ADPKD:

Learn more about

Tolvaptan (JINARC)

Dr Catriona Shaw

Kidney Consultant

Kings College Hospital

London

With thanks to Dr Graeme Wood (Salford) and PKD Charity

Learn more about tolvaptan

• What is tolvaptan?

• How does it work?

• What research has been

done on tolvaptan?

• Who can take tolvaptan?

• How well might tolvaptan

work for me?

• Other options?

Types of ADPKD

1. Harris PC, Torres VE. Polycystic kidney disease, autosomal dominant. GeneReviews® [Internet].

Last Updated 11 June 2015. 2. Shaw, C, et al. Nephrology Dialysis Transplantation 2014;29:1910-

1918. 3. Cornec-Le Gall E, et al. J Am Soc Nephrol 2013;24:1006-1013.

3

Type 1, 85%

Type 2, 15%

Proportion of ADPKD patients1

What does ADPKD do to the kidneys?

eGFR = estimated glomerular filtration rate (the amount of blood your kidneys can filter in 1 minute).

1. Baur BP. Meaney CJ. Pharmacotherapy. 2014;34:605–616. Image from Torres Mayo <aupCP1047707-94

The speed of ADPKD

progression differs between

patients. 100%

80%

60%

40%

20%

0%

0 10 6020 30 40 50

Patient age (years)

Kid

ney f

uncti

on

(measu

red b

y e

GFR)

Perfect kidney

function

No kidney

function

Cyst growth

What causes cysts to form?

The causes of cysts in ADPKD are complex and not fully understood.

Cyst growth is encouraged by a few different proteins found in kidney

cells including:1

• c-AMP

• Vasopressin

cAMP = adenosine-3’,5’-cyclic monophosphate.

1. Baur BP. Meaney CJ. Pharmacotherapy. 2014;34:605–616. Images from: Wilson P. New Engl J Med 2004;350:151-164.

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A healthy tubuleADPKD: a tubule

with cysts

What is tolvaptan?

• Tolvaptan (brand name: Jinarc®)

• Approved in Europe in May 20151

• For adults with autosomal dominant

polycystic kidney disease (ADPKD) that

is progressing quickly to start taking

before they get poor kidney function:2

• Slows cyst development

• Slows decrease of kidney function

1. www.ema.europa.eu; 2. Tolvaptan (Jinarc) summary of product characteristics, 29/09/16.Image By Vaccinationist (PubChem) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons

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How does tolvaptan slow cyst growth?

Tolvaptan blocks V2, a

receptor for vasopressin

This decreases:

• the amount of cAMP1

• the amount of fluid being

released into the cyst1

1. Baur BP. Meaney CJ. Pharmacotherapy. 2014;34:605–616. 7

Vasopressin

V2 receptor

cAMP

2. Increase in proteins that

cause new cells to grow

Aquaporin

1. Release of fluid

Cell

nucleus

Figure: Simplification of the processes that

vasopressin triggers in cyst epithelial cells

Epithelial cell

Tolvaptan

Why did scientists think tolvaptan might

work as a treatment for ADPKD?

• Early studies showed:1-6

• Tolvaptan reduces the severity of PKD in 5 animal

models of ADPKD

• In human cysts grown in the lab, tolvaptan reduces

cell proliferation and fluid secretion

• V2 receptors are almost all found in the kidney

fewer side effects?

81. Chang MY, Ong AC. Br J Clin Pharmacol 2013;76:524-35. 2. Gattone VH, et al. Develop Gen 1999;24:300-18.

3. Gattone VH, et al. Nature Med 2003;9:1323-6. 4.Torres VE, et al. Nature Med 2004;10:363-4.

5. Wang X, et al. J Am Soc Nephrol 2008;19:102-8. 6. Meijer E, et al. Clin J Am Soc Nephrol 2001;6:361-8.

Clinical trials of tolvaptan: TEMPO

To check whether

tolvaptan:

• Could alter the process

by which ADPKD damages

the kidney

• Is safe for humans

• Improves symptoms and

complications for people

with ADPKD

1. Clinicaltrials.gov NCT00428948; 2. Clinicaltrials.gov. NCT00428948; 3. Clinicaltrials.gov.

NCT01214421.9

TEMPO 2/4A trial over 3 years to find the best dose of

tolvaptan, to check how well patients tolerate the

drug, and to test use of the drug long-term1

TEMPO 3/4A 3-year study to assess how effective tolvaptan is at

slowing ADPKD progression compared with placebo2

TEMPO 4/4A 2-year study to assess how tolvaptan slows ADPKD

progression3

Finished

Finished

Ongoing

Figure: The TEMPO trials

TEMPO 3/4: The pivotal study for tolvaptan

• Tolvaptan versus

placebo

• Phase 3 study

• 1445 patients in

129 sites over

15 countries

• 3-year followup study

Clinicaltrials.gov. NCT00428948 10

Figure: Countries taking part in TEMPO 3/4

TEMPO 3/4: Which patients took part?

