start

Tolvaptan Clinical Trial Results

hello everyone and welcome to our

evening webinar we are here to talk

about the total depth in clinical crowd

ne and I am staff here at the PKD

Foundation and really excited to be here

with you tonight I see that we still

have people kind of pouring into the the

webinar so I'm going to do a little bit

of intro here and I may be stall for

another minute or two so everyone can

get signed in and ready to go and then I

will pass it over so during the there we

go during the presentation if you have

any questions at all please submit them

via the chat box over to your right

I know if you have any trouble with

sound or if you're not seeing the slides

advance please do let us know

um and then obviously if you have any

questions about the topic about the the

content please send those we're gonna

have a Q&A at the end of the talk and we

will answer I'm for I do want you to

keep in mind that we're not gonna be

late so try to keep your questions

brought in feature and definitely on

topic so I know it's really tempting we

have these really amazing clinicians

here with us I'm an attempting to want

to ask them a lot of questions about

just general health but we wanted to

stay focused on this topic tonight and

also keep in mind that we don't offer

medical advice so the information shared

this evening is not intended to be a

substitute for consultations with your

health care professional your doctor

your nephrologist but you know we want

to encourage you to make sure that

you're caring your treatment decisions

are made with your health care

professional team and we are just here

to offer general advice in general

information about this clinical study

and not specific medical advice we are

in fact recording this webinar and will

post it to our website next week if you

registered obviously you're hearing it

now so you've registered um you'll get

an email from us even if you didn't

attend

tonight or maybe you know someone who

was able to make it but they did

register you'll get an email from us

sometime next week with a link directly

to the recording so you can forward that

on to anyone might want to watch and

have missed it and then you can always

submit questions via education at PK

teacher org if you have follow-up

questions from that okay so I'm gonna go

ahead and announce our speakers tonight

we have with us there we go

dr. Ron Peron he is the scientific

director of the clinical and

translational research center I'm the

associate chief of the division of

Nephrology and the medical director of

kidney transplantation at Tufts Medical

Center Ron if any of that is not

accurate you can let me know later he's

a professor he's received obviously

numerous awards and honors including the

title of top doctor from Boston Magazine

for several years and physician of the

Year award from the PKD foundation

foundation because he's so stinking

awesome and amazing he was a member of

the PCC Foundation scientific advisory

committee from 1999 2016 we just let him

off the hook last year so that was like

17 years of service then he asked or of

those years he was the chair and several

years before that he was the vice chair

um

he is you know obviously a long-standing

wide-ranging interest in ADPKD he's run

many clinical investigations on clinical

trials he's an amazing clinician and

works with those patients and I I just

don't think that it's possible to

overstate the impact that ron has made

on PKD research and clinical practice

and we're so so lucky to have him here

tonight to talk about these results and

when it comes to the QA we also have dr.

