dosing • Transient increase in oxidative stress (? ) • Decreased fatigue and improved physical performance • Risk of infection (? ) • Improved Qo. L and mental performance • Increase in plasma NTBI • Interference with concomitant medications PO Iron[b] • Same as IV • More costly than oral iron (drug, travel, and administration costs) • Limited use in patients with chronic inflammatory bowel disease • Pill burden • Limited intestinal absorption • GI AEs a. Fishbane S, et al. Nephrol Dial Transplant. 2014; 29: 255 -259; b. Besarab A, et al. Nat Rev Nephrol. 2010; 6: 699 -710. 42

Treatment Options ESAs Treatment Potential Benefits • ESAs • • Decrease need for RBC transfusions Improvement in quality of life Slower CKD progression Potential Risks • • CV events Stroke Vascular thrombosis Hypertension Challenges • • FDA black box warning Goal Hb < normal 43 Palmer SC, et al. Ann Intern Med. 2010; 153: 23 -33.

IV Iron and Oral Iron Therapy in Patients With Anemic NDD-CKD Without Concomitant ESA Therapy n Treatment Period, wk Mean Change in Hb From Baseline, g/d. L P Value IV sodium ferric gluconate -250 mg iron weekly x 4 36 6 0. 40 <. 01 Oral ferrous sulphate -65 mg iron 3 x/d 39 6 0. 20 NS IV ferumoxytol -- 510 mg iron, 2 doses within 5 days 145 5 0. 62 n/a Oral iron (ferrous fumarate) -100 mg iron 2 x/d for 21 days 43 5 0. 13 n/a Tagboto IV iron sucrose -200 mg iron/wk x 4 82 4 0. 53 <. 0001 Tagboto IV ferric carboxymaltose -800 mg iron (single infusion) 30 4 0. 73 n/a Reference Agarwal Spinowitz Regimen Agarwal R, et al. Am J Nephrol. 2006; 26: 445 -454. Spinowitz BS, et al. J Am Soc Nephrol. 2008; 19: 1599 -1605. Tagboto S, et al. J Ren Care. 2009; 35: 18 -23. IV Iron Oral Iron Mean 0. 57 0. 17 Median 0. 58 0. 17 45

Anemia Associated With CKD Iron Deficiency Absolute Iron Deficiency Functional IRON IV IRON PO or IV IRON IMPROVED HEMOGLOBIN 46

Association Between High IV Iron Doses and Mortality in Hemodialysis • DOPPS analyzed associations between IV iron dose and outcomes in >32, 000 patients on hemodialysis over 9 years • Increased risk of mortality among patients given higher doses of IV iron >300 mg/mo • For monthly iron doses normalized to body weight, there was an increased risk of CV-related mortality at >6 mg/kg per month vs 1 -2 mg/kg/mo • Hospitalization risk was elevated at IV iron dose >300 mg/mo vs 100– 199 mg/mo 47 Bailie GR, et al. Kidney Int. 2015; 87: 162 -168.

Anemia Associated With CKD EPO Deficiency “Absolute” EPO Deficiency “Functional”: EPO Hyporesponsive EPO Analogue EPO EPO EPO IMPROVED HEMOGLOBIN 48

Red-Flags Raised With ESA Use 49 Nakhoul G, et al. Cleve Clin J Med. 2016; 83: 613 -624.

Anemia Associated With CKD Iron Deficiency Functional EPO Deficiency “Functional”: EPO Hyporesponsive EPO Analogue IRON IV EPO IRON EPO HEMOGLOBIN AT OR BELOW TARGET 50

New and Emerging Treatment Options for Anemia in CKD • Dialysate Iron Replacement: – Ferric Pyrophosphate Citrate • Oral Iron Replacement: – Ferric Citrate – Ferric maltol • Oral Hypoxia Inducible Factor Modulators: – …dustats 51

Ferric Pyrophosphate Citrate • New water-soluble IV iron • Carbohydrate free • Indicated for iron replacement and hemoglobin maintenance in patients with CKD on hemodialysis • Added to bicarbonate dialysate solution; transfers across dialyzer membrane • Donates iron directly to transferrin; delivers iron directly to the bone marrow • Must be given in low doses • Common AEs in trials – Procedural hypotension, muscle spasms, headache, extremity pain, peripheral edema, dyspnea, pyrexia 52 Fishbane SN, et al. Nephrol Dial Transplant. 2015; 30: 2019 -2026.

