Groningen PKD Expertise Center. Groningen PKD Expertise Center. Groningen PKD Expertise Center. Groningen PKD Expertise Center

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1 Human polycystic kidney disease. From evolving therapies towards clinical use Prof.dr. Ron T. Gansevoort Chair PKD Expertise Center University Medical Center Groningen The Netherlands Conflict of Interest Consultant for Otsuka (manufacturer of tolvaptan) and Ipsen (manufacturer of lanreotide) Steering Committee member of the TEMPO, OVERTURE, REPRISE and DIPAK studies Number of patients starting renal replacement therapy according to cause of renal failure Incidence (per million of the age related popula5on) ERA-EDTA Registry data 9 countries with complete FU 88.5 million people Year Diabetes Hypertension Primary kidney diseases Urological problems ADPKD Starting RRT Data on file Spithoven, Kramer, Jager, Gansevoort et al Pathophysiology of a renal collecting duct cell Fluid transport PC1 Urine flow PC2 CFTR Apical membrane channels Ca2 Cl- Cell proliferation Ras /B-Raf/ ER MEK/ERK PKA Cell growth Ca2 Nucleus TSC1 PC1 Protein TSC2 PC2 translation mtor mtor camp inhibitors ATP AC V2R Somatostatin SSTR Basolateral membrane V2R analogs antagonist Blood flow Somatostatin Vasopressin Zittema et al, Capita Selecta Nephrology 213 Other evolving treatment options Clinical trials Tyrosine kinase inhibitors (e.g. Bosutinib ) Triptolide (from Chinese herbs) Statins Experimental Raf inbitors (e.g. Sorafinib ) CDK inhibitors (e.g. Roscovitin ) PPARγ agonists (e.g. Pioglitazone ) Biguanidine derivates (e.g. metformin) EGF receptor pathway inhibitors Etc etc etc Chang and Ong Br J Clin Pharmacol 213 8, 6,, 2,, -2, Total Kidney Volume (% change per year) p=.5 p<.1 2 mg /2 mg N= Phase 2b, multicenter RCT, 2 yr FU or bosutinib 2 mg or mg N=172 ADPKD, egfr>6, TKV>75 ml Tyrosine kinase inhibitors egfr (ml/min/1.73m 2 ) Follow-up (months) Withdrawal rate Drug Total 5% 39% Bosutinib 2 2% 1% mg Bosutinib mg 55% 9% 2 mg /2 Pfizer Clinicaltrials.gov 216 Somatostatin analogues Change in mgfr 3 yr Multicenter RCT, 3 yr FU 79 ADPKD patients with egfr > ml/min1.73m 2 or octreotide 2 mg im once every 28 days NS Change in mgfr 1 3 yr ALADIN trial Lancet 213 1

2 Somatostatin analogues Multicenter RCT, 3 yr FU 79 ADPKD patients with egfr > ml/min1.73m 2 Octreotide 2 mg or placebo im every 28 days ALADIN trial Lancet 213 Vasopressin V2 receptor antagonists Total Kidney Volume 5.5 % per yr 2.8 % per yr 9%, p<.1 Kidney function 3.7 ml/min/yr 26%, p< ml/min/yr NEJM 212 efficacy and tolerability Comparison with other renoprotective agents NEJM 1993 NEJM 199 NEJM 21 NEJM 21 NEJM 212 DM Various DM DM ADPKD ACEi Low BP LPD A2A A2A V2RA Annual egfr loss Active Effect % -28% -28% -15% -15% -26% Withdrawal rate -7% -2% -19% -23% What may this imply for clinical practice? Extrapolation of the results 1 Cost-effectiveness report accepted the UK NICE Institute Liver function abnormalities with tolvaptan - Transaminase rather than bilirubin increase Hy s law cases Watkins et al, Drug Safety 215 Time course of liver function test abnormalities with tolvaptan 6/3 mg ASAT ALAT Bili indirect Bili direct Re-occurence on re-exposition Nearly all LFT abnormalities occur within 18 months after start of TX Occur gradually Most often only transaminases Reversible 9/3 mg ASAT ALAT Bili indirect Bili direct Watkins et al, Drug Safety 215 2