Terry watt Nick here she's gonna help

out with that part she's an associate

professor of medicine and the division

of Nephrology at the University of

Maryland where she's established an

inherited renal disease clinic she's an

investigator just like dr. Peron in

several multicenter trials include

tempo and reprise that old action trials

that we're gonna discuss here um just

the same as what doctor Peron has done

she leads the Baltimore polycystic

kidney disease research and clinical

course Center she's been a member of the

foundation scientific advisory committee

since 2006 served as the chair for

several years and just kind of past that

that over in October of this year so

she's just recently our past chair she's

serving as a member of our board of

trustees and has dedicated her career to

research and treatment and I know all of

her patients would agree that she's

among the absolute best of our

nephrologist out there and we're just

really happy to have them both with us

so with that I am going to pass it over

to dr. Peron I did yours thank you okay

Alexis you're seeing my screen yep good

okay great thank you very much Alexis

thank you very much for inviting me to

give this presentation and for that

over-the-top introduction so I'm very

pleased to report the reprise clinical

trial results using tool bapt in I'm

sure everyone on the call is familiar

with ADPKD as a hereditary systemic

disorder with bilateral kidney cyst and

a progressive decline in GFR or kidney

function leading to kidney failure in

about half of the patients by the

mid-50s in addition there are external

manifestations which you can liver cysts

brain aneurysms and heart valve issues

so how do we find treatments for PKD

well we can develop new drugs from

scratch but we can use existing drugs in

a new way this is called repurposing and

drugs are developed based on laboratory

and clinical research

answered by institutions by the PKD

foundation the NIH the Veterans

Administration the Department of Defense

in the pharmaceutical industry it's

important to understand how it is that

we can actually go about developing and

creating medication and then selling it

in the United States so all medications

must be approved by the US FDA the Food

and Drug Administration and they must be

safe and effective so this is a law so

they could flower Hera's drug amendments

password to ensure drug efficacy that

means they work and greater drug safety

meaning that they're they're not going

to harm you and this requires

substantial evidence from adequate and

well controlled trials so that's why we

do clinical trials we we do clinical

trials to find out if drugs are safe and

if drugs are effective well I'll talk a

little bit about a hormone called

vasopressin and base impressin is a

hormone that regulates your water

balance and if you drink a lot of water

you make urine that's very light and

clear and if you don't drink very much

water your urine is dark yellow and when

your urine is dark yellow that means you

have a lot of basic recipe well it turns

out vasopressin is bad for polycystic

kidney and shown here on the left side

are a group of experiments and rats and

mice where vasopressin is blocked using

this drug called OB c-23 one opc3 one

two six zero and this is the control a

kidney and you can see that the drug

that blocked the base of pressin

receptor markedly reduce assisted

genesis in each of these animal models

in another animal model if you add sugar

to the water the rats drink more water

and as a result there they suppress

vasopressin and the rats that drink a

lot of water have smaller kidneys that

are less cystic but the most elegant

experiment involves genetically knocking

out vasopressin so the middle kidney in

this slide where my arrow is pointing to

is from a rat which has the PKD gene

but has the vasopressin gene knocked out

and you can see that in the absence of

basic pressin there's virtually no

sister Genesis and when you give this

drug ddavp which is a synthetic form of

vasopressin you cause more assists to

develop and this occurs both in male and

female rats

so vasopressin is a very important

hormone that affects sister genesis and

appears to make it worse well in 2012

the results of the first home app 10

trial were published and this is not the

reprieve study this is the tempo 3/4

study and the tempo 3/4 study showed

that 12 app 10 which blocks vasopressin

decrease the growth of kidneys that is

total kidney volume by about half so the

blue line reflects the 12 abdun treated

patients and the red dashed line

reflects the placebo treated patients

and the effective 12 app yet over a

three-year period was to reduce the

growth of kidneys by about 50% and in

different subgroups 12 app 10 was more

effective in people with larger kidneys

shown here and in people who were older

than 35 versus younger than 35 so the

effect was not diminished in people who

were more severely affected the change

in GFR or kidney function was measured

as shown here by a complicated formula

shown as reciprocal serum creatinine but

again toe mapped in is shown in blue

placebo is shown in red and toe BAP 10

slowed the rate of deterioration of

kidney function over a three-year period

in addition the benefit was also present

in people with larger kidneys versus

smaller kidneys in people older than 35

versus younger than 35 in people with

Jia far less than 80 or GFR greater than

80 so it seemed to work throughout the

disease although the inclusion criteria

for tempo 3-4 was down to CKD 1 & 2

so the summary of the top ten results

for ADPKD are shown on this slide I just

showed you the tempo three four results

that tempo reduced the decline in GFR

from ten point one to six point eight

MLS per minute over three years in

patients with an estimated creatinine

clearance greater than sixty this three

point three MLS per minute difference

was maintained for two additional years

when all patients received told a peon

and an open-label extension study called

tempo for four and with monitoring every

four months liver enzyme elevations that

were greater than three times the upper

lid of normal occurred in about four

point four percent of captain and one

percent of placebo treated patients and

severe but reversible Linzer liver

