FDA Perspectives on Erythropoiesis-Stimulating Agents (ESAs) for Anemia of Chronic Renal Failure: Hemoglobin Target and

1. FDA Perspectives onErythropoiesis-Stimulating Agents (ESAs) for Anemia of Chronic Renal Failure:Hemoglobin Target and Dose Optimization Joint Meeting of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Ellis F. Unger, M.D. Deputy Director for Science (Acting) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER) September 11, 2007

2. Outline • What is the correct hemoglobin target for ESAs for anemia of chronic renal failure? • Randomized controlled clinical trials • Observational data • ESA responsiveness • Dose optimization challenges • Potential path forward

3. Approved Erythropoiesis-Stimulating Agents (ESAs) for Anemia of Chronic Renal Failure: • Epoetin alfa (Epogen® /Procrit®): 1989 • Darbepoetin alfa (Aranesp®): 2001

4. What is the Correct Hemoglobin Target (or Range) for ESAs in Anemia of Chronic Renal Failure?

5. Randomized Controlled Clinical Trials of Discrete Hemoglobin Targets: • “Normal Hematocrit” • CHOIR • CREATE

6. Normal Hematocrit Study Goal: Assess risks and benefits of achieving a “normal” hematocrit in hemodialysis patients with clinically evident CHF or ischemic heart disease Conducted: 1993 to 1996, with follow-up through 7/1997

7. Normal Hematocrit Study: Design • Open label • All subjects received Epoetin alfa • 1:1 randomization to: • low hematocrit = 30±3% (Hgb ~10±1 g/dL); or • “normal” hematocrit = 42±3% (Hgb ~14±1 g/dL) • At entry, patients: • clinically evident ischemic heart disease or CHF • on hemodialysis • clinically stable on Epoetin alfa • 1°endpoint: Time to death or non-fatal MI

8. Normal Hematocrit Study Results: • Randomization: n = 634 to “normal” hematocrit (42 ± 3%) n = 631 to low hematocrit (30 ± 3%) • Terminated early “Our study was halted when differences in mortality between the groups were recognized as sufficient to make it very unlikely that continuation of the study would reveal a benefit for the normal-hematocrit group and the results were nearing the statistical boundary of a higher mortality rate in the normal hematocrit group.” NEJM, 1998

9. Normal Hematocrit Study Results: Hematocrit (%) Time (months) Mean (95% CI) Hematocrit by Study Month (NEJM, 1998)

10. Normal hematocrit group Low hematocrit group Normal Hematocrit Study Results: final log rank p = 0.01 Probability of death or non-fatal MI (%) Time (months) Death or Non-Fatal MI by Study Month (NEJM, 1998)

11. Normal Hematocrit Study Results: Components of Primary Endpoint

12. Normal Hematocrit Study: • Negative Association Between Mean Hemoglobin (throughout study) and Mortality: Lower target Higher target n= FDA analysis of data collected through 7/5/97

13. Normal Hematocrit Study Summary: • Hemodialysis patients with clinically evident CHF or ischemic HD • Targeting a hematocrit of 42 ± 3% versus 30 ± 3% (Hgb ~14 ± 1 versus ~10 ± 1 g/dL) associated with increased mortality and cardiovascular morbidity. • Somewhat paradoxically, higher mean hemoglobin concentrations were associatedwith survival in both treatment arms.

14. CHOIR Study Design • Open label, Epoetin alfa • Patients • no Epoetin alfa in past 3 months • not on dialysis • hemoglobin < 11 g/dL • 1:1 randomization to hemoglobin 11.3 or 13.5 g/dL • Primary endpoint: composite of mortality, CHF hospitalization, non-fatal stroke, non-fatal MI

15. CHOIR Study Results • Randomization: 715 to hemoglobin of 13.5 g/dL 717 to hemoglobin of 11.3 g/dL • Terminated early “The DSMB recommended that the study be terminated in May 2005 at the time of the second interim analysis…because the conditional power for demonstrating a benefit for the high-hemoglobin group was less than 5% for all plausible values of the true effect for the remaining data.” NEJM, 2006