3 EMA: The indication for tolvaptan To slow the progression of cyst development and renal insufficiency in autosomal dominant polycystic kidney disease (ADPKD) in adults with CKD stage 1 to 3 at initiation of treatment with evidence of rapidly progressing disease 1 JIRC (tolvaptan) Summary of Product Characteristics Ron T. Gansevoort 1, Mustafa Arici 2, Thomas Benzing 3, Henrik Birn, Giovambattista B. Capasso 5, Adrian Covic 6, Olivier Devuyst 7, Christiane Drechsler 8, Kai-Uwe Eckardt 9, Francesco Emma 1, Bertrand Knebelmann 11, Yannick Le Meur 12, Ziad Massy 13, Albert CM Ong 1, Alberto Ortiz 15, Franz Schaefer 16, Roser Torra 17, Raymond Vanholder 18, Andrzej Wiecek 19, Carmine Zoccali 2, Wim Van Biesen N= Rate of TKV growth (% per year) -.% P<.1 efficacy vs CKD stage -6.% P< % P= CKD1 CKD2 CKD3 Torres et al, cjasn in press Post-hoc analysis of the TEMPO 3: trial Rate of egfr change (ml/min/1.73m2 per year) CKD1 CKD2 CKD3-15.5% P= % P<.1-31.% P<. CKD stage 3b The indication for tolvaptan should not include CKD stage 3b N=2 The indication for tolvaptan CKD stage should be indexed for age EMA: The indication for tolvaptan To slow the progression of cyst development and renal insufficiency in autosomal dominant polycystic kidney disease (ADPKD) in adults with CKD stage 1 to 3 at initiation of treatment with evidence of rapidly progressing disease JIRC (tolvaptan) Summary of Product Characteristics 3

4 Wording refers to historical data! Historical change in egfr - Most patients have serial egfr values, but not all - What cut-off value to choose to indicate rapidly progressing disease? - Consensus: >2.5 ml/min/1.73m 2 per yr loss over a period of 5 years, or confirmed >5 ml/min/1.73m 2 in one year. - Can change in egfr be measured with such reliability? Miss B, 26 yr Mister S, yr Mister A, 32 yr Miss H, 1 yr Wording refers to historical data!!! Historical change in TKV - What cut-off to choose? Consensus: >5% growth/yr. - How many patients have serial MRI data available? - Can change in TKV be measured in clinical practice with such reliability? Historical data may be of help, but often absent or difficult to interpret In case there are no historical data, or in case these data are not reliable, then we have to use contemporary data to predict a high likelihood of rapid disease progression. Use TEMPO inclusion criteria? - Age 18 5 years - Cockroft-Gault creatinine clearance 6 ml/min - TKV 75 ml TKV indexed for height and age 1: Future egfr decline (ml/min/1.73 m 2 per year) by subclass te: no difference between males and females in average slope! egfr slope Irazabal et al JASN 21 PKD mutation analysis Average age at start of RRT = 58 yrs Cornec-Le Gall JASN 213

5 The PRO-PKD score: mutation symptoms Average age at start of RRT = 58 yrs Cornec-Le Gall JASN 215 ERA-EDTA position statement on the use of tolvaptan for ADPKD A hierarchical treatment decision diagram (NDT 216) Yes Yes Yes Yes Fast progression Indication for treatment Predicted fast progression Indication for treatment CKD stage by age a : at age < 3 yr: CKD 1-3a (egfr > 5 ml/min/1.73m 2 ) at age 3- yr: CKD 2-3a (egfr 5-9 ml/min/1.73m 2 ) at age -5 yr: CKD 3a (egfr 5-6 ml/min/1.73m 2 ) Historical egfr decline b, with no other confounding cause than ADPKD c : 1) confirmed egfr decline 5 ml/min/1,73 m 2 in one year d and/or 2) confirmed egfr decline 2,5 ml/min/1,73 m 2 per year over a period of five years or more e? Yes Possibly fast progression Re-evaluate Data not available or not reliable (e.g. in CKD 1) Historical kidney growth in typical ADPKD: (ht)tkv increase more than 5% per year by repeated measurements ( 3) f? Preferable by MRI (ellipsoid equation) g, if not available then by another reliable method (CT) Data not available or not reliable Predicted progression by baseline httkv indexed for age and/or genotype: 1) httkv compatible with Mayo class 1C, 1D or 1E h and/or 2) truncating PKD1 mutation early symptoms (i.e., a PRO-PKD score >6) i? Data not available or not reliable Predicted progression by family history: Family history with most ADPKD patients reaching ESRD 58 yr j Likely slow progression, or egfr/age outside indication treatment Selecting the right patient for treatment More than only setting an indication Recommendation 8.1: We recommend discussing adverse effects and impact on lifestyle with patients when considering starting tolvaptan. Recommendation 8.2: We recommend taking into account contra-indications and adverse effects such as hepatic toxicity and other precautions as listed in SMPC text when considering starting tolvaptan (i.e. monthly liver function testing during 18 months). Recommendation 8.3: We recommend that prescription and documentation of safety monitoring of tolvaptan is performed under supervision of physicians with expertise in managing ADPKD and tolvaptan use. Summary is the first disease modifying drug for the treatment of ADPKD licensed in Europe. Consideration should now be given to patients suitable to receive the drug and the practicalities of its use. Patients eligible for treatment should be selected based on clinical factors that indicate or predict rapid disease progression (i.e. egfr for age, htkv for age, type of mutation clinical signs), but also on patient-specific factors (like motivation and lifestyle consideration). Clinicians will need to appreciate the special considerations for treatment, including the impact of tolvaptan s aquaretic side effects on daily activities and social life, to ensure adherence and persistence. EXTRA SLIDES Change in egfr (ml/min/1.73m 2 ) Persistence of tolvaptan s treatment effect? p<.5 Double-blind placebo controlled RCT Time (months) Crossing over to tolvaptan 31 placebo and 557 tolvaptan treated patients from TEMPO 3 / continued open label tolvaptan Off treatment All patients open-label TEMPO / study Torres et al, in preparation 5

