1 4 5 2 3 6 Introduction Pharmacodynamic Results Safety Results HematideTM, a Synthetic Peptide-Based Erythropoiesis Stimulating Agent, Maintains Hemoglobin in Hemodialysis Patients Previously Treated with Epoetin Alfa (EPO) A. Besarab1, S. Zeig2, R. Geronemus3, P. Pergola4, F. Whittier5, R. Zabaneh6, B. Schiller7, M. Kaplan8, N. Levin9, S. Wright10, S. Swan11, R. Wintz12, D. Wombolt13, R. Leong14, W. Lang14, M. Franco14, AM. Duliege14 1Henry Ford Hospital, Detroit, MI, 2Pines Clinical Research, Pembroke Pines, FL, 3South Florida Nephrology Associates, Lauderdale Lakes, FL, 4Renal Associates, San Antonio, TX, 5Clinical Research Ltd., Canton, OH, 6Northwest Louisiana Nephrology, Shreveport, LA, 7Satellite Health Care, Mountain View, CA, 8Nephrology Associates, Nashville, TN, 9Renal Research Institute, New York, NY, 10US Renal Care of SEA, Pine Bluff, AR, 11Davita Clinical Research, Minneapolis, MN, 12UCLA, Los Angeles, CA, 13Clinical Research Associates of Tidewater, Norfolk, VA, 14Affymax, Inc., Palo Alto, CA Poster #99 National Kidney Foundation 2007 Spring Clinical Meetings (CM.07), April 10–14, 2007, Orlando, Florida Correspondence: Anatole Besarab, MD, Henry Ford Hospital, Div. of Nephrology & Hypertension, 2799 W. Grand Blvd., Detroit, MI 48202, USA; phone: +1 (313) 916-2713. Introduction Pharmacodynamic Results 1 4 Hematide Administration: After EPO therapy was discontinued on study entry, up to 6 Hematide doses were administered Q4W, each as an IV bolus over 30 seconds The 4 dosing cohorts included here used one of the following dosing strategies: An EPO-to-Hematide conversion factor (CF); e.g., “CF 0.05” patients were dosed with 0.05 mg/kg Hematide Q4W for every 100 U/kg/week EPO A weight-based (“mg/kg”), tiered dosing, based on a 4-tiered EPO dose range, with or without a 1-week transitional period during which EPO was withheld prior to Hematide dosing Dose adjustment guidelines were used to maintain Hb levels between 10.0 and 12.5 g/dL Figure 2: Mean (±SD) Hb Change from Baseline 2 Injection 6 Injection 5 Injection 4 Injection 3 Injection 2 Injection 1 -2 -1 1 4 8 12 16 20 24 Time (wks) Mean Hb Change from Baseline (g/dL) CF 0.05 CF 0.066 mg/kg, with transition mg/kg, without transition Hematide is a novel synthetic, PEGylated, peptidic erythropoiesis stimulating agent that binds to and activates the erythropoietin receptor Hematide is being developed for the treatment of anemia in chronic kidney disease (CKD) Main study objectives include: Determine the range of intravenous (IV) Hematide doses that maintain hemoglobin (Hb) within ±1 g/dL of baseline in hemodialysis (HD) patients whose Hb levels had previously been stable on EPO therapy Evaluate the safety profile of IV Hematide administered every 4 weeks (Q4W) Preliminary results from 4 dose cohorts (90 patients) are presented here Mean Hematide doses administered across all 4 dosing cohorts increased progressively from 0.083 (±0.036) mg at Injection 1 to 0.102 (±0.073) mg at Injection 6 Of 485 doses administered, 21% (100 of 485) were dose increases and 11% (54 of 485) were dose reductions, compared to previous doses 78% (1547) of 1994 Hb values were maintained between 10.0 and 12.5 g/dL, 7% (144) were <10.0 g/dL, and 6% (119) were >13.0 g/dL Figure 1: Mean Reticulocyte Change from Baseline -100 -50 50 100 150 4 8 12 16 20 24 Time (wks) Mean Reticulocyte Change from Baseline (10 9 /L) Injection 6 Injection 5 Injection 4 Injection 3 Injection 2 Injection 1 CF 0.05 CF 0.066 mg/kg, with transition mg/kg, without transition Safety Results Study Design Demographics & Baseline Characteristics 5 2 3 107 (65%) of 165 patients reported one or more AEs. Twelve patients reported AEs that were related to Hematide, including fatigue (3 patients), weakness (2), rash (2), and worsening hypertension (1). 85 SAEs were reported from 48 of 165 patients; 84 SAEs were reported to be non-drug related, and one Grade 2 infusion reaction responding to outpatient intervention was considered probably related to Hematide Five (3%) patients died during the study; these were from cardiac arrest (3), respiratory failure/sepsis (1), and pneumonia/sepsis (1). None of these deaths were reported to be related to Hematide. The safety profile was characteristic of the HD patient population Design: Phase 2, multi-center, open-label, sequential, dose-finding study Population: Adult HD patients with stable Hb levels maintained by EPO for 8 weeks prior to study entry Selected Entry Criteria: Patients ≥18 years of age Clinically stable on HD for ≥6 months EPO maintenance therapy between 60 and 375 U/kg/week for 8 weeks prior to study entry 3 Hb values between 10.0 and 12.5 g/dL in the 3 weeks prior to study entry Number of Patients: 165 patients from 11 treatment cohorts of 15 patients per cohort. Data reported here on 90 patients from 4 dose cohorts. Clinical Endpoints: Pharmacodynamic: Hb and reticulocyte levels, Hematide dose adjustments, and red blood cell transfusions Safety: Adverse events (AEs) and serious adverse events (SAEs) Table 1: Demographics and Baseline Characteristics (Mean ±SD) CF 0.05 (n=30) CF 0.066 (n=15) mg/kg, with transition (n=15) mg/kg, without transition (n=30) All patients (n=90) Gender (M:F) 17:13 8:7 10:15 13:17 48:42 Age (yr) 60 (±14) 67 (±12) 55 (±19) 58 (±16) 60 (±16) Weight (kg) 79 (±18) 88 (±26) 79 (±15) 75 (±16) Hb (g/dL) 11.5 (±0.6) 11.4 (±0.6) 11.5 (±0.5) TSAT (%) 49 (±20) 53 (±17) 59 (±16) 32 (±10) 45 (±19) Ferritin (g/L) 786 (±513) 888 (±413) 1074 (±643) 666 (±457) 811 (±516) Conclusions 6 Mean reticulocyte increases were observed after every Hematide injection, with peak increases noted at approximately 2 weeks post-injection (Figure 1) Mean Hb levels across all 4 dosing cohorts were maintained within ±1 g/dL of baseline (Figure 2) Mean Hb values across all cohorts were 11.2 (± 1.1), 11.2 (± 1.2), and 11.2 (± 1.0) g/dL four weeks after Injections 4, 5, and 6, respectively Patients dosed by conversion factor or by a weight-based, tiered dosing strategy, in conjunction with dose adjustment guidelines, had mean Hb levels maintained within ±1 g/dL of baseline Hematide may be dosed Q4W (~monthly) in HD patients Hematide is well tolerated and is pharmacodynamically active Hematide will be evaluated in Phase 3 studies in both HD and predialysis CKD patients Baseline patient characteristics were similar across the dosing cohorts (Table 1), except for the “mg/kg, without transition” group which had a higher proportion of female patients Mean baseline Hb across all 4 dosing cohorts was 11.5 (±0.6) mg/dL