IgA-Nephropathy: an update on treatment Jürgen Floege

IgA-Nephropathy: an update on treatment Jürgen Floege Division of Nephrology & Immunology juergen.floege@rwth-aachen.de

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011 If you were my IgAN patient in 2016 No Problem Minor urinay findings, GFR and BP normal (bi-)annual checks for at least 10 years

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011 If you were my IgAN patient in 2016 No Problem Stratify Risk Minor urinay findings, GFR and BP normal Proteinuria >0.5-1 g/d ± GFR reduced ± hypertension (bi-)annual checks for at least 10 years Supportive therapy optimize for 3-6 months

Floege & Eitner, JASN 2011 Floege & Feehally Nat Rev Nephrol 2013 Supportive Therapy of IgA Nephropathy Level 1 Recommendations Control blood pressure (sitting systol. BP in the 120s) ACEI or ARB therapy (uptitrate + maybe combine) Avoid dihydropyridine type calciumchannel-blockers Control protein intake Level 2 Recommendations Restrict NaCl- and fluid-intake, diuretics Non-dihydropyridine type calciumchannel-blockers Control all components of the metabolic syndrome Aldosteronantagonist, ß-blocker Stop smoking Allopurinol Empiric NaHCO 3 therapy, independent of metabolic acidosis ALL As many measures as possible Other measures to retard progression Avoid NSAIDs (max. 1-2 tbl. per week) Avoid severe, prolonged hypokalemia Avoid phosphate-containing laxatives Ergocalciferol to correct vitamin-d deficiency Control hyperphosphatemia and hyperparathyroidism

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011 If you were my IgAN patient in 2016 No Problem Stratify Risk Minor urinay findings, GFR and BP normal Proteinuria >0.5-1 g/d ± GFR reduced ± hypertension (bi-)annual checks for at least 10 years Supportive therapy optimize for 3-6 months GFR >50 ml/min GFR 30-50 ml/min GFR 30 ml/min Proteinuria <1 g/d +GFR = Proteinuria 1 g/d ± GFR Supportive therapy critically discuss immunosuppression Supportive therapy No immunosuppress. (except RPGN) Supportive + 6 months corticosteroid Supportive

Tesar V et al, J Am Soc Nephrol 2015; 26: 2248-58 VALIGA-Consortium: Corticosteroids in IgAN 1147 European patients of the VALIGA cohort Retrospective analysis (incl. Propensity Score Match) of corticosteroid effects Baseline-GFR 50 ml/min Baseline-GFR >50 ml/min Patients without event (50% GFRreduction or GFR<15 ml/min) p = 0.01 RAS-Blocker only Steroid + RAS-Blocker p = 0.25

Trial phase (3 years) Run-in phase (6 months) Eitner F et al, J Nephrol 2008; 21: 284-9 www.clinicaltrials.gov Trial Design IgAN, 18-70 years, GFR 30 ml/min, proteinuria > 0,75 g/d PLUS hypertension (> 140/90) or GFR < 90 ml/min Optimized supportive therapy Responder proteinuria < 0,75 g/d optimized supp. therapy; periodically proteinuria Drop-Out proteinuria > 3,5 g/d GFR loss > 30% GFR < 30 ml/min proteinuria 0,75 g/d Non-Responder proteinuria 0,75 g/d Randomization Optimized supportive therapy (SUP) Optim. supp. therapy + immunosuppression (IMM)

Rauen T et al, N Engl J Med Dec 4, 2015 Immunosuppression GFR 60 ml/min GFR 30-59 ml/min Prednisolone initially 40 mg/d tapering to 7,5 mg/d after 6 months Prednisolone 0,5 mg/kg p.o./48h Cyclophosphamide 1,5 mg/kg/d p.o. Azathioprine 1,5 mg/kg/d 0 2 4 6 12 24 36 month 0 1 2 3 12 24 month 36 Pozzi et al. Lancet 1999; 353: 883 Ballardie et al., J Am Soc Nephrol 2002; 13:142

Rauen T et al, N Engl J Med Dec 4, 2015 Run-in Phase: Blood pressure Non-Responders (proteinuria 0.75 g/d after 6 months) Start of Run-In End of Run-In 27% HTN I 3% HTN II 30% high-normal 15% optimal 25% normal 8% HTN I 21% high-normal 1% HTN II 49% normal 21% optimal < 140/90: 70% 91%

Rauen T et al, N Engl J Med Dec 4, 2015 3-Year Trial Phase: Primary End Points SUP events/total IMM OR (95%-CI) p-value In full clinical remission (prot. < 0.2 g/g plus egfr loss < 5 ml/min/1.73 m 2 ) WCS 4/80 14/82 4.82 (1.43-16.3) 0.011 ACA 4/68 14/66 5.33 (1.54-18.5) 0.008-1 0 1 2 3 ln favours SUP favours IMM egfr loss 15 ml/min/1.73 m² WCS 24/80 28/82 1.20 (0.61-2.33) 0.602 ACA 16/72 14/68 0.91 (0.40-2.05) 0.817-1 0 1 2 ln favours IMM favours SUP

