CKD anemia -Green

7/9/21

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The Role of the Pharmacist in the Management of Anemia in Chronic Kidney Disease Patients

Chelsea Green, PharmD, BCPS, CPh

BayCare Saint Anthony’s Hospital – Transitions of Care Pharmacist

[email protected]: (727) 825-1615 or (727) 351-2242

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Disclosure• I have no financial interests or financial disclosures to make

• I represent myself, my knowledge and my experiences

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Learning Objectives• Review the causes and underlying pathophysiology of anemia in

patients with chronic kidney disease (CKD)

• Describe the role of hypoxia inducible factor (HIF) in CKD anemia and the rationale for developing therapy that targets prolyl hydroxylase (PH)

• Assess current options for treating anemia in patients with CKD

• Evaluate emerging data and clinical implications of HIF stabilization/PH inhibition as a strategy to address anemia in CKD

• Review the pharmacist role in patient care and management of therapy options

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Definition and Classification of Anemia and CKD

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Anemia• Absolute reduction of the total number of circulating red blood cells (RBCs)• Defined as reduction in one or more of the major RBC measurements:

• Hemoglobin (Hb) concentration• Hematocrit (HCT)• RBC count

• World Health Organization (WHO)• Men hemoglobin <13 g/dL• Women hemoglobin <12 g/dL

Supplemental Facts• Hb - g/dL or g/L

• To convert to mmol/L, the hemoglobin in g/dL can be multiplied by 0.62

• HCT known as packed cell volume (PCV) - calculated• HCT = MCV x RBC count/10 – with RBC count in millions/microL and the mean corpuscular volume (MCV) in femtoliters [fL])

• RBCs - RBCs contained in a specified volume of whole blood

Adeli K,. Clinical Chemistry 2015; 61:1075 Van den Bossche J. Clin Chem Lab Med 2002; 40:69. World Health Organization. Nutritional anemias Update to date for graphics

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Kidney Disease Improving Global Outcomes (KDIGO) defined as:CKD is defined as abnormalities of kidney structure or function, present

for >3 months, with implications for health

CKD

Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77

Criteria for CKD (either of the following present for >3 months)

Markers of kidney damage (one or more)

• Albuminuria (AER ≥30 mg/24 hours; ACR ≥30 mg/g [≥3 mg/mmol])

• Urine sediment abnormalities• Electrolyte and other abnormalities due to

tubular disorders• Abnormalities detected by histology• Structural abnormalities detected by imaging• History of kidney transplantation

Decreased GFR Decreased eGFR <60 ml/min/1.73 m2 (GFR categories G3a–G5)

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• KDIGO recommendations• Cause of disease• Six categories of eGFR (G)

• Three categories of albuminuria (A)

Staging of CKD

Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77 Update to date for graphics

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CKD Symptoms• Nausea, vomiting,

loss of appetite• Weakness and fatigue• Sleeping problems• Changes in urination• Decreased mental

sharpness• Muscle twitching cramps

• Swelling of legs, ankles, feet

• Chronic pruritis• Chest pain • Shortness of breath• Treatment resistant

hypertension


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Why to DefineDiscuss and predict

prognosis

Evaluation of cause

Evaluate progression and chronicity

Follow-up management and prevention

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CKD Complications• Metabolic acidosis• Secondary

hyperparathyroidism• Bone disease and

hyperphosphatemia• Heart and blood vessel

disease• Hyperkalemia• Gout

• Fuld retention – edema, HTN, pulmonary edema

• Sexual dysfunction –erectile dysfunction, pregnancy complications

• Decreased immune response

• Irreversible renal damage• Anemia


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Discussion Question 1Case: A 54-year-old man with diabetes, hypertension, can coronary artery disease is being

treated for chronic kidney disease. His estimated glomerular filtration rate has declined over the past 2 years from 40 to 14 mL/min/1.73m2. The patient reports increased fatigue and asks about the causes of his anemia. Red blood cell indexes are normal, and iron test results and serum folate and vitamin B12 concentrations are found to be normal.

