Erythropoiesis stimulating agents in chronic kidney disease

1. Rajeewa Dassanayake Senior Registrar in Nephrology Erythropoiesis stimulating agents in chronic kidney disease

2. ESA in CKD “Erythropoietin is arguably the best example of the therapeuticbenefits of molecular biology / biotechnology in clinical medicine”

3. History • 1906 RBC production regulated by hormones, later purified and confirmed as erythropoietin • 1970s EPO stimulates production of red cells and could lead to a treatment • 1980s clinical trial was successful • Published in NEJM in 1987 • 1985 gene identified • 1989, FDA approval • More recently newer erythropoiesis stimulating agents (ESAs)

4. Anaemia – definition • NKF • < 12 g/dl for women • < 13.5 g/dl for men • Eur Best Prac Gdlnes for Mx of Anemia in CRF • <11.5 g/dl in women • < 13.5 g/dl in men <70 years ofage • < 12 g/dl in men > 70 years of age.

5. Causes • Erythropoietin deficiency • Medications • ACE/ARB, metformin, fibrates, thiazolidinediones • Inflammation • mediators,such as interleukins and tissue necrosis factorblunt erythropoietin effect • Platelet dysfunction • with GI bleeding, shortens erythrocyte survival (30–60%) • Haemolysis • secondary to uremic toxins • Chronic blood loss • from phlebotomy and HD • Malnutrition • Deficiencies • of iron, folate, and vitamin B12

6. Impact • Fatigue, dizziness, SOB • Reducedcognitive function / mental acuity and quality of life • CVS complications – LVH, CCF • With T2DM1 • Independent riskfactor for loss of kidney function. • Cardiovasculardisease • Independently increase the risk of retinopathy • Thought to hasten the progression of diabetic neuropathy • Need for blood transfusions • O'Mara NB. Diabetes Spectrum 2008

7. Benefits of correction • Cardiac function1 • Stabilization of renal function1 • has been associatedwith treatment of the anemia of CKD • Exercise capacity • endurance, energy, mobility • Patient satisfaction • quality-of-lifescores, sexual function, cognition, less depression,and better socialization • Reduction in hospitalization and mortality2,3,4 • Silverberg DS et al. Nephrol Dialysis Transplant 2003 • Collins AJ et al. J Am Soc Nephrol2001 • Collins AJ, Ma JZ, Ebben J. SeminNephrol2000 • Regidor DL et al. J Am Soc Nephrol2006

8. Treatment

10. Targets • NKF K/DOQI-target Hb 11–12g/dl • FDA: 10 – 12 g/dl • “Maintaining higher hemoglobin levels in patientswith chronic kidney failure increases the risk for death andfor serious cardiovascular reactions such as stroke, heart attack,or heart failure.“ • Hb variability is common • Clinicalsignificance of transient excursions is less clear. • May be associated with worseoutcome

11. Normal Hematocrit Study(NHS)1 • RCT of 1233 HDpts with established heart disease. • Complete correction vs partial correction • Strong trend for nonfatal MI or death in higher Hb group • Besarab A et al. N Engl J Med 1998

12. The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) Trial • 1432 pts • Hb 13.5 Vs 11.5 g/dL • Conc: Hb of 13.5 g/dL associated with cardiovascular risk and no improvement in QOL • Singh AK et al. CHOIR Investigators N Engl J Med 2006

13. The Cardiovascular Reduction Early Anemia Treatment Epoetin Beta (CREATE) Study • 603 patients with CKD • Early (Hb 11 - 12.5 g/dL) intervention to target Hb 13 -15 g/dL • Late (Hb < 10.5 g/dL) intervention to target Hb 10.5 -11.5 g/dL • 1ry outcome – death / defined CV event • No statistically significant difference • Quality of life better with higher Hb • Recommended partial correction of anemia and not routine normalization • Drueke TB et al. CREATE Investigators. N Engl J Med 2006

14. The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) and Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF) • Ongoing RCTs • May provide critical guidance for the future management of anemia and ESA safety at highertarget Hb levels • de Francisco ALMNephrol Dialysis Transplant 2009

15. Erythropoietin • Indistinguishable from endogenous erythropoietin • Binds the dimerized erythropoietin receptor on the surface of erythroid progenitor cells. • Triggers a variety of responses by several signaling pathways • Results in cell proliferation and inhibits apoptosis of the erythroid progenitor cells • Highly effective at stimulating erythropoiesis1 • Eschbach JW et al. N Engl J Med 1987

16. Current and future erythropoietic agents for the treatment of CKD anemia • Protein-based ESA therapy      • epoetin (alfa, beta, delta, omega)     • biosimilar EPO     • darbepoetin alfa •  CERA     •  SEP      • EPO fusion proteins          • EPO–EPO          • GM-CSF–EPO          • Fc-EPO         •  CTNO 528 • Small-molecule ESA      • peptide-based (e.g., Hematide)      • non–peptide-based • Other strategies for stimulating erythropoiesis      • prolylhydroxylase inhibitors (HIF stabilizers)      • GATA inhibitors      • HCP inhibitors      • EPO gene therapy

