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Normocytic normochromic anemia is a common complication in chronic kidney disease and is associated
with many adverse clinical consequences. Erythropoiesis-stimulating agents (ESAs) and adjuvant iron therapy
represent the primary treatment for anemia in chronic kidney disease. The introduction of ESAs into clinical
practice was a success story, mediating an increase in hemoglobin concentrations without the risk for recurrent
blood transfusions and improving quality of life substantially. However, recombinant ESAs are still expensive
and require a parenteral route of administration. Moreover, concern has arisen following randomized clinical
trials showing that higher hemoglobin targets and/or high ESA doses may cause significant harm. This,
together with changes in ESA reimbursement policy in some countries, has resulted in a significant reduction in
ESA prescribing and the hemoglobin level targeted during therapy. Several attempts are being made to
develop new drugs with improved characteristics and/or easier manufacturing processes compared with
currently available ESAs, including new treatment approaches that may indirectly improve erythropoiesis. We
give an update on the new investigational strategies for increasing erythropoiesis, examining in depth their
characteristics and possible advantages in the clinical setting and the caveats to be aware of at the present
stage of development.
Am J Kidney Dis. 67(1):133-142. 2016 by the National Kidney Foundation, Inc.
INDEX WORDS: Chronic kidney disease (CKD); renal anemia; erythropoiesis; erythropoiesis stimulating
agent (ESA); erythropoietin (EPO); hypoxia-inducible factor (HIF); HIF stabilizer; prolyl hydroxylase
inhibitor; EPO receptor; gene therapy; activin trap; end-stage renal disease; chronic renal insufficiency;
dialysis; review.
enhance the synthesis of alloantigenic antibodies, Box 1. New Strategies Under Development to Stimulate
reducing the likelihood of patients subsequently Erythropoiesis
receiving a kidney transplant. Excessive iron use may Not Directly Targeting the EPO Receptor
cause harm as well.10 HIF stabilizers
In the last 2 decades, recombinant forms of EPO FG-4592 (Roxadustat)
have been engineered to have structural modications AKB-6548
GSK1278863
that increase half-life and accommodate a wider BAY 85-3934 (Molidustat)
administration schedule. However, health systems JTZ-951
cannot afford to pay more for a secondary advantage, DS-1093a
as attested by the limited success of methoxy- Activin traps
Mechanism of
Agents Drugs Action Summary of Preclinical Data Reference
EPO mimetic peptides AGEM400(HES), CNTO 530, EPO receptor Efficient stimulation of hematopoietic 11-14
CNTO 531 activation progenitor cells
EPO fusion proteins EPO-EPO dimers, EPO-CPT, EPO receptor Increased erythropoietic activity and half-life 15-21
EPO-(CPT)3, albumin-EPO activation compared to the native endogenous
hormone in vitro and in mice
Agonistic antibodies to Mouse IgG, Ab12, Ab12.6 EPO receptor Relatively poor EPO receptor activation by 22-24
the EPO receptor (ABT-007) activation mouse monoclonal antibodies; in vitro
potency and in vivo erythropoietic efficacy
in mice by human agonistic antibodies
Ab12 and Ab12.6
Inducers of dimerization Chemical inducer of EPO receptor Exclusive stimulation of erythroid cells upon 25
of EPO receptor dimerization (CID) activation perioral administration to transgenic mice
intracellular domain
Note: See Box 1 for expansions of abbreviations.
those treated with peritoneal dialysis. Moreover, these assigned 1:1:1 to FG-4592 low or high dose or pla-
agents induce physiologic EPO levels, unlike the cebo. At the end of the 8-week treatment period,
abnormally high peak concentrations usually observed participants showed mean maximum Hb level in-
with standard ESA therapy, which may be harmful.36 creases from baseline of 2.6 g/dL in the high-dose
The rst promising molecule of this class was cohort and 1.8 g/dL in the low-dose cohort,
FG-2216 (FibroGen Inc), which was withdrawn compared to 0.7 g/dL in the placebo group. The
following a case of fatal hepatitis. The same com- percentage of patients achieving Hb levels $ 11 g/dL
pany then developed roxadustat (FG-4592). In 117 was higher in those receiving the active drug than
nondialysis-dependent patients with CKD, those who placebo. Interestingly, patients who received roxadu-
were randomly assigned to roxadustat (4 doses esca- stat showed small decreases in blood pressure similar
lating from 0.7 to 2.0 mg/kg administered 2 or 3 times to the placebo group. In still another study, FG-4592
weekly) had a higher Hb response rate than those was found effective in achieving anemia correction in
receiving placebo. Roxadustat also achieved good ESA-naive patients receiving peritoneal dialysis, with
anemia correction (Hb increased on average by 2 g/dL a safety prole similar to the HD population.42
in 3 months) in ESA-naive HD patients who had se- Akebia Therapeutics is developing another prolyl
vere anemia and were iron decient in many cases.37 hydroxylase inhibitor, AKB-6548. After successfully
According to the interim analysis of another phase undergoing phase 2a clinical development in CKD
2 study of HD patients, FG-4592 produced an in- stages 3 and 4, the drug has recently been evaluated in
crease in mean Hb levels of w1 g/dL from baseline in a phase 2b, randomized, double-blind, placebo-
the 2 cohorts receiving the highest doses (1.5 and controlled study.43 This 20-week study enrolled 209
2.0 mg/kg). Conversely, those randomly assigned to nondialysis-dependent patients with CKD stages 3 to
recombinant human EPO experienced a slight 5 who were randomly assigned 2:1 to active treatment
decrease in Hb levels during the 6-week follow-up or placebo. The initial dose was 450 mg once daily,
period.38 In FG-4592treated patients, the improve- with dose adjusted in accordance to the patients Hb
ment in erythropoiesis accompanied a reduction in level response based on the AKB-6548 titration al-
serum hepcidin levels. It is still unknown whether this gorithm. Preliminary results showed that the primary
is a direct or indirect effect related to HIF stabiliza- end point, dened as achieving or maintaining mean
tion. Excess hepcidin is the main cause of functional Hb levels $ 11 g/dL or increasing Hb $ 1.2 g/dL
iron deciency and iron-restricted erythropoiesis in above the pretreatment value, was met in 54.9% who
patients with CKD.39,40 Whatever the underlying received AKB-6548 compared with 10.3% in the
mechanism(s), the possibility that HIF stabilization placebo group. The drug was generally well tolerated.