Question 1: What is the mostly likely cause or causes of the patient’s anemia?

a) Diabetes mellitusb) Relative erythropoietin deficiencyc) Iron deficiencyd) Multiple myeloma

AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026

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Anemia of CKD“No other natural disease came as close to hemorrhage for impoverishing the red particles of the blood”

- Sir Robert Christison 1839

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Prevalence• Anemia twice as prevalent in people with CKD as in the

general population • Decreased erythropoietin (EPO) production

• Approximately 15% of CKD patients and increasing frequency at higher stages

• Low rates of treatment• Diabetes mellitus - earlier onset and increased severity

Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77 AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026

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15Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77 AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026

Risk FactorsRisk Factors

• Low eGFR • Increased age

• Increased inflammation• Age related co-morbidities -

absorption• Female gender• Race/ethnicity

Common causes• Relative erythropoietin deficiency• Iron deficiency• Blood loss• Reduced erythrocyte survival duration• Inflammation• Infection• Underlying hematologic disease• Hyperparathyroidism (dialysis)• Hemolysis• Nutritional deficits

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Anemia Symptoms

• Dizziness, loss of concentration• Pale skin• Chest pain• Shortness of breath• Weakness or fatigue• Cold intolerance


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Clinical Impact• Poor quality of life• Increased all-cause mortality• Increased cardiovascular (CV) mortality• Major adverse cardiac event (MACE)• Hospitalizations• CKD progression to hemodialysis (HD)

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Evaluation of CKD Anemia• Focused history and physical examination• Blood testing

• Complete metabolic panel • Complete blood cell count• Reticulocyte count• Serum ferritin – iron stored• Transferrin saturation (TSAT) – circulating iron• Folic acid• Vitamin B12

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PathophysiologyDevelopment of anemia in CKD patients


Decreased erythropoietin (EPO)• Kidney hormone stimulating RBC

production• Hypoxia stimulates EPO production

Functional Iron Deficiency (FID) -Hepcidin regulation• Impaired mobilization – stores and delivery • Mediated by hepcidin• At high levels impairs dietary iron absorption

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Pathophysiology - EPO

AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026 Image Source: NLM)

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Pathophysiology – Hypoxia Inducible FactorHypoxia Sensing:The HIF System• Proteins

continuously expressed• HIFα with sufficient

oxygen are hydroxylated

• HIFꞵ not sensitive to hydroxylation

• HIF-prolyl hydroxylases require oxygen


Hypoxia• Prevents HIFα

degradation• HIFα moves into

cell • Binds with HIFꞵ• Increase oxygen-

sensitive gene transcription • EPO +

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Pathophysiology – Hypoxia Inducible FactorHypoxia Sensing:The HIF System• HIFα

• HIF-1α• HIF-2α• HIF-3α

• Regulated by hydroxylation at a carboxy-terminal asparagine residue by FIH


• Factor-inhibiting HIF (FIH) prevents the recruitment of transcriptional coactivators

• HIF activity limited

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Pathophysiology – Iron and Hepcidin• Iron deficiency difficult to estimate in non-HD CKD

• HD looses ≥2000mg of iron yearly• HD iron losses from occult blood loss, infection, surgical

procedures, venipuncture, with dialysis, retention of blood by the dialysis apparatus, impaired absorption from elevated hepcidin

• Liver protein – Hepcidin concentrations:• Increase in response to increased iron storage in the body• Decrease when iron deficiency is present


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Pathophysiology – Hepcidin• Elevations:

• Internalize ferroportin into cells• Limits iron circulation *through enterocytes and storage tissues

• Reduces the mobilization of stored iron• Impair dietary iron absorption

• Hepcidin elevated with inflammation• Iron restricted for EPO

• Recognizable in HD patients with ↓ transferrin saturation (decreased circulating iron) with ↑ serum ferritin (elevated iron storage)

• Iron limited during infectionAJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026

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Discussion Question 2Which factor is most responsible for sensing cellular hypoxia?

a) Erythropoietinb) Hepcidinc) Hypoxia-inducible factor (HIF)-prolyl hydroxylased) Fibroblast growth factor 23e) Ferroportin


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Treatment

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Patient / Treatment Goals• Improve quality of life• Limit therapy adverse effects• Improve therapy and ESA response• Identify additional anemia causes


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• Kidney Disease: Improving Global Outcomes

KDIGO: Iron Initiation for CKD


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29Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77 AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026

Route Replacement ConsiderationsOral

• Inexpensive• Readily available• No IV access required

Intravenous

• Rapid repletion required• Symptomatic anemia• Previous non-responder to

oral iron therapy

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Oral Iron


• Non-hemodialysis• Ferrous sulfate• Ferrous fumarate• Ferrous gluconate

• Hemodialysis• Phosphate binders– Ferric citrate – Sucroferric oxyhydroxide

• Daily dosing• Alternate day dosing*

• Adherence concerns• Between meals• Bedtime schedule• Set dosing schedule

(Monday, Wednesday, Friday)

