The Role of Calcineurin The Role of Calcineurin Inhibitors in the - PowerPoint PPT Presentation

The Role of Calcineurin The Role of Calcineurin Inhibitors in the Treatment Inhibitors in the Treatment of Idiopathic Membranous of Idiopathic Membranous Nephropathy Nephropathy Membranous Nephropathy Membranous Nephropathy Conference, Conference, March 30- -31, 2007, 31, 2007, March 30 Bergamo, Italy Bergamo, Italy Fernando C. Fervenza, MD Fernando C. Fervenza, MD Associate Professor of Medicine Associate Professor of Medicine Division of Nephrology and Hypertension Division of Nephrology and Hypertension Mayo Clinic College of Medicine Mayo Clinic College of Medicine Rochester, MN Rochester, MN

Cyclosporine in Progressive MN Cyclosporine in Progressive MN Patients Characteristics at Entry Patients Characteristics at Entry Cyclosporine Placebo Cyclosporine Placebo n=9 n=8 n=9 n=8 Age (range) 44 (22-59) 40 (20-61) Age (range) 44 (22-59) 40 (20-61) Males (%) 8 (89) 6 (75) Males (%) 8 (89) 6 (75) Creatinine ( µ µ mol/L) 186 ± ± 65 204 ± ± 81 Creatinine ( µ µ µ µ mol/L) 186 ± ± ± ± 65 204 ± ± ± ± 81 µ µ ± ± ± ± C cr (mL/min/1.73 m 2 ) 51 ± ± 20 46 ± ± 16 C cr (mL/min/1.73 m 2 ) ± ± ± ± 51 ± ± 20 46 ± ± 16 ± ± ± ± Proteinuria (g/day) 11.5 (9-18) 12.8 (4-21) Proteinuria (g/day) 11.5 (9-18) 12.8 (4-21) Serum albumin (g/L) 29 ± ± 6.6 30 ± ± 9.2 ± ± ± ± Serum albumin (g/L) 29 ± ± 6.6 30 ± ± 9.2 ± ± ± ± Systolic BP/mm Hg 141 ± ± 6 138 ± ± 16 Systolic BP/mm Hg 141 ± ± ± ± 6 138 ± ± ± ± 16 ± ± ± ± Diastolic BP (mm Hg) 82 ± ± 12 83 ± ± 7 Diastolic BP (mm Hg) 82 ± ± ± ± 12 83 ± ± ± ± 7 ± ± ± ± Ultra structural stage 2.2 (1-4) 2.0 (1-4) Ultra structural stage 2.2 (1-4) 2.0 (1-4) Interstitial fibrosis (0-4+) 0.9 (0-1) 0.4 (0-1) Interstitial fibrosis (0-4+) 0.9 (0-1) 0.4 (0-1) Tubular atrophy (0-4+) 0.7 (0-2) 0.3 (0-2) Tubular atrophy (0-4+) 0.7 (0-2) 0.3 (0-2) Observation period (mo) Observation period (mo) Part 1 9.3 (6-13) 9.7 (7-12) Part 1 9.3 (6-13) 9.7 (7-12) Part 2 10.1 (4-13) 8.9 (4-13) Part 2 10.1 (4-13) 8.9 (4-13) Post-med 20 (0-41) 22 (6-56) Post-med 20 (0-41) 22 (6-56) Total 49 (17-75) 48 (25-88) Total 49 (17-75) 48 (25-88) Cattran et al: Kl 47:1130, 1995 Cattran et al: Kl 47:1130, 1995 CP1134827-25

Improvement in Rate of Change in Creatinine Clearance Improvement in Rate of Change in Creatinine Clearance Cyclosporine Cyclosporine -2.4 vs - 2.4 vs - -0.7 0.7 110 100 90 80 Creatinine Creatinine 70 clearance clearance 60 50 (mL/min) (mL/min) 40 30 20 10 0 Death Death Placebo Placebo Dialysis Dialysis -2.2 vs 2.2 vs - -2.1 2.1 - 110 100 90 80 Creatinine Creatinine 70 clearance clearance 60 50 (mL/min) (mL/min) 40 30 20 10 0 -15 -10 -5 0 5 10 15 20 25 30 35 40 Months from randomization Months from randomization Cattran D: Curr Op Nephrol Hypert 5:427, 1996 Cattran D: Curr Op Nephrol Hypert 5:427, 1996 CP1134827-9

