ADPKD, what have the last 10 years taught us? Arlene B. Chapman MD Professor of Medicine Director, Section of Nephrology University of Chicago

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1 2016 ADPKD, what have the last 10 years taught us? Arlene B. Chapman MD Professor of Medicine Director, Section of Nephrology University of Chicago

2 2016 Can we TRUMP the cysts?

3 Disclosures Consultant for KADMON, GENZYME, OTSUKA

4 ADPKD 4th leading cause of ESRD No race is favored Dominantly inherited >3,000,000 worldwide Cysts Kidneys Liver Pancreas Spleen Brain Begins in utero Grantham JJ. N Engl J Med. 2008;359:

5 Disorder MIM Frequency Gene Chromosome Protein Length (bp) HEREDITARY RENAL CYSTIC DISEASES ADPKD :700 1:15,000 PKD1 PKD2 16p13.3 4q22.1 Polycystin 1 Polycystin 2 ARPKD :40,000 PKHD1 6p12.2 Polyductin (fibrocystin) TSC :10,000 TSCI 9q34.13 Hamartin TSC2 16p13.3 Tuberin GCKD Not available MCKD :50,000 MCKD1 MCKD2 (UMOD) FJN Protein size (aa) Exon # SNP HNF-1ß 17cen-q21.3 TCF2 protein :100,000 NPHP1 NPHP2/INVS NPHP3 NPHP4 NPHP5/IQCB1 NPHP6/CEP29 0 NPHP7/GLIS2 NPHP8/RPGRI P1L NPHP9/NEK8 1q21 16p12.3 Uromodulin q13 9q31 3q22.1 1p q q p q q11.1 Nephrocystin-1 Inversin Nephrocystin-3 Nephroretinin Nephrocystin-5 Nephrocystin-6 Nephrocystin-7 Nephrocystin-8 Nephrocystin-9 VHL :53,000 VHL 3p25.3 Von hippel lindau

6 Current Ultrasound Diagnostic Criteria for ADPKD Family History < 40 years: 3 cysts bilaterally years: 4 cysts bilaterally 60 years: 8 cysts bilaterally Revised Pei Criteria 2009, 2012 No Family History 20 cysts distributed bilaterally with a consistent phenotype

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8 Extra-renal Manifestations of ADPKD: Liver Cystic Disease

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10 Renal Morbidities Associated With ADPKD Chapman A. et.al. American Society of Nephrology Meeting By age 30, over 50% have at least one complication

11 Polycystins 1 and 2 Two genotypes: PKD1 85% ESRD age 55 PKD 2 15% ESRD age 72 Gallagher AR et al. Adv Chronic Kidney Dis. 2010;17:

12 Genetic factors of progression in ADPKD Strong genic and allelic effect on phenotype Cumulative Probability of Survival to ESRD P< Mutation of PKD2: Median age at ESRD: 77.8 yrs Non truncating mutation of PKD1: Median age at ESRD: 65.8 yrs N=1271 Truncating mutation of PKD1: median age at ESRD: 55.1 yrs Cornec-Le Gall E, JASN 2013 Genkyst Cohort update: 2015, non published data

13 Current Results of Genetic Screening in ADPKD Identification of >95% of PKD2 mutations Identification of 85% of PKD1 mutations Cost of sequencing for mutation detection in PKD1/PKD2 is high (>$3,000) and preapproval for insurance coverage is difficult Mutation confirmation in other family members required for potential mutations in PKD1 more so than PKD2 individuals

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17 Cell Calcium Is Involved in Promoting Cell Proliferation Torres VE. Adv Chronic Kidney Dis. 2010;17:

18 Mechanism of Fluid Secretion Into Cysts in Response to AVP Wallace DP. Biochim Biophys Acta. 2011;1812: Sullivan LP et al. Physiol Rev. 1998;78:

19 Characteristics of ADPKD That Associate with ESRD Genotype: > 95% PKD1 individuals demonstrate renal cysts by age 30 Hypertension: occurs in 60% with intact renal function by age 30 Proteinuria: is not a common feature of this disease, but has important prognostic implications Gross hematuria: > 50% will have had an episode by age 40 ALL CHARACTERISTICS HAVE NOW BEEN SHOWN TO MEDIATE THEIR RISK THROUGH KIDNEY VOLUME

20 Cyst Burden and Patient Complications in ADPKD Healthy Tissue Cyst Development and Enlargement Vasculature Function Age Signs & Symptoms Urinary Concentrating Defects Hypertension Dull Pain & Discomfort Proteinuria

21 Kidney function (%) ADPKD Progression Concentrating defect, Hypertension, Proteinuria Pain, Hematuria, Stones, Infections Age (years) Torres Mayo <aupcp