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Oral Iron

Update to date for graphics

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Intravenous Iron


• Highly efficacious• Standard of care for hemodialysis patients

• Consider for non-HD CKD patients with:• Severe iron deficiency (TSAT <12%)• Severe anemia (Hb <7 g/dL) in asymptomatic patients• Risk of ongoing blood loss • History of side effects to oral iron• History of not responding adequately to oral iron (1-3 months)

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Intravenous Iron – Therapy Choices


• Ferumoxytol – two doses of 510mg a week apart• Preferred for fewer doses required to replete stores

• Iron sucrose – five doses of 200mg over two weeks• Ferric gluconate in sucrose complex – three to four 250mg dose once

weekly• Ferric carboxymaltose – two doses of 750mg in same week• Ferric derisomaltose (formerly iron isomaltoside) – single dose

20 mg / kg (max 1000mg) as single infusion• Low-molecular-weight iron dextran – test dose then, single dose 500-

1000mg• Greater frequency of allergic reaction

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Intravenous Iron


• Therapy choices (continued)• Considerations: cost, formulary/purchasing agreements, insurance

coverage, and number of visits/time required to administer the full dose• Larger volumes / single dose administration possible with iron dextran,

ferumoxytol, ferric carboxymaltose, and ferric derisomaltose• Risk for hypotension and hypersensitivity reactions

• All have been associated with anaphylaxis, however low (<0.5%) for non-dextran preparations

• Consider infection risk (avoid use with active infection) and vein compromise

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Monitoring


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Discussion Question 3Case: A 76-year-old woman with diabetes mellitus and stage 4 CKD is evaluated for progressive anemia. Blood test results are notable for the following values: serum potassium, 5.5 mEq/L; serum creatine, 3.2 mg/dL; and elevated serum calcium, 12.6 mg/dL. Hb concentration is 7.5 g/dL with normal erythrocyte indexes. Serum ferritin concentration is 358 ng/mL and TSAT is 20.2%.

Question 3: In addition to erythropoietin deficiency, what other cause of anemia is important to exclude in this case?

a) Iron deficiencyb) Hyperparathyroidismc) Malignancyd) Hypothyroidisme) Endocarditis


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• Intravenous iron in patients undergoing dialysis

Landmark Trials in Anemia and CKD

Normal Hematocrit (NHCT)• ↑ HCT levels (42% vs 30%)

associated with higher incidence of death, MI

CREATE (CKD, non-ESRD)• Association between high Hb (13

– 15 vs 10.5 – 11.5) and adverse CV outcomes

TREAT• Goal Hb 13, no reduction in risk of

adverse outcomes (death, kidney, CV); Increased risk of stroke, VTE

DRIVE• IV Ferric gluconate increases Hb in

patients with Ferritin ≥5000 ng/dL and TSAT < 25% and adequate epoetin

PIVOTAL• “Proactive” iron strategy associated with

less cost and better outcomes

CHOIR (CKD, non-ESRD)• Association show between high

Hb (13.5 vs 11.3) and primary composite outcome (death, MI, HF and stroke)

1998 2006 2009

2007 2018

Post by: Xavier Vela – Nephrology Fellow Network

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Erythropoietin Stimulating Agents (ESAs)• Strong evidence to support treatment at Hb < 9 g/dL• KDIGO Guidance

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Erythropoietin Stimulating Agents (ESAs)• KDIGO on ESA initiation

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Erythropoietin Stimulating Agents (ESAs)


Initiation considerations• Functional limitations

• Bedbound• Dementia

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• Targeting Hb 10 to 11.5 g/dL• Consider lowest effective doses and administration

frequency• ESA serum half-life of ESAs may not always correlate with frequency

• Subcutaneous (subcut) administration preference• Epoetin - subcut ~30% less dose required versus IV• Darbepoetin - subcut and IV similar efficacy

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Therapy ChoicesEpoetin • Approximated unit vial dosing 50 to 100 units/kg/week• 4000 - 10,000 units subcut weekly OR 10,000 to 20,000 units subcut every 2 weeks

• Consider lower with pretreatment Hb levels near 10 g/dL

Darbepoetin• 60 to 200 mcg subcut every two to four weeks

Methoxy polyethylene glycol-epoetin beta • 0.6 mcg/kg by IV/subcut every 2 weeks and monthly dosing subsequently

Epoetin alfa-epbx• First US epoetin "biosimilar”

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Therapy ChoicesEpoetin • Approximated unit vial dosing 50 to 100 units/kg/week• 4000 - 10,000 units subcut weekly OR 10,000 to 20,000 units subcut every 2 weeks