Ferric Pyrophosphate Citrate Role in Iron-Restricted Anemias Inflammation IL-6 Liver Hepcidin Spleen Duodenum Plasma Fe-Tf Red blood cells Ferric pyrophosphate citrate Bone marrow Ganz T. Blood. 2003; 102: 783 -788; Atanasiu V, et al. Eur J Haematol. 2007; 78: 1 -10; Basseri RJ, et al. J Crohns Colitis. 2013; 7: e 286 -e 291. 53

Safety and Efficacy of Ferric Pyrophosphate Citrate: CRUISE-1 and CRUISE-2 54 Fishbane SN, et al. Nephrol Dial Transplant. 2015; 30: 2019 -2026.

Ferric Citrate Phase 3 Dialysis Study Safety Assessment Period Efficacy Assessment Period Open Label Ext Ferric Citrate n = 96 Ferric Citrate n = 292 Ferric Citrate Placebo n = 96 Washout (2 weeks) Active Control (AC) (sevelamer and/or calcium) n = 149 Baseline Wk 12 Randomization Lewis JB, et al. J Am Soc Nephrol. 2015; 26: 493 -503. Wk 24 Wk 36 Wk 48 Secondary endpoints: • Mean change in serum ferritin • Mean change in TSAT • Cumulative iron use • Cumulative ESA use • Mean change in hemoglobin Wk 56 52 -week Long-term safety data Up to 2 y Primary efficacy: Mean change in serum phosphorus 55

Ferric Citrate Increased Serum Ferritin in Dialysis Patients 1000 Ferritin (Mean), ng/m. L 900 Active Control Ferric Citrate 800 * * Week 24 Week 36 Week 48 Week 52 * 700 600 500 400 300 200 100 0 Baseline Means and SDs shown. *P <. 0001. Lewis JB, et al. J Am Soc Nephrol. 2015; 26: 493 -503. Week 12 56

Ferric Citrate Increased TSAT In Dialysis Patients 50 Active Control 45 Ferric Citrate TSAT, % 40 35 30 25 20 Baseline Week 12 Week 24 Week 36 Week 48 Week 52 57 Lewis JB, et al. J Am Soc Nephrol. 2015; 26: 493 -503.

Hb Remains Stable With Long-Term PO Ferric Citrate Use in Dialysis Patients Mean Hb, g/d. L Active Control Ferric Citrate (n = 132) (n = 245) Baseline (Day 0) 11. 7 11. 6 Week 52 11. 1 11. 4 Change From Baseline -0. 6 -0. 2 Least Squares Mean Difference P Value 0. 4 <. 05 58 Lewis JB, et al. J Am Soc Nephrol. 2015; 26: 493 -503.

Ferric Citrate Decreased IV Iron Use • Ferric citrate demonstrated a 52% decrease in median IV iron intake compared with the active control group over 52 weeks (P <. 0001) Last 6 and 9 Months with No IV Iron in the Study Patients, % Active Control 70 60 50 40 30 20 10 0 Ferric Citrate 58 42 24 11 9 Months 6 Months 59 Umanath K, et al. J Am Soc Nephrol. 2015; 26: 2578 -2587.

Ferric Citrate Decreased ESA Use • Ferric citrate demonstrated a 24% decrease in median ESA intake compared with the active control group over 52 weeks (P <. 05) 12, 000 10, 000 8000 6000 4000 2000 0 1 st Quarter 2 nd Quarter 3 rd Quarter 4 th Quarter Ferric Citrate Mean ESA Units/wk Linear (Ferric Citrate Mean ESA Units/wk) Active Control Mean ESA Units/wk Linear (Active Control Mean ESA Units/wk) Umanath K, et al. J Am Soc Nephrol. 2015; 26: 2578 -2587. 60

Ferric Citrate SAEs Summary (Dialysis) Reduction in cardiac and infection SAEs noted after 52 weeks of treatment with ferric citrate n (%) Ferric Citrate N = 292 Active Control N = 149 113 (39. 1) 73 (49. 0) Cardiac disorders 21 (7. 3) 18 (12. 1) Infections 36 (12. 5) 27 (18. 1) GI 20 (6. 9) 19 (12. 8) Type of SAE All SAEs 61 Lewis JB, et al. J Am Soc Nephrol. 2015; 26: 493 -503.

