Embed Size (px)
Citation preview
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 Gro
ning
en P
KD
Exp
ertis
e C
ente
r
0
5
10
15
20
25
30
1980 1985 1990 1995 2000 2005 2010
Year
Incide
nce
(perm
illionofth
eagerelatedpo
pula5o
n)
Diabetes
Hypertension
Primary kidney diseases
Urological problems
ADPKD
Starting RRT
ERA-EDTA Registry data 9 countries with complete FU 88.5 million people
Data on file Spithoven, Kramer, Jager, Gansevoort et al
Number of patients starting renal replacement therapy according to cause of renal failure
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
Pathophysiology of a renal collecting duct cell
Zittema et al, Capita Selecta Nephrology 2013
PC1 PC2
Ca2+
ER
Ca2+
Ras/B-Raf/MEK/ERK
cAMP
TSC1TSC2
mTOR
Nucleus
Proteintranslation
V2R
PC1
Cl-
Somatostatin Vasopressin
Somatostatinanalogs
V2Rantagonist
mTORinhibitors
CFTRchannels
ATP+
—
PKA
PC2
Cell proliferationCell growth
—+
+
+
+
++
+
+
+
—
—
+
UrineflowApical membrane
BasolateralmembraneBlood flow
+ +
—
ACSSTR
Fluid transport
PC1 PC2
Ca2+
ER
Ca2+
Ras/B-Raf/MEK/ERKRas/B-Raf/MEK/ERK
cAMPcAMP
TSC1TSC2TSC1TSC2
mTORmTOR
Nucleus
Proteintranslation
V2R
PC1
Cl-
Somatostatin Vasopressin
Somatostatinanalogs
V2Rantagonist
mTORinhibitors
CFTRchannels
ATP+
—
PKAPKA
PC2
Cell proliferationCell growth
—+
+
+
+
++
+
+
+
—
—
+
UrineflowApical membrane
BasolateralmembraneBlood flow
+ +
—
ACSSTR
Fluid transport
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
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 2013 G
roni
ngen
PK
D E
xper
tise
Cen
ter
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
Total Kidney Volume (% change per year)
-14
-12
-10
-8
-6
-4
-2
0 0 5 10 15 20 25 30
eGFR (ml/min/1.73m2)
-2,0
0,0
2,0
4,0
6,0
8,0
p=0.005
p<0.0001
N= 33 27 21 Placebo 200 mg 400/200 mg
Phase 2b, multicenter RCT, 2 yr FU Placebo or bosutinib 200 mg or 400 mg N=172 ADPKD, eGFR>60, TKV>750 ml
Pfizer Clinicaltrials.gov 2016
Follow-up (months)
Tyrosine kinase inhibitors
Withdrawal rate Drug Total Placebo 5% 39% Bosutinib 200 mg 24% 41% Bosutinib 400 mg 55% 90%
Placebo
200 mg
400/200
Multicenter RCT, 3 yr FU 79 ADPKD patients with eGFR >40 ml/min*1.73m2 Placebo or octreotide 20 mg im once every 28 days
ALADIN trial Lancet 2013
Somatostatin analogues
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
Change in mGFR 0 – 3 yr Change in mGFR 1 – 3 yr
NS
2
Somatostatin analogues
Multicenter RCT, 3 yr FU 79 ADPKD patients with eGFR >40 ml/min*1.73m2 Octreotide 20 mg or placebo im every 28 days
ALADIN trial Lancet 2013 G
roni
ngen
PK
D E
xper
tise
Cen
ter
Total Kidney Volume Kidney function
N=1445 ADPKD, placebo or tolvaptan 90/30 mg Age 18-50 yr, eCrCl>60 ml/min, TKV>750 mL
5.5 % per yr
2.8 % per yr ↓ 49%, p<0.001
3.7 ml/min/yr
2.7 ml/min/yr ↓ 26%, p<0.001
TEMPO study NEJM 2012 G
roni
ngen
PK
D E
xper
tise
Cen
ter
Vasopressin V2 receptor antagonists
Gro
ning
en P
KD
Exp
ertis
e C
ente
r Tolvaptan efficacy and tolerability Comparison with other renoprotective agents
Annual eGFR loss
NEJM 1993
NEJM 1994
NEJM 2001
NEJM 2001
NEJM 2012
DM
Various
DM
DM
ADPKD
Placebo Active Effect
Withdrawal
rate
NA
-3.9
-3.9
-5.2
-6.5
-3.7
NA
-2.8
-2.8
-4.4
-5.5
-2.6
-35%
-28%
-28%
-15%
-15%
-26%
-47%
NA
NA
-24%
-19%
-23%
ACEi
Low BP
LPD
A2A
A2A
V2RA
What may this imply for clinical practice?
