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Erythropoietin Mimetic Peptides, Other approaches and New IV Iron Preparations: What Data Do We Have? What Data Do We Need? Anatole Besarab MD, FACP.

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Presentation on theme: "Erythropoietin Mimetic Peptides, Other approaches and New IV Iron Preparations: What Data Do We Have? What Data Do We Need? Anatole Besarab MD, FACP."— Presentation transcript:

1 Erythropoietin Mimetic Peptides, Other approaches and New IV Iron Preparations: What Data Do We Have? What Data Do We Need? Anatole Besarab MD, FACP Director of Clinical Research Division of Nephrology and Hypertension Henry Ford Hospital Detroit, MI

2 Disclosure Dr Besarab has received grant support, been a consultant or has received honoraria ESA Related Iron Related Affymac American Regency Labs Akebia Amgen Colorado Labs Aventis Pharmaceuticals Bayer Rockwell Int Fibrogen Hoechst-Marion-Rousell Schein Medgenics Roche Watson

3 The development of ESAs and IV iron preparations over the last 20 years
Macdougall IC and Ashenden M. Adv Chronic Kidney Dis 2009;16:117−130

4 Erythropoietin and Iron: Both Important
About 3-4 Days Proliferation, maturation & survival (apoptosis) Iron dependence Erythropoietin Erythroblast Iron About 10-14 days Erythropoietin (EPO) is needed in the first stage (from progenitor cells in the burst-forming and colony –forming unit-erythroid to proerythroiblast) but not the second precursor cell stage Main Points Erythropoietin is the essential growth factor required for RBC development. Erythropoietin stimulates the survival, differentiation, and proliferation, of early progenitor cells at the BFU-E and CFU-E stages, allowing them to mature into RBCs. CFU-E cells have significantly more erythropoietin (EPO) receptors than BFU-E and depend on erythropoietin for survival. Background Information  All hematopoietic cells are derived from an original pool of pluripotent stem cells. The most primitive progenitor cells committed exclusively to the erythroid cell line are the burst-forming units-erythroid (BFU-E) cells.  In contrast, colony-forming units-erythroid (CFU-E) are more differentiated. Stimulated CFU-E cells can form reticulocytes within about 8 days. The most important functional differences between BFU-E and CFU-E cells is that the latter have significantly more EPO receptors, and depend on erythropoietin for survival. In vitro experiments have shown that CFU-E cells survive only a few hours in the absence of erythropoietin. EPO is critical for multiplication and differentiation processes of BFU-E and CFU-E where increasing dependence and sensitivity to EPO is manifest. EPO receptors expressed by CFU-E and proerythroblast stages diminish during the final stages of erythroid differentiation such that reticulocytes and erythrocytes are devoid of EPO receptors  Iron is not an erythropoietic stimulant and does not replace the need for exogenous erythropoietin in patients on dialysis. Erythropoietin and iron work synergistically—erythropoietin is the essential stimulus for RBC production, and iron is an important substrate that supports the proper formation of the heme portion of Hb.  Note that it takes about days to get a cell to maximally incorporate iron into Hb, and only 3-4 days in which to do it in. since the process is a continuous one. one should never have a state wherein iron delivery for hemoglobin synthesis is ever limited References Hillman RS. Finch CA. Red Cell Manual, 7th ed. Philadelphia, PA: F.A. Davis Company; 1996:Chapter 1. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood 1993;81:2844–2853. Papayannopoulou T, D’Andrea AD, Abkowitz JL, Migliaccio AR. Biology of erythropoiesis, erythroid differentiation, and maturation. In: Hoffman R, Benz, EJ, Shattil SJ, et al. Hematology Basic Principles and Practice, 4th ed. Philadelphia, PA; Elsevier Churchill Livingstone : About 15-21 Days About 1-2 Days EPO dependence Pluripotent Stem Cell Burst-Forming Unit-Erythroid Cells (BFU-E) Colony-Forming Unit-Erythroid Cells (CFU-E) Proerythro- blasts Erythro- blasts Reticulocytes RBCs Hillman RS, et al. Red Cell Manual, 7th ed. Philadelphia, PA: F.A. Davis Company; 1996:chap 1. Papayannopoulou T, et al. In: Hoffman R, et al. eds. Hematology: Basic Principles and Practice, 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005:chap 20. Brock. Iron Metabolism in Health and Disease. W.B. Saunders Co; 1994