• Consider lower with pretreatment Hb levels near 10 g/dL

Darbepoetin• 60 to 200 mcg subcut every two to four weeks

Methoxy polyethylene glycol-epoetin beta • 0.6 mcg/kg by IV/subcut every 2 weeks and monthly dosing subsequently

Epoetin alfa-epbx• First US epoetin "biosimilar”

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ESA Monitoring

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• Target specific clinical goals• Minimize hospitalizations or transfusions• Optimize management of heart failure

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ESA TargetsPopulation Targets Conclusion

Besarab et al1998

• n = 1233• 29 months• Epoetin alfa

HD • Hct 30%• Hct 42%

• No clear benefit of the higher Hct target• Trend toward increased mortality risk

Drueke et al2006

• n = 603• 3 years

NDDCKD • Hb goal 10.5 -11.5 g/dL

• Hb goal 13.0 -15.0 g/dL

• Positive quality-of-life benefit• Non–statistically significant trend to increased

risk for death in the higher Hb target group

Singh et al2006

• n = 1432• 16 months• Epoetin alfa

NDDCKD • Hb goal 13.5 g/dL

• Hb goal 11.3 g/dL

• Clinical benefits for the higher Hb group• Significant safety signals; increased

cardiovascular events in a composite end point (driven by increased risk for death and increased risk for hospitalizations for CHF)

Pfeffer et al2009

• n = 4038• 29 months• Darbepoeti

n alfa

DM + NDDCKD

• Hb goal 13 g/dL (actual achieved median Hb was 12.5 g/dL)

• Placebo

• No substantial benefit of the treated group • Major safety risk; increased risk for stroke

(HR,1.92; 95%; CI, 1.38-2.68) and increases in thromboembolic complications

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Discussion Question 4Case: A 76-year-old woman with diabetes mellitus and stage 4 CKD is evaluated for progressive anemia. Blood test results are notable for the following values: serum potassium, 5.5 mEq/L; serum creatine, 3.2 mg/dL; and elevated serum calcium, 12.6 mg/dL. Hb concentration is 7.5 g/dL with normal erythrocyte indexes. Serum ferritin concentration is 358 ng/mL and TSAT is 20.2%.

Would initiation of ESA be appropriate?

a) Yesb) Noc) Response in chat


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Hypoxia Inducible Factor –Prolyl Hydroxylase InhibitorsData10/7/2019 Nobel Prize in Physiology or Medicine jointly 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

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Pathophysiology – Hypoxia Inducible FactorThe HIF System• HIFα (1-3)• Prolyl hydroxylase

(PH) require oxygen

• Hypoxia prevents HIFα degradation

• HIFα moves into cell and binds with HIFꞵ


• Heterodimer initiates DNA hypoxia response elements (HREs)

• HIF-2α• Gene activation

(kidneys and liver) for transport, uptake, mobilization of iron

• Hepcidin downregulation

• Reduces iron export from hepatocyte and reticuloendothelial cells

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Pathophysiology – Hypoxia Inducible Factor• Regulation

controlled by prolyl hydroxylase domain (PHD) enzymes• PHD1• PHD2• PHD3

• PHD activity dependent on hydroxylation at 2 proline residues

NEJM. 2017;376:1965-1971

• PHD enzyme for activity require:• Oxygen and 2-

oxoglutarate as co-substrates

• Iron and ascorbateas cofactor

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Novel Oral PHD InhibitorsGeneric Brand Investigational

NameSponsor Investigational

statusRoxadustat Evrenzo ®

Ai Rui Zhuo ®FG-4592ASP1517; AZD9941

FibroGen, Astellas, & AstraZenec

• Use in Japan (11/20)• US NDA tentatively

scheduled 7/15/21• NDA approval in China

and EU MAA (8/21)Daprodustat Duvroq ® GSK-1278863 GlaxoSmithKline • Phase III (10/18)

• Use in Japan (6/20)Vadadustat Vafseo ® AKB-6548

MT-6548Akebia • NDA submission 3/30/21,

accepted 6/1/21 Molidustat BAY 85-3934 Bayer • Phase III (6/19)

• Use in Japan (1/21)Enarodustat Enaroy ® JTZ-951 Japan Tobacco • Use in Japan (9/20)

Desidustat ZYAN1 Zydus • Phase II (India)

NDA = New drug application

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PHD Inhibitors Pharmacodynamics and Pharmacokinetics

Generic Investigational Name

Participantsn =

Half-life, h

Dosing frequency

Metabolizing enzymes

Roxadustat FG-4592ASP1517 AZD9941

15 12-13 3x / weekly • CYP2C8, major

Daprodustat GSK-1278863 25 4.5 Daily • CYP2C8, major• CYP3A4, minor

Vadadustat AKB-6548MT-6548

8 4 Daily • UGT1A9, major

Molidustat BAY 85-3934 9 N/A Daily • UGTs

Enarodustat JTZ-951 6 N/A Daily • CYP2C8, CYP2C9, CYP3A4

Desidustat ZYAN1 56 N/A Q 48 h • Not reported

Kidney Int Suppl (2011). 2021 Apr; 11(1): 8–25.