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23 Inter-observer variability: 2.1% Intra-observer variability:2.4% Day-to-day variability: 2.4%

24 Increased Kidney Volume is Due to Increased Cyst Volume Total Kidney Volume Total Cyst Volume Kidney growth is highly variable and each individual has their own growth curve Measurement variability= Inter-observer 2.1%, Intra-observer 2.4%, Day-to-Day 2.4% Grantham, NEJM CRISP 2006; Chapman Kidney Int 64; , 2003

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27 Average Standardized Unit 1 Change from Baseline Change in Kidney Volume Precedes Change in Kidney Function httkv GFR Years of follow-up p<0.05 for httkv change from baseline; # p<0.05 for GFR change from baseline; httkv=heightadjusted total kidney volume; 1 Percent Change Standardized to a common unit; NIH CRISP Studies; Chapman CJASN 7:479, 2012

28 Sensitivity AUROC = % CI = (0.79, 0.90) Sensitivity = 74% Specificity = 75% Cut Point = 600 (cc/m) Specificity Baseline predictors of CKD Stage 3 endpoint Variable Units AUC Sensitivity Specificity Cut-point 95%CI of AUC P* httkv cc/m (0.79, 0.90) Serum Creatinine mg/dl (0.67, 0.82) 0.02 BUN mg/dl (0.70, 0.83) 0.04 Urine Albumin mg/d (0.61, 0.78) MCP-1 pg/mg (0.68, 0.83) 0.02 Baseline age y (0.59, 0.74) < 0.001

29 Effect of Kidney Growth Rate on Development of ESRD Chapman, AB Unpublished.

30 GFR Compensation for Loss of Parenchyma Loss of Compensated Nephrons Grantham JJ et al. Clin J Am Soc Nephrol. 2006;1:

31 Progressive Rise in Total Kidney Volume Signs and Symptoms of Injury Develop Long Before ADPKD Reaches End Stage Grantham JJ Unpublished.

32 Estimating TKV Using the Ellipsoid Equation W L D Typical values for a cystic kidney L = 15 cm, W = 8 cm, D = 7 cm Volume = 3.14/6 x 15 x 8 x 7 = 440 cc Volume/height = 440 cc/1.73 m = 254 cc/m O Neill WC et al. Am J Kidney Dis. 2005;46:

33 Predicting CKD Stage 3 (iothalamate clearance) utilizing MR and US within 8 years

34 Assessment of TKV and Kidney Length Predictors of CKD Stage 3 in CRISP Participants Method AUC ROC sensitivity specificity Optimal cut point httkv (MR) ml/m % 75.0% 600 ml httkv (US) ml/m % 73.2% 630 ml KL (MR) cm % 92.3% 16.7 cm KL (US) cm % 80.8% 16.8 cm

35 Classification by Estimated Rate of Growth (from age and starting HtTKV = 150 ml/m) Subclass 1E > 6% Subclass 1D 4.5 6% 1E 4000 HtTKV (ml/m) Subclass 1C 3 4.5% Subclass 1B 1.5 3% Subclass 1A 1.5% 1C 1A Patient Age (Years) Irazabal. J Am Soc Nephrol 26: , 2015

36 SUMMARY OF CRISP FINDINGS Renal progression in ADPKD is marked by cyst expansion and increases in renal volume prior to loss of renal function Complications including hypertension, gross hematuria, pain, nephrolithiasis, and urinary tract infections occur long before reductions in GFR httkv significantly associates with a decline in GFR and the relationship between httkv and GFR increases with increasing time of followup. HtTKV significantly predicts decline in GFR years before its occurrence

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38 Baseline TKV and egfr in ADPKD clinical trials 0.35 Ong. A et al. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet vol 385 (2015)

39 Effect of therapeutic interventions Ong. A et al. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet vol 385 (2015)

40 Vasopressin-V 2 Receptor Antagonists Modified from Torres Lancet

41 TOLVAPTAN IN ADPKD Tolvaptan - a highly potent and selective AVP V2 receptor antagonist. Has been shown to slow the progression of PKD in preclinical trials. Currently approved for the treatment of hypervolemic and euvolemic hyponatremia in US Approved in Japan, Canada and Europe as a therapy to slow down the progression of ADPKD in patients with rapidly growing kidneys. LaRiviere WB, Irazabal MV, Torres VE. Novel therapeutic approaches to Autosomal Dominant Polycystic Kidney Disease. Translational research : the journal of laboratory and clinical medicine. 2015;165(4):

42 TEMPO 3:4 TRIAL The Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes (TEMPO) 3:4 trial Phase 3, multicenter, randomized, doubleblinded, placebo-controlled, parallel-group clinical study, designed to assess the impact of tolvaptan therapy on the progression of ADPKD. Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med Dec 20;367(25):