may decrease hepcidin levels and possibly improve A phase 2 open-label study designed to examine the
iron utilization is promising. In both the above efcacy, safety, and tolerability of AKB-6548 in HD
studies, no liver toxicity was reported. patients is ongoing (ClinicalTrials.gov identier
More recently, data were presented about another NCT02260193).
phase 2 double-blind placebo-controlled trial in GlaxoSmithKline are also developing an HIF
China41 in which 91 nondialysis-dependent patients prolyl hydroxylase inhibitor (GSK1278863). In 2011,
with CKD with Hb levels , 10 g/dL were randomly they concluded a phase 2a, randomized, single-blind,
FG-4592 (Roxadustat) Fibrogena Phase 2 studies completed (NDD CKD, HD, PD); phase 3 studies ongoing
(NDD CKD, HD, PD)
AKB-6548 Akebia Therapeutics Phase 2 studies completed (NDD CKD) or ongoing but not recruiting (HD)
GSK1278863 Glaxo Smith Kline Phase 2a studies completed (NDD-CKD, HD); phase 2b studies ongoing, but
not recruiting (NDD CKD)
BAY 85-3934 (Molidustat) Bayer Pharmaceuticals Phase 2b studies ongoing (NDD CKD, HD)
JTZ-951 Akros Pharmaceuticals Phase 1 study completed (HD)
DS-1093a Daiichi Sankyo Phase 1 study ongoing (CKD 3b-4)
Abbreviations: CKD, chronic kidney disease; HD, hemodialysis; NDD, nondialysis-dependent; PD, peritoneal dialysis.
a
Collaboration with Astra Zeneca in the United States and China and with Astellas Pharma for Europe, Japan, the Middle East, and
South Africa.
regarding the use of HIF prolyl hydroxylase inhibitors induce erythroid differentiation.67,68 Two potential
in kidney anemia come only from abstracts. Despite nonexclusive indirect mechanisms have been proposed
the promise of a new class of erythropoietic com- for the effects of sotatercept on human erythropoiesis.69
pounds, careful development is still required due to The rst relates to the binding of ACTRIIA ligands,
the wide range of biological pathways in which HIF resulting in modulation of their function regarding
transcription factors are involved. erythroid development. As a second possible mecha-
nism, by neutralizing TGFb family members, sota-
Activin Traps tercept can modulate the SMAD signaling pathway in
Activins are dimers of inhibin b-type chains and stromal cells, leading to changes in the transcription of
belong to the transforming growth factor b (TGFb) SMAD target genes that encode proteins affecting
superfamily. They trigger growth and differentiation erythroid development.70 For example, the expression
by binding to type I and type II serine-threonine kinase of angiotensin II, which can stimulate erythropoiesis
receptors, which are transmembrane proteins.60 Acti- directly and indirectly by EPO production, is increased,
vin, bone morphogenic proteins, and several other whereas the expression of VEGF, considered an in-
members of the TGFb family contribute to regulation hibitor of erythropoiesis, is suppressed.69 Sotatercept is
of erythropoiesis either by directly affecting erythroid currently being evaluated in patients with CKD 5D
progenitor or precursor cells or by altering the (ClinicalTrials.gov identier NCT01146574) in a
behavior of bone marrow accessory cells.60-62 These phase 2a, randomized, double-blind, placebo-
actions seem to be mediated by a signaling pathway controlled, single-dose (0.1 mg/kg subcutaneously)
involving the SMAD proteins.60 Note that activin A is study, followed by a double-blind, placebo-controlled,
identical to the erythroid differentiation factor, multiple-dose, dose-escalation study (starting doses of
which is able to cause differentiation of immature 0.3, 0.5, or 0.7 mg/kg subcutaneously every 28 days in
erythropoietic progenitors into mature cells.63 a sequential design for up to 8 doses). The rst results of
Sotatercept (ACE-011; Acceleron and Celgene part 2 of this study have recently been presented.71 At
Corp) is a dimeric fusion protein in which the extra- each dose, sotatercept was well tolerated and showed a
cellular domain of the activin receptor type IIA safety prole comparable to placebo, with a mean
(ACTRIIA) is linked to the Fc portion of the human elimination half-life of 21 to 26 days. The mean peak
immunoglobulin G1 (IgG1) antibody. Sotatercept traps Hb response in the rst 28 days was dose related, the
circulating activin and other members of the TGFb highest response (1.0 g/dL) being observed in the
superfamily that signal through ACTRIIA.64 In a group treated with sotatercept at a 0.7-mg/kg dose.