Mean egfr loss/year (ml/min) Mean egfr loss/year (ml/min) 3-Year Trial Phase: Annual GFR Loss STOP-IgAN (2015) Manno et al. (2009) 0-2 SUP -1.6 IMM -1.5 0-2 Ramipril Steroid + Ramipril -0.56-4 -4-6 -6-6.17-8 -8

Rauen T et al, N Engl J Med Dec 4, 2015 3-Year Trial Phase: Key Safety Data SUP (n=80) IMM (n=82) Patients with at least one SAE 20 25 Total number of SAEs 27 30 Total number of infectious events 111 182 Total number of infectious SAEs 3 8 Death 1 (accident) 1 (sepsis) Malignancy 0 2 Impaired glucose tolerance / diabetes 1 9 Body weight gain ( 5 kg in the first year) 5 14

Hong Zh, ERA Congress Vienna 2016 TESTING trial design V1 (-4wks) Register V2 V3 V4 (0m) V5 (1 m) Randomization V6 (3m) V7 (6m) V9 (12m) V13 (24m)-final (every 12 month) Methylprednisolone/matching placebo 0.6-0.8mg/kg/d (maximal 48mg/d) 2 months tapered at 8mg daily/month Stopped within 6-8 months Final visit- End of Trial ACE inhibitors or ARBs to full dose* blood pressure control as guidelines ACE inhibitors or ARBs to full dose blood pressure control as guidelines ACE inhibitors or ARBs to full dose blood pressure control as guidelines Screening and run-in phase 4 to 12 weeks Placebo Steroids treatment 6-8 months Follow up until 335 events observed Visit every 12 months Sample size: 750 participants, or total 335 primary outcome events 90% power to detect a 30% relative risk reduction for primary outcome Follow-up : 4-6 years

Hong Zh, ERA Congress Vienna 2016 Effect on egfr TESTING: egfr Annual egfr slope*: -1.7 vs -6.8 mls/min/1.73m 2 /yr P=0.031 Methylprednisolone Month Mean D p value 3 5.14 0.0019 6 6.74 <.0001 12 4.62 0.0091 Placebo 24 5.43 0.0088 36 7.67 0.0092 *- defined for each individual patient using the slope from least squares linear regression of all egfr estimates over time 14

Hong Zh, ERA Congress Vienna 2016 TESTING: Safety Outcome Methylprednisol one group (N=136) Placebo group (N=126) P Value Total patients with serious adverse events no. 20 4 0.001 Serious adverse events of infection 11 0 <.001 Fatal infection 2 0 NS Pneumocystis jirovecii pneumonia 3 0 NS Other lung infection 2 0 NS Septic arthritis 1 0 NS Perianal infection 1 0 NS Gastrointestinal serious adverse events 3 1 NS Bone disorders Avascular necrosis 3 0 NS Fracture 1 0 NS New onset diabetes mellitus 2 3 NS 15

TESTING vs STOP-IgAN trial TESTING study STOP-IgAN study Meta-analysis of prior trials Sample size 262 162 488 Race Asian 96.3% Caucasian 3.7% Caucasian Age 38.6 44.5 Female (%) 36.7% 21.5% Blood pressure (mmhg) systolic 124.1 125.5 diastolic 79.5 77.5 Proteinuria (g/d) 2.4 1.7 egfr (ml/min/1.73m 2 ) 59 59 Annual egfr decline in supportive group Annual egfr decline in Steroids group -6.8-1.6-1.7-1.5 Asian 42% Caucasian 58% RR for Kidney failure 0.36 (0.16 to 0.82) NA 0.32 (0.15 to 0.67) 16

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011 If you were my IgAN patient in 2016 No Problem Stratify Risk Minor urinay findings, GFR and BP normal Proteinuria >0.5-1 g/d ± GFR reduced ± hypertension (bi-)annual checks for at least 10 years Supportive therapy optimize for 3-6 months GFR >50 ml/min GFR 30-50 ml/min GFR 30 ml/min Proteinuria <1 g/d +GFR = Proteinuria 1 g/d ± GFR Supportive therapy critically discuss immunosuppression Supportive therapy No immunosuppress. (except RPGN) Supportive + 6 months corticosteroid Supportive?

