welcome [] · ckd stage 1 to 3 evidence of rapidly ... brother esrd 55 dx tp back on hd identified...

WELCOME

ADPKD Information &

Support Day

Saturday 5 November 2016

Salford Royal, Mayo Building

Strategies for delaying CKD progression

• Blood Pressure

• ACE/ARB

• Smoking

• Obesity

• Blood sugar control

• Life style

• Protein restriction

• Lipids

Rationale for Tolvaptan in ADPKDConsistently reduces

disease severity in

pre-clinical animal

models

Reduces ADPKD cell

proliferation and

secretion in human ex

vivo cysts

Restricted

localization of V2R

limits the potential for

side effects Tolvaptan

5/29/2013 6

GrowthDetachmentInitiation

Cysts cause structural disease

Baert 1977; Grantham 1987

Rationale for TEMPO

• Prove disease process could be modified

• Works in theory - what happens in real life?

• Show improvement in symptoms and

complications

• Demonstrate safety

• Used kidney size as surrogate of function

• Cant wait 25 years to show it prevents ESRF

10

TEMPO Studies: Extensive Clinical Trial

Program Evaluating Tolvaptan in ADPKD

1. Clinicaltrials.gov

Tolvaptan

Efficacy and Safety in

Management of

Polycystic kidney disease and it’s

Outcomes

Dose selection, tolerability,

long-term exposure(248/249/250)

(TEMPO ; 3 years)

Pivotal Efficacy(251)

(TEMPO ; 3-year

study)

Disease Modification(271)

(TEMPO ; 2-year

study)

OPUK/0415/JIN/1217 Date of preparation April 2015

11

TEMPO 3:4 Was a Phase 3 Multi-Centre Study Which

Enrolled Patients From 129 Sites in 15 Countries

1. Torres VE et al. (2012). N Engl J Med. 367(25): 2407-18.

Argentina

United States

CanadaRussia

Japan

Australia

Belgium

Denmark

France

Germany

Italy

Netherlands

Poland

Romania

United Kingdom


12

TEMPO 3:4 Study Design: Patients Randomized to

Tolvaptan or Placebo Over a 3-Year Period

TLV, tolvaptan.


• In TEMPO 3:4, 1,445 patients were randomised (2:1) to tolvaptan (at the highest of three twice-

daily dose regimens that the patient found tolerable) or placebo.


13

TEMPO 3:4 Key Entry Criteria: Subjects Had Large

Kidney Volumes and Preserved Kidney Function

• Inclusion criteria

– 18-50 years, male and female with diagnosis of ADPKD by Ravine

criteria

– eCrCl ≥60 mL/ min (by Cockcroft-Gault)

– Rapidly progressive kidney growth (total volume ≥750 cc) by MRI at

randomization

• Exclusion criteria

– Safety contraindications including: non-compliance with therapies,

reproductive precautions, unawareness of thirst, severe allergic

reactions to compounds with similar chemical structure as tolvaptan

– Contraindications to or interference with MRI assessments

– Concurrent conditions or taking therapies likely to confound endpoint

assessments or prevent completion of the trial

eCRCl, estimated creatinine clearance

1. Torres VE et al. (2012). N Engl J Med. 367(25): 2407-18.OPUK/0415/JIN/1217 Date of preparation April 2015

14

TEMPO 3:4: Trial Endpoints

Sequential Endpoints* Description

Primary • Annualized rate of change in total kidney

volume

Key Secondary • Time to multiple ADPKD progression events:

• 25% decline in reciprocal serum

creatinine

• Hypertension development/progression

• Kidney pain development/progression

• Albuminuria development/progression

Next secondary • Rate of change in kidney function

Other secondary • Mean arterial pressure change or time to

blood pressure change category change in

normotensive subjects

• Reduction in blood pressure medication in

hypertensive subjects

• Kidney pain


*Study endpoints were ordered hierarchically into groups and tested sequentially using ‘gatekeeper’ procedures in which

subsequent tests were only performed if the test for the previous endpoints were significant


15

TEMPO 3:4: Baseline Characteristics Were Generally

Well-balanced Between Treatment Groups


16

TEMPO 3:4: Baseline Characteristics Were Generally

Well-balanced Between Treatment Groups


17

TEMPO 3:4: TKV Increased 2.8% Per Year With

Tolvaptan vs. 5.5% Per Year With Placebo

6/1315 (0.5%) placebo and 3/2370 (0.1%) tolvaptan outlier data points are not shown.

eCrCl, estimated creatinine clearance


Primary endpoint tested

firstTolvaptan slows polycystic kidney growth in ADPKD

Month

Baseline 12 24 36

Perc

en

t C

han

ge

fro

m B

aseli

ne

To

tal

Kid

ne

y V

olu

me

(m

L)

