Ajay K. Singh, MBBS, FRCP, MBA

Attending Nephrologist, Brigham and Women’s Hospital

Senior Associate Dean for Postgraduate Medical Education, Harvard Medical School

Anemia Management: Update and Best Practices

Ajay K. Singh Bio

• Attending Nephrologist, Brigham and Women’s Hospital

• Senior Associate Dean for Postgraduate Medical Education, Harvard Medical School

• Research interests: Anemia of CKD and CKDu

• Clinical interests: managing patients with CKD

Disclosures• Consultant – GSK, Chair of Ascend program

for HIF stabilizer (PHI) Daprodustat

• Stock: Gilead

Case History

• 62-yo woman with 10-year history of CKD from diabetes; slowly worsening renal function. Past medical history of a right CVA stroke. She sees you in the office. Feels great. Working, exercising, eating well. Lab data shows BUN 48, Cr 4.2, eGFR 18, Hb 8.9 g/dL, Tsat 30%, ferritin 282.

• What do you do?

A. Start patient on an ESA –darbepoetin alfa 40 mcg/week

B. Empirically treat her with a course of intravenous iron

C. Check stool guaiac, and if all right, continue to observe her

Case History

• 62-yo white woman with 10-year history of CKD from diabetes; slowly worsening renal function. Past medical history of a right CVA stroke. She sees you in the office. Feels great. Working, exercising, eating well. Lab data shows BUN 48, Cr 4.2, eGFR 18, Hb 9.1 g/dL, Tsat 30%, ferritin 282.

• What do you do?

A. Start patient on an ESA –darbepoetin alfa 40 mcg/week

B. Empirically treat her with a course of intravenous iron

✓ Check stool guaiac, and if all right, continue to observe her

Should One Treat?

• In our case = no

• She’s not symptomatic; doing fine

• Also, h/o stroke!

• Would work up the anemia and make sure that she is not bleeding

• Remember: No evidence that mild anemia treatment is a disease-modifying treatment. Treat for symptoms.

US FDA ESA label: 12/11❑For patients with CKD not on dialysis:

• Consider initiating ESA treatment only when

the hemoglobin level is less than 10 g/dL….

3.2: In initiating and maintaining ESA therapy, we recommend

balancing the potential benefits of reducing blood transfusions

and anemia-related symptoms against the risks of harm in

individual patients (e.g., stroke, vascular access loss,

hypertension). (1B)

We recommend using ESA therapy with great caution, if at all, in

CKD patients with active malignancy—in particular when cure is

the anticipated outcome—(1B), a history of stroke (1B), or a

history of malignancy (2C).

The KDIGO Anemia GuidelinesKI supplement Aug 2012

Hb Target

• Target for treatment should be?

– KDIGO < 11.5 g/dL

– FDA<11 g/dL

• What about the lower number?

– KDIGO>9 g/dL

– FDA>10 g/dL

• Why 9 g/dL

• In dialysis patients, evidence from the Normal Hematocrit Study

• In non dialysis patients, evidence from the TREAT study

• Why 11.5 g/dL

– Normal Hematocrit study (9-11), CREATE, CHOIR (11.3 vs. 13.5), TREAT (>9 vs. 13)

Trials of Anemia Targets in CKD

• Normal Hematocrit

• CHOIR study

• TREAT study

Worrisome safety signals

Normal Hematocrit Study

Besareb A et al NEJM 339:584-590, 1998

N=1233 HD patientsDeath or MI10 g vs. 145 g

No Improvement in hrQOL

Algorithm for Anemia Management

Hb <11 g/dL

Major causes: Iron deficiency, erythropoietin deficiency and inflammation

Likely iron deficiencyFerritin <100 ng/mL and/or Tsat <20%

Treat with oral iron for at least 3

months, if tolerated

Stool positive for occult blood

Likely inflammationAlbumin <3.5 g/L

ferritin >500 ng/mLhsCRP >2

Likely ESA deficiency stateNormal iron storesNormal folate/B12

No evidence for inflammation

No evidence of occult blood loss

Establish Hb trigger for ESA initiation<11 g/dL, patient symptomatic or transplant candidate

9-10 g/dL, most patients<9 g/dL prior stroke, active malignancy

Inflammation inducerameliorated

Case (cont.)