Patients without event (50% GFR-reduction or GFR<15 ml/min) Tesar V et al, J Am Soc Nephrol 2015; 26: 2248-58 VALIGA-Consortium: Corticosteroids in IgAN Mean Proteinuria at Baseline [g/day] < 1 1- <3 3 p = 0.97 p = 0.03 RAS-Blocker only Steroid + RAS-Blocker p = 0.001

A few therapeutic approaches of unproven value

Pozzi C et al. J Am Soc Nephrol 2010 Therapy of IgA-Nephropathy - Combination Steroid + Azathioprine - Steroid+Aza n=101 6 months Pozzi -scheme additionally azathioprine (1.5 mg/kg) Steroid n=106 6 months Pozzi -scheme 100 80 60 40 20 0 Renal function (% patients without 50% increase of s-creatinine) 89% 88% 84% 83% 0 1 2 3 4 5 6 7 Follow-up (years) No difference in proteinuria Markedly higher side effects of combination therapy

Modified after Floege J, Nat Clin Pract Nephrol 2006; 2: 16 Mycophenolate Mofetil Therapy in IgA Nephropathy Country MMF Placebo Baseline S-Crea Proteinuria Histo ACE-I. AT-1 Bl. Outcome MMF vs. Control Belgium n=21 n=12 Maes B et al, Kidney Int 2004 USA n=17 n=15 Frisch G et al, NDT 2005 China n=20 n=20 76% 1.5±0.1 1.4±0.1 85% 2.6±1.2 2.2±0.7 30% 1.5±0.2 1.7±0.2 Tang S et al, Kidney Int 2005 and Kidney Int 2010 USA n=27 n=25 Hogg R et al, Am J Kidney Dis 2015 China n=31 Chen X et al, Zhonghua Yi Xue Za Zhi 2005 n=31 (steroid) 62% Mean egfr 105? 1.9±0.3 1.3±0.4 2.7±1.6 2.7±1.4 1.8±0.2 1.9±0.3 Mean UP/Cr 1.8 g/g grade II-IV Churg 70% grade V Haas 85% grade II-III Haas MEST score mild???? No MMF benefit No MMF benefit Proteinuria reduced GFR stable No MMF benefit Proteinuria reduced + crea stable

Fervenza F et al, J Am Soc Nephrol in press A randomized controlled study of rituximab for patients with advanced IgA nephropathy 24hr Proteinuria in Control Group (N = 17) Baseline Day 91 Day 168 Day 258 Day 352 Time (day) 24hr Proteinuria in Ritumab Group (N = 17) Baseline Day 91 Day 168 Day 258 Day 352 Time (day)

So, supportive only for everyone?? Maybe there are alternatives

Fellstrom B et al, ASN Kongress 2015 NEFIGAN Trial: design RUN-IN PHASE 6 months Optimize RAS Blockade* TREATMENT PHASE 9 months NEFECON 16 mg/day NEFECON 8 mg/day FOLLOW-UP PHASE 3 months 2 week tapering at 8 mg/day 2 week placebo tapering Main Inclusion criteria: 18 years Biopsy-verified IgAN UPCR 0.5 g/g OR Urine protein 0.75 g/day egfr 45 ml/min/1.73m 2 PLACEBO 2 week placebo tapering *Optimized RAS Blockade throughout Treatment and Follow-up Phases

Mean (SEM) change from baseline in egfr (ml/min/1.73 m 2 ) Fellstrom B et al, ASN Kongress 2015 NEFIGAN Trial: egfr* 6 4 2 0-2 -4-6 NEFECON 8 mg/d Placebo NEFECON 16 mg/d -8-10 1 3 6 9 12 Month Treatment period Follow-up period *egfr estimated with CKD-EPI equation using serum creatinine

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011 If you were my IgAN patient in 2016 No Problem Stratify Risk Minor urinay findings, GFR and BP normal Proteinuria >0.5-1 g/d ± GFR reduced ± hypertension (bi-)annual checks for at least 10 years Supportive therapy optimize for 3-6 months GFR >50 ml/min GFR 30-50 ml/min GFR 30 ml/min Proteinuria <1 g/d +GFR = Proteinuria 1 g/d ± GFR Supportive therapy critically discuss immunosuppression Supportive therapy No immunosuppress. (except RPGN) Supportive + 6 months corticosteroid Supportive? Highly proteinuric pts? Nefecon?

Floege & Feehally, Nat Rev Nephrol 2013 Floege & Eitner, J Am Soc Nephrol. 2011 If you were my IgAN patient in 2016 Attention! Acute or rapid loss of GFR Nephrotic syndrome or RPGN AKI (Macrohematuria or other etiology) Supportive therapy Supportive therapy + Immunosuppression

Cumulative renal survival [%] IgAN Lv J, et al, J Am Soc Nephrol 2013; 24: 2118-2125 Vasculitic IgAN (RPGN-variant) >50% glomerular crescents and RPGN course 113 chinese patients At time of biopsy: 66±16% crescents Crea 4.3±3.4 mg/dl Aggressive immunosuppression (n = 43) Only ESRD predictor: S-creatinine at biopsy No immunosuppr. (n = 70) All patients Months