double-blind phase 1 trial of healthy postmenopausal Based on observed changes in Hb levels, drug admin-
women, treatment with a single intravenous injection of istration once every 2 weeks instead of once every 4
sotatercept was accompanied by enhanced bone for- weeks has been suggested.72 This is currently being
mation and decreased bone resorption.65 Surprisingly, investigated in a phase 2 study (ClinicalTrials.gov
this trial showed an unanticipated increase in Hb level, identier; NCT01999582), entailing intravenous and
red blood cell number, and hematocrit.65 Treatment subcutaneous administration of escalating doses of
with sotatercept also increased Hb and hematocrit levels sotatercept every 2 weeks in HD patients.
in a phase 2 trial of patients with multiple myeloma in Sotatercept also has other activities that are of po-
parallel with improvement in bone lesions.66 tential relevance in the CKD setting. The drug can inhibit
The clinical observation that an activin-sequestering hepcidin transcription in hepatocytes73 because the
agent such as sotatercept stimulates erythropoiesis is hepcidin promoter contains bone morphogenic protein
hard to reconcile with the reported ability of activin to responsive SMAD-binding elements.74 Activin B has
been shown to play a critical role in hepcidin induction EPO receptor though their amino acid sequence is
by inammation75 and therefore represents a specic completely different from the hormone.85,86 EMP-1,
target for treatment of anemia due to inammation.72 an oligopeptide containing 20 amino acids joined by
Sotatercept has demonstrated stimulating effects on a disulde bridge between 2 cysteine residues, was
bone formation,64 which are believed to be mediated synthesized in 1998.87 However, its short in vivo half-
through its interaction with activin.76 The administra- life and relatively weak binding to the EPO receptor
tion of ACE-011 and its murine counterpart RAP-011 hampered its clinical use.
cause bone loss and osteoporosis to be reversed in In order to increase effectiveness, peptide di-
various animal models.77,78 In CKD mouse models for mers that use either chemical linkers or polymeric
vascular calcication, RAP-011 inhibits SMAD- polyethylene glycol linkers have been constructed.
dependent signaling, blocks aortic osteoblastic transi- The CNTO molecules (Centocor) were developed
tion, increases vascular smooth muscle function, and by using the MIMETIBODY platform, in which a
decreases CKD-stimulated vascular calcication.79,80 given active peptide is connected with an amino
The effects of sotatercept on bone mineral density acid linker to an immunoglobulin Fc domain. The
and vascular calcication were evaluated by using peptide remains capable of interacting with its
quantitative computed tomography81 in the above receptor, while extended pharmacologic properties
mentioned study in HD patients.71 A small interim data are provided by the Fc fragment. Fc fusion tech-
set showed an apparent dose effect on multiple pa- nology has been introduced to generate long-
rameters of CKDmineral bone disorder, including acting antagonistic drugs, such as those targeting
increasing femoral neck cortical bone mass, decreasing TNFR (tumor necrosis factor receptor) and CTLA-
lumbar spine bone mass, and slowing progression of 4 (cytotoxic T-lymphocyteassociated antigen
vascular calcication.82 Considerable differences in 4).88 CNTO 528, obtained by fusion of 2 EMP-1
baseline characteristics of patients may inuence these molecules with a human IgG1 Fc domain, stimu-
results, and the number of participants was small. Thus, lated erythropoiesis after a single intravenous
though sotatercept may address unmet needs in ESRD administration at ascending doses in phase 1
with favorable effects on CKDmineral bone disorder, studies in healthy volunteers.89,90
these results need to be conrmed in larger populations. Peginesatide (originally named Hematide; Affymax/
Another investigational ligand-trapping fusion pro- Takeda), a small dimeric peptide conjugated to a pe-
tein (Luspatercept; ACE-536; Acceleron/Celgene gylated moiety, was approved by the US Food and
Corp) containing the extracellular domain of human Drug Administration in 2012 for treatment of anemic
activin receptor type IIB (ACTRIIB) modied to reduce adult patients receiving dialysis. It is a long-acting
activin binding shows erythropoietic activity and pro- ESA, with dose requirements irrespective of the
motes the maturation of late-stage erythroid precursors administration route. The drug corrected anemia