6 Cumulative Event Hazard ameliorates disease progression - Worsening kidney function and pain % reduction in risk of worsening renal function (= 25% egfr decline) HR:.39 ( ) p<.1 BL Cumulative Event Hazard % reduction in risk of renal pain HR:.6 ( ) p=.7 BL NEJM 212 Liver function abnormalities with tolvaptan: - Time course on group level - Watkins et al, Drug Safety 215 Change in ACR (%) effect on other kidney outcomes - Change in albuminuria vs placebo baseline Week Time (months) FU1 FU2 TEMPO 3: study Gansevoort et al, in preparation (Serious) Adverse Events (N=961) (N=83) Patients withdrawn 23. % 13.8 % Due to Aderse Event 15. % 5. % Due to Aquaretic Adverse Event 8.3 %. % AEs >1% and significantly more common in tolvaptan group Thirst 55.3 % 2.5 % Polyuria 38.3 % 17.2 % cturia 29.1 % 13. % Pollakiuria 23.2 % 5. % AEs >1% and significantly more common in placebo group Renal pain 27. % 35. % Haematuria 7.8 % 1.1 % Urinary tract and kidney cyst infection 8.3 % 12.6 % Elevated laboratory values at any visit Serum sodium >15 meq/l. % 1. % Serum uric acid >7.5 mg/dl 6.2 % 1.7 % Liver function abnormalities.9 %. % 3 NEJM 212 Clinical considerations when selecting patients for treatment Which CKD stages? - Only CKD stages 1 3a, not stage 3b - But index CKD stage for age, - -5 yr old with CKD stage 1 cannot be a fast progressor - do not prescribe at age >5 years Evidence of rapid progressive disease: historical data feasible? - Historical loss of egfr >2.5 ml/min/1.73m 2 over 5 years - Historical growth in TKV >5% High likelihood of rapid disease progression (risk prediction) - May classification: TKV indexed for height and age - MRI, volumetry or estimation with ellipsoid equation - US, ellipsoid equation (or just length >16.5 cm) - PRO-PKD score (mutation analysis clinical symptoms) PKD patients in renal replacement therapy Numbers costs in the EU 27 zone 2, 31,7 39, 6,2 52,8 Direct medical costs: ~1.6 billion Euro/yr NDT 21 Spithoven, Kramer, Jager, Gansevoort et al 6

7 Other indicators Prognostic indicators - Size: TKV for age and length (MRI or US) - Genetics: 1 PKD1 (especially truncating mutations) - Demographics: Family history of young age at ESRD - Symptoms: 2 Early hematuria, hypertension or pain - Biomarkers: 3 Plasma copeptin concentration?? Urinary excretion tubular damage markers?? Kidney function, especially reliable historical change in kidney function, overrules all other prognostic indicators. 1. Cornec - le Gal, JASN Cornec - le Gal, JASN Boertien et al, NDT 212 and Boertien et al, AJKD 213. Meijer et al, AJKD 21 and Boertien et al, Kidney Int 212 Managing tolvaptan associated aquaretic side effects Aquaretic side effects are common, as expected from tolvaptan s mode of action, and occur early in treatment Polyuria, thirst, nocturia, dry mouth In TEMPO 7.9% of patients discontinued treatment due to an aquaresis related adverse event Most discontinuations occur in the first 3 months of treatment. Aquaretic response especially high in subjects with normal egfr 1 - >6.3 liter: liter per day liter: liter per day - <3 2.9 liter: liter per day Provide counselling on the right type of fluids (avoid calories) and avoid diuretics because of risk electrolyte abnormalities 1. Boertien et al, Kidney Int 213 Translating data into a clinical perspective When considering prescribing tolvaptan: - First clinic visit patient education and assessing motivation - Start treatment at the second clinic visit or later - Weekly uptitration to highest tolerable dose (max 9 / 3 mg) (or monthly at the discretion of patient / physician) During titration check tolerability, AEs, egfr, electrolytes, LFTs - Be aware of the initial acute and reversible GFR decrease Additional: - Follow-up / education can be managed by nurse / clinic staff - LFTs can be assessed at local lab - Risk management program (RMP) may vary by country 7