Patients who could take part:

18-50 years old

AND

Creatinine clearance at least

60 ml per minute

(~eGFR 60ml/minute)

AND

Large kidneys (MRI

TKV>750ml)

Patients were not able to take

part if:

not safe, e.g. allergies

If not able to have MRI scans

If they had other conditions

or were taking other

medicines that might effect

the accuracy of the study

readings

MRI = magnetic resonance imaging.

1. Torres VE, et al. N Engl J Med. 2012; 367:2407–2418. 11

TEMPO 3/4: What treatment did patients

receive?

1. Torres VE, et al. N Engl J Med. 2012; 367:2407–2418. 12

Patient

joins

trial

Placebo

Morning: pill

Night: pill

Week 1 Week 2

Tolvaptan

Morning: 90 mg

Night: 30 mg

Week 3 to Month 36

Placebo

Morning: pill

Night: pill

Placebo

Morning: pill

Night: pill

Tolvaptan

Morning: 40 mg

Night: 15 mg

Tolvaptan

Morning: 60 mg

Night: 30 mg

Tolvaptan

Morning: 60 mg

Night: 30 mg

Tolvaptan

Morning: 40 mg

Night: 15 mg

Tolvaptan

Morning: 40 mg

Night: 15 mg

or

55%

21%

24%

TEMPO 3/4: What did the study measure?

1. Torres VE, et al. N Engl J Med. 2012; 367:2407–2418. 13

Primary endpoint:

• Change in total kidney volume (size) each year

secondary endpoints:

• The length of time before:

• Patient’s GFR fell by 25%

• Patient developed hypertension, or it worsened

• Patient developed kidney pain, or it worsened

• Patient had albumin in their urine (albuminuria)

• How quickly kidney function was falling

• Blood pressure changes

• In patients with high blood pressure (hypertension),

less blood pressure medication being needed

• Kidney pain

TEMPO 3/4: More about the people taking

part (baseline characteristics)

• The average age was 39 years

Women 10 in 20 (50%)

White (most others Asian) 17 in 20 (85%)

Had high blood pressure (hypertension) 16 in 20 (80%)

Taking an ‘ACE inhibitor’ for hypertension 8 in 20 (40%)

Average eGFR (ml/minute/1.73m) ~81 in both groups

• Other medications used included angiotensin receptor blockers,

beta-blockers and calcium channel blockers

ACE inhibitor = angiotensin-converting enzyme inhibitor.

1. Torres VE, et al. N Engl J Med. 2012; 367:2407–2418. 14

TEMPO 3/4: More about the people taking

part (baseline characteristics)

At the beginning of the trial, some patients had:

Blood in their urine (haematuria) 7 in 20 (35%)

Kidney pain 10 in 20 (50%)

Kidney stones (nephrolithiasis) 4 in 20 (20%)

A urinary tract infection 6 in 20 (30%)

Low red blood cells (anaemia) 2 in 20 (10%)

Protein in their urine (proteinuria) 5 in 20 (25%)

1. Torres VE, et al. N Engl J Med. 2012; 367:2407–2418. 15

TEMPO 3/4: What effect did tolvaptan have

on kidney growth?

16

• Gradual increase in total kidney

volume (size) in both groups

• But patients receiving tolvaptan

had less kidney growth

• Average total kidney volume

increased:

• 5.5% every year with placebo

• 2.8% every year with

tolvaptan

• A statistically significant

difference

TEMPO 3/4: What effect did tolvaptan have

on kidney function

17

• Gradual decrease in kidney

function in both groups

• But, a smaller decrease within the

tolvaptan group

• Kidney function decrease

estimated by creatinine levels:

• 3.81 mg/ml every year with

placebo

• 2.61 mg/ml every year with

tolvaptan

• eGFR:3.7ml/min/year with

placebo

• eGFR:2.7ml/min/year with

tolvaptan

TOLVAPTAN group: 1ml/minute/year slower rate of eGFR decline

TEMPO 3/4: What effect did tolvaptan have

on kidney pain?

18

• Tolvaptan reduced the chance of

getting clinically significant

kidney pain by about a third

• Clinically significant kidney pain

at 3 years:

• 12 in every 100 (12%) of patients

on tolvaptan

• 20 in every 100 (20%) of patients

on placebo

TEMPO 3/4: Did tolvaptan work for

all types of patients in the trial ?