Anemia in NDD-CKD • As CKD progresses, patients become iron deficient and anemic; however: – Many nephrologists refrain from administering IV-iron and EPO in their offices due to safety and logistical concerns – > 80% of US pre-dialysis clinics do not have IV equipment – Current oral iron formulations (mostly ferrous iron) are marginally effective, with inadequate absorption and significant GI AEs • Consequently, an effective oral ferric iron supplement could be an ideal solution – No oral iron supplements are FDA approved 62

Safety and Efficacy of Ferric Citrate for Treatment of Iron Deficiency Anemia in Patients With NDD-CKD Ferric Citrate Screening R 1: 1 2 Week Ferric Citrate Placebo 16 Week Randomized Double-Blind Placebo-Controlled 8 Week Safety Extension Period Primary endpoint: proportion of patients who achieved a ≥ 1. 0 g/d. L increase in hemoglobin at any time during a 16 week randomized period 63 Fishbane S, et al. J Am Soc Nephrol. 2017. [Epub ahead of print]

Ferric Citrate Increases TSAT and Ferritin in Patients With NDD-CKD 64 Fishbane S, et al. J Am Soc Nephrol. 2017. Epub ahead of print.

Ferric Citrate Increases Hb in Patients With NDD-CKD The increase in hemoglobin in the ferric citrate arm is comparable to IV iron in studies with no ESA background therapy 65 Fishbane S, et al. J Am Soc Nephrol. 2017. Epub ahead of print.

Safety of Ferric Citrate for Treatment of Iron Deficiency Anemia in Patients With NDD-CKD 66 Fishbane S, et al. J Am Soc Nephrol. 2017. Epub ahead of print.

New Drugs: HIF-PHI (the …dustats) Low Oxygen (eg, high altitude) HIF-α HIF-PH Enzymes HIF-α Normal Oxygen HIF-α HIF-PH Enzymes HIF-α degrades rapidly HIF-α HIF-β Gene Transcription Degradation (No Gene Transcription) 69 Maxwell PH, et al. Nat Rev Nephrol. 2016; 12: 157 -168.

New Drugs: HIF-PHI Normal Oxygen HIF-PH Enzymes HIF-α degradation prevented HIF-PH Inhibitors HIF-α HIF-β Gene Transcription 70 Maxwell PH, et al. Nat Rev Nephrol. 2016; 12: 157 -168.

Role of HIF-PHI in Iron-Restricted, EPO-Deficient Anemias Inflammation IL-6 ? Liver Hepcidin Spleen Plasma Fe-Tf Duodenum Red blood cells EPO Kidneys EPO Ganz T. Blood. 2003; 102: 783 -788; Atanasiu V, et al. Eur J Haematol. 2007; 78: 1 -10; Basseri RJ, et al. J Crohns Colitis. 2013; 7: e 286 -e 291. Bone marrow 71

Emerging HIF-PHIs (the …dustats) Compound Phase Status Roxadustat 3 Phase 3 trials Active since May 2013 Vadadustat 3 Phase 3 trials Active since December 2015 Daprodustat 3 Phase 3 trials Active since fall 2016 Molidustat 2 Phase 2 studies completed DS-1093 1 Pilot/dosing studies completed JTZ-951 1 Phase 1 studies completed Recruitment goal for Phase III trials - Roxadustat 4025 pts; Vadadustat 5700 pts; Daprodustat 7500 pts 72

Vadadustat Maintained Hb Levels Throughout 20 Weeks in Patients With NDD-CKD • Met primary endpoint (54. 9% vs. 10. 3%, P <. 0001) • Mean Hb change of 1 g/d. L • Only 4. 4% of patients experienced excursions beyond 13 g/d. L (6 patients) • Vadadustat treatment increased Hb levels and maintained them at the clinically desired range while minimizing excursions ≥ 13. 0 g/d. L Box and whiskers plot represents 10 th, 25 th, 75 th, and 90 th percentiles, median is the line within the box, mean is symbol within the box. MITT population – included patients in the ITT population who had a baseline and at least one post-baseline Hb measurement. Pergola PE, et al. Kidney Int. 2016; 90: 1115 -1122. 73

Vadadustat Increased TIBC, Decreased Ferritin and Hepcidin in Patients With NDD-CKD Total Iron-Binding Capacity Ferritin Hepcidin • Vadadustat treatment improved iron mobilization Box and whiskers plot represents 10 th, 25 th, 75 th, and 90 th percentiles, median is the line within the box, mean is symbol within the box. MITT population – included patients in the ITT population who had a baseline and at least one post-baseline Hb measurement. Pergola PE, et al. Kidney Int. 2016; 90: 1115 -1122. 74

Summary and Conclusions • Despite disparate effects on serum ferritin levels, drugs that increase delivery of iron to bone marrow help maintain Hb while decreasing ESA (and IV iron) use Drug Class Iron Ferric Pyrophosphate Citrate Route TSAT Ferritin ESA Dose IV Dialysate a No N/A ? ( ) ? Ongoing Ferric Citrate PO HIF-PHI PO IV Iron Use Safety c/w IV Iron MACE Studies No 75 *Compared with placebo, IV iron use restricted in placebo patients.