5 Erythropoiesis is affected by local levels of cytokines and interleukins
IL-6 TGF-β TNF-α TRAIL IL-6, interleukin-6; TGF-b; transforming growth factor-b; TNF-a; tumour necrosis factor-a; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand 7 7

6 Why is there a need for new ESAs or new Approaches ?
1) Failure to achieve optimal benefits 2) Risks: are these the same for all ESA irrespective of duration of action? 3) PRCA: probably a non issue with commercial well studied agents but may be with some “me too” generics 4) High Cost 5) Need to reduce Hb variation Maybe be influenced by the pharmacokinetic duration of action of the ESA Coordinating the sequential steps of erythrocyte production 6. Fear of iron: decreased but have we gone too far?

7 Endogenous Erythropoietin (EPO) and Current Erythropoiesis-Stimulating Agents (ESAs): Same Mechanism of Action BCL-XL Caspase-3 Gene transcription Nucleus Cytochrome c release Mitochondria Erythropoiesis “survival” “proliferation” “differentiation” Adapted from: Eur Arch Psychiatry Clin Neuro .2001;251:

8 Hematide (Affymax / Takeda)
Synthetic peptide-based ESA (dimeric, PEGylated) No structural homology with EPO Activates EPO receptors Currently completed Phase 3 studies Hematide immunologically distinct from EPO Anti-EPO Abs do not cross-react with/neutralise Hematide PEGylation Spacer Linker Peptide EpoR EpoR Cell surface 2

9 Hematide (peginesatide)
14 patients in the UK, France, and Germany Ab-mediated PRCA Treated with Hematide 0.05 mg/kg q4wks 60 14.0 50 13.0 40 12.0 % ofPatients Receiving RBC Transfusions During Each Study Month 30 Mean (SD) Hb Concentration (g/dL) 11.0 20 10.0 10 9.0 8.0 BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Study Months Macdougall IC et al, N Engl J Med Nov 2009.

10 Hematide Pharmacokinetics: half-life
Agent Population Mean (± SE) Half-life (h) IV SC Hematide Healthy volunteers1 Predialysis CKD patients1 35-68 39-104 Epoetin alfa Healthy volunteers2 HD, CAPD patients3,6 6.8 ± 0.6 6.5 ± 12.7 19.4 ± 2.5 Epoetin beta 8.8 ± 0.5 24.2 ± 2.6 Darbepoetin alfa Peritoneal dialysis patients3 25.3 ± 2.2 48.8 ± 5.2 CERA Healthy volunteers4 Peritoneal dialysis patients5 133 ± 10 134 ± 19 137 ± 22 139 ± 20 Hematide’s serum half-life is similar to darbepoetin alfa, longer than epoetin alfa or beta, and shorter than CERA 1. Hematide Investigators Brochure (Affymax data on file) 2. Halstenson et al. Clin Pharmacol Ther. 1991;50: 3. Macdougall et al. J Am Soc Nephrol. 1999;10: 4. Dougherty et al. ASCO 2004. 5. Macdougall et al. Clin J Am Soc Nephrol. 2006;1: 6. Boelart et al. Peritoneal Dialysis Int.1989; 9:95-98; Kindler et al. Nephrol. Dial Transplant. 1989; 4: 13

11 AFX01-04: Correction of Anemia (Hgb ≥11 g/dL & Hgb Increase ≥ 1 g/dL From BaseLine)
36 77 92 80 95 100 69 64 93 10 20 30 40 50 60 70 90 4 Weeks 8 Weeks 12 Weeks Duration of Treatment Correction of Anemia (% of Patients) 0.025 mg/kg SC (n=15) 0.05 mg/kg SC (n=45) 0.075 mg/kg SC (n=15) 0.05 mg/kg IV (n=15) Same as Dr. Fishbane’s presentation. 14 14 14