enzyme elevation occurred in three out

of one thousand two hundred and seventy

one to have a pinch rated patients I'm

now going to talk to you about the

reprieve study this was presented last

Saturday at the week ago Saturday at the

four ology meetings during kidney week

and was published simultaneously online

a New England Journal of Medicine Andhra

priest stands for replicating evidence

of preserved renal function the best

nation called apt down safely and ADPKD

just to be clear the reprieve trial

finished in April excuse me there's a

lot of paper rattling in the background

perhaps you could moot your commute your

microphones the reprieves trial finished

in April 2017 and the objectives in the

rupee's trial were to ascertain the

effect of Tove appt tend to slow EGFR

decline and to evaluate its overall

safety and liver safety with monthly

monitoring in later stage ADPKD patients

with GFR between 25 and 65 ml s per

minute the entry criteria included a

diagnosis of ADPKD ages 18 to 55 with

the GFR between 25 and 65 or in older

individuals GFR between 25 and 44

and evidence of progression as shown by

a decline in GFR of greater than two MLS

per minute per year prior to entry and

of course no previous treatment with toe

BAP yet this was a worldwide study

performed in 213 sites in 21 countries

across six continents shown in blue on

this slide I'm now going to talk about

the trial design and end points this is

a complicated design because it was

designed to decrease the number of

people who would drop out of the study

as I think everyone knows toe mapped in

makes you pass large quantities of urine

and in the first trial some people

dropped out because they couldn't

tolerate passing that large amount of

urine and having to drink all the water

required to prevent from becoming

dehydrated so there was an eight week

period during which time people were

screened they were given a placebo for

one week and for the next two weeks

everyone received told apt in both the

control group and the experimental group

and then during this three-week period

you had to be able to tolerate a dose of

12 aptean of at least 60 milligrams in

the morning morning and 30 milligrams in

the afternoon and you could tolerate a

higher dose but you couldn't you had to

tolerate no less than 60 30 at this

point people were randomized to

double-blind treatment with either 12

aptean or placebo and you could go as

low as 45 15 or as up as high as 90 30

during this time period the follow-up

measurements were obtained off of 12 opt

in between 7 and 40 days post treatment

and I'm now going to talk about the

measurements that were done to ascertain

the effect of 12 apnea

so the affective told mapped in was

compared to measurements of EGFR

estimated GFR taken pretreatment off

drug and post-treatment

off drug when there was a mean of at

least three mean of 3G afar's taken at

each of these periods this was the

primary endpoint the difference in GFR

between pretreatment and post treatment

off drug the secondary endpoint was the

slope of GFR from the placebo run end

that is these dashed blue lines to

follow up I'll talk now about the study

population characteristics the two

groups had a mean age of 47 years and

these patients are older than patients

were in the tempo 3 for study at age 39

years and in addition their GFR was

lower approximately 41 MLS permitted as

compared to the tempo 3 for study where

the EGFR was 81 so about half the level

of GFR and about 8 years older than the

tempo 3 for study and this slide shows

the primary endpoint as I mentioned the

off treatment baseline compared to the

off treatment end of study and toe

mapped in reduced the decrement in a GFR

by one point two seven MLS per minute

for one point seven three meters where

this was highly significant meaning that

it had very unlikely to have occurred by

chance alone and the effect was in most

of the subgroups

however in individuals older than age 55

which was a smaller group there was not

an effect of 12 apt in that could be

detected in a study in smaller groups of

non-caucasian and in those with

relatively well-preserved kidney

function that is with a GFR between 60

and 65 these are all small subgroup

whereas Tom aptean was effective and all

of the other groups and if we look at

the EGFR slope again told that bin

reduced the GFR slope by about one

similar to the change in from beginning

to end and the effects were similar in

the subgroups so CKD three a B and four

benefited older individuals seem to have

less of in effect as did the

non-caucasians and the people with very

early disease regarding the individuals

over age 55 it's likely that these

people were very slowly progressive and

that's why they were unable to show a

difference now I mentioned that people

had to go through a period of time

during which they were all on Tove apt

in and during this time everyone was on

twelve apt and during that time and 6.8%

of individuals discontinued the drug and

about four point six percent of those

were due to a narcotic aqua retic effect

meaning they peed a lot they more than

they could stand and they weren't able

to tolerate it and if you look at the

symptoms related to large volume

urination polyuria meaning you go a lot

nocturia meeting you go at night thirst

means you have to drink a lot of water

polydipsia and dry mouth are going along

with having to drink a lot of water you

can see between 10 and 30 percent of

individuals experience this effect

during the single blind run-in period

however after randomization the number

of people experiencing these urinary or

aqua retic symptoms was much lower and

only 2.2 percent of individuals

discontinued due to an aqua retic effect

i mentioned the issue of liver enzyme

abnormalities and in the told apt in

group monitored monthly these occurred

at 5.6 percent at a time in the placebo

group at one point two percent

and there were no severe elevations of

liver functions and in all cases these

enzyme elevations return to normal after

discontinuation of the medication so the

conclusions of this study is that toll

babkin reduced the decline in EGFR from

3.6 to 2.3 for MLS per minute over one

year in patients with reduced GFR

between 25 and 65 MLS per minute so with

the other study the tempo 3/4 study this

