1. SSIM KAUH2008 Erytropoietin Past & Future By: Dr. Abdullah T. Al-Mohamadi Demnostartor By: Dr. Abdullah T. Al-Mohamadi Demnostartor King Abdulaziz University Hospital King Abdulaziz University Hospital

2. Today’s Agenda (●) Definition (●) Definition (●) Historical background (●) Structure and Regulation of Erythropoieten Gene Gene (●) Epo-sites of production and functions (●) Erythropoietic stimulating agents (●) Therapeutic uses (●) Anemia of chronic kidney disease (●) Efficacy and benefits in patients with CKD SSIM KAUH2008

3. Today’s Agenda (●) Uses of Erythropoietic Stimulating Agents (●) Uses of Erythropoietic Stimulating Agents outside the setting of uremia outside the setting of uremia (●) Anemia of cancer (●) Anemia of cancer (●) ? Safety (●) ? Safety (●) Side effects (●) Side effects (●) Peptide Mimetic (●) Peptide Mimetic (●) Recommendations (●) Recommendations (●) Conclusion (●) Conclusion SSIM KAUH2008

4. Erythropoietin (EPO) Erythropoietin (EPO) (●) Endogenous glucoprotein (●) Endogenous glucoprotein (●) Member of an extensive cytokine (●) Member of an extensive cytokine family that include growth family that include growth hormone, prolactin, G-CSF and hormone, prolactin, G-CSF and others others SSIM KAUH2008

5. (●) Discovered by miyake etal in 1977 from urine of anemic patients. urine of anemic patients. (●) Recombinant human EPO (rhuepo) became available in 1985 became available in 1985 (●) (rhuepo) epoetin alfa was introduced into clinical practice for correction of into clinical practice for correction of anemia of renal failure in 1989. anemia of renal failure in 1989. (●) Jo Douglas Rizzo. Erythropoietin: A paradigm for the development of practice Guidelines. ASH;2001. Guidelines. ASH;2001. Historical Background SSIM KAUH2008

6. Production and Functions (●) 90% produced by a population of interstitial fibroblasts located in the interstitial fibroblasts located in the kidney’s deep cortex and outer medulla. kidney’s deep cortex and outer medulla. (●) less than 10% is produced by the liver. SSIM KAUH2008

7. Production and Functions: cont. (●) Hypoxia will cause an exponential increase in the number of EPO-producing cells i.e in the number of EPO-producing cells i.e negative feedback loop-low 0 2 =production of negative feedback loop-low 0 2 =production of EPO EPO (●) Epo is not stored within the kidney it is released as it is formed. released as it is formed. (●) Upon binding of EPO to EPO receptor autophosphorylation and activation of JAK-2 autophosphorylation and activation of JAK-2 will occur, thereby triggering the signal will occur, thereby triggering the signal transduction cascade necessary for EPO’s transduction cascade necessary for EPO’s biologic activity. biologic activity. SSIM KAUH2008

8. SSIM KAUH2008 (●) Gene is located on chromosome 7 (●) Gene is located on chromosome 7 (●) Epo has a compact globular structure (●) Epo has a compact globular structure consisting of 4 α-helical bundles has two consisting of 4 α-helical bundles has two domains, necessary for binding to the Epo domains, necessary for binding to the Epo receptor. receptor. (●) Transcription of the EPO gene is (●) Transcription of the EPO gene is regulated by Hypoxia – inducible factora-1 regulated by Hypoxia – inducible factora-1 (HIF-1) (HIF-1) Structure and Regulation of Erythropoietin Gene

9. Structure and Regulation of Erythropoietin Gene: cont. (●) Hypoxia is the fundamental, best understood understood physiologic stimulus of Epo production. physiologic stimulus of Epo production. (●) In the absence of hypoxia, Epo expression is suppressed by degradation of (HIF-1) is suppressed by degradation of (HIF-1) (●) Benjamin L et al. Regulation of the Erythropoietin gene. Blood 1999. SSIM KAUH2008