43 TEMPO 3:4 TRIAL 1445 ADPKD patients, years, with a TKV >750 ml and CrCL>60 ml/min, across 129 sites worldwide were enrolled in the study between January 2007 and January Tolvaptan group therapy: high dose (120mg/day, n=404), medium dose (90mg/day, n=157), or low dose (60mg/day, n=179). Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med Dec 20;367(25):

44 TEMPO 3:4 TRIAL Primary end point: annual rate of percent change in TKV as measured by MRI. Secondary endpoints: measurable decline renal function, including a composite endpoint of investigator-assessed disease progression. Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med Dec 20;367(25):

45 TEMPO 3:4 TRIAL Results: The intention-to-treat analysis of this study showed that tolvaptan slowed the rate of TKV growth (primary endpoint) by 49% from5.5 to 2.8% per year, and the rate of estimated GFR (egfr) loss on treatment (secondary endpoint) by 26% from 3.70 to 2.72 ml/min/1.73 m2 per year during the median observation period of 3 years. Gansevoort RT, Arici M, Benzing T, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice.Nephrology Dialysis Transplantation. 2016;31(3):

46 TEMPO 3:4 TRIAL Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med Dec 20;367(25):

47 TEMPO 3:4 TRIAL The slope of kidney function (as assessed by means of the reciprocal of the serum creatinine level) from the end of dose escalation to month 36, also favored tolvaptan, Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med Dec 20;367(25):

48 TEMPO 3:4 TRIAL Tolvaptan over placebo had lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med Dec 20;367(25):

49 TEMPO 3:4 TRIAL The decrease in kidney pain occurred early and throughout treatment, possibly reflecting a rapid effect on fluid secretion and intracystic pressure. Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med Dec 20;367(25):

50 TEMPO 3:4 TRIAL There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolytefree water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23% vs. 14% in the placebo group). Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med Dec 20;367(25):

51 TEMPO 4:4 EXTENSION TRIAL Two-year open-label extension of the TEMPO 3:4 trial. 976 ADPKD patients received open-label tolvaptan at their highest tolerated dose. Those receiving tolvaptan in TEMPO 3:4 were considered early treatment, and those that received placebo were considered delayed treatment. Torres VE, Chapman AB, Devuyst O,et al. Tolvaptan-treatment of ADPKD confers persistent EGFR improvement: results from the tempo 4:4 extension trial. Nephrol. Dial. Transplant.(2014) 29 (suppl 3): iii5-iii6.

52 TEMPO 4:4 EXTENSION TRIAL Results: Significant improvement in the egfr slope after switching from placebo to tolvaptan (from to ml/min/1.73m2/yr, treatment effect 21%, p=0.048) despite the time difference leading to an increased proportion starting in CKD 3 at TEMPO 4:4 s baseline compared to their own earlier TEMPO 3:4 baseline (37 vs. 15%) Torres VE, Chapman AB, Devuyst O,et al. Tolvaptan-treatment of ADPKD confers persistent EGFR improvement: results from the tempo 4:4 extension trial. Nephrol. Dial. Transplant.(2014) 29 (suppl 3): iii5-iii6.

53 TEMPO 4:4 EXTENSION TRIAL Torres VE, Chapman AB, Devuyst O,et al. Tolvaptan-treatment of ADPKD confers persistent EGFR improvement: results from the tempo 4:4 extension trial. Nephrol. Dial. Transplant.(2014) 29 (suppl 3): iii5-iii6.

54 TEMPO 4:4 EXTENSION TRIAL 5-year early treatment slope (N=554) in TEMPO 3:4 and TEMPO 4:4 combined remained significantly different from the delayed treatment placebo slope (N=422) in TEMPO 3:4 (-2.92 vs ml/min/1.73m2/yr, treatment effect 20%, p<0.0001) (see Figure). Torres VE, Chapman AB, Devuyst O,et al. Tolvaptan-treatment of ADPKD confers persistent EGFR improvement: results from the tempo 4:4 extension trial. Nephrol. Dial. Transplant.(2014) 29 (suppl 3): iii5-iii6.

55 TEMPO 3:4 POST HOC ANALYSIS-1 Patients were randomly assigned 2:1 to splitdose tolvaptan (45/15, 60/30, or 90/30 mg daily as tolerated) or placebo. The primary endpoint was annualized rate of TKV change. Clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3. Torres VE, Higashihara E, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial. Clin J Am Soc Nephrol Feb 23. pii: CJN

56 TEMPO 3:4 POST HOC ANALYSIS-2 Effects of tolvaptan on albuminuria as a continuous variable. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR). Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower Gansevoort RT, Meijer E, Chapman AB, Czerwiec FS, Devuyst O, Grantham JJ, Higashihara E, Krasa HB, Ouyang J, Perrone RD, Torres VE; TEMPO 3:4 Investigators. Albuminuria and estimated tolvaptan in autosomal-dominant glomerular polycystic kidney disease: results of filtration the TEMPO 3:4 Trial. Nephrol rate Dial Transplant. (egfr) Dec 17. pii: gfv422.