Cyclosporine in Progressive IMN Cyclosporine in Progressive IMN Cyclomen Study, Follow- -Up 12 Months Up 12 Months Cyclomen Study, Follow CsA Conservative CsA Conservative n=10 n=11 n=10 n=11 Before Final Before Final Before Final Before Final Proteinuria 6.8±0.9 7.5±7.9 4.0±0.5 2.8±0.7 Proteinuria 6.8±0.9 7.5±7.9 4.0±0.5 2.8±0.7 (g/24 hr) (g/24 hr) CCr 49.3±6.5 44.1±9.1 47.8±7.3 46±7.9 CCr 49.3±6.5 44.1±9.1 47.8±7.3 46±7.9 (mL/min/1.73 m 2 ) (mL/min/1.73 m 2 ) Remissions 2 4 Remissions 2 4 ESRD 3 1 ESRD 3 1 Pisoni et al: JASN, 2000 (abstract) Pisoni et al: JASN, 2000 (abstract) CP1256850-7

Cyclosporine in Steroid- -Resistant MN Resistant MN Cyclosporine in Steroid Baseline Demographic and Laboratory Data Baseline Demographic and Laboratory Data of 51 Randomized Patients of 51 Randomized Patients Placebo Cyclosporine Placebo Cyclosporine Initial n=23 n=28 Initial n=23 n=28 Age range 49 ± ± 14 47 ± ± 11 ± ± ± ± Age range 49 ± ± 14 47 ± ± 11 ± ± ± ± Gender (M:F) 16/7 26/2 Gender (M:F) 16/7 26/2 Blood pressure (mm Hg) Blood pressure (mm Hg) Systolic 138 ± ± 16 137 ± ± 18 Systolic 138 ± ± ± ± 16 137 ± ± ± ± 18 ± ± ± ± Diastolic 84 ± ± 9 84 ± ± 7 ± ± ± ± Diastolic 84 ± ± 9 84 ± ± 7 ± ± ± ± Racial group, No. (%) Racial group, No. (%) Caucasians 20 (87) 24 (86) Caucasians 20 (87) 24 (86) African-American 0 (0) 1 (4) African-American 0 (0) 1 (4) Other/mixed 3 (13) 2 (10) Other/mixed 3 (13) 2 (10) Serum albumin (g/dL) 2.7 ± ± 0.6 2.8 ± ± 0.6 ± ± ± ± Serum albumin (g/dL) 2.7 ± ± 0.6 2.8 ± ± 0.6 ± ± ± ± Serum creatinine (mg/dL) 1.1 ± ± 0.3 1.3 ± ± 0.5 Serum creatinine (mg/dL) 1.1 ± ± ± ± 0.3 1.3 ± ± ± ± 0.5 ± ± ± ± Creatinine clearance 95 ± ± 37 90 ± ± 27 Creatinine clearance 95 ± ± ± ± 37 90 ± ± ± ± 27 ± ± ± ± (mL/min/1.73 m 2 ) (mL/min/1.73 m 2 ) Proteinuria (g/day) 8.8 ± ± 4.7 9.7 ± ± 5.3 ± ± ± ± Proteinuria (g/day) 8.8 ± ± 4.7 9.7 ± ± 5.3 ± ± ± ± Urine urea (g/day) 9.5 ± ± 3.6 10.3 ± ± 4.0 Urine urea (g/day) 9.5 ± ± ± ± 3.6 10.3 ± ± ± ± 4.0 ± ± ± ± Data ± ± SD ± ± Data ± ± SD ± ± Cattran et al: Kl 59:1484, 2001 Cattran et al: Kl 59:1484, 2001 CP1134827-26

Cyclosporine in MGN Cyclosporine in MGN Cyclosporine Placebo Cyclosporine Placebo 0 28 23 28 23 1 CR 4 PR 18 NR 26 1 CR 4 PR 18 NR 2 CR 19 PR 7 NR 2 CR 19 PR 7 NR Weeks Weeks 52 2 CR 11 PR 8 R 1 CR 2 PR 2 R 18 NR 1 CR 2 PR 2 R 18 NR 2 CR 11 PR 8 R (1) (1) (1) (1) (2) (2) (2) (2) (1) (8) (8) (1) (8) (8) (1) (1) (1) (1) 2 CR 9 PR 10 R 7 NR 1 CR 2 PR 3 R 3 R 17 NR 78 2 CR 9 PR 10 R 7 NR 1 CR 2 PR 17 NR Cattran et al: Kidney Int 59:1484, 2001 Cattran et al: Kidney Int 59:1484, 2001 CP1134827-24

