Download - 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
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
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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
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
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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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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
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
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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
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
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
AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026
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
AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026
• 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
AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026
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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
AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026
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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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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
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
• 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
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
• 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
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
• 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
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
• 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)
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
Initiation considerations• Functional limitations
• Bedbound• Dementia
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Erythropoietin Stimulating Agents (ESAs)
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
• 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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Erythropoietin Stimulating Agents (ESAs)
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
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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Erythropoietin Stimulating Agents (ESAs)
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
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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Erythropoietin Stimulating Agents (ESAs)
Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77
• 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
AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026
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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
AJKD (2018) doi: https://doi.org/10.1053/j.ajkd.2017.09.026
• 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
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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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56*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 • 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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57*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 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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58*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 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
Interventional, Phase 3
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
Interventional, Phase 3
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
Interventional, Phase 3
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
Interventional, Phase 3
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
Interventional, Phase 2
GSK, USA (multiple)
252
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
Interventional, Phase 3
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
Interventional, Phase 1
GSK, Maryland, USA
49
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)
8
Study to Assess the Pharmacokinetics of GSK1278863A Coadministered With a High Fat Meal or an Inhibitor of CYP2C8 (Gemfibrozil) (DDI)
Completed 12/2010No results postedUpdated 06/09/2017
Anemia GSK1278863 vs GSK1278863 + food vs Gemfibrozil
Interventional, Phase 1
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
Interventional, Phase 2
GSK, USA (multiple)
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GSK1278863 Effects on Eccentric Exercise-Induced Muscle Damage
Completed 06/2015No results postedUpdated 05/09/2017
Tendon injuries
GSK1278863 vs placebo
Interventional, Phase 1
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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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
Completed 09/2010No results postedUpdated 01/14/2021
CKD AKB6548 Interventional, Phase 2
USA (multiple) 22
Safety and Efficacy Study for AKB-6548 in Subjects With CKD and Anemia
Completed 05/2011No results postedUpdated 11/18/2018
AnemiaCKD
AKB6548 Interventional, Phase 2
USA (multiple) 10
A Single Dose Study of Oral Vadadustat in Subjects With Normal and Impaired Hepatic Function
Completed 10/2018No results postedUpdated 03/22/2019
Hepatic impairment
AKB6548 Interventional, Phase 1
USA (multiple) 24
Effect of AKB-6548 on Cardiac Repolarization Intervals in Healthy Volunteers
Completed 04/2014No results postedUpdated 11/14/2018
Healthy volunteers
VadadustatVadadustat (high) Placebo vsMoxifloxacin
Interventional, Phase 1
Indiana, USA 50
Effects of Ferrous Sulfate on the Pharmacokinetics of AKB-6548
Completed 02/2015No results postedUpdated 11/14/2018
Healthy volunteers
AKB6548 vsFerrous sulfate
Interventional, Phase 1
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
Completed 10/2018No results postedUpdated 03/22/2019
Healthy volunteers
Vadadustat Interventional, Phase 1
Maryland, USA 54
Study of Vadadustat in Hemodialysis Patients With Anemia Switching From Epoetin Alfa (FO2RWARD-2)
Completed 05/2020No results postedUpdated 09/16/2020
AnemiaDialysis CKD
AKB6548 vsAKB6548 3x/wk vsEpoetin alpha
Interventional, Phase 2
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
Completed 09/2013No results postedUpdated 01/27/2021
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
Completed 07/2019No results postedUpdated 01/25/2021
CKD BAY853934 Interventional, Phase 1
Germany 40
Combined Single / Multiple Dose Escalation Study in Patients With Renal Anemia Due to CKD
Completed 12/2013No results postedUpdated 07/15/2015
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)
Completed 10/2015No results postedUpdated 09/20/2019
AnemiaCKD
BAY853934 vsEpoetin alfa/beta
Interventional, Phase 2
Germany 201
Maintenance Treatment of Anemia in Pre-dialysis Subjects With CKD on Darbepoetin Treatment Versus BAY85-3934 (DIALOGUE 2)
Completed 11/2015No results postedUpdated 09/19/2019
AnemiaCKD
BAY853934 vsDarbepoetin alfa
Interventional, Phase 2
USA (multiple) 126
A Study of Molidustat for Maintenance Treatment of Renal Anemia in Non-dialysis Subjects (MIYABI ND-M)
Completed 07/2019No results postedUpdated 01/29/2021
AnemiaCKD
BAY853934 vsDarbepoetin alfa
Interventional, Phase 3
Japan 164
A Study of Molidustat for Correction of Renal Anemia in Dialysis Subjects (MIYABI HD-C)
Completed 10/2018No results postedUpdated 01/29/2021
AnemiaCKD
BAY853934 Interventional, Phase 1
Japan 26
A Study of Molidustat for Treatment of Renal Anemia in Peritoneal Dialysis Subjects (MIYABI PD)
Completed 07/2019No results postedUpdated 01/29/2021
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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