-30

-20

-10

0

10

20

30

40

50PlaceboTolvaptan

MMRM

p<0.0001

N=458; 5.5%/yN=819; 2.8%/y; P<.0001

-4-3-2-101

All Patients

TKV > 1500 mL

TKV < 1500 mL

eCrCl > 80 mL/min

eCrCl < 80 mL/min

Non-hypertension

Hypertension

Age > 35 Years

Age < 35 Years

Female

Male

Favors Tolvaptan

TKV Slope Reduction(%/year)


18

Renal Function

Slope Reduction

TEMPO 3:4 Other Secondary Endpoint of Rate of

Kidney Function Decline Favored Tolvaptan

1. Data on file. 2. Torres VE et al. (2012). N Engl J Med. 367(25): 2407-18.

Month

4 8 12 16 20 24 28 32 36

Ch

an

ge

in

Kid

ne

y F

un

cti

on

(Recip

rocal

Seru

m C

reati

nin

e [

mg

/mL

]-1)

-50

-40

-30

-20

-10

0

10

20

30

40

50 PlaceboTolvaptan

Week3/EOT

n = 842; -2.6 mg/ mL-1/y; P <.001N = 464; -3.8 mg/ mL-1/y

Ch

an

ge i

n R

en

al

Fu

ncti

on

a

-1 0 1 2 3

All Patients

TKV > 1500 mL

TKV < 1500 mL

eCrCl > 80 mL/min

eCrCl < 80 mL/min

Non-hypertension

Hypertension

Age > 35 Years

Age < 35 Years

Female

Male

Favors Tolvaptan

Renal Function Slope Reduction

(mg/ml)-1/yearReduction, mg/mL-1/y

Consistent >30% Slowing Over 3 years

Tolvaptan slows renal function decline in ADPKD1-2

3.8 ml vs 2.61 ml per year

Tolvaptan Effect on rate of eGFR lossComparison with other renoprotective agents

1. Lewis EJ et al. N Eng J Med 1993;329:1456-62 2. Brenner BM,et al. N Eng J Med 2001;345:861-69;3. Lewis EJ, et al. N Eng Med 2001;345:851-604. Torres VE et al. N Eng J Med 2012: 367:2407-18

Disease Drug Placebo Active Effect

NEJM 20124 ADPKD Tolvaptan -3.7 -2.6 -26%

NEJM 20012 DM Losartan -5.2 -4.4 -15%

NEJM 20013 DM Irbesartan -6.5 -5.5 -15%

NEJM19931 DM Captopril NA NA -5%

21

TEMPO 3:4 Tolvaptan Reduced The Risk of

Clinically Significant Renal Pain in ADPKD

HR = 0.64 (95% CI 0.47‒0.89)

P = .01 by Cox ModelC

um

ula

tive E

vent H

azard

Placebo

Tolvaptan

Study Month


22

TEMPO 3:4: Aquaresis-related AEs Were More

Common in Tolvaptan-treated Patients


0 10 20 30 40 50 60 70 80 90 100

Nasopharyngitis

Pollakiuria

Headache

Nocturia

Renal pain

Hypertension

Polyuria

Thirst

Placebo

Tolvaptan

Adverse events occurring in >20%

of patients are shown:

While the incidence of aquaretic adverse events was higher in the tolvaptan group, the

incidence of ADPKD-related adverse events was higher in the placebo group


Tolvaptan Dropout RatesComparison with other renoprotective agents

1. Lewis EJ et al. N Eng J Med 1993;329:1456-62 2. Brenner BM,et al. N Eng J Med 2001;345:861-69;3. Lewis EJ, et al. N Eng Med 2001;345:851-604. Torres VE et al. N Eng J Med 2012: 367:2407-18

Disease Drug Rate

NEJM 20124 ADPKD Tolvaptan 23%

NEJM 20012 DM Losartan 24%

NEJM 20013 DM Irbesartan 19%

NEJM 19931 DM Captopril 47%

24

Hepatic Adverse Events Were Reported in

TEMPO 3:4

Tolvaptan Placebo

Abnormality Subjects Subjects Meeting Criteria

% Subjects Subjects Meeting Criteria

%

ALT >3x ULN 958 42 4.4 484 5 1.0

ALT >3x ULN with

bilirubin >2x, but

ALP <2x ULN

(Hy’s laboratory

criteria)

957 2 0.2 484 0 0

Death or liver

failure

0 0 0 0

1. Data on file. 2. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf (accessed 17 December 2014)

ALP, alkaline phosphatase; ALT, alanine aminotransaminase; ULN, upper limit of normal

Tolvaptan has been associated with idiosyncratic and reversible elevations of blood

alanine and aspartate aminotransferases (ALT and AST) with infrequent cases of

concomitant elevations in total bilirubin.


http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf

•License Indications for Tolvaptan (May 2015)

To slow the progression of cyst development and renal insufficiency

ADPKD in adults

CKD stage 1 to 3

Evidence of rapidly progressing disease

•NICE guidance (Nov 2015)

To slow the progression of cyst development and renal insufficiency

ADPKD in adults

CKD stage 2 to 3


But how do you define rapid progression?