in vivo.83 Interestingly, treatment with EPO and ACE- effectively in large studies carried out in both non
536 produces a synergistic erythropoietic response.83 dialysis-dependent patients with CKD91 and those
A phase 1, ascending-dose, randomized, double-blind, with chronic kidney failure treated by dialysis.92
placebo-controlled, clinical trial of ACE-536 in Concerns about cardiovascular safety were raised in
healthy volunteers has recently been completed.84 view of higher incidences of death, unstable angina,
Thirty-two postmenopausal women were randomly and arrhythmia in nondialysis-dependent patients
assigned in sequential cohorts of 8 participants each to with CKD treated with peginesatide.91 However, they
receive up to 2 doses of ACE-536 (0.0625-0.25 mg/kg) were not conrmed by a prespecied combined
or placebo (3:1 randomization) administered subcuta- analysis of the dialysis and nondialysis trials. Given
neously every 2 weeks. ACE-536 was well tolerated and its EPO-unrelated structure, the drug was also used
no serious or severe adverse events occurred. Hb levels for the treatment of EPO-related pure red cell apla-
increased dose dependently, beginning 7 days after sia.93 Just one year after commercialization, Affymax
treatment initiation, and were maintained for several and Takeda instituted a voluntary recall of the drug
weeks following treatment.84 These ndings support following postmarketing reports of serious acute hy-
ongoing phase 2 clinical trials of ACE-536 in patients persensitivity reactions that could be life-threatening
with b-thalassemia and myelodysplastic syndromes. or fatal.94 Approximately 0.02% of patients re-
ceiving the rst dose of the drug intravenously died.
NEW ERYTHROPOIETIC STRATEGIES TARGETING The cause of the hypersensitivity reactions has not
THE EPO RECEPTOR been claried.
EPO Mimetic Peptides Epoetin Fusion Proteins
EPO mimetic peptides (EMPs) are a group of A number of attempts have been made to create
synthetic cyclic peptides capable of stimulating the EPO fusion molecules with enhanced erythropoietic
6. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of dar- 24. Lacy SE, DeVries PJ, Xie N, Fung E, Lesniewski RR,
bepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl Reilly EB. The potency of erythropoietin-mimic antibodies cor-
J Med. 2009;361(21):2019-2032. relates inversely with afnity. J Immunol. 2008;181(2):1282-1287.
7. Pisoni RL, Fuller DS, Bieber BA, et al. The DOPPS Practice 25. Suzuki N, Mukai HY, Yamamoto M. In vivo regulation of
Monitor for US dialysis care: trends through August 2011. Am J erythropoiesis by chemically inducible dimerization of the eryth-
Kidney Dis. 2012;60(1):160-165. ropoietin receptor intracellular domain. PLoS One. 2015;10(3):
8. KDIGO Anemia Work Group. KDIGO clinical practice e0119442.
guideline for anemia in chronic kidney disease. Kidney Int Suppl. 26. Haase VH. Regulation of erythropoiesis by hypoxia-
2012;2:S279-S335. inducible factors. Blood Rev. 2013;27(1):41-53.
9. Locatelli F, Brny P, Covic A, et al; ERA-EDTA ERBP 27. Semenza GL. Hypoxia-inducible factors in physiology and
Advisory Board. Kidney Disease: Improving Global Outcomes medicine. Cell. 2012;148(3):399-408.
guidelines on anaemia management in chronic kidney disease: a 28. Kapitsinou PP, Liu Q, Unger TL, et al. Hepatic HIF-2
European Renal Best Practice position statement. Nephrol Dial regulates erythropoietic responses to hypoxia in renal anemia.
Transplant. 2013;28(6):1346-1359. Blood. 2010;116(16):3039-3048.
10. Hung SC, Tarng DC. ESA and iron therapy in chronic 29. Scortegagna M, Ding K, Zhang Q, et al. HIF-2alpha reg-
kidney disease: a balance between patient safety and hemoglobin ulates murine hematopoietic development in an erythropoietin-
target. Kidney Int. 2014;86(4):676-678. dependent manner. Blood. 2005;105(8):3133-3140.
11. Sathyanarayana P, Houde E, Marshall D, et al. CNTO 530 30. Mastrogiannaki M, Matak P, Keith B, Simon MC,
functions as a potent EPO mimetic via unique sustained effects Vaulont S, Peyssonnaux C. HIF-2alpha, but not HIF-1alpha,
on bone marrow proerythroblast pools. Blood. 2009;113(20): promotes iron absorption in mice. J Clin Invest. 2009;119(5):
4955-4962. 1159-1166.
12. Bugelski PJ, Makropoulos D, Spinka-Doms T, et al. Dif- 31. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible
ferential effects of long-lived erythropoietin receptor agonists in factors and the response to hypoxic stress. Mol Cell. 2010;40(2):
rats. Pharm Anal Acta. 2011;2(7):133. 294-309.
