Okay, let's go on to the PCSK9's. So this is a whole new
world for you guys because you are entering medicine at a time
that's really very exciting. These class of drugs which are
monoclonal antibodies are changing the entire landscape of
medicine. You are getting drugs that no longer follow the
normal rules of pharmacology. So all of that stuff we've
been learning about, binding curves and everything has changed.
I very much encourage you to watch the immunology lecture
through Lecturio because it's going to explain how these
drugs are working in different systems. Let me explain to you
why these drugs are so exciting using cholesterol control as
an example. But remember this stuff, this monoclonal antibody
stuff, it's in every system, whether it's dermatology, or
rheumatology, or bone mineral physiology. The immune globulins
and the monoclonal antibodies are so exciting as to make me
want to see what happens in the next 15 years no matter what.
This is really exciting stuff. The only downside of these
agents is they are really hard to pronounce. So if you'll
forgive me, I'm going to use the trade names instead of the
generic names because I can barely get my mouth around them.
Praluent, Repatha are monoclonal
antibodies that are humanized.
So if you look at the suffix of these drugs, it
will tell you what percentage are humanized and not.
And if it ends in -umab then you
know that it's fully humanized.
These are not drugs in a typical sense.
These are immune globulins that
are binding to your target.
And they are not cleared by the liver or the kidney.
They are cleared by the reticuloendothelial system.
So this is a linear, non-specific clearance pathway.
It doesn't follow normal pharmacological rules.
The other way that we get rid of these drugs from the
body is what's called 'target mediated disposition'.
Once again normal pharmacology rules don't apply.
They are a non-linear, saturatable clearance pathway.
The large size of this molecule means
that there is no clearance by the kidney.
The large size of these molecules mean that they
generally will not cross the blood-brain barrier
or the blood-uterine barrier.
And also, the whole idea behind pKa and whether
or not it's protonated or not is completely moot
because polarity doesn't really
apply to a molecule this big.
And in comparison to how big these
molecules are to regular drugs,
if you are to imagine a regular
drug to be the size of my thumb,
then the monoclonal antibody would
be roughly the size of a building.
So they are very large-sized molecules and like
I said, normal pharmacology rules don't apply.
Let's talk about the baseball glove analogy again.
So I'm gonna do the baseball glove analogy
without looking at the picture here
and then we are gonna look at the picture together.
So remember that this baseball
glove is the LDL receptor.
It catches LDL just like a baseball.
It's internalized into the
cell, and when it's in the cell
it will either release the LDL to get broken
down and go back up to the surface to catch more,
or sometimes it gets clipped shut so that it
as well as the LDL particle are broken down.
Now, if it and the LDL particle are broken down, then
there is a signal inside the cell to make more LDL.
Let's talk about that clip.
That clip is PCSK9.
That clip's job is to bind LDL
and the baseball glove together
so that both of them will get broken down.
And what ends up happening is you
have more LDL receptor expression.
So let's now look at our diagram here.
So LDL binds to the receptors on the
surface of the cell, that's our baseball.
The LDL receptor and the LDL
itself are internalized through
receptor-mediated phagocytosis or endocytosis.
The LDL is then broken down in the endosomes.
Normally the LDL goes back up to the surface.
Meanwhile, the PCSK9 gets
released into the bloodstream.
The PCSK9 clips on to the LDL-receptor complex.
The PCSK9, which is the ligand, the LDL receptor
and the LDL are all degraded at the same time.
Now you have less LDL at the
surface of the cell, right?
The LDL receptor cycling is reduced,
more PCSK9 means less LDL receptors.
Now, monoclonal antibodies attach to that PCSK9
molecule and block PCSK9 from doing its job.
This allows more LDL receptor
expression and clearance from the blood.
So that means there are now,
because there is no more clips,
all of the baseball gloves are going to the surface
and all of the baseball gloves are now catching LDL.
So that's in medical term we say, more LDL receptor
expresion and more LDL clearance from the blood.
Now, remember that intracellular
cholesterol concentrations are high.
So the hepatocyte itself is going
to manufacture less cholesterol.
The end result is that there is less
intracellular cholesterol production.
Number 2, there are more LDL receptors
to reduce the blood levels of LDL.
And number 3, there is markedly lower LDL levels.
Okay, that's pretty complicated
stuff but that just goes to show you
that these new drugs are really quite effective.
The beauty of these drugs is this -
Number 1, side effects are almost zero.
The only major side effect we see
are the injection site reactions.
Number 3, when we talk about how much we use them,
most of the agents are given once
a week or once every 2 weeks.
So it involves one injection once
a week or once every 2 weeks.
And there may be one in the future that's
going to be a once a month injection.
So we are really quite excited about this.
The other thing that's quite interesting
and I can't believe i'm saying this is that
we actually have monoclonal antibodies
in multiple therapeutic areas.
So instead of having people take
5 or 6 drugs at the same time,
we can now have them come in to
the offices once or twice a month
and get their injections at multiple times,
and I imagine we'll be doing studies looking
at multiple injection sites in the future.
And there is no reason why we shouldn't be able
to give an injection for their cholesterol,
an injection for their rheumatoid arthritis, an
injection for their skin disease all at the same time.
That's why these drugs are so exciting.
Some of the monoclonal antibody therapies,
not in cholesterol but in other areas,
are actually given once every 3 months.