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PHD Inhibitors – Adverse Reactions

Generic Most frequent Occasional RareRoxadustat • Nasopharyngitis

• Back pain, fatigue• Muscle spasm• Diarrhea/Vomiting• Decreased appetite• Hypertension• Decreased TSAT• Headache• Hyperkalemia

Daprodustat

Vadadustat

Molidustat

Enarodustat • HTN • Retinal hemorrhage• Eczema

• VTE (0.7%) • PE (0.1%)• Brain stem infarction (0.1%)

Desidustat

Kidney Int Suppl (2011). 2021 Apr; 11(1): 8–25.

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55*The lower margins of the 95% CIs of the LS mean treatment differences were above the non-inferiority margin of − 0.75 g/dL for both the US and EU primary endpoints, indicating the noninferiority of roxadustat and epoetin alfa.

Roxadustat - PHD Inhibitor

Drugs (2019) 79:563–572

Key Clinical HD Trials • SIERRAS - n = 741

• Noninferior roxadustat vs epoetin alfa in HD-CKD over 1.9 years– US endpoint - 28- 52 weeks - Mean change Hb from baseline (10.3 g/dL) 0.39 and 0.09 g/dL (*least

squares mean treatment difference 0.48 g/dL); 95% CI 0.37–0.59– EU endpoint - 28-36 weeks - Mean change Hb from baseline (10.3 g/dL) 0.54 and 0.02 g/dL (*LS mean

treatment difference 0.53 g/dL); 95% CI 0.39–0.67

• Time to first blood transfusion, significantly (p = 0.0337) reduced the risk of blood transfusion by 33% compared with epoetin alfa - HR 0.67

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Roxadustat - PHD Inhibitor

Drugs (2019) 79:563–572

Key Clinical HD Trials • HIMALAYAS - n= 1043

• Noninferior to epoetin alfa for the treatment of anemia in newly initiated HD over 1.8 years– US endpoint - 28- 52 weeks - Mean change Hb from baseline (8.4 g/dL) 2.57 and 2.36 g/dL (*least squares

mean treatment difference 0.18 g/dL); 95% CI 0.08–0.29)– EU endpoint - 24 weeks – achieving Hb response 88 and 85%; lower margin of the 95% CI (− 0.9 to 7.6%)

between-group difference was above the non-inferiority margin of − 15% o Hb response was defined as an Hb level of ≥ 11 g/dL and an Hb increase of ≥ 1 g/dL

– TSAT levels, reticulocyte Hb and serum iron levels did not significantly differ from baseline levels in patients receiving oral or intravenous iron supplementation (n = 32), but decreased significantly in patients receiving no iron (all p < 0.05 vs. baseline)

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Roxadustat - PHD InhibitorKey Clinical non-HD Trials • ANDES - n= 922

• Effectiveness roxadustat versus placebo for the treatment of anemia in CKD 3-5 over 1.7 years– US endpoint - 28- 52 weeks - Mean change Hb from baseline (9.1 g/dL) 2.0 vs. 0.16 g/dL; p < 0.0001– EU endpoint - achieving Hb response 86 and 7%; p = 0.0007)

o Hb response was defined as an Hb level of ≥ 11 g/dL and an Hb increase of ≥ 1 g/dL

– Roxadustat significantly reduced the risk of rescue therapy by 81% vs placebo (HR 0.19; p < 0.0001)

o Rescue therapy was defined as administration of ESA or IV iron in the first 52 weeks of treatment

– Time to first blood transfusion, significantly roxadustat reduced the risk of blood transfusion by 74% (HR 0.26; p < 0.0001)

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Roxadustat - PHD InhibitorKey Clinical non-HD Trials • OLYMPUS – n = 2781

• Significant and clinically relevant improvement from baseline in Hb levels averaged over weeks 28–52 was seen with Roxadustat relative to placebo

• ALPS• Superiority of roxadustat both in terms of Hb response rate in the first 24 weeks of

treatment and Hb change from baseline at weeks 28–52 (coprimary endpoints)