13. Greindl A, Kessler C, Breuer B, et al. AGEM400(HES), a 32. Rabinowitz MH. Inhibition of hypoxia-inducible factor
novel erythropoietin mimetic peptide conjugated to hydroxyethyl prolyl hydroxylase domain oxygen sensors: tricking the body into
starch with excellent in vitro efcacy. Open Hematol J. 2010;4:1-14. mounting orchestrated survival and repair responses. J Med Chem.
14. Kessler C, Greindl A, Breuer B, et al. Erythropoietin 2013;56(23):9369-9402.
mimetic compound AGEM400(HES) binds to the same receptor as 33. Kato A, Hishida A, Kumagai H, Furuya R, Nakajima T,
erythropoietin but displays a different spectrum of activities. Honda N. Erythropoietin production in patients with chronic renal
Cytokine. 2012;57(2):226-237. failure. Ren Fail. 1994;16(5):645-651.
15. Dalle B, Henri A, Rouyer-Fessard P, et al. Dimeric eryth- 34. Shimizu S, Enoki Y, Sakata S, Kohzuki H, Ohga Y,
ropoietin fusion protein with enhanced erythropoietic activity Matsumura K. Erythropoietin response to acute hypobaric or
in vitro and in vivo. Blood. 2001;97(12):3776-3782. anaemic hypoxia in gentamicin-administered rats. Acta Physiol
16. Sytkowski AJ, Lunn ED, Risinger MA, Davis KL. An Scand. 1994;151(2):225-231.
erythropoietin fusion protein comprised of identical repeating 35. Priyadarshi A, Periyasamy S, Burke TJ, Britton SL,
domains exhibits enhanced biological properties. J Biol Chem. Malhotra D, Shapiro JI. Effects of reduction of renal mass on renal
1999;274(35):24773-24778. oxygen tension and erythropoietin production in the rat. Kidney
17. Fares FA, Ganem S, Hajouj T, Agai E. Development of a long- Int. 2002;61(2):542-546.
acting erythropoietin by fusing the carboxyl-terminal peptide of hu- 36. Unger EF, Thompson AM, Blank MJ, Temple R. Eryth-
man chorionic gonadotropin beta-subunit to the coding sequence of ropoiesis stimulating agentstime for a reevaluation. N Engl J
human erythropoietin. Endocrinology. 2007;48(10):5081-5087. Med. 2010;362(3):189-192.
18. Fares F, Havron A, Fima E. Designing a long acting 37. Besarab A, Chernyavskaya EN, Motylev I, et al. FG-4592, an
erythropoietin by fusing three carboxyl-terminal peptides of hu- oral hypoxia-inducible factor propyl hydroxylase inhibitor, corrects
man chorionic gonadotropin b subunit to the n-terminal coding anemia without iron supplementation in incident dialysis patients
sequence. Int J Cell Biol. 2011;2011:275063. [ASN abstract TH-OR096]. J Am Soc Nephrol. 2012;23:21A.
19. Schriebl K, Trummer E, Lattenmayer C, et al. Biochemical 38. Provenzano R, Goodkin D, Klaus S, et al. Evaluation of
characterization of rhEPO-Fc fusion protein expressed in CHO FG-4592, a novel oral hypoxia-inducible factor prolyl hydroxylase
cells. Protein Expr Purif. 2006;49(2):265-275. inhibitor, to treat anemia in hemodialysis patients [abstract 188].
20. Penno CA, Kawabe Y, Ito A, Kamihita M. Production of Presented at: National Kidney Foundation Conference; April 26-
recombinant human erythropoietin/Fc fusion protein by geneti- 30, 2011; Las Vegas, NV.
cally manipulated chickens. Transgenic Res. 2010;19(2):187-195. 39. Finberg KE. Regulation of systemic iron homeostasis. Curr
21. Joung CH, Shin JY, Koo JK, et al. Production and char- Opin Hematol. 2013;20(3):208-214.
acterization of long-acting recombinant human albumin-EPO 40. Sun CC, Vaja V, Babitt JL, Lin HY. Targeting the
fusion protein expressed in CHO cell. Protein Expr Purif. hepcidin-ferroportin axis to develop new treatment strategies for
2009;68(2):137-145. anemia of chronic disease and anemia of inammation. Am J
22. Schneider H, Chaovapong W, Matthews DJ, et al. Homo- Hematol. 2012;87(4):392-400.
dimerization of erythropoietin receptor by a bivalent monoclonal 41. Qian JQ, Chen N, Chen J, et al. A randomized, double-
antibody triggers cell proliferation and differentiation of erythroid blind, placebo controlled trial of FG-4592 for correction of ane-
precursors. Blood. 1997;89(2):473-482. mia in subjects with chronic kidney disease in China [ASN
23. Elliott S, Lorenzini T, Yanagihara D, Chang D, Elliott G. abstract FR-OR011]. J Am Soc Nephrol. 2013;24:38A.
Activation of the erythropoietin (EPO) receptor by bivalent anti- 42. Besarab A, Tak Mao Chan D, Dua SL, et al. Hypoxia
EPO receptor antibodies. J Biol Chem. 1996;271(40):24691-24697. inducing factor propyl hydroxylase inhibitor FG-4592 corrects
anemia in peritoneal dialysis [ASN abstract SA-OR087]. J Am Soc in heart via Na/Ca21 exchanger in developing rats. Cell Physiol
Nephrol. 2013;24:91A. Biochem. 2014;34(2):313-324.