• Some patients experienced greater or smaller effects of tolvaptan

• Tolvaptan slowed kidney growth in all patient subgroups:

Over or under 35 years old

With or without high blood pressure

Creatinine clearance at least 80 ml/min or below 80 ml/min

Large kidneys (total volume at least 1.5 litres) or smaller

• Tolvaptan also slowed kidney function decline for all subgroups

But the difference versus placebo wasn’t significant for patients:

Under 35

Without high blood pressure

1. Torres VE, et al. N Engl J Med. 2012; 367:2407–2418. 19

• Adverse events: 97% of patients

• 5 in every 20 patients (23%) stopped taking tolvaptan before the trial end

• Due to troublesome adverse events in two-thirds

• 3 in every 20 (13%) patients stopped taking placebo

• Adverse events more common with tolvaptan* often linked to an increase in

water excreted in the urine (aquaresis), leading to:

Thirst 55 in 100 (55%)

Producing more urine 30 in 100 (38%)

Urinating more often 23 in 100 (23%)

Needing to urinate at night 29 in 100 (29%)

*Adverse events happening in at least 1 in 10 patients, and significantly more often with tolvaptan.

TEMPO 3/4: Did patients get any side

effects?

1. Torres VE, et al. N Engl J Med. 2012; 367:2407–2418. 20

• Most people taking placebo also reported at least one adverse event

• Adverse events that were more common with placebo* than tolvaptan were usually linked to ADPKD:

Kidney pain 35 in 100 (35%)

Blood in urine 14 in 100 (14%)

Urinary tract infection 13 in 100 (13%)

*Adverse events happening in at least 1 in 10 patients, and significantly more often with placebo.

Serious adverse events with tolvaptan (uncommon):

Changes in liver function picked up on blood tests

Headache

Chest pain

TEMPO 3/4: Did patients get any

side effects?

1. Torres VE, et al. N Engl J Med. 2012; 367:2407–2418. 21

Serious adverse events more

likely with placebo:

Kidney infection

Kidney stone

Cyst infection

Cyst bleeding

TEMPO 3/4: Did patients get any

side effects?

22

Who can potentially take tolvaptan?

How are new drugs usually approved for use by the NHS in the UK?

EMA = European medicines Agency; NICE = National Institute of Health and Clinical Excellence;

SMC = Scottish Medicines Consortium.23

The manufacturer uses clinical trial results to apply to the European Medicines Agency

(EMA) for a license for the drug to be sold to treat a specific disease

The EMA makes a decision based on the quality, safety and effectiveness of the drug

Newly licensed drugs are reviewed by experts who recommend to the

NHS whether the drug should be routinely available, and to which

patients, based mainly on how much patients may benefit and value for

money (e.g. NICE and SMC)

Who can potentially take tolvaptan?

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ADPKD

Aged 18 and over

CKD stage 2 or 3

Evidence of rapidly progressive

disease

Or:

Kidney function measured at least

twice over the space of at least 6

months, and these tests show that

your GFR is falling by at least 5

ml/min each year

How do doctors decide whether your ADPKD

is progressing rapidly?

UK’s Renal Association

recommendations1

ADPKD is rapidly progressing if:

Total kidney size can be measured on

scans and the results show your

kidneys are growing quickly (e.g.

becoming 5% larger each year)

Or:

Kidney function measured at least 5

times over the last 5 years, and these

tests show that GFR is falling by at

least 2.5 ml/min each year

1. Renal Association Working Group on Tolvaptan. Guideline commentary, 06/05/2016. 25

If I am thinking about Tolvaptan with my

kidney doctor: things to consider

It can mean quite a change in lifestyle:

Drinking 3-4 litres of fluid a day (at least)

Need to pass urine very frequency

Monthly blood tests for liver function (and

kidney) monitoring

You must not get pregnant or breast feed when

taking tolvaptan

Other medications can interact

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Are there any other treatments?

Healthy active lifestyle

Control of high blood pressure

Control of high cholesterol

Increased water intake ? (3 litres~)

Pain management

Surgery

Somatostatin analogues (PLD)

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In summary:

Tolvaptan (JINARC) is licensed for use in ADPKD in

adults with evidence of rapidly progressive kidney

disease

Potential benefits

1. slowing of rate of kidney growth

2. Slowing of rate of decrease in kidney function

There are potential side effects and lots of monitoring

to consider

Excellent blood pressure control, healthy balanced life

style are also important

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Where can I find out more?

If you’d like to find out more about

tolvaptan, we recommend you speak

with your kidney specialist.

You can also contact the PKD

Charity’s helpline for more

information:

• Call: 0300 111 1234 (Monday to

Friday, 10.00 to 16.00)

• Online form:

www.pkdcharity.org.uk/contact-

us

Useful links:

• PKD Charity website

• Research article of TEMPO 3/4

• NICE guidance on tolvaptan

• SMC guidance on tolvaptan

• UK Renal Association commentary

on tolvaptan

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Any questions?

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