181126_Bruce_Kirkham 26 Nov
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Hi, I'm professor Bruce Kirkham,
I am a rheumatologist at Guy's
and St. Thomas' hospital in London
and today I'd like to talk to you
about ixekizumab
and the ixekizumab clinical trial
program in psoriatic arthritis.
But first of all,
let's talk about ixekizumab.
Ixekizumab is a monoclonal
antibody directed to IL-17A
and you can see that the IL-17A
is an important proinflammatory
cytokine in psoriatic arthritis,
spondyloarthropathy
in general and also in psoriasis.
Now ixekizumab is an
IgG4 molecule,
which is being engineered,
so it doesn't bind complement
to reduce unwanted side effects.
It also has a very high affinity
to IL-17A,
so we can use a very effective dose
in a small volume.
Now the half-life of ixekizumab
is 13 days,
so the injection can be given
once every four weeks,
when a patient is in a stable state.
The dose for patients with
psoriatic arthritis is two injections
that come in 80mg injections;
the starting dose is two injections,
i.e. that is 160mg,
and then one injection 80mg
every four weeks following that.
For patients with moderate
to severe psoriasis,
they need a higher dose and
so they actually start with 160mg
followed by a single 80mg injection
every two weeks for up to 12 weeks
and after 12 weeks they carry on
with 80mg every four weeks.
Turning to the clinical trial program,
this trial program is
the SPIRIT program.
There are three studies,
two studies have finished already,
the SPIRIT-P1,
which is in patients who failed
or not had conventional DMARDs.
Then there is the SPIRIT-P2 study
in patients who have failed
TNF-blocker drugs.
The SPIRIT-H2H study
is a study of head-to-head
properly powered to see if there is
a difference between ixekizumab
and adalimumab
in patients with psoriatic arthritis.
Looking at the SPIRIT-P1 study,
this study had one of its outcomes
to see if ixekizumab inhibited
x-ray progression,
so the patients were enriched for
patients who could have
progressions,
so they either had a high CIP
or they had an aversion
at inclusion in this study.
Patients had failed a DMARD
or not had a DMARD,
and there was an adalimumab arm
in that study
as a comparator to see
if there was efficacy,
but the patients
were not powered to see
if there is a difference
in outcome between the arms.
The study drugs were either 80mg
every two weeks or every four weeks
in the SPIRIT-P1
and the SPIRIT-P2 study,
but I'll only be talking about the dose,
which is now being used
in clinical practice,
which is 80mg every four weeks.
The SPIRIT-P2 study
is a very large study of patients
who had either incomplete response
to previous TNFblocker drugs,
now interestingly,
like in real practice,
some of the patients had failed
either one or two,
and so 30% of patients had actually
failed two TNF-blocker drugs.
Some patients, about 10%,
had had intolerance.
So, let's go on
and talk about the studies
that have been completed,
the P1 and P2 studies.
So, looking at the study,
the primary outcome measure,
this is P1, is the ACR 20,
and here we have the ACR 20,
50 and 70 outcomes.
You can see
a significant better outcome
in the study drug
compared to placebo.
This to remind you
that we are talking about
the 80mg every four-week dose,
which is the licensed dose
of ixekizumab.
Now when we look at the P2 study,
you can see a very similar outcome
in ACR 20, 50 and 70 for the P2,
which is patients who have failed
a TNF blocker drug.
Now you may remember that the
SPIRIT-P1 had an adalimumab arm,
and here we have the ACR response
to adalimumab in the trial,
and you see
that the response to adalimumab
is what you would expect
with that drug.
Also, we must remember
that the study was not powered
or designed to make comparisons
between the different arms
of the study,
i.e. ixekizumab and adalimumab.
Now when we look at the P2,
the patients who have either had
methotrexate
or not had methotrexate,
is there a difference in outcome?
And with most other drugs
and biologics in psoriatic arthritis,
we see that either
with or without methotrexate
makes no meaningful difference
in outcome.
Now when we talk about the P2,
the interesting there is
that some of the patients had failed
two TNF blocker drugs,
so we are really looking at a
high-need group, quite hard to treat.
And you can see here patients
who had either failed one
or two TNF blocker drugs
had good outcomes to ixekizumab.
So, this is very important,
because the patients who failed two
TNF blocker drugs have a high need.
There is a small number of patients
who had intolerance
and again they respond to ixe,
although some patients say,
she had a placebo response, but
the numbers are very small here
and it's hard to understand
what that means.
When we move on and look
at the longer-term outcomes.
So we have here the 24-week data.
Now, 24-week data is the placebo
controlled part of the study
and then we have the gold standard,
NRI or non-responder imputation.
That is really the gold standard way
of looking at long-term data.
We can see data here up to week 52
and we can see that the very good
response at week 24 is maintained.
And here we are looking
at the ACR 50 data,
because we want to look at
something that is clinically relevant.
You can see
that it is maintained up to 52 weeks.
This is the SPIRIT-P1 study.
In the SPIRIT-P2 very similar
longterm outcomes achieved,
very good response at week 24
is maintained over to week 52.
Now, the P1 study finished earlier
than the P2 study,
so we actually have data now
up to three-year data.
So, this is week 156
and this is using a slightly
modified non-responder imputation.
And you can see that over time,
the very good outcomes of either
ACR 50 or ACR 70
are maintained up to three years.
So, we have a very good
short-term response
followed by very good continuation
of that response for up to 3 years.
Now, just looking
at the x-ray changes.
As we said before,
the SPIRIT-P1 study had patients
who we thought would actually have
a progression of x-ray change,
and you can see here
at the grey bars,
that the patients on placebo
had some x-ray change
and a significant inhibition
of x-ray change
in patients who received ixekizumab.