43. Akebia announces positive top-line results from its phase 60. Maguer-Satta V, Bartholin L, Jeanpierre S, et al. Regulation
2b study of AKB-6548 in non-dialysis patients with anemia related of human erythropoiesis by activin A, BMP2, and BMP4, members
to chronic kidney disease. http://ir.akebia.com/releasedetail.cfm? of the TGFbeta family. Exp Cell Res. 2003;282(2):110-120.
ReleaseID5878191. Accessed March 2, 2015. 61. Yu J, Maderazo L, Shao LE, et al. Specic roles of activin/
44. A phase IIa, randomized, single-blind, placebo-controlled, inhibin in human erythropoiesis in vitro. Ann N Y Acad Sci.
parallel-group study to evaluate the safety, pharmacokinetics, and 1991;628:199-211.
efcacy of 28-day repeat oral doses of GSK 1278863A in anemic pre- 62. Zermati Y, Fichelson S, Valensi F, et al. Transforming
dialysis and hemodialysis-dependent patients. GlaxoSmithKline growth factor inhibits erythropoiesis by blocking proliferation and
website www.gsk-clinicalstudyregister.com/study/112844#rs. accelerating differentiation of erythroid progenitors. Exp Hematol.
Accessed March 2, 2015. 2000;28(8):885-894.
45. A repeat-dose, open-label, parallel-group study to assess 63. Murata M, Eto Y, Shibai H, Sakai M, Muramatsu M.
the pharmacokinetics of GSK1278863 and metabolites in normal Erythroid differentiation factor is encoded by the same mRNA as
subjects and subjects with impaired renal function. GlaxoSmith- that of the inhibin beta A chain. Proc Natl Acad Sci U S A.
Kline website www.gsk-clinicalstudyregister.com/study/115573#rs. 1988;85(8):2434-2438.
Accessed March 2, 2015. 64. Raje N, Vallet S. Sotatercept, a soluble activin receptor
46. Studies ltered by compound GSK 1278863. GlaxoSmith- type 2A IgG-Fc fusion protein for the treatment of anemia and
Kline website www.gsk-clinicalstudyregister.com/compounds/gsk bone loss. Curr Opin Mol Ther. 2010;12(5):586-597.
1278863#ps. Accessed March 2, 2015. 65. Ruckle J, Jacobs M, Kramer W, et al. Single-dose, ran-
47. Flamme I, Oehme F, Ellinghaus P, Jeske M, domized, double-blind, placebo-controlled study of ACE-011
Keldenich J, Thuss U. Mimicking hypoxia to treat anemia: (ActRIIA-IgG1) in postmenopausal women. J Bone Miner Res.
HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythro- 2009;24(4):744-752.
poietin production without hypertensive effects. PLoS One. 66. Abdulkadyrov K, Salogub G, Khuazheva N, et al. ACE-011, a
2014;9(11):e111838. soluble activin receptor type IIa IgG-FC fusion protein, increases he-
48. Boettcher MF, Lentini S, Kaiser A, Flamme I, Kubitza D, moglobin (Hb) and improves bone lesions in multiple myeloma pa-
Wensing G. First-in-man study with BAY 85-3934a new oral tients receiving myelosuppressive chemotherapy: preliminary analysis.
selective HIF-PH inhibitor for the treatment of renal anemia [ASN Blood. 2009;114(22). (ASH Annual Meeting Abstracts):Abstract 749.
abstract THPO1090]. J Am Soc Nephrol. 2013;24:347A. 67. Yu J, Shao L, Vaughan J, Vale W, Yu AL. Characterization
49. Safety, tolerability, PK and PD study of JTZ-951 in anemic of the potentiation effect of activin on human erythroid colony
subjects with end-stage renal disease. U.S. National Institutes of formation in vitro. Blood. 1989;73(4):952-960.
Health website https://clinicaltrials.gov/ct2/show?term5jtz-951 68. Shao l, Frigon NL Jr, Young AL, et al. Effect of activin A
&rank52. Accessed March 2, 2015. on globin gene expression in puried human erythroid progenitors.