10Extrapolation of the TEMPO study results
Cost-effectiveness report accepted the UK NICE Institute Gro
ning
en P
KD
Exp
ertis
e C
ente
r
Liver function abnormalities with tolvaptan - Transaminase rather than bilirubin increase
N=1445 ADPKD, placebo or tolvaptan 90/30 mg Age 18-50 yr, eCrCl>60 ml/min, TKV>750 mL
TEMPO study Watkins et al, Drug Safety 2015
Hy’s law cases
Gro
ning
en P
KD
Exp
ertis
e C
ente
r Time course of liver function test abnormalities with tolvaptan
Occur gradually
Most often only transaminases
Reversible
Re-occurence on re-exposition
N=1445 ADPKD, placebo or tolvaptan 90/30 mg Age 18-50 yr, eCrCl>60 ml/min, TKV>750 mL
60/30 mg
90/30 mg
ASAT ALAT Bili indirect Bili direct
ASAT ALAT Bili indirect Bili direct
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
TEMPO study Watkins et al, Drug Safety 2015
Nearly all LFT abnormalities occur within 18 months after start of TX
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 JINARC (tolvaptan) Summary of Product Characteristics Gro
ning
en P
KD
Exp
ertis
e C
ente
r
Ron T. Gansevoort1, Mustafa Arici2, Thomas Benzing3, Henrik Birn4, Giovambattista B. Capasso5, Adrian Covic6, Olivier Devuyst7, Christiane Drechsler8, Kai-Uwe Eckardt9, Francesco Emma10, Bertrand Knebelmann11, Yannick Le Meur12, Ziad Massy13, Albert CM Ong14, Alberto Ortiz15, Franz Schaefer16, Roser Torra17, Raymond Vanholder18, Andrzej Wiecek19, Carmine Zoccali20, Wim Van Biesen18
Torres et al, cJASN in press Post-hoc analysis of the TEMPO 3:4 trial
0
1
2
3
4
5
6
7
8
267 158 402 214 147 84
Rate of TKV growth (% per year)
-6
-5
-4
-3
-2
-1
0 CKD1 CKD2 CKD3
Rate of eGFR change (ml/min/1.73m2 per year)
CKD1 CKD2 CKD3 N=
-40.4% P<0.0001
-60.4% P<0.0001
-39.8% P=0.0004
-15.5% P=0.23
-29.1% P<0.0001
-31.0% P<0.000
Tolvaptan Placebo
Tolvaptan Placebo
Tolvaptan efficacy vs CKD stage
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
The indication for tolvaptan should not include CKD stage 3b
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
N=42
N=1445 ADPKD, placebo or tolvaptan 90/30 mg Age 18-50 yr, eCrCl>60 ml/min, TKV>750 mL
CKD stage 3b
The indication for tolvaptan CKD stage should be indexed for age
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
N=1445 ADPKD, placebo or tolvaptan 90/30 mg Age 18-50 yr, eCrCl>60 ml/min, TKV>750 mL
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
JINARC (tolvaptan) Summary of Product Characteristics Gro
ning
en P
KD
Exp
ertis
e C
ente
r
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/1.73m2 per yr loss over a period of 5 years, or confirmed >5 ml/min/1.73m2 in one year. - Can change in eGFR be measured with such reliability?
Gro
ning
en P
KD
Exp
ertis
e C
ente
r How to define “evidence of rapidly progressing disease”?
74
76
78
80
82
84
86
88
90
92
94
23-8-2011
23-11-2011
23-2-2012
23-5-2012
23-8-2012
23-11-2012
23-2-2013
23-5-2013
23-8-2013
23-11-2013
23-2-2014
23-5-2014
23-8-2014
0
20
40
60
80
100
120
140
160
180
5-12-2007
5-6-2008
5-12-2008
5-6-2009
5-12-2009
5-6-2010
5-12-2010
5-6-2011
5-12-2011
5-6-2012
5-12-2012
5-6-2013
5-12-2013
5-6-2014
5-12-2014
90
95
100
105
110
115
120
125
130
23-2-2010
23-6-2010
23-10-2010
23-2-2011
23-6-2011
23-10-2011
23-2-2012
23-6-2012
23-10-2012
23-2-2013
23-6-2013
23-10-2013
23-2-2014
23-6-2014
23-10-2014
23-2-2015
60
70
80
90
100
110
120
130
140
12-4-2007
12-10-2007
12-4-2008
12-10-2008
12-4-2009
12-10-2009
12-4-2010
12-10-2010
12-4-2011
12-10-2011
12-4-2012
12-10-2012
12-4-2013
12-10-2013
12-4-2014
12-10-2014
12-4-2015
Miss H, 41 yr Mister S, 40 yr
Miss B, 26 yr Mister A, 32 yr
Gro
ning
en P
KD
Exp
ertis
e C
ente
r How to define “evidence of rapidly progressing disease”?