12 A Phase 2 Study of the Safety and Efficacy of Hematide™/Peginesatide for the Maintenance Treatment of Anemia in Patients With Chronic Kidney Disease Who Are on Hemodialysis or Do Not Require Dialysis and Were Previously Treated With Darbepoetin Alfa

13 Study Design: Conversion Study
Open-label, single arm, switching from darbepoetin alfa Primary Objective: To determine whether peginesatide treatment can maintain Hb levels following conversion from darbepoetin alfa treatment Secondary Objectives: Proportion of patients maintaining Hb target of g/dL after conversion To Evaluate the safety and tolerability of peginesatide Titration 1 to 18 Evaluation 19-24 Period: Screening Week: to -1 n~ 182 n ~ 80 n = 102 Peginesatide Q4W IV or SC Visits Every Other Week Visits Every Week Enrollment

14 Primary and Secondary Endpoints
Value (95% CI) Primary Endpoint Mean (95% CI) change in Hb from Baseline to the Evaluation Period, g/dL 92 0.04 (–0.14, 0.23) Secondary Endpoints Patients with Hb within 10.0–12.0 g/dL during Evaluation, % (95% CI) 71% (61%, 81%) Patients with Hb change within ±1 g/dL from Baseline during Evaluation, % (95% CI) 74% (64%, 83%) Red blood cell transfusions, % (95% CI) 101 4% (0.0, 8.3) Time Period (range of weeks) n= Few patients discontinued the study No particular safety concerns were raised However, this study was not designed to definitively determine the safety of peginesatide.

15 Hematide (peginesatide) - the Phase 3 clinical trial programme

16 Hematide™ Phase 3 Clinical Trial Summary
Study Description Sample Size (Hematide vs Control) Geographic Origin PEARL 1 AFX01-11 Comparison with darbepoetin alfa for the correction of anemia in patients not on dialysis (SC) ~300:150 US PEARL 2 AFX01-13 US/ Europe EMERALD 1 AFX01-12 Comparison with epoetin alfa for the maintenance treatment of anemia in HD patients previously treated with EPO (IV) ~500:250 EMERALD 2 AFX01-14 Comparison with epoetin alfa for the maintenance treatment of anemia in HD patients previously treated with EPO (IV/SC)

17 PEARL Study Design 0 to 24 Hematide™ 0.025 mg/kg Q4W SC
Period: Screening Week: to 0 Correction 0 to 24 Evaluation 25 to 36 Long-term 37 to 52+ n~900 n=450 n=150 Darbepoetin 0.75 mcg/kg Q2W SC Hematide™ mg/kg Q4W SC Hematide 0.04 mg/kg Q4W SC Randomization (1:1:1 ratio) Enrollment period 52 weeks ~104 weeks First patient Last patient End of study

18 (following a 1-week ESA-free interval)
EMERALD Study Design Period: Screening Week: to 0 Titration 0 to 28 Evaluation 29 to 36 Long-term 37 to 52+ n~1260 n=630 n=420 n=210 Hematide Q4W IV (following a 1-week ESA-free interval) EPO 1-3x per week IV Randomization (2:1 ratio) Enrollment period 52 weeks ~104 weeks First patient Last patient End of study

19 Composite Safety Endpoint (CSE) Results
Total Events Adjudicated: Events in 734 Patients Dialysis+Non-Dialysis Peginesatide (N=1722) Control (N=869) Patients with CSE Events 385 (22%) 188 (22%) Hazard Ratio 1.06 90% CI / 95% CI (0.91, 1.23) / (0.89, 1.26) solid line = peginesatide dotted line = control 25 25

20 CSE Overall and by Dialysis, Non-Dialysis: Event-Free Rate (Kaplan-Meier Survival)
peginesatide (N=656) darbepoetin (N=327) Patients with CSE Events 142 (22%) 56 (17%) Hazard Ratio 1.34 90% CI (1.03, 1.73) 95% CI (0.98, 1.82) solid line = peginesatide dotted line = darbepoetin Dialysis peginesatide (N=1066) epoetin (N=542) Patients with CSE Events 243 (23%) 132 (24%) Hazard Ratio 0.95 90% CI (0.79, 1.13) 95% CI (0.77, 1.17) solid line = peginesatide dotted line = epoetin 26