• 62-yo woman …

• 2 years following initial presentation, she feels fatigued with minor tasks; has difficulty getting out of bed. Hb is 8.9 g/dL; iron stores replete. She is started on ESA (darbepoetin alfa 40 mcg q week). Her Hb responds and she feels better. 6 months later, she develops an ulcer on her foot. Her Hb starts to drift down, despite a gradual 3-fold increase in her darbepoetin alfa dose (now at 120 mcg q weekly)

QuestionWhich one

of the following

statements is correct?

A. The patient should be treated with a course of IV iron.

B. The patient requires a blood transfusion in order to get her Hb into the 11–12 g/dL range recommended by the NKF.

C. The most likely cause of her ESA resistance is the diabetic foot ulcer. You should not escalate her ESA dose; instead focus on treating her foot ulcer.

D. She should be treated with an anabolic steroid.

QuestionWhich one

of the following

statements is correct?

A. The patient should be treated with a course of IV iron.

B. The patient requires a blood transfusion in order to get her Hb into the 11–12 g/dL range recommended by the NKF.

✓ The most likely cause of her ESA resistance is the diabetic foot ulcer. You should not escalate her ESA dose; instead focus on treating her foot ulcer.

A. She should be treated with an anabolic steroid.

ESA HyporesponsivenessESA resistance, or hyporesponsiveness, patients who do not achieve the desired hemoglobin (Hb) concentration despite higher than usual doses of ESAs or who require increasingly higher ESA doses to maintain an Hb concentration1

• KDOQI Definition: A failure to achieve and/or maintain

target hemoglobin levels at an erythropoietin dose of

450 IU/kg/week when administered intravenously, or 300 IU/kg/week when administered subcutaneously

1SOURCE: Berns J. https://www.uptodate.com/contents/hyporesponse-to-erythropoiesis-stimulating-agents-esas-in-chronic-kidney-disease

Causes of ESA Hyporesponsiveness

• Iron deficiency

• Inflammation – infectious and chronic microinflammatory

– Failed kidney allograft

– Chronic infection (TC, diabetic ulcer, amputation stump infection)

• Inadequate dialysis

• Hyperparathyroidism

• Carnitine deficiency

• Drugs: ACE-I/ARB

• Aluminum overload

• Nutritional: Folate, vitamin B12, vitamin C deficiency

• Malignancy

• Hematological disorders

Risk Factors for ESA Hyporesponsiveness*

Singh AKS et al, ASN 2020

*Primary definition of ESA hyporesponsiveness included a two-part definition: a baseline ESA Resistance Index

(ERI) ≥2 U/kg/week/g/L, or treatment at baseline with a very high standardized ESA dose ≥450 U/kg/week.

ESA Hyporesponsiveness

Singh AKS et al, ASN 2020

CKD

Iron Supplementation

InflammationVitamin D Deficiency

Reduced GFR

Reduced Iron Releasefrom Cells of RES

Reduced Gut Iron Absorption

Iron Restricted Erythropoiesis

↑ HEPCIDIN

Panwar B, Gutiérrez OM. Semin Nephrol. 2016.

Pathophysiology of CKD Anemia

Babitt JL, Lin HY. J Am Soc Nephrol. 2012.

*ESA = Erythropoietin stimulating agent

Iron Regulation by Hepcidin

Therapeutic Plan for ESA Hyporesponsivess

Diagnose ESA Hyporesponsivess

Avoid repeated escalations in ESA Dose

Identify correctable vs non correctable causes

Easily correctableAbsolute iron deficiencyVitamin B12/folate deficiencyHypothyroidismACEi/ARBNon-adherence

Impossible to correctHemoglobinopathiesBone marrow disorders

Potentially correctableFunctionalIron deficiency

InfectionInflammation

UnderdialysisBleedingHyperparathyroidis,MalignancyMalnutritionPRCA

Empirically treat with iron

Empirically treat with iron

Where are We Now?