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?
Gro
ning
en P
KD
Exp
ertis
e C
ente
r How to define “evidence of rapidly progressing disease”?
• 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 – 50 years - Cockroft-Gault creatinine clearance ≥60 ml/min - TKV ≥750 ml
Gro
ning
en P
KD
Exp
ertis
e C
ente
r How to define “evidence of rapidly progressing disease”?
Irazabal et al JASN 2014
TKV indexed for height and age to predict high likelihood of rapid disease progression
- 4.7
- 3.4
- 2.5
- 1.2
- 0.1
eGFR slope1
1: Future eGFR decline (ml/min/1.73 m2 per year) by subclass Note: no difference between males and females in average slope ! G
roni
ngen
PK
D E
xper
tise
Cen
ter
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
Cornec-Le Gall JASN 2013
Average age at start of RRT = 58 yrs
PKD mutation analysis to predict high likelihood of rapid disease progression
5
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
Cornec-Le Gall JASN 2015
The PRO-PKD score: mutation + symptoms to predict high likelihood of rapid disease progression
Average age at start of RRT = 58 yrs
ERA-EDTA position statement on the use of tolvaptan for ADPKD A hierarchical treatment decision diagram (NDT 2016)
Likely slow progression, or eGFR/age outside indication
No treatment
Predicted fast progression
Indication for treatment
Fast progression
Indication for treatment
Possibly fast progression
Re-evaluate
Yes Yes Yes Yes
Yes No
Data not available or not reliable (e.g. in CKD 1)
No
Data not available or not reliable
Data not available or not reliable
CKD stage by agea: at age < 30 yr: CKD 1-3a (eGFR > 45 ml/min/1.73m2) at age 30-40 yr: CKD 2-3a (eGFR 45 - 90 ml/min/1.73m2) at age 40-50 yr: CKD 3a (eGFR 45 - 60 ml/min/1.73m2)
Predicted progression by family history: Family history with most ADPKD patients reaching ESRD ≤ 58 yrj
Historical eGFR declineb, with no other confounding cause than ADPKDc: 1) confirmed eGFR decline ≥ 5 ml/min/1,73 m2 in one yeard and/or 2) confirmed eGFR decline ≥ 2,5 ml/min/1,73 m2 per year over a period of five years or moree?
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)
Predicted progression by baseline htTKV indexed for age and/or genotype: 1) htTKV compatible with Mayo class 1C, 1D or 1Eh and/or 2) truncating PKD1 mutation + early symptoms (i.e., a PRO-PKD score >6)i?
No
No
No
Gro
ning
en P
KD
Exp
ertis
e C
ente
r 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
• Tolvaptan 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.
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
EXTRA SLIDES
p<0.05
* * *
* * * * *
* *
* *
* * *
*
All patients open-label Tolvaptan
Tolvaptan Placebo
*
Off
treat
men
t
Double-blind placebo controlled RCT
Time (months)
Cha
nge
in e
GFR
(mL/
min
/1.7
3m2 )
314 placebo and 557 tolvaptan treated patients from TEMPO 3/4 continued open label tolvaptan
TEMPO 4/4 study Torres et al, in preparation
Persistence of tolvaptan’s treatment effect?
