i'm here to talk about the orion
study program which evaluated a new and
novel ldl cholesterol lowering therapy called and
closer in
nicholas eren is a small a interfering
are in a substance which up blocks
the translation of the message are a
day for pc as canine protein inside
the deliver sell
ibm modulator modifies the body's natural processes
for
either augmenting or inhibiting transcription of message
irony for protein through something called the
risk r i s c or are
any induced silencing complex located inside otters
ourselves a great friends and colleagues in
massachusetts discovered this pathway in the late
nineties i believe in one
the nobel prize in medicine a few
years later
for showing it said benefit and within
just a couple of decades now several
therapies have been developed which use that
pathway or exploit that pathway or modify
that pathway to rub really look at
to
you altering disease processes and improving life
for patients so in closer and was
developed between the medicines company and another
company in massachusetts as a new and
novel inhibitor of ldl cholesterol exploiting or
modifying or augmenting that pathway to speak
to prevent the translation of message are
in a for pc as canine protein
or you may be asking what does
this have to do with cholesterol well
as you're probably well aware of tcs
canine is one of the major regulators
now in the body of plasma ldl
cholesterol levels a when you have a
and up regulate
chin or again of function of pc
as canine you have very high lifted
levels and that's because pc as canine
as a protein
it signals to the body
to destroy the ldl receptor on the
surface of the liver
does blocking the absorption of ldl by
the liver from plasma and by blocking
that absorption it raises plasma levels of
ldl and conversely if you have a
loss of function of pc s canine
or low circulating levels of dcs canine
pretty genetic reason you have very low
ldl
levels and more importantly those populations who
uniquely have a loss of function of
pc as keen on the have very
low cardiovascular disease risks so what's this
was discovered by helen hobbes as group
in dallas in the mid two thousands
he became a prime target for exploitation
or it yeah development to lower ldl
color
wrong and i think all of us
are now familiar with the monoclonal antibodies
are alley rocha map and even look
i'm ab
which lower ldl cholesterol sixty percent with
or without a stat and drugged and
are very potent at lowering ldl cholesterol
because they bind pc as canine and
prevented from causing the recycling and removal
of the ldl receptor on the liver
and thus liver in a sense over
expresses ldl receptors in by having more
of them
it removes ldl from plasma it puts
it into the cytoplasm which also then
by raising ldl a levels of the
cytoplasm you inhibit the de novo synthesis
of cholesterol so it's a wonderful pathway
to exploit utilize to lower plasma ldl
cholesterol levels the downside of monoclonal us
in summer in some by mainly opinion
of
some is that they require injections every
two weeks or twenty six times a
year and some of us may be
all of us as patients often forget
to take our medications on a consistent
basis even if you skip a dose
once in a while because you're busy
traveling are working or just don't feel
well so there have been searches for
therapies which can be given less often
and and closer and is one such
therapy it works through a slightly different
mechanism than the monoclonal antibodies toward pc
as canine remember the monoclonal antibodies find
pc as canine and plasma while and
closer and inhibits the translation of message
irony and the production of pc as
canine protein in the body
the closer and can be administered about
twice a year at least that's how
we've tested it in the face three
orion studies it could be given less
often or more often giving it less
often would result in little bit less
of an ldr reduction giving it more
often would not really augment ldl reduction
that much more so it was chosen
to be given his twice
a year so it's a therapy that's
given as a small injection of about
one and a half ccs of of
the liquid that is given every six
months in patients and it lowers ldl
cholesterol by fifty to fifty five percent
the how did we discover this well
we did three large phase three randomized
trials of the orion nine ten and
eleven studies respectively
orion nine was conducted in south africa
in several other nations in the european
and african comments in patients who had
heterozygous familial hypercholesterolemia are very high levels
of ldl who typically do not respond
well or at all to stand therapy
ryan ten was conducted solely in the
united states i was the principal investigator
and we had the little over fifteen
hundred patients with atherosclerotic cardiovascular disease or
a or cbd who were randomized one
to one to placebo or and closer
and and followed for eighteen months for
ldl lowering a ryan eleven was alma
east identical to a ryan ten it
was led by carsick ray in the
united kingdom
about eighty to eighty five percent of
the patients and or i and eleven
had a a cvt and about fifteen
percent had risk factor equivalents
so we had a nice collection of
patients most of which had a a
cvt some of which had fh and
a small number had respect republic so
we could test all three populations and
and twenty twenty one the journal of
american college of cardiology jack published our
pools level analysis of inclusive ran across
all free programs are you could find
the individual study results in the new
england's
journal from the preceding year but i
thought it would be helpful to just
go over the pool results because that
gives us the best insight into how
closer and works so all the studies
involved randomized patients on day one to
either placebo or inclusive ran so both
groups received injections neither group new which
they were getting so was a double
blind study
and the people that the person that
principal investigators of positions did not know
if their patients receiving closer and or
placebo as well
now and closer and is given as
an injection on day one and then
we give a boost your go sunday
ninety just like we see a booster
dose now with cope with vaccines with
the aren't a vaccines
and then every six months after that
booster you getting closer and so on