Despite Epo therapy costing billions of dollars each year, anemia is sub-optimally treated in CKD patients

– Normalization of Hb associated with increased mortality and CVD risk

• No consistent and meaningful improvement in quality of life

• Patients treated to subnormal Hb target of 10-11 g/dL

– Patients require SC/IV injection, increased visits to health care provider

– Higher health systems costs

USRDS 2016 Annual data report. www.USRDS.org.

Guidelines

CHOIR

TREAT

Bundled Payments

HbUnmetneed

CKD Anemia – the Unmet Need

HIF Biology

• In 1991 HIF-1 discovered, a protein with DNA binding activity to the erythropoietin gene

• The two isoforms or subunits of HIF-1 regulate target gene in response to hypoxia

• HIF-1α is mainly under the control of oxygen sensing prolyl-4-hydroxylase enzymes) 2,3

• 2019 Nobel Prize in Physiology or Medicine awarded to William G. Kaelin Jr, Sir Peter J. Ratcliffe, and Gregg L. Semenza “for their discoveries of how cells sense and adapt to oxygen availability.”

1Proc Natl Acad Sci U S A. 1991;88:8725-8729. 2Proc Natl Acad Sci U S A. 1995;92: 5510-5514. 3Nat Rev Drug Discov. 2009;8:139-152.

ProlylHydroxylase

HIFα

STOP

No epo genetranscription

Translocate to nucleus

+ epo genetranscription

HIFα

O2

HIFα

VHL

Attaches to von Hippel-Lindau (pVHL)

Normoxia

Hypoxia

OH

OH

OH

OH

degradation by 26S Proteosome

PHI Agents“HIF stabilizers”e.g., Roxa, Vada, Dapro

HIF stabilized

HIFα/ßcombine to

form heterodimer

HIF Mechanism

Oxygen sensing and the HIF system

HIF

1α /2 α

VHL

HIF-dependent genes

HIF

1α /2 α

HIF β

regulators of

cell-specific

expression

O2

OH

oxoglutarate CO2

succinate PHD-1

PHD-2

PHD-3 FIH

degradation

EPO

3

1

2

4

Rare mutations causing HIF

activation lead to polycythemia

• PHD-2

• HIF-2

• VHL

- VHL-syndrome (cancer)

- Chuvash polycythemia

Percy et al., PNAS 2006

Ladroue et al., NEJM 2008

Percy et al., NEJM 2008

Percy et al., Blood 2008

Gale et al., Blood 2008

Furlow et al., JBC 2009

Chuvashia – a Russian Republic

Chuvash polycythemia • endemic in Chuvash population

in Russia

• majority likely originated

from a single founder event

• 598 C > T mutation in VHL;

R200W (Arg Trp)

Mild inhibition of HIF-2α

Degradation

• Polycythemia

• No enhanced tumor incidence

• Reduced life expectancy

(due to polycythemia ?)

• Mild organomegaly

• Pulmonary hypertension

Slide source – K.-U. Eckardt

Erlangen-Nürnberg

Example of Mutations in Oxygen Sensing Apparatus

Single dose study with a PHD-I in humans

(FG 2216)

time (h)

pla

sm

a E

PO

(m

U/m

l)

healthy controls

time (h)

anephric HD patients

extrarenal (hepatic)

EPO production

time (h)

nephric HD patients

extrarenal (hepatic)

+ renal

EPO production

preserved EPO production capacity

Bernhardt et al.