10. SSIM KAUH2008 (●) Figure.1. (●) Figure.2.

11. Erythropoietin: cont (●) The erythroid progenitors and precursors have the EPO receptors. have the EPO receptors. (●) Number of receptors in (BFU-E) more than (CFU-E) and the receptor expression (CFU-E) and the receptor expression decreases with erythroid maturation. decreases with erythroid maturation. SSIM KAUH2008

12. Erythropoietin: cont (●) EPO is crucial for proliferation and survival of CFU-E s and their irreversible survival of CFU-E s and their irreversible terminal differentiation. terminal differentiation. ● Lawerence et al: Erythropoietin, iron and erythropoiesis: Blood, 2000. SSIM KAUH2008

13. SSIM KAUH Figure 3 *EPO-Epo receptor interaction *Maturation of BFU-E  CFU-E *EPO mechanism

14. Available options for the Management of Anemia (●) Red blood cell transfusion (●) Transfusion related (●) Transfusion related complications complications (●) Transfusion transmitted infection (●) Transfusion transmitted infection (●) Immunologic sensitization (●) Immunologic sensitization (●) Iron overload syndrome (●) Iron overload syndrome SSIM KAUH2008

15. Available options for the Management of Anemia: cont. (●) Volume overload (●) Volume overload (●) Transfusion reaction (●) Transfusion reaction (●) Immune suppression (●) Immune suppression (●) Vamvakas, et al. Deleterions Clinical effects of transfusion-Associated Immunomodulation: fact of fiction? Blood 2001;97:1180-93 SSIM KAUH2008

16. SSIM KAUH2008 (2) Androgen (●) Side effects of Androgen (●) Side effects of Androgen (●) Acne (●) Acne (●) Virilization (●) Virilization (●) Priapism (●) Priapism (●) Peliosis hepatis (●) Peliosis hepatis (●) Disturbed liver function test (●) Disturbed liver function test (●) Risk of hepatocellular (●) Risk of hepatocellular carcinoma carcinoma

17. Erythropoietic Stimulating Agents (●) Epoetin alfa ( types of rhuepo ) (●) Epoetin beta (●) Darbepoetin alfa ~ long ½ life ((●)) Choice between different agents is best decided by the decided by the (●) practitioner (●) patient (●) staff (●) convenience (●) compliance (●) availability (●) cost SSIM KAUH2008

18. Therapeutic Uses Therapeutic Uses (1) Anemia of chronic kidney disease (●) Mainstay of treatment for anemia of end (●) Mainstay of treatment for anemia of end stage renal disease. stage renal disease. (●) First FDA approved indication. (●) First FDA approved indication. (●) Erythropoietic agents are recommended (●) Erythropoietic agents are recommended to stimulate erythropoiesis (Grade 1B) to stimulate erythropoiesis (Grade 1B) SSIM KAUH2008

19. Therapeutic Uses: cont. (●) No prospective randomized studies that (●) No prospective randomized studies that directly compared outcomes with erythropoietic agents vs. transfusion. erythropoietic agents vs. transfusion. (●) Among hemodialysis patients. It is administered intravenously rather than administered intravenously rather than subcutaneously (Grade 2B). subcutaneously (Grade 2B). SSIM KAUH2008

20. Anemia of CKD: cont. (●) Among predialysis and peritoneal dialysis patients it should be given dialysis patients it should be given subcutaneously rather than subcutaneously rather than intravenously (Grade 1 B) intravenously (Grade 1 B) ● NKF-DOQI Clinical Practice Guidelines for Anemia of Chronic Renal Failure. ANJ Kidney Dis. 2006 SSIM KAUH2008

21. *Criteria* (1) Initial Hb level of 11/g/dl; or less. (2) Other treatable causes of anemia should be excluded or treated if present. excluded or treated if present. (3) Iron status should be evaluated. (4) The dose should be titreated slowly. (5) Targeting Hb level of 12g/dl (Grade 2 C) ~ not targeting Hb levels above 13g/dl; ~ not targeting Hb levels above 13g/dl; (Grade 1 B). (Grade 1 B). ● NKF- DOQI Clinical Practice Gudielines for Anemia of Chronic Renal Failure. AMJ Kidney Dis. 2006. SSIM KAUH2008

