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 and bococizumab which does not have a trade
name yet as of the time of making this lecture 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
immuneglobulins 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 mute 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
recycling is reduced. More PCSK9 means less LDL receptors.
Now, monoclonal antibodies attach to that PCSK9 molecule
and block PCSK9 from doing it's job, right. 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 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 0.
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 should'nt 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.