Crossing over to tolvaptan
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
6
Tolvaptan
Placebo
0.3
0.2
0.1
0.0
BL 4 8 12 16 20 24 28 32 36
Cum
ulat
ive
Even
t Haz
ard
36% reduction in risk of renal pain
HR: 0.64 (0.47 - 0.89) p=0.007
0.3
0.2
0.1
0.0
Cum
ulat
ive
Even
t Haz
ard
Tolvaptan
Placebo
62% reduction in risk of worsening renal function
(= 25% eGFR decline)
HR: 0.39 (0.26 - 0.57) p<0.0001
BL 4 8 12 16 20 24 28 32 36
Tolvaptan ameliorates disease progression - Worsening kidney function and pain -
N=1445 ADPKD, placebo or tolvaptan 90/30 mg Age 18-50 yr, eCrCl>60 ml/min, TKV>750 mL
TEMPO study NEJM 2012
Gro
ning
en K
idne
y C
ente
r
Liver function abnormalities with tolvaptan: - Time course on group level -
N=1445 ADPKD, placebo or tolvaptan 90/30 mg Age 18-50 yr, eCrCl>60 ml/min, TKV>750 mL
TEMPO study Watkins et al, Drug Safety 2015 G
roni
ngen
PK
D E
xper
tise
Cen
ter
-50
-40
-30
-20
-10
0
10
20
base
line
Week 3
4 8 12
16
20
24
28
32
36
FU1 FU2
Time (months)
Cha
nge
in A
CR
(%)
* * * * * *
* *
*
N=1445 ADPKD, placebo or tolvaptan 90/30 mg Age 18-50 yr, eCrCl>60 ml/min, TKV>750 mL
TEMPO 3:4 study Gansevoort et al, in preparation
Tolvaptan effect on other kidney outcomes - Change in albuminuria vs placebo -
Gro
ning
en P
KD
Exp
ertis
e C
ente
r
34
Gro
ning
en K
idne
y C
ente
r Tolvaptan (N=961)
Placebo (N=483)
Patients withdrawn 23.0 % 13.8 % Due to Aderse Event 15.4 % 5.0 % Due to Aquaretic Adverse Event 8.3 % 0.4 %
AEs >10% and significantly more common in tolvaptan group
Thirst 55.3 % 20.5 % Polyuria 38.3 % 17.2 % Nocturia 29.1 % 13.0 % Pollakiuria 23.2 % 5.4 %
AEs >10% and significantly more common in placebo group Renal pain 27.0 % 35.0 % Haematuria 7.8 % 14.1 % Urinary tract and kidney cyst infection 8.3 % 12.6 %
Elevated laboratory values at any visit Serum sodium >150 mEq/L 4.0 % 1.4 % Serum uric acid >7.5 mg/dL 6.2 % 1.7 % Liver function abnormalities 0.9 % 0.4 %
(Serious) Adverse Events
N=1445 ADPKD, placebo or tolvaptan 90/30 mg Age 18-50 yr, eCrCl>60 ml/min, TKV>750 mL
TEMPO study NEJM 2012
Clinical considerations when selecting patients for treatment
• Which CKD stages? - Only CKD stages 1 – 3a, not stage 3b - But index CKD stage for age,
- 40-50 yr old with CKD stage 1 cannot be a fast progressor - do not prescribe at age >50 years
• Evidence of rapid progressive disease: historical data feasible? - Historical loss of eGFR >2.5 ml/min/1.73m2 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)
Gro
ning
en P
KD
Exp
ertis
e C
ente
r PKD patients in renal replacement therapy Numbers + costs in the EU 27 zone
24,000 31,700
39,000 46,200
52,800
1993 1998 2003 2008 2013
Direct medical costs: ~1.6 billion Euro/yr
NDT 2014 Spithoven, Kramer, Jager, Gansevoort et al
Gro
ning
en K
idne
y C
ente
r
7
• Prognostic indicators
- Size: TKV for age and length (MRI or US)
- Genetics: 1PKD1 (especially truncating mutations)
- Demographics: Family history of young age at ESRD
- Symptoms: 2Early hematuria, hypertension or pain
- Biomarkers: 3Plasma copeptin concentration??
4Urinary excretion tubular damage markers??
Kidney function, especially “reliable” historical change in kidney function, overrules all other prognostic indicators.
1. Cornec - le Gal, JASN 2013 2. Cornec - le Gal, JASN 2015 3. Boertien et al, NDT 2012 and Boertien et al, AJKD 2013 4. Meijer et al, AJKD 2010 and Boertien et al, Kidney Int 2012 G
roni
ngen
PK
D E
xper
tise
Cen
ter Other indicators
to predict high likelihood of rapid disease progression 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 eGFR1
- >60 + 4.3 liter: 1.7 → 6.0 liter per day - 30-60 + 3.1 liter: 2.8 → 5.9 liter per day - <30 + 2.9 liter: 3.1 → 6.1 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 2013
Gro
ning
en K
idne
y C
ente
r
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 90 / 30 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
Gro
ning
en K
idne
y C
ente
r