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Phase III OLYUMPUS and ROCKIES Trial meet primary

endpoints in CKD anemia

Global Phase III pooled analysis

confirmed CV safety

Phase III trials prove significantly

increased Hb levels OLYUMPUS and ROCKIES Trials

NDA submission to FDA for Roxadustat

in patients with anemia of CKD

FibroGen announcement of FDA acceptance of NDA

Update on regulatory review

FibroGen provides regulatory update

FDA Advisory Committee to review NDA 7/15/2021

Development Timeline for Roxadustat

4/6/21

https://www.drugs.com/history/roxadustat.html

3/1/212/11/20 12/18/20

5/14/1912/20/18 11/7/19 2/11/20

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Roxadustat - PHD InhibitorOngoing trials• Recruitment is underway in a randomized, double-blind placebo-

controlled phase 3 study (NCT03263091) assessing the efficacy and safety of roxadustat in the treatment of anemia in patients with lower risk MDS and low red blood cell transfusion burden. The study plans to enroll 184 patients and the primary efficacy endpoint is the achievement of transfusion independence for ≥ 56 days

Status• Approved use 12/17/2018 in China Japan for anemia HD-CKD

Drugs (2019) 79:563–572

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Roxadustat Clinical Trials

ClinicalTrials.gov

Title Status / Dates Conditions Intervention Characteristics Location NSafety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis

Complete 12/16/2019

Anemia FG4592 vsEpoetin alfa

Interventional, Phase 3

USA 2133

Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis

Complete 12/16/2019

AnemiaESRD

FG4592 vsPlacebo


USA 2781

Roxadustat in the Treatment of Anemia in End Stage Renal Disease (ESRD) Patients on Stable Dialysis (Pyrenees)

Complete 02/21/2021

AnemiaESRD

FG4592 vsEpoetin alfaDarbepoetin alfaIron


Belgium 838

Roxadustat in the Treatment of Anemia in Chronic Kidney Disease (CKD) Patients, Not on Dialysis, in Comparison to Darbepoetin Alfa (Dolomites)

Complete 03/29/2021

CKD + anemia FG4592 vsDarbepoetin alfa


Bulgaria.. 616

Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis (ALPS)

Complete 12/17/2020

CKD + anemia FG4592 vsPlacebo


Bulgaria.. 594

Evaluation of Efficacy and Safety of Roxadustat for the Treatment of Chemotherapy Induced Anemia

RecruitingExpected completion 5/2021

Chemotherapy induced anemia

FG4592 Interventional, Phase 2

USA 100

Efficacy and Safety of FG-4592 for Treatment of Anemia in Subjects With Lower Risk MDS

RecruitingExpected completion 5/2023

Low MDS FG4592 vsPlacebo

Interventional, Phase 2 and 3

China 175

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Daprodustat - PHD Inhibitor

ClinicalTrials.gov

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Daprodustat Clinical Trials

ClinicalTrials.gov

Title Status / Dates Conditions Intervention Characteristics Location N

A Study to Evaluate Safety and Efficacy of GSK1278863 in Non-Dialysis Dependent (NDD) Subjects With Anemia Associated With CKD

Completed 06/06/2016 Anemia GSK1278863 vs rhEPO


GSK, USA (multiple)

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Efficacy and Safety Study of GSK1278863 in Japanese Hemodialysis Subjects With Anemia Associated With CKD Who Are Not Taking Erythropoiesis Stimulating Agents

Completed 07/13/2018 Anemia GSK1278863 vs Iron


GSK, Japan 28

Effects of GSK1278863A on Pulmonary Artery Pressure in Healthy Volunteers

Completed 11/2012No results postedUpdated 06/09/2017

Anemia GSK1278863 vs placebo


GSK, Maryland, USA

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Study to Assess the Pharmacokinetics of GSK1278863 in Subjects With End Stage Renal Disease Undergoing Peritoneal Dialysis

Completed 03/11/2019 Anemia GSK1278863 Interventional, Phase 1

GSK, USA (multiple)

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Study to Assess the Pharmacokinetics of GSK1278863A Coadministered With a High Fat Meal or an Inhibitor of CYP2C8 (Gemfibrozil) (DDI)


Anemia GSK1278863 vs GSK1278863 + food vs Gemfibrozil


GSK, India 23

Study of GSK1278863 to Reduce Ischemic Events in Patients Undergoing Thoracic Aortic Aneurysm Repair

Completed 12/07/2017 Surgical Procedures

GSK1278863 vs placebo


GSK, USA (multiple)

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GSK1278863 Effects on Eccentric Exercise-Induced Muscle Damage