22. Efficacy and Benefits in Patients with CKD (●) A large number of retrospective and prospective studies have noted the prospective studies have noted the ability of EPO to raise the Hb level. ability of EPO to raise the Hb level. *up to 95% response* *up to 95% response* SSIM KAUH2008

23. Benefits (1) Improved quality of life parameters particularly vitality and sleep. particularly vitality and sleep. (2) Increased cognitive function and cerebral blood flow. blood flow. (3) Improve left ventricular function and exercise-mediated cardiac ischemia. exercise-mediated cardiac ischemia. SSIM KAUH2008

24. Benefits: cont. (4) Relief a variety of uremic signs and symptoms, such as sexual dysfunction symptoms, such as sexual dysfunction in men, and impaired carbohydrate and in men, and impaired carbohydrate and cortisol metabolism. cortisol metabolism. (5) Mobilize iron stores (5) Mobilize iron stores (●) NKF-DOQI Clinical Practice Guidelines for Anemia of Chronic Renal Failure. AMJ Kidney Dis. 2006. SSIM KAUH2008

25. Uses of (ESA) Outside the Setting of Uremia The current applications are many ■ HIV-related anemia ■ Chemotherapy-induced anemia ■ Perisurgical setting ■ Autologous blood collections ■ Anemia of prematurity SSIM KAUH2008

26. Uses of (ESA) Outside the Setting of Uremia: cont. ■ Anemia of cancer ■ Anemia of cancer ■ Anemia associated with MM ■ Anemia associated with non-Hodgkin lymphoma ■ Acceleration of erythroid repopulation after allogeneic BMT allogeneic BMT ■ Hyporegenerative anemia in patients undergoing organ transplantation and receiving undergoing organ transplantation and receiving cyclosporin A to avoid rejection cyclosporin A to avoid rejection SSIM KAUH2008

27. Uses of ESA Outside the Setting of Uremia ■ Adjuvant for phlebotomy ■ Anemia of rheumatoid arthritis ■ Anemia of inflammatory bowel disease. ■ Anemia in Jehova’s witness ■ Pure RBC aplasia, MDS ■ Induction of Hb F synthesis in SCA and Thalassemia. Thalassemia. ■ Orthostatic hypotention ■ Mario Cazzola et al. Use of recombinant Human erythropoietin outside the setting of uremia. Blood Vol. 89, 1997. Vol. 89, 1997. SSIM KAUH2008

28. FDA approved indications (1) Anemia related to therapy with AZT in (1) Anemia related to therapy with AZT in HIV infected patients HIV infected patients (2) Anemia in patients with non-myeloid (2) Anemia in patients with non-myeloid malignancies where anemia is due to the malignancies where anemia is due to the effect of concomitantly administered effect of concomitantly administered chemotherapy. chemotherapy. SSIM KAUH2008

29. FDA approved indications: cont. (3) The treatment of anemia in patients (3) The treatment of anemia in patients scheduled to undergo elective, non- cardiac, scheduled to undergo elective, non- cardiac, non-vascular surgery to reduce the need for non-vascular surgery to reduce the need for allogenetic blood transfusion. allogenetic blood transfusion. (4) Patients at high risk of perioperative (4) Patients at high risk of perioperative transfusions with significant anticipated transfusions with significant anticipated blood loss. blood loss. J. Douglas Rizzo. Erythropoietin: A Paradigm for the development of Practice Guidelines ASH 2001 SSIM KAUH2008

30. Anemia of Cancer*ASH/ASCO/NCCN EORTC Guidelines ■ (rhuepo) approved for use in 1993 40-50% of patients with solid tumors and 60-70% of patients with with solid tumors and 60-70% of patients with hematologic malignancies are anemic at the time hematologic malignancies are anemic at the time of diagnosis. of diagnosis. ■ Data suggests that anemia in cancer patients is vastly under recognized and under treated. is vastly under recognized and under treated. ■ Fatigue is the most reported limiting symptom. ■ Adversely affects the QOL. SSIM KAUH2008