J Am Soc Nephrol 2010

Single Dose Study of PHI in HumansFG2216

Slide source – K.-U. Eckardt

Erlangen-Nürnberg

523

6637

PH2B RHEPO CONTROL (5000 U IV/WK)

CLIMBERS AT 4500 M PH2B DAPRODUSTAT

Peak Epo levels in Epo treated and PHI treated dialysis patients

Peak EPO 14x higher in rhEPO vs climber

Peak E

PO

conce

ntr

ations

(IU

/L)

rEPO 5000u Climber 4500m PHI

3 leading PHIs

RoxadustatDaprodustat Vadadustat

(Yeh et al, 2017)30

• Similar MOA, different biophysical properties, all oral agents

Attributes Daprodustat Vadadustat Roxadustat

Half life Short ( T1/2=1.5-4hr) Short (T1/2 ~5-7 hr) Long (T1/2 ~12-19 hr)

Metabolism Hydroxylation. Active metabolite Glucuronidation, Inactive metabolite Unknown, presumed inactive metabolite

Excretion Mostly liver metabolism Liver metabolism +Renal excretion Primarily liver (?)

Tissue Distribution(rodent)

Broad distribution (liver, kidney, lung, BM.Low in skeletal muscle)

Unknown Unknown

SOURCE: Provenzano, 2020, J. Clin. Pharm; Balzo et al, 2020, JPET; Zuk et al, 2019 ASN poster; Chavan 2019 ASN poster; Hara, 2015, Drug Metab. Pharm, Daprodustat IB

Dosing 1 mg-12 mg (QD), 6 mg- 48 mg TIW 150-400 mg (QD or TIW) 60-300 mg (QD or TIW

Phase 2a, 2b Dialysis and Non-dialysis all PHI agents

Special Interest (based on HIF-PHI Mechanism of Action)

• Cancer-related mortality and tumor

progression and recurrence

• Pulmonary artery hypertension (PAH),

Cardiomyopathy

• Proliferative retinopathy, macular edema,

choroidal neovascularization

• Exacerbation of rheumatoid arthritis

No Safety Signal

Phase 3 Program

• Roxa

• Chinese studies, NEJM 2019

• Approved in China and Japan

• ASN presentations 2019, 2020 ≈ 80 abstracts

• July 14, 2021 FDA Adcom

• Vada

• Approved in Japan

• NEJM, April 2021

• Dapro

• Japanese studies, CJASN 2020

• Approved in Japan

ASCEND-D, ASCEND-ND and ASCEND-ID Program

11

Non dialysis Dialysis Incident Dialysis

Randomized, open-label (sponsor-blind), active-controlled, parallel-group

Correction & maintenance* Maintenance* Correction &

maintenance**

n = 4500(945 events)

n = 3000(945 events)

n=300

1. ESA naïve2. Rx with ESA

Rx with ESA(HD &PD)

1. ESA naïve2. Rx with ESA

daprodustat vs darbepoetin alfa

daprodustat vs epoetin alfa (HD)

vs darbepoetin alfa ((PD)

daprodustat vs darbepoetinalfa

ASCEND CVOT Program

*Chair of Executive Steering Committee and Publication Steering Committee: Ajay K. Singh

*

ASCEND Program –Other Studies

• ASCEND-BP Study, N=88

• Randomized, open-label, parallel-group study in HD subjects with anemia of CKD

• Hypothesis: daprodustat would be associated with less effects on BP than rhEPO

• ASCEND-NHQ Study, N=614

• Randomized, Double-Blind, Placebo-Controlled study in (rhEPO) naïve non-dialysis participants

• Hb, Mean Change in SF-36 Vitality Domain, Common AEs, SAEs, and adjudicated MACE

• ASCEND-TD study, N= 270 Dapro, N=137 rhEPO

• Randomized, double-blind, active-controlled study of daprodustatadministered three-times-weekly in hemodialysis patient

Conclusions

• Current guidelines on anemia treatment

– FDA 10-11 g/dL goal

• ESA hyporesponsiveness is an important factor in anemia treatment

– Multifactorial

– Hepcidin and inflammation

• Unmet need in anemia treatment

– Discovery of oxygen sensing mechanism has led to development of PHIs

• 3 PHI’s under development

– Roxadustat

– Vadadustat

– Daprodustat

• PHIs non-inferior to Epo and its analogues for Hb. Safety similar to Epo

• More convenient oral dosing

• But are HIF stabilizers (PHIs) better?