Patient Selection/Guidelines

1) European (ERA-EDTA)

2) Scottish (SMC)

3) UK Renal Association

Accurate diagnosis genetics not mandatory

Concept of rapid disease progression

Stage 1 Scotland; Stage 3B excluded in ERA

Age ERA >50yrs ineligible; RA SMC no specific age

No gold standard imaging technique

UK Renal Association Jan 2016(RA Working Group on Tolvaptan in ADPKD)


Change in GFR > 2.5ml per year with at least 5 measures over 5 years

Or

Change GFR > 5mls over 12 months (>1 measure 6 months apart without cofounders)

Tolvaptan ?

Effect is small

Doesn’t delay dialysis

Go for live donor instead

Too complicated to use

Its liver toxic

Expensive

Side effects outweigh benefits

Patients don’t want it

108 CKD 2-3 PKD Pts Salford 2016

CKD Stage 2-3 108

How many have GFRs from 5 years ago?

57 have results

20 have decline >2.5ml/year

Challenges

Patient ID not easy/comprehensive/ownership

Admin time Access to labs radiology

Data on progression not visible

Patient selection is key medical time+++

Clinic capacity is an issue

Patient pathway not set in stone

Patient Selection/Guidelines

1) European (ERA-EDTA)

2) Scottish (SMC)

3) UK Renal Association

Renal Assn

2016

PROPKD Score

The points allocated to each variable in the PROPKD score was determined using hazard ratios.A PROPKD score of greater than 6 was associated with a significantly high risk of decline in renal function(mean rate of eGFR decline 4.4ml/min/year)A urological event is defined as either frank haematuria, cyst infection or flank pain related to cysts.

APKD and Type of mutations

Median age ESRD

PKD1 (T) = 56yr

PKD1 (NT) = 68yr

PKD2 = 80yr741 patients

519 pedigrees

Cornec-Le Gall et al, JASN 2013

Mayo Calculator

90

80

70

60

50

40

30

20

10

0

age

Variation in age at kidney failure in ADPKD

within and between families (Ritz. 1996)

JB 50yr ADPKD Self Employed Plasterer

Strong FH Mother ESRD 58 Dx transplanted RIP 72 complications PTLD

Brother ESRD 55 Dx Tp back on HD

Identified age 30 on USS

Hypertension CKD 3 Hypothyroid Haemorrhagic cyst

Medication BZF Amoldipine Bisoprolol Ramipril Moxonidine Thyroxine

Aware of Tolvaptan from previous clinic visits

Eligible identified from MDT >5ml/year 3 readings

Invited by post Jinarc patient information sent

Renal Pharmacist for drug education

Titrated weekly over 3 weeks

Comments

Very enthusiastic to start

He increased fluid intake test out increased UO

Uses “My Water Balance” app to monitor input

Best run of health in last 5 years

Pain greatly improved 6 week pain free longest ever

Passes urine 4 time hr for 2 hrs after morning dose predictable response

Nocturia 3-4 finds this managable

Salford Clinic Use of Tolvaptan

60-70 Eligible Not all suitable

Invited 32 Targeted low GFRs

19 had Pharmacist led drug education

15 commenced treatment 3 didn’t feel it fit lifestyle

1 new type 1 DM

None have stopped treatment

All tolerated side effects

All feel it has been beneficial - pain

Otsuka Support for Tolvaptan

Reduced cost

Patient information leaflet

Physician information leaflet

Prescriber checklist / Drug alert docs

Patient helpline

ADPKD website

Risk management program – education

Independent nurse service provision

Support to PKD charity/CME etc

Tolvaptan ?

Effect is small – most potent renoprotective

agent yet and cumulative

Doesn’t delay dialysis – it has to

Go for live donor instead – save for later

Too complicated to use – can be

Its liver toxic – Risk management program

Expensive – similar to EPO

Side effects outweigh benefits – Pt choice cigs

Patients don’t want it – ask them!

45

TEMPO 3:4 Results Support 1-year Delay in Disease

Progression With Every 3 Years of Tolvaptan

Treatment

1. FDA Briefing Document Statistical Review, pg 112-113.

ESRD Projection: 1.5–3.6-year delay

46-y-old patient

eGFR 70 mL/min/1.73 m2

20-y-old patient

eGFR = 88.3mL/min/1.73 m2

ESRD Projection: >10-year delay

Pre

dic

ted

eG

FR

, m

L/m

in/1

.73m

2

Pre

dic

ted

eG

FR

, m

L/m

in/1

.73m

2

Time, y Time, y

• Estimated 4-year delay in time to eGFR <15 mL/min/1.73 m2 (ie, dialysis or transplant)

• Trial results support projection of 1-year delay in disease progression for every 3 y of treatment


welcome [] · ckd stage 1 to 3 evidence of rapidly ... brother esrd 55 dx tp back on hd identified...

Documents