31. Anemia of Cancer*ASH/ASCO/NCCN EORTC Guidelines: cont. ■ Exclude other causes of anemia. ■ Assessment and periodic monitoring of iron store is indicated. indicated. ■ Support treating anemia in cancer patients with Hb level of 9-11g/dl to target Hb levels of 12g/dl. level of 9-11g/dl to target Hb levels of 12g/dl. ■ Minimize transfusion requirement and resolve clinical symptoms associated with anemia. clinical symptoms associated with anemia. ■ New EORTC guidelines for the treatment of anemia in patients with cancer:2005 ■ NCCN Practice Guidelines in Oncology: Cancer and Treatment Related Anemia 2006. ■ J. Douglas R et al. EErythopoietin: A paradigm for the development of Practice Guidelines. ASH:2001. SSIM KAUH2008

32. Anemia of Cancer*ASH/ASCO/NCCN EORTC Guidelines: cont. ●Titration of ESAS to the lowest effective maintenance dose, adjusting symptoms rather than Hb levels. ● Data from different kind of studies provide support that ESA results in statically significant mean Hb increase of above 1g/dl after 4 weeks and 2 g/dl after 8 weeks. SSIM KAUH2008

33. Anemia of Cancer*ASH/ASCO/NCCN EORTC Guidelines: cont. ● Continuing treatment beyond 6 to 8 weeks in the absence of response dose weeks in the absence of response dose not appear to be beneficial. not appear to be beneficial. ● Response rates up to 75% ● Gernot B et al. Risks and Benefits of Erythropiesis-Stimulating Agents in Cancer Management. Seminars in Hematology 2007. SSIM KAUH2008

34. Safety of Erythropoietic Agents Overview ● Data continue to accumulate regarding the increased risk of mortality and of the increased risk of mortality and of possible tumor promotion. possible tumor promotion. ● As of March, 2007 increased mortality has been observed…when strategies were been observed…when strategies were designed to achieve and maintain Hb level designed to achieve and maintain Hb level above 12g/dl. above 12g/dl. SSIM KAUH2008

35. Safety of Erythropoietic Agents Overview: cont. ● Metastatic breast cancer, head and neck cancer~a trend toward higher neck cancer~a trend toward higher mortality among patients receiving mortality among patients receiving the drug. the drug. SSIM KAUH2008

36. FDA Warning Letter ● There are insufficient data from adequate and well controlled studies designed to assess effects on survival or tumor promotion. ● Reconsideration of risks benefit ratio. ● FDA label update 11-08-2007. ● FDA patient information. SSIM KAUH2008

37. Possible effects on the course of underlying disease. (●) EPO receptors are found on several malignant cell (●) EPO receptors are found on several malignant cell lines eg. head and neck, lung, ovarian, breast lines eg. head and neck, lung, ovarian, breast uterine, prostate, hepatocellular and renal cell uterine, prostate, hepatocellular and renal cell carcinoma. carcinoma. (●) Induction of EPO receptors were associated with (●) Induction of EPO receptors were associated with neoangiogenesis, tumor hypoxia and infiltrating neoangiogenesis, tumor hypoxia and infiltrating tumors, ↓ loco regional control. tumors, ↓ loco regional control. (●) Increased thrombovascular events with increased (●) Increased thrombovascular events with increased morbidity and potential increased mortality. morbidity and potential increased mortality. SSIM KAUH2008

38. Conclusion ● Over treatment of anemia to a Hb more than 12g/dl as well as insufficient treatment have each been associated with unfavorable clinical courses. ● FDA says use minimum dose possible to get Hb no higher than 12g/dl and stop one chemotherapy have been completed. ● Patients should be well informed about possible side effects and survival disadvantage. SSIM KAUH2008

39. Therapeutic Abuses ● Used in sports to improve endurance ● Now detected from naturally occurring EPO by protein markers appearing EPO by protein markers appearing post injection. post injection. SSIM KAUH2008

