Okay. So, let's use a case study, and we're
going to give a little background on myostatin in terms of what it does.
How many people have, well, we'll get into more detail about it.
So some of you may have heard about it, some of you may not have.
But let's talk about the rationale. So, what myostatin is, it's a gene that
exists in all of us and what it does is that it negatively regulates muscle
growth. So, what we have here is an example from
an animal study in mice. And we see that the mouse on the right is
larger in size, and then when you do, upon Gross anatomy and inspection you see
where, here in this figure. This[LAUGH] thigh's much larger, it's,
it's , leaner in terms of its muscle mass.
So in essence what this study found was that these were mice that had knock outs,
of GDF-8, which is the same term as myostatin.
So GDF-8 is the same as myostatin. So when they're deficient in myostatin we
saw that their muscle growth was unregulated and so they had larger
increases in muscle mass. So, it exists in all of us to negatively
regulate so that our muscles don't get too big or they don't get too small, so
it's a negative regulator of muscle growth.
And so, in these knock out mice, they had increased muscle mass but also other
areas of improved glucose tolerance. reduced fat accumulation and no obvious
toxic effects. Now, this was in New England the New
England Journal of Medicine of a child, case report, true story.
Where this child had a mutation in his myostatin gene.
So, a little bit of background on this case report.
This was a healthy woman. who was a former professional athlete,
who gave birth to a son. And at birth the newborn appeared, and I
quote, extraordinarily muscular. With protruding muscles in his thighs.
So if you get a chance they have pictures of the, or they actually have the image
of his leg. And its just like[SOUND], you know it's,
it's pretty, pretty amazing. But on physical examination everything is
normal. So he had you know.
And, and what they decide is that we're going to follow this child for a couple
years. But at six days of age, they did an
ultrasound, they confirmed that he had larger muscle mass, muscle size, so
muscle hypertrophy. And then they followed him for about four
and a half or five years and the saw just a, a very large increase in muscle size
and strength. And I know this is really interesting.
At four and a half years he was able to hold two three kilogram dumbbells.
So that's seven, eight pounds horizontally.
So, I hate to say this, I probably can't do that these days.
But you have a four and a half year old child able to do that.
I think, it's just pretty amazing. So what they, they did this thing, let's
do a little bit more work. Let's look it as his myostatin.
And so he had a mutation, and that mutation resulted in a loss of function
of myostatin. So his myostatin didn't work.
It was actually, you could think of it as turned off.
And because of that there's no longer that regulation on muscle growth so for
that child his muscle mass, muscle strength, muscle size, all increased.
So this slide kind of is eluding to, alright let's think of if we wanted to
develop some type of therapeutic agent. To myostatin and one consideration is,
what if we inhibit the action of myostatin.
So the rationale is that, if we were to inhibit the myostatin pathway blockade we
saw in the case examples with the mouse and with the child.
We're going to get changes, primarily an increase in skeletal muscle growth.
And skeletal muscle lea, leanness. If you kind of do kind of a 180 and you
think turning it kind of the other way around.
Instead of trying to turn it off, what if we activate it?
are, is there data out there, in terms of what do we know?
In term, in, in the literature, in terms of in patients where myostatin is turned
on. And there's actually some evidence.
in HIV patients, they go through quite a bit of muscle wasting.
Also in cancer patients. cancer cachexia and also muscle, muscle
wasting. And there's a couple studies out there
that show. In those, in those, in those patients,
they actually have their myostatin turned on, turned on like revved up if you will.
So you almost kind of get a sense where you have a potential subject or patient
population to treat this. And the idea that if we do develop
something to block the effects of myostatin.
Can we help in terms of patients that maybe that have a loss of muscle mass,
maybe to preserve muscle mass, or even to actually build muscle mass.
So that's where we want to go with this potential investigational agent.
Blocking the effects of myostatin in an effort to either preserve or increase
muscle mass and size. So, using that example let's relate that
back to our inclusion, exclusion criteria.
So as I eluded earlier from that context of a phase one study.
If we desire healthy subjects, one thing that always comes up is well how do you
define as granular as you can a healthy subject?
Can they be on any type of prescription or over-the-counter medications?
Generally, what I've, what you generally will see is that if they're on a
prescription for some type of chronic condition.