ANEMIA IN CKD: WEIGHING THE EVIDENCE FOR IRON DEFICIENCY MANAGEMENT OPTIONS Approaches and Challenges in Treating Iron Deficiency Anemia in Patients With CKD Geoffrey A. Block, MD Director of Research Denver Nephrology Denver, Colorado

Case Study: "Barry" • 58 -year-old man on HD for 3 y • End-stage kidney failure due to hypertensive nephropathy • Known chronic liver disease due to hepatitis C • On EPO alfa 4000 units x 3/wk + IV iron 200 mg monthly • Lab results – – Hb 9. 4 g/d. L Ferritin 1145 µg/L TSAT 18% CRP 2 mg/L 77 Macdougall IC, et al. Kidney Int. 2016; 89: 28 -39.

Case Study: "Barry" What would you do next? 1. Continue present dose of EPO and IV iron 2. Increase his dose of EPO and continue IV iron 3. Increase his monthly prescription of IV iron and continue same dose of EPO 4. Increase his dose of EPO and his monthly dose of IV iron 5. Continue EPO and reduce monthly iron dose 78

Audience Response Question Pathologic iron overload is indicated by which of the following? 1. 2. 3. 4. Serum ferritin above 600 Serum ferritin above 800 Serum ferritin above 1000 There is no specific threshold above which the serum ferritin indicates pathologic iron overload? 79

Iron Compartmentalization in the Body • It has been hypothesized that parenchymal iron excess and labile iron can be harmful while iron sequestered within cells of the reticuloendothelial system may be of less concern Size of the circles denotes the relative proportion of iron in various compartments 80 Hoffmann Hematology Basic Principles and Practice, 2012.

Iron Deficiency vs Overload PROBLEM: • There is no feasible method to determine total body iron content and thus the present definition of iron deficiency and iron overload rely on FUNCTIONAL consequences of decreased or increased iron stores and surrogate markers DEFINITION: • Iron overload is a condition of increased total body iron that is associated with time-dependent organ dysfunction and pathologic iron overload is associated with signs of organ dysfunction that are related to the excess iron 81 Macdougall IC, et al. Kidney Int. 2016; 89: 28 -39.

Ferritin: Assessing Iron Overload • Hyperferritinemia is not synonymous with iron overload • Serum ferritin does not differentiate iron stored in parenchymal cells or RES – Serum ferritin does not always correlate with liver iron content • Experience from patients with hemochromatosis suggests that combination of high TSAT and ferritin may be better indices as markers of parenchymal iron excess 82 Macdougall IC, et al. Kidney Int. 2016; 89: 28 -39.

Ferritin as a Risk Factor • Like hepcidin, ferritin is just as likely to reflect an inflammatory response as an iron-replete state[a] • In the general population, elevated serum ferritin is associated with increased risk for MI and carotid plaques • In patients with CKD, the association between ferritin levels and outcomes is not clear • Prospective controlled studies are needed to assess whether elevated ferritin merely represents a risk marker or is an actual risk factor 83 a. Wish JB. Clin J Am Soc Nephrol. 2006; 1(suppl 1): S 4 -S 8.

Hepcidin and CV Risk • Some studies suggest that hepcidin upregulation may increase CV risk in the general population. However, there is limited evidence in CKD patients. ↑ Intracellular lipids Ox-LDL Iron trapping ↑ Oxidative ↑ Inflammation ↑ Apoptosis Unstable plaque Erythrocytosis Fpn 1 degradation Atherosclerosis Hepcidin Macrophage ↑ ↑ ↑ ↓ ↓ Iron Macrophage IL-6 MCP-1 TNF-α MMP-2 SMCs Collagen Potential mechanism of hepcidin-mediated plaque instability 84 Li JJ, et al. Arterioscler Thromb Vasc Biol. 2012; 32: 1158 -1166.