16. CHOIR Study Results mean hemoglobin (g/dL) time (months) Mean (95% CI) Hemoglobin by Study Month (NEJM, 2006)

17. CHOIR Study Results Primary Composite Endpoint High hemoglobin group Probability of composite event Low hemoglobin group Time (months)

18. CHOIR Study Results: 1° Endpoint Components

19. CHOIR Study Results • Negative Association Between Mean Hemoglobin (throughout study) and Mortality: Lower target Higher target n= FDA exploratory analysis

20. CHOIR Summary • For pre-dialysis patients, administration of Epoetin alfa to target a Hgb of ~13.5 versus 11.3 g/dL is associated with increased mortality and CHF hospitalization. • Paradoxically, higher mean hemoglobin concentrations were associatedwith survival in both treatment arms.

21. CREATE Study Design • Open label, Epoetin beta • Patients • mild anemia (hemoglobin 11 to 12.5 g/dL) • not on dialysis • no prior ESAs • 1:1 randomization to normal hemoglobin (13 – 15 g/dL) or subnormal hemoglobin (11 – 12.5 g/dL) • Epoetin beta begun in subnormal group once hemoglobin < 10.5 g/dL

22. CREATE Study Design & Results • Primary composite endpoint: sudden death, MI, acute heart failure, stroke, TIA, angina requiring hospitalization, peripheral vascular disease complication or cardiac arrhythmia requiring hospitalization • Randomization: 301 to normal hemoglobin (13–15 g/dL) 302 to subnormal hemoglobin (11–12.5 g/dL)

23. CREATE Study Results Median (SD) Hemoglobin by Study Month NEJM, 2006

24. CREATE Study Results • Primary endpoint events (NEJM, 2006): - 58/301 in normal hemoglobin group - 47/302 in sub-normal hemoglobin group • HR 0.78 (95% CI 0.53 – 1.12) • Few endpoint events despite broad composite endpoint • Results directionally support lower hemoglobin target

25. Observational Data – 58,058 U.S. HD Patients: Database from DaVita, Inc. Regidor DL, Kopple JD, Kovesdy CP, et al. J Am Soc Nephrol. 2006;17:1181.

26. NKF K/DOQI Guidelines (2006) “Cohort-based observational trials and cross-sectional analyses of large medical databases…consistently show that higher achieved hemoglobin values (including ≥ 12 g/dL) are associated with improved patient outcomes …. The failure of observational associations to be confirmed by interventional trials renders use of observational evidence unsuitable to support the development of an intervention guideline statement.” www.kidney.org/professionals/KDOQI/guidelines_anemia/cpr21.htm

27. Data to Support Ideal Hemoglobin Target (1): ↓ morbidity/mortality ↑ morbidity/mortality Normal hematocrit (hemodialysis) 10 14 ? ↓ morbidity/mortality ↑ morbidity/mortality 11.3 CHOIR (pre-dialysis) 13.5 Observational data, by association only

28. Data to Support Ideal Hemoglobin Target (2): • Observational data from HD patients • Exploratory analyses of NHCT and CHOIR • associations between higher mean hemoglobin concentration achieved and survival • Association does not prove causality • Achieved hemoglobin ≠ hemoglobin target. • J-shape relation suggests that there is some Hgb concentration that is excessive in the CRF population.

29. Data to Support Ideal Hemoglobin Target (3) • Perhaps patients who achieve higher hemoglobin concentrations have less advanced renal disease and lower CV disease burden  better outcomes. • We are not aware of a RCT that demonstrates, in a convincing way, that a higher hemoglobin target is associated with less cardiovascular morbidity and mortality than a lower target.