is suggested that told map 10 is

effective over a broad range of disease

and may delay and stage kidney disease

liver elevation enzymes and rupees were

similar those in tempo 3/4 and 4/4 were

reversible and there were no cases of

severe liver toxicity possibly due to

more frequent monitoring and early

interruption of toll babkin well before

we turn to the question and answer

session I thought that it would be

useful to preempt the some of the

burning questions that some of you may

have so the trial results have been

submitted and accepted by the FDA on

October 24th 2017 the FDA decision on

approval will be no later than April

24th 2018 that is six months and it's

possible it could be earlier other

questions you might have are what are

the indications that is what what does

the label say about who should take to

lap down and these issues are under

review by the FDA and I don't know the

answer right now and for example who

should take told apt in what age group

what GFR level what tkv level again

these are under review by the FDA and we

don't know the answer right now in other

countries where 12 aptean has been

approved for example Canada Europe Japan

Switzerland etc the indications for

using told map in our

having evidence of rapid progression or

a high risk of progression and this

could be related to actually measuring

the rate of change of GFR or actually

measuring changes in total kidney volume

but we don't know what this will be in

the United States and then because of

the elevation of the liver enzymes that

occurred they will very likely be a REM

strategy REM stands for risk evaluation

and mitigation strategy and again this

is under review I don't know what it'll

turn out to be but in Canada for example

liver function tests must be obtained

monthly for the first team first 18

months the drug is dispensed by a

specialty pharmacy only after liver

function tests are reviewed so at least

in Canada you have to get your liver

function test measured every month and

only after you have the measured can you

get access to the drug through the

specialty pharmacy and I will reiterate

we don't know exactly what the REMS is

going to be in the United States so at

this point Alexis I can turn the podium

back to you and happy to answer any

questions that you may want to go back

to on your slides okay so first of all

an early question we got was was

hydration controlled or how is hydration

controlled through the study groups or

not controlled tracked I think is the

word that I'm looking for

and would it impact the outcomes so can

you talk a little bit about that sure

so hydration was not specifically

measured that is people were not

required to measure how much water or

other fluids they drank or how much

urine they made but everyone was

encouraged to drink at least to thirst

and when you make a lot of urine you get

thirsty and that's a very strong driver

of of hydration in addition we monitored

the level of sodium in the blood and if

the sodium level if you're not drinking

enough water and you're taking two lap

down the sodium level goes up so this

was monitored very closely throughout

the study everyone is encouraged to

drink large amounts of water because

suppressing vasopressin is thought to be

beneficial in in ADPKD so I was just

going to China and say that if if the

group on the sugar pill or placebo were

drinking large amounts of water if

anything that might make the trial

results less remarkable you know that's

right so the control group was

encouraged to drink lots of large

amounts of water so they may actually

suppress their vasopressin more than

people would otherwise do okay great so

we also received this question ahead of

time via email kind of earlier today

someone was just asking about polycystic

liver disease and told Afton so is there

is there any is there anything to

comment on I know that that hasn't been

tested but if you do have PLD is table

apt in something that you should

consider avoiding or taking or is there

anything about to say about that or is

that just more of a we don't really know

kind of a question

well there's there aren't vasopressin

receptors in the liver cysts so there's

no reason why told app ten would benefit

the liver per se in terms of the liver

toxicity it's not thought to be related

to liver cysts that's being looked at

and so one would whether you have liver

cysts disease or not it would be if you

were otherwise found to be eligible if

told apt in was eventually approved by

the FDA then it would be okay to take

okay so could you go back to the slide

where it shows for the reprise study who

the participants were like you know male

versus female Caucasian versus non

Caucasian do you know which one I'm

referring to this one here yes so we

have a couple of questions about that so

one person is wondering it seems and

they they felt that it appeared the

population favored Caucasian males which

I don't I don't know that's really well

the sex difference was not significant

fifty one percent versus forty nine

percent the you know PKD affects all

races and all its president of all

countries I don't know why

non-caucasians didn't sign up they

certainly were eligible they were fewer

Asian patients in this study for one

reason the study was not done in Japan

there was a separate study going on in

Japan and I could go to the the map and

you can these are the countries now

these the sizes of the countries don't

reflect the population of patients from

each of those countries for example even

though Russia is the largest country

shown on the map that certainly did not

have a large number of participants in

the trial so what you're saying is that

the lack of non-caucasian participants

isn't something by design or you know

indicative of anything other than the

patients who met the inclusion criteria

and were able to be in the study it

wasn't it right so you know centers were

this studies where those studies were

done invited participants irrespective

of race gender

and other characteristics as long as

they met the general inclusion criteria

I was just gonna say that I think the

issue of having predominantly Caucasian

participants in clinical trials is kind

of a an issue that has is the case and

many other trials not just the PKD