17. Darbepoetin alpha • A 2nd generation ESA • 2 amino acid substitutions • Greater metabolic stability • Elimination t½ 25.3 hrs (vs 8.5 hrs) • weekly or every other week • RCT in over 500 HD pts • wkly darbepoetin alfa as effective as epoetin 3 times weekly • Nissenson AR et al. Am J Kidney Dis 2002

18. CERA • Addition of a large polymer chain into the erythropoietin molecule • Elimination t ½ 130 hrs • (vs 8.5 hours for epoetin alpha and 25.3 hours for darbepoetin alpha) • Given 3 to 4 weekly is safe and effective

19. Multicentre RCTs1 • long-term tight control of Hb in over 800 HD pts converted from epoetin to CERA once every 2 weeks or once monthly • Achieved irrespective of the patients' age, gender, or diabetic status • CERA once every 2 wks Vs Darbepoetin alpha in 324 non HD, ESA-naïve pts, similar response rates (97.5% Vs 96.3% • Ongoing -monthly CERA Vs darbepoetin alpha in dialysis pts • 2006 ASN Annual Meeting

20. Erythropoietin-mimetic peptides • Hematide • in phase 2 of clinical development • Binds erythropoietin receptor • causes cell proliferation and differentiation • Stimulate erythropoiesis in multiple species, to produce a sustained increase in hemoglobin levels. • Well tolerated • A pegylated peptide • has a long duration of action that allows for once monthly dosing. • Other possible benefits • Stability at room temperature • Lack of crossreactivity with antierythropoietin antibodies

21. Hypoxia-inducible factor (HIF) stabilizer • The first oral ESA. In phase 2 of clinical development • Stabilises HIF • a transcription factor • activates erythropoietin during hypoxic conditions • regulates iron absorption, metabolic response, and vasculogenesis • May surpass effectiveness of erythropoietin • ability to stimulate iron absorption • suppress the negative effects of proinflammatory cytokines on red blood cell production

22. Dosage of Erythropoietin • Adult 50 to 100 Units/kg thrice a week • Children 50 Units/kg thrice a week • Increase Dose by 25% if: • Hb< 10 g/dL and not increased 1 g/dL after 4 wks • Hb decreases <10 g/dL • Reduce Dose by 25% if: • Hb approaches 12 g/dL or • Hb increases > 1 g/dL in any 2-week period • <10g/dL over12-weeks: • do not administer higher doses • lowest dose avoid recurrent transfusions • Evaluate • Discontinue if responsiveness does not improve

23. Dosage of Darbepoetin / CERA • Darbepoetin: • Initially 0.45 mcg/kg wkly • Appr conversion is 200 IU of epoetin alpha to 1 mcg of darbepoetin alpha. Follow manufacturer recommendations • CERA: • Initially 0.6µg/kg fortnightly • Conversion: follow manufacturer recommendations • Convert to monthly dosing when Hb stable, at double the fortnightly dose • Dose adjustments as for erythropoietin • Follow manufacturer instructions for administration of all ESAs

24. ESA resistance • Hyporesponse is common CKD • Defined as • Significant increasein dose requirement for maintenance • Significant decrease in Hb at constant dose • Failure to achieve Hb of 11 g/dl despite an ESA dose equivalent to epoetin > 500units/kg/week

25. Causes of ESA resistance1 • The most common causes are iron deficiency and inflammatory disorders • Compliance should also be checked • Other Causes • chronic blood loss • hyperparathyroidism/osteitisfibrosa • aluminium toxicity • haemoglobinopathies (e.g. a- and b-thalassaemias,sickle cell anaemia) • vitamin deficiencies (e.g. folate or vitamin B12) • multiple myeloma, myelofibrosis, other malignancies • malnutrition • haemolysis • inadequate dialysis • adverse effects of certain drugs [e.g. cytotoxic and immunosuppressive agents, ACE/ARBs] • Nephrol Dial Transplant 2004

26. Management of epo resistance • Iron deficiency • Absolute Fe deficiency found in 2.8% of Sri Lankan HD pts, while 44.4% had both SF and TS in range indicating risk of overload1 • Inflammation2 • Detect and treat occult infection • Optimise dialysis procedure • Optimise heart failure management • ?pentoxyfylline • ?vitamin E • Malnutrition • Herath CA, Dassanayake RT, Mendis DSN. 2007 • de Francisco ALM, Stenvinkel P, Vaulont s. NDT 2009

27. Diabetes associated with higher ESA requirements • Low endogenous erythropoietin concentrations • Rossert J et al. Nephrol Dial Transplant 2007

28. Adverse effects • Hypertension • Access clotting • ?Neovascularisation1 • ?enhancement of cancer growth1 • ?protection of nervoussystem, myocardium, and other tissues1 • Bunn FH. Blood 2007

29. Syndrome of PRCA • First described in 1980s • Marrow failure with selectivereduction or absence of erythroid precursors • All epoetin molecules(epoetin-, darbepoetin, and epoetin-β) reported in inducingcases • Attributed Tween in place of human albumin as stabilizer. • Interacts with rubber, enhancing antigenicity • Modifications in the manufacturingand storage of epoetin have resulted in a dramatic (>80%)reduction • Singh AK . Clin J Am Soc Nephrol 2008

30. Thank you!