30. Dose Optimization Challenges; ESA Responsiveness

31. 1. Could we prospectively identify hypo-responders, at higher risk of cardiovascular events?2. If hypo-responders could be identified, how should they be treated? Dose Optimization Challenges; ESA Responsiveness

32. Survival by Hemoglobin (Normal HCT Study) Less responsive to ESAs Lower target Higher target n= FDA analysis of data collected through 7/5/97

33. Survival by Mean Weight-Adjusted Epoetin Alfa Dose (Normal HCT Study) Dose and responsiveness are inversely rated Fraction surviving Highest dose; less responsive to ESAs FDA exploratory analysis time (months)

34. Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (1) • FDA exploratory analysis • NHCT study provided unique opportunity to assess ESA-responsiveness. • Stable HD patients, maintained on Epoetin alfa; hematocrit 27 to 33% for 4 weeks • Subjects randomized to “normal” hemoglobin target group had standard protocol-mandated ESA “challenge” • Epoetin alfa dose increased by factor of 1.5 on study entry

35. Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (2) • Epoetin alfa-responsiveness calculated for patients who received constant weekly Epoetin alfa dosing for 2 to 6 weeks following study entry. • Responsiveness ºslope of hemoglobin-time relation throughout the 2- to 6-week period (linear regression).

36. Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (3) • 618 patients randomized to “normal” hemoglobin target • EPO-responsiveness could be calculated for 414: • 117 patients experienced a decrease in hemoglobin, despite a 50% increase in Epoetin alfa dose • 297 patients experienced no change or an increase in hemoglobin: divided in quintiles

37. Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (4) Assessments: • Survival by initial Epoetin alfa-responsiveness • Overall Epoetin alfa responsiveness (mean hemoglobin concentration throughout study) by initial Epoetin alfa response

38. Initial Epoetin Alfa Responsiveness Does Not Predict Subsequent Mortality in the NHCT Study FDA exploratory analysis

39. Initial Epoetin Alfa Responsiveness Does Not Predict Subsequent Mortality in the NHCT Study FDA exploratory analysis

40. Initial Epoetin Alfa Responsiveness Does Not Predict Overall Hgb Response in the NHCT Study less initial response more initial response Mean Hgb throughout study (g/dL) 0 Hgb rate of change with initial 50% increase in EPO dose (g/dL/week) FDA exploratory analysis

41. Could we prospectively identify hypo-responders, at higher risk of cardiovascular events?In the NHCT Study, where patients had protocol-mandated 50% increase in EPO dose on study entry:Initial Hgb response did not predict subsequent mortality, and did not predict overall Hgb response.* ESA responsiveness may need to be assessed on ongoing basis.

42. ESA-Hyporesponsiveness in a Single Patient:

43. Conclusions: Dose Optimization Challenges; ESA Responsiveness (1)- Prospective identification of hypo-responders may be difficult (i.e., erythropoietic response to an ESA challenge)- Identification of hypo-responders is feasiblein practice

44. Conclusions: Dose Optimization Challenges; ESA Responsiveness (2)For hypo-responsive patients, the labeling suggests a search for causative factors, but does not explicitly state a maximum ESA dose, or what constitutes an adequate attempt to raise hemoglobin.KeyUnansweredQuestion: whether less responsive patients or those with specific risk factors would experience fewer cardiovascular events if attempts were not made to raise their hemoglobin to some “ideal” target.

45. Dose Optimization Challenges

46. Dose Optimization Challenges • ESA labeling warns against excessive rate of rise of Hgb (> 1 g/dL per 2 weeks) • Is risk related to hemoglobin response?

47. Dose Optimization Challenges: Cycling in a Subject from the Normal Hematocrit Study

48. Dose Optimization Challenges: Cycling in a Subject from the Normal Hematocrit Study

49. Dose Optimization Challenges: Cycling in a Subject from the Normal Hematocrit Study Week 50, hemoglobin 9.9, rate of change 0.6 g/dL/week Week 49, hemoglobin 9.3

50. Normal Hematocrit Study:“Dynamic” Analysis of Relations Between Serious Cardiovascular Events, Prevailing Hemoglobin, and Preceding Hemoglobin Rate of Change serious CV events/ patient-yr [Hemoglobin] (g/dL) Hemoglobin rate of change (g/dL/wk) FDA Analysis