They probably would not be enrolled in a healthy volunteer study.
some times you see people when they get a cold they will take over the counter
medication. And it's something where at that moment
they may not be able to be enrolled. So you give them a wash-out period.
Meaning a period of thirty days where then after thirty days you can say
alright all that drug they took to treat a cold is probably washed out.
Or no longer in a system. Then we can look at enrolling that that,
subject at the time, at that time. can they have any existing disease states
again, if you're looking for the truest, most technical sense of healthy subjects,
the answer's probably no. But if you take it from a phase one study
and you're looking at this in cancer patients then you see how the rules can
change. Or the IE criteria can change.
Are there specific laboratory cut off values for exclusions?
A lot of times to really get down to the the level of granularity for healthy
subjects. They'll have cut off values of making
sure that they have their kidneys are working.
And making sure that their liver is working.
So they'll have very specific lab cut off values to kind of quote unquote define
that. In terms of designing IE criteria, when
you are thinking about designing and creating these, you want to consider a
couple, several things. How does this drug work?
What's its mechanism of action? What's its potential side effect profile,
and the potential for drug interaction? So let's look at our myostain inhibitor.
Let's say, hypothetically, wanted to use this and study this in muscle loss, let's
say in cancer patients for this example. So, what we know about its mechanism of
action on muscles. We can pretty much determine that you
know what, if we have patients, cancer patients, who are taking let's say,
steroids. They're taking maybe a growth hormone,
and, you, you'll see steroids are used commonly in cancer patients to help with
nausea and vomitting from chemotherapy. So it may be something where you know
what, we know that steroids and growth hormones have an influence on effecting
muscle mass, muscle size. So if they're on it, they're probably not
going to be in our clinical study. Let's look at it from the perspective of
medications that are known to be somewhat harmful or have negative effects on
muscle. So there's a class of drugs called statin
drugs and they can cause muscle injury such as they call it rhabdomyolosis,
well, rhabdo is what I for short. But we would interpret that, you know
what, because of its effect of, on muscle, if subjects or patients are on a
statin drug, they probably are going to be excluded.
What's the potential for drug-drug interactions if, let's say we're
designing this myostatin inhibitor as a pill or tablet and we want to take it by
mouth? We need to be careful in terms of other
drugs that are effected potentially by its absorption of the drug.
So this has an effect on muscle size, muscle mass.
So I don't need to say much about professional baseball players, but then
there's this potential for abuse, or misuse.
So how do you potentially, do you need to have criteria to assess aberrant drug
seeking behaviors in patients who are potentially enrolled in this.
another thing is, how do we make this available?
If we do get this eventually approved, we may have to have limited availability.
And we may have to impose certain regulatory restrictions by way of having
this as a controlled substance. So I just talked about how an IE criteria
are a set of rules in terms of how to run a study.
But you'll see sometimes that in your best efforts to make them as granular as
possible, as detailed as possible. Sometimes you're a little too good, or a
little too restrictive, I should say, and that can impact your study enrollment.
It can impact where you may have trouble enrolling the certain number that you
need for us, to meet your sample size. So, can they be revised?
That's a question that commonly comes up in terms of when you're working in
clinical operations. And yes it can be revised as long as you
don't compromise the study outcome and increasing confounding in variables.
So, the examples I can provide here is an a myostatin example.
Let's say you had, criteria where you can only include subjects with a specific
body mass index, BMI. And 18 to 30 is what, is considered quote
on quote normal. But, you know, as we all know, most of us
in the U.S, or at least you can see, you know, from the reports from the CDC.
many Americans, unfortunately, don't fit into this BMI.
A lot of them have BMIs greater than 30, so they're considered overweight.
can be considered obese with a much higher BMI.
So it, for this example it would be possible to revise the BMI to make it a
little, a little bit more, a lar-, a little larger range.
With the, with the caveat that your not, you shouldn't be, you will not be
compromising study outcomes. And you shouldn't be, hopefully
minimizing, or not increasing confounding variables.
I, I must admit based on my experiences working for a pharmaceutical company
before this position. This was a huge source of protocol
deviations, meaning a lot of the sites that ran or conducted the study would
just enroll a subject. and not pay as much attention to the IE
criteria. And a lot of times from a pharmaceutical
company perspective. You wouldn't find out until after they
were enrolled, they were dosed, and it's just an unfortunate, unfortunate, and a
very significant source of protocol deviation.