Tendon injuries

GSK1278863 vs placebo


GSK, Maryland, USA

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Akebia announces 52 week efficacy/safety data from two

phase III studies in Japan

Akebia announces positive results with use in anemia CKD

dialysis and non-dialysis

NDA submission to FDA for anemia

CKD dialysis and non-dialysis

NEJM Phase III publication Akebia announcement of FDA acceptance of

NDA

Development Timeline for Vadadustat

https://www.drugs.com/history/vadadustat.html

11/9/19 3/30/21v5/5/20

4/28/21 6/1/21

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Vadadustat - PHD Inhibitor

Therapeutics and Clinical Risk Management 2021:17 155–163

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Vadadustat Clinical TrialsTitle Status / Dates Conditions Intervention Characteristics Location N

Study to Assess the Safety and Pharmacokinetics of AKB-6548 in Subjects With CKD, Stages 3 and 4


CKD AKB6548 Interventional, Phase 2

USA (multiple) 22

Safety and Efficacy Study for AKB-6548 in Subjects With CKD and Anemia


AnemiaCKD

AKB6548 Interventional, Phase 2

USA (multiple) 10

A Single Dose Study of Oral Vadadustat in Subjects With Normal and Impaired Hepatic Function


Hepatic impairment

AKB6548 Interventional, Phase 1

USA (multiple) 24

Effect of AKB-6548 on Cardiac Repolarization Intervals in Healthy Volunteers


Healthy volunteers

VadadustatVadadustat (high) Placebo vsMoxifloxacin


Indiana, USA 50

Effects of Ferrous Sulfate on the Pharmacokinetics of AKB-6548


Healthy volunteers

AKB6548 vsFerrous sulfate


Michigan, USA 10

A Study in Evaluating Bioequivalence of Test and Reference Vadadustat 450 MG and 150 MG Tablets and to Determine Food Effect on the 450 MG Tablet


Healthy volunteers

Vadadustat Interventional, Phase 1

Maryland, USA 54

Study of Vadadustat in Hemodialysis Patients With Anemia Switching From Epoetin Alfa (FO2RWARD-2)


AnemiaDialysis CKD

AKB6548 vsAKB6548 3x/wk vsEpoetin alpha


USA (multiple) 175

ClinicalTrials.gov

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Molidustat - PHD Inhibitor

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Molidustat Clinical Trials

ClinicalTrials.gov

Title Status / Dates Conditions Intervention Characteristics Location NSingle Dose Group Stratified Study in Renal Impaired and Healthy Aged and Gender Matched Subjects


Anemia BAY853934 Interventional, Phase 1

Germany 56

To Investigate Pharmacokinetics (Absorption, Distribution, Elimination), Safety and Tolerability of a Single Oral Dose of 75 mg Molidustat Tablet in Male and Female Subjects Requiring Hemo- or Peritoneal Dialysis Compared to Healthy Subjects


CKD BAY853934 Interventional, Phase 1

Germany 40

Combined Single / Multiple Dose Escalation Study in Patients With Renal Anemia Due to CKD


CKD BAY853934 Interventional, Phase 1

Germany 44

Maintenance Treatment of Anemia Associated With CKD in Hemodialysis Subjects on Epoetin Alfa / Beta Treatment Versus BAY85-3934 (DIALOGUE4)


AnemiaCKD

BAY853934 vsEpoetin alfa/beta


Germany 201

Maintenance Treatment of Anemia in Pre-dialysis Subjects With CKD on Darbepoetin Treatment Versus BAY85-3934 (DIALOGUE 2)


AnemiaCKD

BAY853934 vsDarbepoetin alfa


USA (multiple) 126

A Study of Molidustat for Maintenance Treatment of Renal Anemia in Non-dialysis Subjects (MIYABI ND-M)


AnemiaCKD

BAY853934 vsDarbepoetin alfa


Japan 164

A Study of Molidustat for Correction of Renal Anemia in Dialysis Subjects (MIYABI HD-C)


AnemiaCKD

BAY853934 Interventional, Phase 1

Japan 26

A Study of Molidustat for Treatment of Renal Anemia in Peritoneal Dialysis Subjects (MIYABI PD)


AnemiaCKD

BAY853934 Interventional, Phase 3

Japan 51

A Study to Learn More About the Long-term Safety and Effectiveness of Molidustat as a Treatment for Japanese Men and Women With Renal Anemia

Not yet recruitingPosted 05/24/2021 CKD +

anemiaBAY853934 Observational Japan 1500

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Enarodustat - PHD InhibitorKey Clinical Trials • SYMPHONY HD - n = 173