day one day ninety and that every
six months thereafter so they had a
total of four injections over five hundred
and forty days where an eighteen month
study timeline and we measured it's it
multiple time points with the primary in
points of the study being number one
what was the absolutely
action and ldl compared to baseline at
day five ten and then what was
the time average reduction and ldl between
days ninety five forty
by going to every six months dosing
having closer and right it's one thing
to prove that you could lower includes
ran a single time point but if
the patience levels spike up and down
constantly right it would be less effective
than than having a smooth continuous reductions
we wanted to test that as well
it's a we pool the data from
all three trials and that's a total
of a little over thirty six hundred
and fifty patients the average age in
the study was about sixty four years
in the glittering group of sixty four
point one and the placebo group sixty
three point nine
about two thirds were men
ninety percent we're caucasian
and ninety two percent were on staten
therapy in about eight percent were not
so the not be on a stat
staten for the studies you had to
prove staten intolerance by trying to er
three stat and and not be able
to tolerate them
about thirteen to fourteen percent of patients
run is that a my present it
like i said about eighty five percent
had a a cvt about fifteen percent
had risk equivalents
some of those of over half almost
sixty percent had risk scores greater than
twenty percent over a ten year time
period only seventeen percent were smokers about
thirty five to forty percent had type
two diabetes and a little less than
twenty percent had done
and heterozygous fh
the average cholesterol ldl cholesterol prior to
randomization was around a hundred and ten
to one hundred and eleven pre randomization
for ldl total cholesterol around a hundred
ninety hdl cholesterol around forty eight forty
nine and a pool ipo protein be
levels were almost a hundred in both
groups bible protein needle
like a protein a levels were also
measured as were triglycerides and they were
the same between both groups the median
pc as canine values and placebo were
three eighty nine and in treatment group
or three ninety six
so what we saw over a time
it over over the study was that
it day five ten there was a
fifty one percent reduction and ldl on
top of staten therapy in all comers
he was as high as fifty eight
percent in the orion ten trial i
believe that as low as in the
forties in the fh steady better cooling
all groups to go
either see get more real world assessment
it was about fifty one percent and
the time average reduction and ldl was
also fifty one percent there was a
fairly smooth reduction and you can look
at figure two and the jack paper
and see those changes nicely laid out
when we look at absolute levels of
ldl lowering there was a fifty three
milligrams per deciliter lowering and l d
so if you're patient came in with
that ldl one hundred and ten on
average they we get about fifty three
milligrams of lowering so they would be
down below sixty ah
on treatment which would be an amazing
reduction in ldl for someone with a
a cbd because we know that for
every roughly wonder millie more of ldl
reduction we see it almost two percent
reduction in clinically events which is quite
remarkable now we didn't study clinical events
of the strauss we can't tell you
that it translates into the
that but we believe it will and
there's an orion for trial going now
which looks at cardiovascular outcomes in a
similar population it's with very nicely powered
with a little over twelve thousand patients
at the be it's it's being run
by the the group at oxford under
the leadership of professor rory collins and
also cool led by the timmy group
and remark sabatini leadership that
and dates at night then rolling nicely
and it will add a lot of
additional data but what we saw would
be a ryan nine ten and eleven
pool data is a very robust reduction
and ldl ah it's i just mentioned
pc as canine values were also reduced
about eighty one percent
with includes saran and a total cholesterol
reduced about thirty two percent all of
the average a cholesterol so the non
hdl cholesterol was reduced forty six percent
and april protein be also a known
factor for a a cbd was reduced
by forty two percent so across the
board they were favorable changes
as in the like of protein profile
ah favoring treatment with closer it and
we did a subgroup analyses with forced
plots that you can see in figure
four of the jack publication
and it showed consistent benefit in men
versus women in lean b m eyes
vs overweight vs obese versus those on
high intensity stat and versus those on
low intensity or non high intensity stat
and then roughly seventy percent of patients
run high intensity staten who were taking
status
people on is that am i bore
other non staten lippert lowering drugs have
the same reduction is those on staten
and even those not taking any leopard
modifying therapy had pretty robust reductions of
about fifty percent
no one of the questions i ask
and we answered in the jack paper
was the following if you have a
patient in whom you want to lower
their ldl from say a hundred to
seventy what's the likelihood you can get
there with standard of care vs adding
and ran to stand
word of care and standard of care
for most patients today as the staten
but for those who are intolerant it
might be as that a my lip
of the doj gas it or even
nothing right because many of our patients
just aren't tolerating oral therapies so what
we found is that if you look
at our patient population again we think
this is representative of the high risk
population in
in europe the united states in africa
so a a cbd or heterozygous fh
about fifty percent of the time little
less than fifty percent forty five percent
of the time he can get to
an ldl less than one hundred with
staten or usual care and over eighty
percent of the time he can get
there with him closer and so very
important because be think about the heterozygous
fh patients who have l
yells of one seventy to two fifty
to get down to less the the
hundreds pretty amazing so we feel that
eighty percent achieving that is remarkable
if we look at the newer threshold
that the guideline documents are now targeting
so such as seventy milligrams per deciliter