trials and this I think is something

that the community has to work on to try

to you know broaden and draw in people

of all different ethnicities absolutely

okay so there were other questions about

that and I've lost them there are a lot

of questions coming in so I'm just I'm

gonna say now we might not get to all of

them but I will do my best to meet the

themes of the questions coming in

someone is asking this is it when

someone's asking about the two-week run

in periods and would it have reduced

sort of the difference between the

treatment and the placebo and how was

this address so I I find that that's an

interesting question can you talk about

that run-in period and why that was

necessary and would that have had any

impact on the results so the the run-in

period was designed actually requested

by the FDA to avoid the problem of

people dropping out of the twelve abdun

arm because they couldn't tolerate the

medication so in the tempo three four

study more people dropped out of the

twelve apt in group than the placebo

group although there were dropouts in

the placebo group even in the tempo

three-fourths study because people's

couldn't tolerate the aqua the effect of

drinking so much water so everyone in

the run end period had to tolerate a

minimum of 60 milligrams in the morning

30 milligrams in the afternoon of told

Afghan if you couldn't tolerate that you

were not randomized at that point once

you tolerated that

you were randomized to double-blind

treatment either told Apted or placebo

now remember the primary endpoint was

pretreatment off drug baseline the mean

of three EGFR measurements compared to

the primary post treatment off drug

follow-up which again was the mean of

three estimated GFR s so I don't believe

the run-in period affected the results

and it was very effective at screening

out people who couldn't tolerate the

medication great so we've had a couple

of questions about this idea of rapidly

progressive or high-risk individuals so

can you talk a little bit about what

that means when you refer to rapidly

progressing people and in terms of the

trial and how how about all kind of

plays together so rapidly progressive

disease can refer to a rapid decline in

in GFR and in the in this trial the

entry criteria for ages 18 to 55 was

simply to have a GFR between 25 and 65

for people older than 55 there was an

additional criteria for progression so

let's say for example you get to age of

55 or 60 and your GFR as normal well

wouldn't make any sense to put you in a

clinical trial because you're not

progressing you know you're not getting

worse you don't really need a medication

so older people with well-preserved

kidney function are progressing more

slowly so that's that's why they were a

criteria for progression in people older

than age 55 regarding who should get

told mapped in if it's approved as I

mentioned we don't know what the

requirements will be by the FDA if it is

approved but in other countries there is

a criteria for rapid progression because

of because of the

the effective toll bapt in and make you

produce large amounts of urine and the

possible effect on liver function test

you would only wanted you would only

want to give it to people who you think

would in which the risk benefit ratio

was worth it

so for example people that know risk of

progression you wouldn't put them on a

drug with side effects I was just going

to add that the research community has

spent quite a bit of effort and trying

to understand who is more likely to

progress more quickly and so there are

different algorithms being developed so

if you are young and have very large

kidneys the likelihood that you're going

to progress is much higher than if

you're 70 and have a large kidney so

there are different algorithms that have

been developed by a number of groups to

try to identify those people who are

more likely to progress would someone be

able to take this drug so if if they're

young and they're rapidly progressing

and this does preserve function how long

can they take the drug before they have

to stop her before some other side

effects is it short term or long term er

what are your thoughts on that well

patients have been taking toll bapt in

for more than ten years starting from

the very early phase two studies and the

initial toll babkin study that that

started in I believe 2006 and many

people are still taking the medication

without any long-term consequences there

has we have we haven't looked beyond 10

years just because it hasn't been used

longer than that I was just going to add

that I think additional study you know

has now if the drug does become approved

it'll I think it'll be instructive to

figure out if the effects

Syst over the full course of ten years

because the studies have not you know

have been relatively short so I think it

will be helpful to try and look at that

question in a formal way once the drug

is approved if it is yeah although the

the tempo for for study which I didn't

review showed that the effect was

sustained for at least five years as

long as it was measured so was it was

addressed formally for at least that

long it's a period of time so I think

it's also important to mention that the

other indication that this drug is

approved for its intended for a short

term usage right so it's it there's

another reason that people would be on

tol baktun and it goes by a different

name but so some people I there's

there's a lot of sort of questions

coming through about well my doctor told

me it was just for short-term or I was

prescribed but can't get it because I

don't have the other indication so can

you comment on the other use of this

drug and how that's not the same thing

as using it for Toback art for ADPKD

well Taub apt in was approved for the

treatment of hyponatremia that is a low

level of salt in the blood due to water

water excess and it's marketed under the

name of Sam Scott the label for Sam

Scott indicates it's only to be used for

hyponatremia so that your doctor

shouldn't prescribe that for polycystic

kidney disease

the other issue as I mentioned is that

if one was if told Apted was approved

it's important that the liver function

tests are measured on a monthly basis

for at least the first 18 months so for

the treatment of the low sodium as dr.