57 TEMPO 3:4 POST HOC ANALYSIS-2 During follow-up, higher baseline ACR was associated with more rapid egfr loss (P < for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placeboand decreased in tolvaptan-treated patients (+0.23 versus mg/mmol). The beneficial effect of tolvaptan on TKV growth and egfr loss was stronger in patients with higher baseline ACR. Gansevoort RT, Meijer E, Chapman AB, Czerwiec FS, Devuyst O, Grantham JJ, Higashihara E, Krasa HB, Ouyang J, Perrone RD, Torres VE; TEMPO 3:4 Investigators. Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial. Nephrol Dial Transplant Dec 17. pii: gfv422.

58 TOLVAPTAN IN VARIOUS LEVELS OF KIDNEY FUNCTION To determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR. Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120mg/d in weeks 1, 2, and 3, respectively). Boertien WE, Meijer E, de Jong PE, et al. Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function. Am J Kidney Dis Jun;65(6):

59 TOLVAPTAN IN VARIOUS LEVELS OF KIDNEY FUNCTION OUTCOMES: Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers). Boertien WE, Meijer E, de Jong PE, et al. Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function. Am J Kidney Dis Jun;65(6):

60 TOLVAPTAN IN VARIOUS LEVELS OF KIDNEY FUNCTION In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs. Boertien WE, Meijer E, de Jong PE, et al. Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function. Am J Kidney Dis Jun;65(6):

61 Changes in Medical Management Age of diagnosis: before 1950: 39 years : 27 years BP medication use 1991:32% 2008:62% ACEI/ARB use: 1991: 7% 2008: 46% SBP/DBP mmhg 1991: 142/ : 133/80 in ADPKD Patch et al, Lancet, 2013

62 Hypotheses Study A: Low (95-110/60-75 mmhg) versus standard ( /70-80 mmhg) BP control will reduce the rate of disease progression measured by change in TKV. Study A and B: Dual blockade of the RAAS with ACE-I and ARB will reduce the rate of disease progression as compared to ACE-I therapy alone. 62

63 Two Clinical Trials: HALT A and B Study A years and healthy baseline egfr > 60 mls/min Study B: years baseline egfr > 25 and < 60 mls/min Outcomes: Primary and secondary differ 63

64 Primary and Secondary Endpoints Primary Study A: Percent change in TKV Study B: Time to death, ESRD or 50% reduction in egfr Secondary Slope of egfr Urine albumin and aldosterone excretion LVMI, RBF and RVR (Study A only) Frequency of all-cause and cardiovascular hospitalizations QOL, pain, PKD related symptoms 64

65 Home BP and Urinary Aldosterone Excretion Levels A B SBP end of study = 13.4 (11.8, 15.0) DBP end of study = 9.3 (7.9, 10.8) NEJM Nov 15, 2014 (online) Low slope=-8.50%/yr Standard slope=-7.39%/yr Diff (95% CI)= (-3.07, 0.60) p=

66 Annualized % Change in TKV Ln(TKV) ml Low slope=5.67%/year Standard slope=6.57%/year Diff (95% CI)=-0.96 (-1.55, -0.24) P=0.006 NEJM Nov 15, 2014 (online) 66

67 egfr Slope Low Low -3.1 ml/min/4 mo Standard -3.1 ml/min/4 mo Standa +0.5 ml/min/4 mo p< ml/min/4 mo p<0.001 Low long term slope = -2.7 ml/min/yr Standard long term slope = -3.1 ml/min/yr p=0.05 Low overall slope = -2.9 ml/min/yr Standard overall slope = -3.0 ml/min/yr p=0.55 NEJM Nov 15, 2014 (online)

68 Conclusions Low blood pressure treatment in young healthy hypertensive ADPKD patients with RAAS blockade is Well tolerated and Safe And results in a 14.2% slower rate of TKV growth over 5 years Reducing proliferation, fluid secretion and normalizing cell-cell interactions are important in ADPKD. Early intervention at specific 68 times of growth may be most beneficial.

69 THANK YOU!

70 Acknowledgements National Institutes of Health PKD Foundation All PKD patients and their families The CRISP and HALT UO1 Consortium Members Boehringer-Ingelheim Pharmaceuticals Inc Merck & Co Inc 70