40. Clinically Relevant Side Effects ■ Safe and well tolerated (●) Hypertension (●) Hypertension In 20-30% after IV administration~less In 20-30% after IV administration~less likely after subcuntaneous use. Mostly in likely after subcuntaneous use. Mostly in chronic renal failure. chronic renal failure. (●) Hypertensive encephalopathy and seizures (●) Hypertensive encephalopathy and seizures may occur when EPO causes a rapid rise may occur when EPO causes a rapid rise in BP. in BP. SSIM KAUH2008

41. Clinically Relevant Effects: cont. (●) Thrombotic and cardiovascular events are rare~target Hb >12g/dl rare~target Hb >12g/dl (●) 200 patients were treatd with Eprex in European countries from 1998-2004 had pure European countries from 1998-2004 had pure red cell aplasia. This complication is now red cell aplasia. This complication is now encountered rarely and was probably caused by encountered rarely and was probably caused by defective formulation rather than inherent defective formulation rather than inherent antigenicity. antigenicity. SSIM KAUH2008

42. Small Molecule EPO Mimetics (●) Synthesized from random peptide (libraries) displayed on filamentous phage (bacterial virus) on filamentous phage (bacterial virus) (●) It is 14-20 a.a in lengths can bind to Epo receptors and activate signal transduction cascade. activate signal transduction cascade. (●) “Hematide” is peptide that has been developed, stable pegylated with long ½ life. It is now being evaluated in pegylated with long ½ life. It is now being evaluated in phase 2 both in renal patients and patient with cancer. phase 2 both in renal patients and patient with cancer. (●) Safe, well tolerated and without unwanted immunological side effects. immunological side effects. SSIM KAUH2008

43. Concerns and Caveats Concerns and Caveats (●) It has become increasingly apparent that EPOR is present on a wide range of normal cells with possible beneficial effects. range of normal cells with possible beneficial effects. Thought to protect neural network by NF - Kappa β stimulation. Thought to protect neural network by NF - Kappa β stimulation. Evidence that neuroprotective nature of EPO is useful post-CVA Evidence that neuroprotective nature of EPO is useful post-CVA May be used in treatment of stroke victims. May be used in treatment of stroke victims. (●) There is concern that EPO may contribute to the pathogenesis of proliferative diabetic retinopathy through pathogenesis of proliferative diabetic retinopathy through stimulation and proliferation and migration of vascular stimulation and proliferation and migration of vascular endothelial cells. endothelial cells. (●) H. Franklin Bun. New agents that stimulate Erythropoiesis. Blood, 1 Feb. 2007. SSIM KAUH2008

44. SSIM KAUH2008 ???Cost

45. Conclusion ●Take Home Messages● (●) Two decade ago, recombinent human erythroprotein was introduced into clinical, erythroprotein was introduced into clinical, practice, now millions of patient throughout the practice, now millions of patient throughout the world are receiving it. world are receiving it. (●) Administration of recombinent human erythropoietin should be to patients who are very erythropoietin should be to patients who are very likely to respond and benefit from this treatment. likely to respond and benefit from this treatment. SSIM KAUH2008

46. Conclusion: cont. (●) Demanding a well designed trails to address safety issue in cancer patient with chemotherapy safety issue in cancer patient with chemotherapy associated anemia using currently approved associated anemia using currently approved dosing regimens in generalizable tumor type. dosing regimens in generalizable tumor type. (●) The search goes on for orally active antianemic therapies, better tolerated and hopefully, much therapies, better tolerated and hopefully, much less costly. less costly. SSIM KAUH2008

47. Conclusion: cont. (●) A growing body of evidence indicates that EPO has tissue protective effects and EPO has tissue protective effects and prevent tissue damage during ischemia prevent tissue damage during ischemia and inflammation. and inflammation. (●) Cost: benefit ratio to the use of ESA needs to be refined and validated for many needs to be refined and validated for many indication. indication. (●) Evidence based Guidelines for other clinical applications are warranted applications are warranted SSIM KAUH2008