21 CSE (=“On Study”) vs. “On Drug” Sensitivity Analysis
27

22 Conclusions Peginesatide, administered once monthly, increases and maintains Hb levels in CKD patients not on dialysis and to maintain Hb levels in CKD patients on dialysis For the CSE analysis pooled across dialysis and non-dialysis populations, the noninferiority criterion are met for peginesatide vs. comparator ESA However, CSE findings in dialysis and non-dialysis are distinct CSE findings in the dialysis population indicate a similar CV safety profile of peginesatide and epoetin Differences in the CSE in non-dialysis patients for peginesatide compared to darbepoetin are being further evaluated 28

23 Current Status Company has announced plans for new drug application only for hemodialysis patients at this time to be submitted some time in Q2 of 2011

24 Differences Between Hematide and Other ESAs
Long Acting Intermediate Acting 2. 1. 3. 4. Short Acting Hematide Mircera Aranesp Eprex/Espo/Epogin/ Neo-Recormon Chemically synthetic peptide, not a protein drug Dialysis: Q4W Maintenance Dose Pre-Dialysis: Q4W Correction Dose Simple Conversion Potential for Room Temperature Stability Potential for Time and Cost Saving No PRCA Treat PRCA This is the current version. Because several portions are revised, I have used our template, not Affymax-Takeda template. 30

25 Activation of HIF under hypoxic conditions
HIF stabilisers Hypoxia-Inducible Factor (HIF) Activation of HIF under hypoxic conditions Gene eg EPO P300 HIF-PH HIF-α O2 HIF-β HRE Inhibition of HIF under normal conditions HIF-PH HIF-α Proteasome OH O2 VHL Proteasomal degradation

26 New ESAs – what’s in the pipeline?
Hematide (peginesatide); EPO-mimetic peptide Amino acid sequences unrelated to native EPO; immunologically distinct; used to treat PRCA Results: hematologic effects comparable to other ESAs HIF (Hypoxia inducible factor) stabilisers AKA: prolyl hydroxylase inhibitors Orally-active inhibitors of HIF prolyl hydroxylase have been synthesized (e.g. FG-2216; FG-4592 – FibroGen) Increase EPO levels, even in CKD patients Stimulate erythropoiesis AT MUCH lower peak EPO levels Suppress hepcidin levels Concerns: specificity (several hundred genes are HIF dependent) In clinical trials (Akebia, Glaxo, Bayer) GATA 2 inhibitors [acts through same pathway as HIFs but just distally] GATA-2 inhibitors (K-11706, K-7174) Inhibit GATA acetylation OR Stimulate GATA de-acetylation Still in animal models EPO gene therapy EPO-secreting modified fibroblasts Hypoxia-dependent EPO-associated adenovirus Phycoerythrin specific EPO encoding B-lymphocyte mRNA HIF ß α GATA-2 EPO gene 5’ACGTGC GATA prolyl hydroxylase inhibitor GATA-2 inhibitors (K-11706, K-7174) Inhibit GATA acetylati OR Stimulate GATA de-acetylation2 HIFα pro HIFα EPO prolyl hydroxylase All increase serum EPO and haematocrit levels in animal models

27 Baseline Serum Iron (Mean ± SEM)
FG-4592, A NOVEL ORAL HIF PROLYL HYDROXYLASE INHIBITOR, ELEVATES HEMOGLOBIN IN ANEMIC STAGE 3-4 CKD PATIENTS Besarab et al Treatment Baseline Serum Iron (Mean ± SEM) % Taking PO Iron Placebo 71.1 ± 4.1 39% 1.5 mg/kg FG-4592 70.4 ± 4.0 57% 2.0 mg/kg FG-4592 73.0 ± 3.9 55% rHuEPO (Schwartz) 72.2 ± 8.7 100% 33 33

28 Mol Ther 2005; 12:

29 Biopump therapy Therapy outline
Ex vivo genetic manipulation of dermal tissue structures for autologous production and delivery of therapeutic proteins Therapy outline Harvesting Ex-vivo genetic manipulation using viral vector Pre- implantation analysis Secretion levels, Dosing, Viability, Sterility Subcutaneous implantation after days Ablation or removal – to reduce dose, if required Now in Phase II clinical trials (Besarab et al.)