Case Study: “Barry” Follow up • "Barry" is also prescribed calcium acetate 2 with each meal to control serum P -- his serum P is 5. 0 mg/d. L. With this additional information, I would: 1. Stop/reduce IV iron and concurrently change to iron-containing P binder 2. Change to iron-containing P binder but make no change to IV iron 3. This has no bearing on clinical decision making 85

Case Study: "John" • 68 -year-old man on HD for 6 y • On EPO and IV iron to maintain ferritin levels above KDIGO minimum • Wants to stop IV iron because of his concerns about "oxidative stress" 86 Macdougall IC, et al. Kidney Int. 2016; 89: 28 -39.

Case Study: "John" What would you do next? 1. Agree to John's request and stop IV iron without further discussion 2. Tell John you will run some tests to assess oxidative stress level 3. Continue with IV iron after explaining the reasons for confusion in the medical literature 4. Do options B and C 87

Case Study: "Tammy" • 67 -year-old woman on HD • Admitted with ruptured diverticular abscess and cutaneous fistula • On weekly protocol: iron sucrose 100 mg/wk (KDOQI Guidelines) and epoetin alfa 6000 units/wk, target Hb 10. 0 to 11. 5 g/d. L • Lab results – Hb 9. 2 g/d. L – Ferritin 335 µg/L – TSAT 10% 88

Case Study: "Tammy" What would you do next? 1. 2. 3. 4. 5. Increase the EPO dose Continue to administer IV iron due to low TSAT Withhold IV iron and increase EPO dose Withhold IV iron and maintain EPO dose Continue with the same dose of EPO and frequency of IV iron 89

REVOKE Study Patients, n Oral Ferrous Sulfate 69 Study Period IV Iron Sucrose 67 104 weeks SAE, (%) 40 (58) 37 (55) SAE infections, (%) 11 (16) 19 (28) There were 27 hospitalized infectious events among 11 participants assigned to the oral iron treatment group and 37 events among 19 participants of the IV iron treatment group (adjusted incidence ratio 2. 12 (95% confidence interval 1. 24– 3. 64, P=. 006). 90 Agarwal R, et al. Kidney Int. 2015; 88: 905 -914.

FIND-CKD Study Patients, n Oral Ferrous Sulfate 312 Study Period IV Ferric Carboxymaltose 304 56 weeks SAE, (%) 59 (19) 75 (25) SAE infections, (%) 12 (3. 8) 11 (3. 6) 91 Macdougall IC, et al. Nephrol Dial Transplant. 2014; 29: 2075 -2084.

Existing Evidence: Inconclusive • Studies in HD, PD, and non-dialysis CKD patients provide conflicting evidence for the association between IV iron and infection risk – Most data are derived from observational studies in HD (subject to confounding) and the few RCTs conducted to date were of short duration or underpowered to assess the risk of infection • Current KDIGO recommendations are still prudent, which call for[a]: – Balancing potential benefits vs risks of IV iron – Avoiding IV iron use in patients with active systemic infections 92 a. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. Kidney Inter Suppl. 2012; 2: 279 -335.

Case Study: "Judy" • 38 -year-old woman with CKD (Ig. A glomerulonephritis) and asthma • Lab results: – – e. GFR 22 m. L/min/1. 73 m 2 Hb 9. 5 g/d. L Ferritin 101 µg/L TSAT 14% • Given IV ferumoxytol 510 mg over 20 min • Judy reports breathing problems, lightheadedness, swelling, new erythematous rash; nurses report slowly falling BP 93

Case Study: "Judy" What do you think is happening, and what should you do next? 1. 2. 3. 4. She may be getting the flu She is having an anaphylactic reaction She is having an anaphylactoid reaction She is having a minor reaction to IV iron 94

Suggested Management of Reactions to IV Iron 95 Macdougall IC, et al. Kidney Int. 2016; 89: 28 -39.

Conclusions • Available data do not allow any firm statement to be made on the potential dangers of high-dose iron use and high ferritin levels • RCTs are needed to assess the safety and efficacy of IV iron therapy using hard clinical endpoints – The ongoing, event-driven PIVOTAL trial, recruiting > 2000 HD patients across 50 UK sites, randomized to a high and low IV iron regimen (planned follow-up of 2 to 4 years) will help to fill this evidence gap • There is consensus that further studies are needed to determine the clinical relevance of iron therapy beyond stimulation of erythropoiesis in CKD, such as patients with CHF, pulmonary arterial hypertension, restless legs syndrome, and premenopausal women with low ferritin • Meanwhile, nephrologists would do well to recognize the benefits and limitations of IV iron therapy 96

ANEMIA IN CKD: WEIGHING THE EVIDENCE FOR IRON DEFICIENCY MANAGEMENT OPTIONS Monday, April 24, 2017 Question and Answer Session All Faculty