Peron said usually you would only use it

in that circumstance maybe for a week or

two it's relatively short-term so

the chance of seeing elevated liver

function studies when it's used for such

a short period of time as unlikely and

also the way Samsa the way the label

reads I believe that has to be started

in the hospital and presumably if told

abdun is approved for PKD that wouldn't

be the case hopefully okay so there

there are a couple of questions about

the different types of ADPKD a night I

think if I'm understanding the questions

correctly we're talking about the

different ad you know the PK t1 vs PK t

to gene and then there's other genes

involved so can you please comment on

the usage potential usage of this drug

when the different genetic causes of PK

d are involved as someone were to know

their genetic background is there one

versus another would this work sort of

indiscriminately for any genetic profile

well I can comment on that the genetics

weren't measured in the tempo 3 for

study during the trial but they were

measured after the trial was done and

analysis was done and the individuals

that benefited most were people who had

more severe disease so that typically is

a peak ad one mutation versus a peak ad

- but it's not necessary to know the

genotype to prescribe the medicine if it

were to be approved by the FDA other

measures are risks such as as dr. Watney

mentioned kidney volume at a certain age

is actually a nice useful way of

estimating progression so it's unclear

how the label the United States will be

written if it's approved but any those

with more severe disease either by loss

of GFR or large kidney volumes at a

young age or have been shown to benefit

in analyses of the tempo 3 for study

okay great so another question that I've

gotten several times is how will how

would this be tracked moving forward so

will reprise participants or tempo

participants will they continue to be

followed so that we can see more of the

sort of outcomes effects long-term

potential side effects things like that

will they be followed or will it if this

drug is approved will that kind of end

and just move into regular usage so

everyone who signed a consent for the

open label continuation study after

reprise was promised

I believe 18 months of participation

during the open label follow-up and I

don't believe there was any plans right

now to formally follow those individuals

after that 18 month period of follow up

there are several questions about how

the dosage was determined the dosage for

different people and how sort of what

that process looks like can you talk

about that

well the going back a long time the the

dosages of twelve aptean were determined

in phase one and phase two studies that

were done prior to the tempo study and

these were based on the effect of twelve

abdun to dilute the urine that is to

make the urine less concentrated and

that's how the dosing regimen was

initially established in addition of the

pharmacokinetics of the drug were

established that is the the blood levels

and of the drug and its metabolites were

established to understand how long it

works and that's why it's being given as

a twice day dosage with typically the

larger dose in the morning and the

smaller dose in the late afternoon to

try and minimize the disruption in in

sleep in the reprieves trial when you

were randomized that you were randomized

to either active

medication or placebo and if you are on

60/30 you went right over to 60/30 if

you're on ninety thirty you went over to

ninety thirty and you were either given

the active medication or the the matched

placebo if you weren't able to tolerate

the 60 30 trial dose as the trial went

on you could down titrate to 45 15 so

the doses would determine after

randomization by tolerance and when the

subjects came for their study visits

they were asked the question could you

tolerate this dose of medication for the

rest of your life and if they could if

they answered yes to that the medication

dose was continued if they said no then

the dose was down titrated to a lower

level which they could tolerate Oh

another question is do you think it

would make sense to periodically stop

treatment to determine if you know just

to see it does that reverse the effect

is it um you know evaluate or content or

consider halting treatment if it's not

doing anything you know would you ever

consider that every you know a couple of

years or something just stopping

treatment for a period of time to see

how that has an effect on tkv and on

function well I think it's very hard to

do an experiment on one patient I think

it did if one was concerned that the GFR

was declining too quickly

one might stop and see if if stopping

the 12 a pin reversed that effect but I

don't know how to look at the effect on

one patients measurements and know if

that drug is working or not working for

them that's why studies are done in in

populations of patients we can look at

the effect in large groups of course if

there's intolerance of the dose or other

side effects that it would make sense to

hold the medication and reassess at that

point okay

I think the other the other thing is

that most of the benefit in terms of

slowing the increase in in kidney volume

actually occurs within the first year so

and then the decline that the GFR

benefit is kind of sustained right well

we don't know exactly how the effect on

Gian kidney volume translates to a

benefit in in GFR but nonetheless the

the GFR benefit of 12 Afghan was

sustained both for the three years of

the temple three for study and for the

two years of the tempo for four

open-label extension so even though the

largest effect on total kidney volume is

seen in the first year nonetheless see

effect on EGFR continues for at least

five years okay so we have several

questions about side effects and

lifestyle limitations so one person is

saying it appears as though the side

effects declined over time is this an

accurate understanding of it or today is

that do they kind of misunderstand and