30 EPODURE was safe and doseable; no antigenic response
Erythropoiesis Sustained 12 months by the EPODURE Biopump in Patients with Chronic Kidney Disease: Further Results of Phase I/II Proof of Concept TrialErythropoiesis Sustained 12 months by the EPODURE Biopump in Patients with Chronic Kidney Disease: Further Results of Phase I/II Proof of Concept Trial Besarab et al EPODURE was safe and doseable; no antigenic response Clinical feasibility demonstrated in 12 pts [4 previously ESA dependent Single EPODURE administration can raise and maintain Hemoglobin levels for months without any injections of ESAs 10-12 pts responded. Two that did not were resistant to ESA

31 What about Iron Iron Deficiency Common in ESRD and CKD Blood loss
Poor iron absorption Interference with iron absorption Acid blockers Phosphate binders Other

32 Iron ESRD History Prior to ESAs, Iron overload common
Due to blood transfusions Was always difficult to prove “toxicity” from the stored” iron unless ferritins > 3000 ng/ml. In ESA era, absolute and functional iron deficiency developed 1993 Iron deficiency common 50% of pts with TSAT < 20% Oral iron could not keep up with erythropoietic needs (parenteral iron gap) 1996 First KDOQI stresses need for IV iron 2010 60-80% of HD pts treated with IV iron Mean Serum ferritin approx 585 ng/ml (min recommended is 200 ng/ml)

33 Iron or EPO Debate EPO IRON
Combine summary with previous EPO Data to support IV Iron in Patients with Serum Ferritin (SFe) > 500 ng/mL Current practice (mean SFe in U.S. HD pts was ng/mL in 2007) Besarab (RCT); DRIVE Study (RCT) Kalantar-Zadeh (Observational): Lowest all-cause and CV death risks with SFe: IV iron < 400 mg/mo associated with improved survival; doses >400 mg/mo correlated with ’d death risk Hemochromatosis unlikely [need acc of 20 g] No association with infection when controlled for time-dependent effects Do not give during active infection Less costly to achieve same Hb NO black box warnings (Fe sucrose & gluconate) vs. ESAs & Fe dextran IRON EPO & iron have multiple functions → essential at physiological levels → harmful at high levels Correlation of M &M with higher ESA dose is statistical → may be clinically unrelated → both caused by underlying systemic disorders Cons for iron: Adverse effects of Fe: chronic in nature IV iron safety data from short-term trials IV iron can increase oxidative stress → IV iron should be used with caution to minimize adverse long-term consequences, particularly in inflamed patients

34 Iron Efficacy and Safety
Variety of studies indicate 20%-60% reduction in ESA dose requirements Improvement in achieved Hb 1000 mg ~ 1 g/dl Hb Generally well tolerated Acute hypotensive reactions ?immune response ?free iron Other No interventional studies on effect on higher level outcomes: morbidity and mortality Long term safety not established No obvious signal of harm from epidemiologic studies on large data bases Unclear benefit beyond Hb and ESA dose

35 Current IV Iron Agents (USA)
Iron dextran Low molecular weight (brand and generic) High molecular weight (brand only) Sodium ferric gluconate Brand and generic Iron sucrose Ferumoxytol Brand only

36 Current Knowledge of Iron preparations
Iron dextran Low molecular weight may be safer Brand and generic versions may not be equivalent Iron sucrose study in Europe1 Unclear if differences in other IV iron agents influence Efficacy Safety 1. Rottenbourg et al NDT 2011: doi /ndt/gfr024 (in print)

