USH2018 Mariya Moosajee Clinical trial design for nonsense mutations treatment of USH2A

USH2018 Mariya Moosajee Clinical trial design for nonsense mutations treatment of USH2A


(Sebastian Klaes) Ok, let’s start. Please take a seat. We will go on with our next session. Inclusion through innovation. When we started with the first
planning for our symposium, maybe 2 years ago, there we thought
we should create a platform for companies and upcoming products
with interest for us Usher people. So we decided to start
with our session, or to create a session
inclusion through innovation. Now we have four
companies, or four approaches, very interesting things which will show
us their newest approaches and products. Our idea is that we are going
to have 10 minutes talks, or 10 minutes presentation
and after the presentation we have time for a few questions. Our first presentation
will be hold by Mariya Moosajee, she is coming from the
Moorfields Eye Hospital from the University College London,
so, are you ready? (Mariya Moosajee) I am ready. (Sebastian Klaes) Ok, then. (Mariya Moosajee) So, good
afternoon ladies and gentlemen, I wanted to say thank you for inviting
me to speak at this conference. The last two days of the
scientific meeting have been inspirational and very informative. I think there is a real
push that it is moving towards clinical
translation and therapies. Today I am going to talk
about clinical trial design for nonsense suppression therapy
for USH2A Ushers disease. So, to start with, I am just
going to quickly go over what a nonsense mutation is. Now this is a single change in a letter in your genetic
code within an instruction part of the gene that leads to the
introduction of an abnormal stop signal. And these are quite common mutations, they can account for up to 70 %
of human genetic disease. Now, what happens in your cells normally
is, you have protein making machinery, that reads the instruction parts
of gene to create protein. When you have a nonsense mutation
or an abnormal stop signal, when your protein making
machinery hits that stop, it just stops and so you end up with
shortened non-functional protein. This is what ultimately leads
to the disease process. What we have done, we have identified
a number of small molecule drugs, the one I am going to talk
about today is Ataluren which has been commercialized by a
company called PTC therapeutics. But when the drug Ataluren binds
to the protein making machinery, it weakens its recognition of
the abnormal stop signal and can overwrite it, leading to the production
of normal full-length protein. And it is able to do that, so
it generates around 20 to 25 % of normal USH2A or whichever
protein that you are missing, and that can be enough in our
patients to actually hold or slow the disease progression down. Ataluren has a large body of evidence
for various different conditions, multi systems and including
retinitis pigmentosa and genes such as USH2A,
USH1C and various others. It has approval for treatment in Europe and in the UK for Duchenne’s
muscular dystrophy, for patients which have
nonsense mutations. And the drug itself is save and
tolerable to be used in children from two years onwards. It’s a powder that is, that is dissolved
in water and is drunk three times a day. So far, there have only
been minimal side effects, so transient diarrhea or nausea when
you first start taking the drug, which subsides after about a week. But there have been no
serious adverse effects or any serious ocular events and
they have treated nearly over a thousand patients with
5 to 8 years follow-up now. And currently there is a phase
2 clinical trial for aniridia, a different eye condition
where children are born without the colored part
of their eyes, their iris, and they develop cataracts,
they have glaucoma. They can have wobbly eyes, nystagmus,
they are born with poor vision. So, this trial is on the way and we hope to see the
results of that in 2020. Now, we want to apply
this drug to Ushers and in order to do that in
a clinical trial setting we need to know what the
outcome measures would be, so we can monitor a
response to treatment. So, what we started to do
was a natural history study of our patients with USH2A. At Moorfields we selected 57 patients that had on average three
clinical visits one year apart. So, we have many more patients, but these were ones
with good data sets. And of those 57 – they
were almost equally divided – a third had nonsense mutations. That is a depiction of a cohort
generally in Usher syndrome Type II, USH2A, 30 % are due
to nonsense mutations, and then a third were
insertions and deletions and 17 were missense mutations. The average age of that
cohort was 40 years and it ranged between patients
that were 15 to 66 years of age. The first thing we did is
look at their visual acuity, their central visual acuity. And there is a graph
behind me on the screens, there is a lot of blue dots and a lot
of lines connecting it, but essentially, if you can see there are
quite a few horizontal lines which means that over time their
vision didn’t change very much. So visual acuity
isn’t the best indicator of a treatment response over
a minimal period of time. We then looked at another parameter, something called optical
coherence tomography or OCT, it’s a scan that most of you will have
each time you go to see your clinician. And it is where we shine infrared
light into the back of the eye, we take a cross section. We measured the area where you
had intact light sensing cells, your photo receptors, and
we measured that area, it is called the ellipse width zone
length over a three year period. What we found was that on average across
the whole range of patients we detected a 7 % reduction in that size
of length of the ellipse widths zone, over a one-year period, but a
22 % change over three years. So, we are detecting
a change every year, but the issue that we have is
that there is a measurement bias, an error that is introduced by people