then the other person is just wondering

if there are other lifestyle limitations

if if you're taking two batches so

alcohol you know you have to watch that

is there do you have to have a certain

exercise regimen or diet or other

lifestyle things that need to be

undertaken with this drug okay let me

let me find the the slide with the I'm

sorry I'm having trouble finding this

slide so okay I think the questioner

might have been referring to this slide

and so this was the sorry the five-week

single-blind period where everyone was

on table apt in for the run-in and for

three weeks so total of five weeks

and they were there were a lot of

aquatic effects you know polyuria

nocturia so related to making a large

amount of urine or drinking a large

amount of fluid they were less during

the one-year double-blind study in part

because some of the people dropped out

and in part because people may have been

able to develop tolerance and my

experience with the medication and

perhaps dr. Wagner can offer hers is

that people tend to tolerate it better

as time goes on I will mention that all

the patients I take care of during the

clinical studies have told apt in know

exactly where all the public toilets are

on their commute to work and they plan

their commute around the timing of the

morning medication so it does have a

powerful effect to make you pass a lot

of urine and people are able to plan

around that in addition the amount of

urine you make is also a function of how

much salt and protein you eat so if you

eat a lot of salt and eat a lot of

protein you'll make more urine on the

other hand if you decrease the amount of

salt and protein in your diet you will

have a lower your an output and be

better able to tolerate the medication

dr. what Nick what was your experience

with patients on tove ab10 yeah I had a

similar experience I think as time goes

on people adjust and what I haven't what

I haven't completely understood is

whether some of it is just you're used

to it and you adjust your life around

going to the bathroom as you said and so

it becomes less bothersome versus the

effects wear off a little bit as time

goes on I think it could be a

combination I would also say that in

terms of starting told optin if it is

started slowly in my experience people

tolerate that a lot better so you know

the gradually ramping up the dose even

to the 45 15 I think can make a big

difference I don't know Ron did

in the tempo 3/4 study and in the

reprieve the dose was up try to titrate

it fairly quickly

it was the two-week up titration and

then the three-week period of time on

till vApp 10 so running it in over 5

weeks I would in practice I would start

it off at a lower dose and allow

toleration of the much lower dose prior

to ramping up okay so can you I just

want to make sure that it's really it's

clear there's been a couple of questions

there was not an increase in GFR but

rather it was a slow in the decline of

GFR correct that's correct

there's been a couple of questions so I

just want to make sure that was clear

why about okay so there there's a couple

of comments in here about water intake

and is it really is it the the drug

that's causing the positive results or

is it just the increased water and then

someone said that there was a study and

I'm not aware of this study but that

doesn't mean much that it's or something

that proves that water protects kidney

function I'm there under the impression

that it could harm kidney function and

so can you just talk a little bit about

so captain and the water intake and how

all that sort of connects well

tove apt in blocks the vasopressin

receptor so that the vasopressin in your

body can't make the kidney hold on to

water and as a result you passed large

amounts of urine you get thirsty and you

drink a lot of fluid and you keep

yourself in balance for people who are

drinking water in order to reduce the

level of vasopressin you you have to

drink anywhere from two to three and a

half liters of water per day and it will

lower the level of vasopressin in your

blood so vasopressin definitely acts on

your kidney by blocking the base of

prescient receptor we believe that this

translates to an effect inside cells

decreasing decreasing the secretion of

fluid into the cysts and also slowing

the rate of growth of cysts cells so a

very specific effect there are no

studies looking at long-term water

intake I was involved in a short-term

study where one could lower the level of

vasopressin as measured by a molecule

called co-captain by increasing water

intake and decreasing the intake of salt

and protein but we didn't look at the

effect on kidney function or kidney

volume we only showed that you could do

that over a very short period of time

okay so there are a number of questions

about pain and is the stove actin have

any impact on pain what does it help

reduce pain or have no effect is there

no connection can you can you comment on

that I think you did comment a little

bit on it so maybe here where you're

talking about back pain and renal pain

and things yes so in the tempo 3/4 study

told apt in decrease the time to

increase the time to development of

kidney pain so people on told Afghan had

less pain or less development of pain

than the placebo group in in this chart

that happens to be up there

renal pain is less in the 12 opt-in

group than in the placebo group and back

pain is less and told Afghan that in the

placebo group so we think by decreasing

the expansion of cysts 12 abdun results

in a decrease in the amount of kidney

pain and the complications related to

cyst enlargement okay there's there's

one question here and I'm actually a

as well although I didn't think to ask

it tonight but were these results a

surprise or were they expected you know

you had the previous trial and then

we've had the tripe temperature on the

open-label trial so were the reprise

study results a surprise well I think

that they were they were close to this

effect you'll recall that the inclusion