and those who are high risk like
type two diabetics are people with hypertension
you get there with usual lifted care
namely stands about twelve percent of the
time and with the addition of and
closer and sixty seven point nine percent
of the times over two outta three
will get to that new threshold
if you're like me and treat people
to a low ldl who had an
acute coronary syndrome like less than fifty
nearly any get their about two percent
of the time with stabbed therapy alone
but with him closer and and understand
you can get their over fifty percent
of the time roughly fifty two percent
of the time which is really remarkable
so i say i as the new
a c c ha guidelines
come out the sheer you're going to
see a new threshold and new targets
of it's going to take additional therapies
like and closer ran and better but
i guess it and monoclonal to get
patients down and we get we have
seen that with include saran you can
get their over half the time to
the less than fifty percent for patients
who already or on stands and still
had some resistance to l the alone
ah if you look at absolute reactions
of ldl they parallel that very nicely
so in summary we find that implicit
ran as a very well tolerated very
effective therapy when given twice yearly and
reads it reduces cholesterol ldl cholesterol by
fifty to fifty five percent consistently oh
with only two injections a year which
is remarkable have some of you may
be single what about side effects right
we always worry about those we didn't
see any unusual preponderance of side effects
the package insert from the ft able
talk about injection site reactions and most
of those are a little redness a
little itchiness small raised area that disappears
after a few days and about seven
or eight percent of patients versus placebo
it two or three percent
we didn't see any changes in muscle
aches any changes in biochemistries of liver
enzymes or muscle enzymes or create nene
or hemoglobin or platelets and we did
see however a smaller a small number
of patients had to reported upper respiratory
like symptoms yellow bronchitis a little cough
for a little ah clearing of the
throat but we'd
didn't see frankly higher numbers of documented
infections we don't know if that's a
real or spurious observation but you'll see
the the package insert
and it seems to be well tolerated
know my lg issues of a heavy
have risen we haven't seen prolong side
effects from and use of in closer
and in in the clinical trials
and we're optimistic bad that with the
orion for trial or it will reduce
outcomes it will reduce hard and points
like death nonfatal am i not as
non fatal stroke sixteen substantially like we've
seen with the monoclonal the me seen
with the stands and so it's an
exciting time now to have a new
are in a base therapy that could
be given
less than
monthly or less than twice every two
weeks like twice a year
ah at a cost that some we
think is the hopefully affordable for most
patients and their will lead to higher
rates of compliance and the really provide
some benefit i had some protection in
case they do forget to take oral
medications for a day or two you
know you have at least have a
drug on board that will consistently and
durably lower ldl cholesterol
martin ask how can we use this
drug today right we don't have outcome
data are we sure it works the
answer is what we don't know but
we have no reason to doubt that
it will not work right every ldl
lowering therapy
to my knowledge has shown reduced events
so i think this is a drug
that you can use ah safely and
effectively and your populations of patients at
high risk people with a a cvt
heterozygous fh individuals who have events were
at risk for events that you can
i get to your ldl threshold goal
with the staten or staten plus other
oral therapy allow
loan and it's very convenient to take
i it's twice yearly after the booster
dose ah and day very well tolerated
with very little side effects we see
it as in an ad on therapy
largely for stands or stat and plus
or other oral therapy when you need
to get the ldl lower and remember
all for the last thirty years lower
has turned out to be better a
in almost all scenarios so i think
we're going to see a big push
by guideline documents to put to to
encourage all of us to lower ldl
cholesterol to what we
to levels beyond where we have usually
taken them and i think we're going
to need injectable therapies like a closer
and or the monoclonal or additional oral
therapies to help us get there
english iran is being sold at a
little different way than the other therapies
most of us we write for a
new limits their people write a prescription
and in closer and you'll need a
prescription as well but it's actually being
developed are delivered through a channel that
is not local pharmacy it's being delivered
as an injectable therapy so has to
be given by you and your office
or by and and fusion center or
an injection center and that was done
intentionally by the sponsor to try to
make it more affordable or because it
has better coverage especially with
medicare patients then a typical prescription benefits
that the out of pocket expenses would
be minimized there's that means it's a
bit of a challenge for us to
figure out how to prescribe it that
i think once you get used to
the system it's pretty easy to do
i've been told by one position in
the phoenix arizona area that it's costing
his patients about four hundred dollars a
year out of pocket for this therapy
going to a local and fusion center
which is i think a remarkable a
value given what it's doing so you'll
want to work with the novartis team
to understand how to prescribe it and
where your
patients can get access to it and
if you decide to dispense it in
your office and have you reward their
staff the inject the patients with it
a novartis will directly sell you the
medicine and work with you on on
how you get paid and then pay
them for it so i think it's
important to talk with them about how
you access this a and
i think get patients will find that
it's likely very easy process once the
once we in the prescribing community get
used to the sort of change our
colleagues and oncology and rheumatology have been
doing this for sometimes a little be
a bit of a transition or paradigm
shift for those of us and cardiology
primary care who will prescribe and closer
and