who are measuring that length. So, to be absolutely accurate, we felt that a one-year time
point was on the carve of where you would detect a treatment response. But if you look at the graph as well, you can see that if we looked at
patients younger than 30 years of age – The dots indicate a patient and the lines
joining them are the change over time. The younger patients have more steeper
lines, showing a steeper decline, whereas the older patients that were 30
plus, their lines are much more gentle. There is not much change going on. So, if were to do a trial, the best
cohort to detect the biggest change would be the younger patients. Another imaging modality we looked at is
called Fundus autofluorescence. Again this would be routinely
undertaken in your clinic visits, where we shine a very bright
flash of light into the eye. And in Usher syndrome we get
this characteristic bright ring around your area of central vision. And we can draw a line
around that ring. And that ring, the
reason that it’s bright, is because that supporting layer
of your light sensing cells, called the retinal pigment epithelium it has a buildup of metabolite products
that cause it to hyperfluores, and this is showing that the cells
are present, but they are sick. They are not working very well, because they are burdened
by this buildup of product, and so they autofluores,
they shine brightly. Now, over time, those cells that were
under stress and are sick and are dying off, so that ring
is encroaching into your area of central vision and is
getting smaller over time. We measured it at one
year and at three years, and we found that on average there
was an 11 % reduction in that ring size over a one-year period and
after three years a 32 % change. So, this is probably a better
parameter than all of the others, but if we combine them all we are more
likely to be able to gage an effect. So, then we come to the
clinical trial design. So, we had patient discussion
groups at Moorfields and some of the members that came to
that are actually in the audience here. And one of the biggest things that they
said was they didn’t feel comfortable with a trial where you were
treating a set of patients and giving the other set a placebo
and not giving that other set of patients the opportunity to
ever have the drug treatment. So, we decided to have
a cross-over trial. One, because this is a rare disease and we need to maximize the number
of patients who are on treatment. But we are giving everyone an
opportunity to be on the drug, but also it will inform us about what
happens after you stopped the drugs. By having a group that is on Ataluren and then having a small
wash-out period, – the drug can be washed out of your
body system after just a month – and then just following those
patients on the placebo, we will be able to see if the change of
decline, the rate of ring constriction or loss of light sensing
cells remain stable or when they start to decline again. And we felt that we needed a two-year
period to be absolutely safe, to be able to gage whether
there was a change at all. So, this is what we decided: Around 20 patients would be on Ataluren and 20 would be on a placebo,
and then have a wash-out period. Then the patients that were on the
placebo will then be given the drug, to see if that would slow
down their degeneration and the other 20 patients
would continue on a placebo and we would monitor the
effect of the drug. For the outcome measure the trial, this drug has never been tested on
a population with retinal disease, so working with the company it was
felt that the primary outcome measure should be safety to ensure
that there were no adverse effects. And as secondary outcome measures we would consider measuring the
auto fluorescent ring size, using OCT to look on
that ellipsoid zone. But we would also look
at visual acuity, because even though those cells
which were brightly fluorescing, were sick, they were still alive, and
if we could provide protein to them, by mechanism of the drug action, then
maybe they would start working better and maybe the vision
would improve slightly. So we wanted to include that. And then there were a
number of other tests that we would include as
exploratory parameters, like visual fields, color
vision, adaptive optics. So, how can you get involved? The first step always is to
establish your genetic diagnosis. If you don’t know the gene
that is causing your condition I urge you to seek out your
clinicians to get genetic testing. If you do know the gene, then it is important to find
out what type of mutation. Because if you have a nonsense mutation then this therapy may
benefit you in the future. And the fact that this
drug works on a mutation, it doesn’t matter what gene causes it, or what the name of your disease is,
if you have a nonsense mutation, you may benefit from this. And if the trial is successful, we hope
to move to a phase three clinical trial, where we involve patients with
all different retinal disorders caused by nonsense mutations. If there is a natural
history study on the way, near where you live, please
participate in that, especially if you are unsure about
going into treatment trials. Because by allowing clinicians
to study your disease, it gives us insides, it helps
us to develop therapies and it helps us with the
outcome measures with trials. And if any of you have any
questions or you would like me to check your genetic mutation,
then please feel free to contact me, using my e-mail address which is
[email protected] And if you need that, I am sure that the
Usher conference will circulate that. And so with that I would
just like to thank my team and special credit to Dr. Adam Dubis, who really lead on the
natural history study. Thank you very much. (applause) (Sebastian Klaes) Thank you very much. We have now time for, I
guess, one question. I don’t see any hands. So maybe you can also use the
opportunity to write Mariya an e-mail, so please feel free.


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