criteria for the tempo of 3/4 study were

based on an estimated creatinine

clearance greater than 60 and it turns

out that there were many people not many

but a number of people with GFR that was

between 45 and 60 so people with more

advanced kidney disease and when

secondary analyses were done of the

tempo trial it showed that people with

CKD 2 & 3 actually benefited the most

from Tove apt in as compared to people

with CKD 1 so there are certainly clues

that the drug worked in people with more

advanced kidney dysfunction but of

course the reason you do a trial is to

find out something and we're not always

we're not always right or but in this

case the trial was beneficial that

showed a benefit and people with more

advanced kidney dysfunction I'll speak

for myself I thought well it the it was

highly statistically significant so that

I thought that the difference was very

robust and so you never know exactly how

that is going to turn out so the p-value

is Rana showing here of less than 0.2

0.3 for study no it was actually pretty

good it was point O for I mean first for

kidney volume it was quite good but not

quite as good for EGF

okay there was one question about table

apt inand cardiovascular disease

are there any connections and he

concerns any positive any any comments

on the connection between those two

cardiovascular disease until wrapped him

I'm not aware of any difference in

cardiovascular events during this one

year trial okay

short and sweet if that's what the

question was

I mean Tove abdun was studied a decade

ago in heart failure not in PKD but I

don't know that that's related to PKD

question yeah I I'm so sorry I lost it I

wanted to ask a question so there have

been several questions around other

studies so you said you know these these

studies are done and you can't

participate but are there other studies

that people can consider participating

in if you know to help drive sort of

research forwards sure well I would send

you to the PKD foundation website look

at the clinical trials tab and see what

you may be eligible for you know that

now many of these new trials are being

done in just a few centers for example

dr. wat Nick and I are and collaborating

on a study of metformin in polycystic

kidney disease there are other trials

going on some of which are not

intervention trials but just studies of

genetic analysis etc so you can look at

the PKD foundation website and see what

you might be eligible for in addition

you could go to clinical trials gov and

search for polycystic kidney disease

clinical trials and see what turns up

that you may be eligible for

there's I think a lot of interest in

studying polycystic kidney disease which

i think is going to be beneficial to

patients in the long run and so I would

urge you to participate in clinical

trials I'll just go back to my this

slide in order to sell drugs in the

United States they have to be approved

by the FDA that's a law passed by

Congress and drugs have to be

efficacious that means they have to work

and they have to have safety and this

evidence comes from adequate and well

controlled trials so if there's no

trials there's no drugs so we do need

you to participate and that will

hopefully improve things for both this

generation and generations to come I

want to echo that it's it's essential

although told apt is a great advance I

think that um there are other drugs out

there and that will also need to be

tested and several people are asking

what the website is for finding the

other clinical studies and so I'm

looking that up right now so that I can

put it into our chat thing so I'll put

it into the chat and send it out to

everyone before the end of the night and

then we will also include that in the

follow-up email that we send can you

also include the link for the PKD

foundation's clinical trial site yeah

that's what I'm talking about yeah yeah

yeah well yeah so all the the studies on

the foundation site actually linked to

the specific clinical trial gov page so

the study the Foundation's page sorry I

just totally blanked for a sec the

Foundation's page is is a great resource

because it will link to the clinical

trial page which can be a little bit

confusing sometimes

but so I just realized I totally lost

track of time it is nine o'clock and I I

think I'd like to give both of you one

more time to say any final comment and

then we'll close this out there were

still questions left in in comments and

I will send those over and see if we

can't get some general commentary out

but we will post this otherwise do you

have any last messages or comments Ronon

Terry well I'll just say this is a I

think a promising time for the study of

treatments for polycystic kidney disease

I'd encourage everyone to participate in

clinical trials and let's hope we

continue to see improvements in in

treatment and delays and progression to

kidney failure though that I think this

is a real milestone it's the first

approved treatment for PKD it's very

exciting and I've just not approved yet

but we're optimistic and I just wanted

to also thank everyone out there who

participated in these studies and stuck

with it did all the visits it's a it's a

lot of work for the participants in it

and I think it benefits the entire

community it's huge okay clinical study

website to everyone so you can see that

it is org slash living - whit - PKD

slash clinical - studies I know that's a

mouthful - look at the chat box I'm in

and also check your email when we send

that out next week and I cannot say

thank you enough to dr. Peron and dr.

Watney for being here tonight and giving

us their time and to everyone for all

the amazing questions you asked and so

sorry we didn't get to the model we'll

look at them later and then certainly

continue to send them to us at education

epic a teacher that org if you have

additional questions otherwise everybody

have a wonderful night and I look

forward to talking to you all the next

time we get together on the webinar

thanks a lot thank you thank you