50. Pilot PK/PD study of DS-1093a in patients with chronic Blood. 1992;79(3):773-781.
kidney disease. U.S. National Institutes of Health website https:// 69. Iancu-Rubin C, Mosoyan G, Wang J, Kraus T, Sung V,
clinicaltrials.gov/ct2/show?term5ds-1093a&rank51. Accessed Hoffman R. Stromal cell-mediated inhibition of erythropoiesis can
March 2, 2015. be attenuated by sotatercept (ACE-011), an activin receptor type II
51. Cheng K, Ho K, Stokes R, et al. Hypoxia-inducible factor- ligand trap. Exp Hematol. 2013;41:155-166.
1alpha regulates beta cell function in mouse and human islets. 70. Blank U, Karlsson S. The role of Smad signaling in he-
J Clin Invest. 2010;120(6):2171-2183. matopoiesis and translational hematology. Leukemia. 2011;25(9):
52. Rankin EB, Rha J, Selak MA, et al. Hypoxia-inducible 1379-1388.
factor 2 regulates hepatic lipid metabolism. Mol Cell Biol. 71. El-Shahawy M, Cotton J, Kaupke J, Kopyt N, Choi S,
2009;29(16):4527-4538. Smith WT. Safety and hemoglobin effects of the rst 28-day dose cycle
53. Zehetner J, Danzer C, Collins S, et al. PVHL is a regulator of sotatercept 0.7 mg/kg compared with lower doses and placebo for
of glucose metabolism and insulin secretion in pancreatic beta correction of anemia in hemodialysis subjects: interim analysis [ASN
cells. Genes Dev. 2008;22(22):3135-3146. abstract TH-PO985]. J Am Soc Nephrol. 2014;25:337A.
54. Krishnan J, Suter M, Windak R, et al. Activation of a 72. Besson-Fournier C, Latour C, Kautz L, et al. Induction of
HIF1alpha-PPARgamma axis underlies the integration of glyco- activin B by inammatory stimuli up-regulates expression of the
lytic and lipid anabolic pathways in pathologic cardiac hypertro- iron-regulatory peptide hepcidin through Smad1/5/8 signaling.
phy. Cell Metab. 2009;9(6):512-524. Blood. 2012;120(2):431-439.
55. Semenza GL. HIF-1: upstream and downstream of cancer 73. Finberg KE, Whittlesey RL, Fleming MD, Andrews NC.
metabolism. Curr Opin Genet Dev. 2009;20(1):51-56. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for
56. Ratcliffe PJ. Oxygen sensing and hypoxia signalling maintenance of systemic iron homeostasis. Blood. 2010;115(18):
pathways in animals: the implications of physiology for cancer. 3817-3826.
J Physiol. 2013;591(8):2027-2042. 74. Truksa J, Lee P, Beutler E. Two BMP responsive elements,
57. Rimoldi SF, Rexhaj E, Pratali L, et al. Systemic vascular STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are
dysfunction in patients with chronic mountain sickness. Chest. critical for BMP, SMAD1, and HJV responsiveness. Blood.
2012;141(1):139-146. 2009;113(3):688-695.
58. Schmid JP, Nobel D, Brugger N, et al. Short-term high 75. Ganz T. Systemic iron homeostasis. Physiol Rev.
altitude exposure at 3454m is well tolerated in patients with stable 2013;93(4):1721-1741.
heart failure. Eur J Heart Fail. 2015;17(2):182-186. 76. Lotinun S, Pearsall RS, Horne WC, Baron R. Activin re-
59. Ma HJ, Li Q, Ma HJ, et al. Chronic intermittent hypobaric ceptor signaling: a potential therapeutic target for osteoporosis.
hypoxia ameliorates ischemia/reperfusion-induced calcium overload Curr Mol Pharmacol. 2012;5(2):195-204.
77. Lotinun S, Pearsall RS, Davies MV, et al. A soluble activin 90. Perez-Ruixo JJ, Krzyzanski W, Bouman-Thio E, et al.
receptor type IIA fusion protein (ACE-011) increases bone mass Pharmacokinetics and pharmacodynamics of the erythropoietin
via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Mimetibody construct CNTO 528 in healthy subjects. Clin
Bone. 2010;46(4):1082-1088. Pharmacokinet. 2009;48(9):601-613.
78. Pearsall RS, Canalis E, Cornwall-Brady M, et al. 91. Macdougall IC, Provenzano R, Sharma A, et al. Pegine-
A soluble activin type IIA receptor induces bone formation and satide for anemia in patients with chronic kidney disease not
improves skeletal integrity. Proc Natl Acad Sci U S A. 2008;105(19): receiving dialysis. N Engl J Med. 2013;368(4):320-332.
7082-7087. 92. Fishbane S, Schiller B, Locatelli F, et al. Peginesatide in
79. Fang Y, Agapova OA, Sugatani T, Malluche H, patients with anemia undergoing hemodialysis. N Engl J Med.
Hruska KA. Treatment of the CKD-MBD with a ligand trap for the 2013;368(4):307-319.
activin receptor type 2A [ASN abstract FR-PO816]. J Am Soc 93. Macdougall IC, Rossert J, Casadevall N, et al. A peptide-
Nephrol. 2014;25:557A. based erythropoietin-receptor agonist for pure red-cell aplasia.