• Noninferiority enarodustat vs darbepoetin alfa weekly over 24 weeks– Target Hb (10-12g/dL) w ithin range - 78.2 and 88.8%– Mean Hb 10.73 and 10.85, difference between arms − 0.12 g/dL*; 95% CI − 0.33, 0.10

• SYMPHONY ND - n = 216• Noninferiority enarodustat vs darbepoetin alfa every 2-4 weeks over 24 weeks

– Target Hb (10-12g/dL) within range - 89.6 and 90.6%– Mean Hb 10.96 and 10.87, difference between arms − 0.09 g/dL**; 95% CI − 0.07, 0.26

*Lower limit of the 95% CI was above the predefined noninferiority margin of − 1.0 g/dL**Lower limit of the 95% CI was above the predefined noninferiority margin of − 0.75 g/dL Drugs (2021) 81:169–174

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Enarodustat - PHD InhibitorOngoing trials• Phase III comparing the efficacy and safety of enarodustat to

that of darbepoetin alfa in renal anemia patients receiving hemodialysis is underway in South Korea• 30weeks, n = 172

Status• Approved use 9/25/2020 Japan for anemia

with CKD

Drugs (2021) 81:169–174

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Desidustat - PHD InhibitorKey Clinical Trials• DREAM-ND Phase III – n = 588

• Active, not recruiting

• DREAM-D Phase III – n = 392• Recruiting

• Phase II – safety confirmed• Randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and

efficacy study, a mean hemoglobin increase of 1.57, 2.22, and 2.92 g/dL in desidustat100, 150, and 200 mg arms, respectively, was observed

Other trials• Completed - Desidustat in the Management of COVID-19 Patients in Mexico• Phase I - Desidustat in the Treatment of Chemotherapy Induced Anemia in US

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Current Therapies vs HIF-PH Inhibitors• Small EPO increases• Genes unrelated to EPO

regulated by HIF affected• With ESA higher

targeted Hb concerns, FDA may likely caution studies with HIF-PH inhibitors targeting Hb levels > 11 g/dL

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Pharmacist Role

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Early RoleDiscuss and predict

prognosis

Evaluation of cause

Evaluate progression and chronicity

Follow-up management and prevention

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Testing For Anemia

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Conclusion• Understand the underlying pathophysiology of anemia in patients with

chronic kidney disease

• Realize the role of hypoxia inducible factor in chronic kidney disease anemia and the rationale for developing therapy that targets prolyl hydroxylase

• Discuss the emerging data and clinical implications of hypoxia inducible factor HIF stabilization/PH inhibition as a strategy to address anemia in chronic kidney disease

• Appropriately assess and recommend therapy and monitoring for treating anemia in patients with chronic kidney disease

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Sources• KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006 May; 47(5): S1-S132.• KDOQI Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Am J Kidney Dis. 2013 Jan; S1-S163.• National Institute for Health and Care Excellence [NICE], 2006:ISBN: 978-1-4731-1149-3 & Pathways• National Institute of Diabetes and Digestive and Kidney Diseases. Anemia in Chronic Kidney Disease; 2014. Available from: URL: https://www.niddk.nih.gov/health-

information/kidney-disease/anemia.• Adeli K. Clinical Chemistry 2015; 61:1075 • Van den Bossche J. Clin Chem Lab Med 2002; 40:69.• World Health Organization. Nutritional anemias.• ClinicalTrials.gov• Hsu C, McCulloch C, Curhan G. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National

Health and Nutrition Examination Survey. J Am Soc Nephrol. 2002;13:504-510. • Symeonidis A, Kouraklis-Symeonidis A, Psiroyiannis A, et al. Inappropriately low erythropoietin response for the degree of anemia in patients with noninsulin-

dependent diabetes mellitus. Ann Hematol. 2006;85(2):79-85.• EPO production - > Richmond TD, Chohan M, Barber DL. Turning cells red: signal transduction mediated by erythropoietin. Trends Cell Biol. 2005;15(3):146-15• AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026• Babitt JL, Lin HY. Mechanisms of Anemia in CKD. J Am Soc Nephrol (2012); 23:1631-1634.• Bikbov B et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. The

Lancet 2020; 395(10225):709–33.

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The Role of the Pharmacist in the Management of Anemia in Chronic Kidney Disease Patients

Chelsea Green, PharmD, BCPS, CPh

BayCare Saint Anthony’s Hospital – Transitions of Care Pharmacist

[email protected]: (727) 825-1615 or (727) 351-2242

Questions?

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CKD anemia -Green