CyA Treatment in Membranous Nephropathy CyA Treatment in Membranous Nephropathy 100 80 Rate of Rate of 60 complete complete remission remission 40 (%) (%) MC MC MGN MGN 20 Censored Censored 0 0 6 12 18 24 Duration of treatment (months) Duration of treatment (months) Merier, NDT 14: 1036, 1999 Merier, NDT 14: 1036, 1999 CP1123327-6

Induction and long- -term treatment term treatment Induction and long Initial Treatment Initial Treatment I) Treatment groups I) Treatment groups • Pred + CsA • Pred + CsA 31 patients 31 patients • CsA alone • CsA alone 20 patients 20 patients II) Treatment regimen II) Treatment regimen • Pred 0.6 mg/kg/day with tapering • Pred 0.6 mg/kg/day with tapering • CsA 2-3 mg/kg/day • CsA 2-3 mg/kg/day Target whole blood 12-hour trough levels Target whole blood 12-hour trough levels 100-200 ng/mL 100-200 ng/mL III) Duration of treatment III) Duration of treatment • 12 months • 12 months Alexopoulos et al. NDT 21: 3127 et al. NDT 21: 3127- -3132, 2006 3132, 2006 Alexopoulos CP1256850-14

Outcome Outcome 6 Months 12 Months 6 Months 12 Months 100 Response of proteinuria Response of proteinuria CsA CsA 80 80 Pred+CsA Pred+CsA (% of patients) (% of patients) 65 64 60 48 40 35 20 19 20 5 0 Complete Partial Complete Partial No relapses No relapses Alexopoulos et al. NDT 21: 3127 et al. NDT 21: 3127- -3132, 2006 3132, 2006 Alexopoulos Alexopoulos et al. NDT 21: 3127-3132, 2006 CP1256850-15

Long Term Treatment of IMN Long Term Treatment of IMN I) Treatment groups I) Treatment groups • Pred + CsA • Pred + CsA 26 patients (11 CR, 15 PR) 26 patients (11 CR, 15 PR) • CsA alone • CsA alone 17 patients (4 CR, 13 PR) 17 patients (4 CR, 13 PR) II) Treatment regimen II) Treatment regimen • Pred • Pred ~0.1 mg/kg/day ~0.1 mg/kg/day • CsA • CsA ~1.5/kg/day over 2 months ~1.5/kg/day over 2 months Proteinuria (g/24 hr) 1.1±1.7 1.1±0.8 CsA dose (mg/day) 105±25 (P+C) 111±40 (C) Follow-up (months) 26±16 18±7 Alexopoulos et al. NDT 21: 3127 et al. NDT 21: 3127- -3132, 2006 3132, 2006 Alexopoulos Alexopoulos et al. NDT 21: 3127-3132, 2006 CP1256850-18

Pred + CsA vs CsA in IMN Pred + CsA vs CsA in IMN Long- -Term Treatment Term Treatment Long Pred + CsA CsA P Pred + CsA CsA P Relapses (no.) 4/26 (15%) 8/17 (47%) <0.05 Relapses (no.) 4/26 (15%) 8/17 (47%) <0.05 * ≥ ≥ 50% increase in proteinuria * ≥ ≥ ≥ ≥ 50% increase in proteinuria ≥ ≥ Time to relapse 10±2 6±4 NS Time to relapse 10±2 6±4 NS (months) (months) Relapsers Non relapsers P I) CsA dose (mg/kg) Pred + CsA 1.0±0.3 1.4±0.5 <0.001 CsA 1.1±0.2 1.5±0.4 <0.003 II) CsA levels (C o ) 72±48 194±80 <0.03 (ng/mL) Alexopoulos et al. NDT 21: 3127 et al. NDT 21: 3127- -3132, 2006 3132, 2006 Alexopoulos Alexopoulos et al. NDT 21: 3127-3132, 2006 CP1256850-20