80. Hruska KA, Agapova OA, Fang Y, Sugatani T, N Engl J Med. 2009;361(19):1848-1855.
Seifert ME, Sung V. Chronic kidney disease (CKD) stimulates 94. Afmax and Takeda announce a nationwide voluntary recall
activin and endothelial to mesenchymal transition (EnMT), of all lots of OMONTYSR (peginesatide) Injection. http://www.
which causes vascular calcication and is inhibited by an activin takeda.com/news/2013/20130224_5664.html. Accessed February
ligand trap [ASN abstract SA-OR063]. J Am Soc Nephrol. 8, 2015.
2014;25:95A. 95. Im SJ, Yang SI, Yang SH, et al. Natural form of non-
81. Leonard MB. A structural approach to skeletal fragility in cytolytic exible human Fc as a long-acting carrier of agonistic
chronic kidney disease. Semin Nephrol. 2009;29(2):133-143. ligand, erythropoietin. PLoS One. 2011;6:e24574.
82. Malluche H, Hurska K, Singh HN, Smith WT. Sota- 96. Roux KH, Strelets L, Brekke OH, Sandlie I,
tercept: initial signal-seeking quantitative computed tomography Michaelsen TE. Comparisons of the ability of human IgG3 hinge
results for bone mass and vascular calcication in hemodialysis mutants, IgM, IgE, and IgA2, to form small immune complexes:
patients treated with escalating doses: interim analysis of ACE- a role for exibility and geometry. J Immunol. 1998;161(8):
011-REN-001 [ASN abstract TH-PO602]. J Am Soc Nephrol. 4083-4090.
2014;25:245A. 97. Idusogie EE, Wong PY, Presta LG, et al. Engineered an-
83. Suragani RN, Cadena SM, Cawley SM, et al. Transforming tibodies with increased activity to recruit complement. J Immunol.
growth factor-b superfamily ligand trap ACE-536 corrects anemia 2001;166(4):2571-2575.
by promoting late-stage erythropoiesis. Nat Med. 2014;20(4): 98. Schuurman J, Perdok GJ, Gorter AD, Aalberse RG. The
408-414. inter-heavy chain disulde bonds of IgG4 are in equilibrium with
84. Attie KM, Allison MJ, McClure T, et al. A phase 1 study of intra-chain disulde bonds. Mol Immunol. 2001;38(1):1-8.
ACE-536, a regulator of erythroid differentiation, in healthy vol- 99. Yang SH, Yang SI, Chung Y-K. A long-acting erythro-
unteers. Am J Hematol. 2014;89(7):766-770. poietin fused with noncytolytic human Fc for the treatment of
85. Livnah O, Stura EA, Johnson DL. Functional mimicry of a anemia. Arch Pharm Res. 2012;35(5):757-759.
protein hormone by a peptide agonist: the EPO receptor complex 100. Study to evaluate safety, tolerability, and pharmacokinetics/
at 2.8 A. Science. 1996;273(5274):464-471. pharmacodynamics of GX-E2 in healthy subjects (GX-E2-P1).
86. Wrighton NC, Farrell FX, Chang R, et al. Small peptides as U.S. National Institutes of Health website https://clinicaltrials.gov/
potent mimetics of the protein hormone erythropoietin. Science. ct2/show/study/NCT02291991?term5GX-E2&rank5.1 Accessed
1996;273(5274):458-464. March 2, 2015.
87. Johnson DL, Farrell FX, Barbone FP, et al. Identication of 101. Study to evaluate the efcacy and safety of GX-E2 in the
a 13 amino acid peptide mimetic of erythropoietin and description anemic patients diagnosed with chronic kidney disease (CKD).
of amino acids critical for the mimetic activity of EMP1. U.S. National Institutes of Health website https://clinicaltrials.gov/
Biochemistry. 1998;37(11):3699-3710. ct2/show/study/NCT02044653?term5GX-E2&rank52. Accessed
88. Huang C. Receptor-Fc fusion therapeutics, traps, and March 2, 2015.
MIMETIBODY technology. Curr Opin Biotechnol. 2009;20(6): 102. Brill-Almon E, Stern B, Ak D, et al. Ex vivo trans-
692-699. duction of human dermal tissue structures for autologous im-
89. Bouman-Thio E, Franson K, Miller B, et al. A phase I, plantation production and delivery of therapeutic proteins. Mol
single and fractionated, ascending-dose study evaluating the Ther. 2005;12(2):274-282.
safety, pharmacokinetics, pharmacodynamics, and immunoge- 103. Neil G. Prolonged secretion of physiological levels of
nicity of an erythropoietin mimetic antibody fusion protein autologous EPO by TARGT. Presented at: XXII Annual Congress
(CNTO 528) in healthy male subjects. J Clin Pharmacol. of the European Society of Gene and Cell Therapy; The Hague,
2008;48(10):1197-1207. the Netherlands; October 23-26, 2014.