37 Targeting Higher Transferrin Saturation and Ferritin Levels Using Ferumoxytol
510 mg Ferumoxytol x 2 if TSAT < 30% and ferritin < 500 ng/ml to 690 patients of a SDO (Mid Atlantic) ESA protocol left unchanged TSAT 24% to 31%, ferritin 349 to 542 at 3 mo, both decreased toward baseline by 6 months Experience at Satellite Health: 61/12,105 doses ; AE rate* per dose administered (0.5 %); Allergic 10/61; anaphylactoid 4/61; hypotension 8/61 For those with baseline Hb > 10 g/dl, EPO dose from 7200 to 5500 U 3x/wk

38 What is on the horizon? Parenteral Non-conventional Oral ?
Ferric carboxymaltose Iron isomaltoside 1000 Non-conventional Dialysate: Sodium Ferric Pyrophosphate Oral ? Ferric citrate

39 Ferric carboxymaltose
Can administer large doses at one time Up to 750 mg IV Currently approved in Europe Phase 3 studies in US FCM vs. iron sucrose

40 Need for additional knowledge on IV iron
Are there true benefits related to patient outcomes? Is there any risk to long term administration? Oxidative stress Inflammation

41 A new way of administering iron to HD patients?
1

42 Sodium Ferric Pyrophosphate
Delivered by dialysate Advantages Convenience Delivery matches needs As iron lost with dialysis, replaced Slower delivery than IV Avoids free iron surges May be well tolerated Phase 2 studies indicate that IV iron may still be required at times Phase 3: CRUISE is underway

43 Hepcidin binding to ferroportin
JAK2; Janus kinase 2 Krushner JP. Blood 2010;115:3425–3426 Kushner JP. Blood 2010;115:17:3425–6. JAK2, Janus Kinase 2

44 Hepcidin regulates iron flow into plasma
Spleen Hepcidin Liver Hepcidin Red blood cells Bone marrow Duodenum Hepcidin Plasma Fe-Tf Ganz T. J Am Soc Nephrol 2007;18:394–400; Ganz T & Nemeth E. Am J Physiol Gastrointest Liver Physiol 2006;290:G199–203

45 Regulation of hepcidin by inflammation
Plasma Fe-Tf Inflammation Liver Spleen Hepcidin Hepcidin Red blood cells Bone marrow Duodenum Hepcidin Ganz T. J Am Soc Nephrol 2007;18:394–400

46 MAb against hepcidin effective in combination therapy for anaemia of inflammation
14 14 12 12 Hb (g/dL) Hb (g/dL) 10 10 p<0.01 p<0.01 p<0.01 p<0.01 8 8 6 13 6 13 Day Day 3X Ab ESA 3X Ab 2.7 4X control Ab 4X Ab ESA 3X control Ab + ESA 4X Ab ESA 4X control Ab + ESA 4X Ab 2.7. 5X Ab ESA Ab 2.7 restored response to ESA treatment in hHepc knock in AI mice Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Administration time of BA, anti-hepcidin (or control) antibody, and ESA or saline control Sasu B et al. Blood 2010;115:3616–3624

47 Conclusions We have used ESA therapy and IV iron compounds to treat renal anemia for 20 years We still do not know the optimum way to use these products in CKD patients as they progress from moderate to end stage renal disease and thereafter Several novel therapeutic strategies for managing renal anemia are on the horizon BA16738 – 132 patients in CERA arm SC, 52 week treatment period (18 week correction, 10 week evaluation, 24 week extension) 264 BA16736 – 126 patients in the CERA arm IV, 52 week treatment period (24 week correction, 28 week evaluation) 168 BA16739 – 310 patients in 2 CERA arms IV, 52 week treatment period 465 BA16740 – 310 patients in 2 CERA arms SC, 52 week treatment period 465 BA17284 – 132 patients in the CERA arm pre-filled syringes, 36 week treatment period 264 BA17283 – 132 patients in the CERA arm IV, 52 week treatment period 264 Total 897 IV patients Total 729 SC patients

48 We know we must individualize
We know we must individualize One size does not fit all!!!!

49 Thank you


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