So, this is the 24-week data.
Looking at the 12-month data,
this is the individual outcomes
for change
in the van der Heide sharp score
over the 52-week period.
You can see that hardly any patients
had any change in the x-ray score.
And that can either be from the data
where all the individual points
are here
or alternatively
we look at the other data,
we are looking at the either patients
with no change
or when there is the smallest
detectable difference,
which probably is
the most useful way of looking at it,
you can see that very few patients
had change in x-ray progression
over the 52-week period.
So, we have a drug
that is useful in a clinical setting
but also inhibits x-ray progression.
So, this is what you really want
from a biologic.
Now turning to other
outcome measures,
obviously, psoriatic arthritis is not just
a disease of joints,
but enthesitis is a very important part
of disease activity.
This is the Leeds enthesitis index,
which was the outcome measure
in this study.
And here we have the SPIRIT-P1
and -P2 data,
showing significant improvements
at week 24 in P1.
In the P2 study
the changes were not significant,
we have to understand that,
because actually by week 52
there were quite a significant number
of patients.
And this looking at the patients
who had complete no enthesitis
at these time points.
So, this is an important outcome,
and we can see that the P1 study
shows a definite change.
Looking at dactylitis, again dactylitis
is another feature of psoriatic arthritis
and we see significant improvements
in dactylitis
in both studies over a 24
and 52-week period.
So, we are really starting
to actually have an effect
on the psoriatic arthritis component,
but as we know
in the study about two thirds
of patients have significant psoriasis
and we see significant psoriasis
in our clinic.
We are looking here at the PASI 90.
Now, we may have got used
to the PASI 75,
but the actual gold standard now
is moving to PASI 90,
because PASI 90 is where patients
have a significant improvement
in quality of life.
And this is because the IL-17 drugs
are actually so good.
So, we have the PASI 90 changes
in the patients
in the ixekizumab studies.
You can see here that in the
SPIRIT-P1 and the SPIRIT-P2 study
PASI 90 responses are very good
and they are maintained
up to week 52.
Now, let's get back to rheumatology.
What about some patient-reported
outcome measures?
As we know, pain is a very important
outcome for our patients.
You can see here
in the SPIRIT-P1 study,
there is a significant reduction in pain
very rapidly up to week 4
they get significant changes and
that's maintained up to week 24.
And the SPIRIT-P2 study shows
very similar changes as well.
So, it means that we are
really starting to have an impact
on the things that are very important
to our patients.
The other patient function is
the HAQ-DI.
So what we are looking at here is
the percentage of patients
who achieved a significant change
in HAQ-DI,
meaning the smallest meaningful
clinical difference.
And we see here that
a significant number of patients
in the SPIRIT-P1
and the SPIRIT-P2 study
achieved this meaningful change
in improvement of the function,
the HAQ-DI.
So, we have better patients,
we have better function
and better skin.
Now looking at safety,
obviously good drugs
sometimes come at a price.
We are looking here
at the SPIRIT studies
and we see here
that there is some minor,
some small number of infections,
very few numbers
of serious infections,
but I think we see here that some
patients had injection site reactions,
so in the Q-4 weekly about 17% of
patients had injection site reactions.
So let's just look at them
in more detail.
And when we see that we see
that almost all of them
had mild injection site reactions.
There were one or two patients
who had more severe
injection site reactions
and they were the patients
who dropped out.
But actually you can see here
that it's a very small number,
so 0.4% of patients actually
stopped the study
because of an injection site reaction.
That is something
that we obviously need to share.
Looking at the other side effects,
the very important side effects which
are really troublesome are rare,
so we are going to look
at the larger database.
You can see here there is a lot of
patients who received ixekizumab,
over 5000 in the psoriasis studies
and about 1200 or 1100
in the psoriatic arthritis studies.
And this is where we can start
to get some meaningful input
on the serious, but rare things
such as the serious infections.
This is the rate per patient
per 100 years,
so we have
serious infections can occur,
but the rates are low;
they are very similar in patients
who had psoriasis
or psoriatic arthritis,
so some of the patients on psoriatic
arthritis have some steroids,
so we don't see an additive effect
in psoriatic arthritis.
There are some candida infections.
This drug inhibits IL-17,
so this is not unexpected,
but they are transient,
they are not severe infections.
We see MACE,
which is the cardiovascular endpoint.
Again, there is no signal for MACE
and also happily
there is no signal
for an increased risk of malignancies.
So, this is very encouraging.
Now, IL-17 inhibition is associated
with very small number of patients
who get worsening of inflammatory
bowel disease or new onset.
We can see here the rate
in the psoriasis population
and in the psoriatic arthritis
population is present but very low.
So, in summary we have seen
that the SPIRIT clinical trial
program shows
that ixekizumab is highly effective
in the treatment of psoriatic arthritis.
It's effective
for the improvement of the signs
and symptoms of psoriatic arthritis,
but also significantly inhibits
radiographic progression.
It can be used in patients who have
either failed conventional DMARDs
or be highly effective in patients
who have failed a TNF blocker drug.
And the interesting thing here is that
it's the same doses used in both the
SPIRIT-P1 and the SPIRIT-P2 study,
so the same dose is recommended
for patients
who have failed a DMARD,
i.e. first biologic
or failed a TNF blocker drug.
The side effect profile
is very acceptable;
it's what you would expect
with an IL-17A drug.
So, in general I think
we have another drug,
which hopefully will be able to help
our patients with psoriatic arthritis.
I'd like to say thank you very much
for listening
and watching this program.