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. Good afternoon, everyone.

My name is Ron Christopher. first off, I wanted to thank Doctors Joe

Ma and Doctor Williams Ettouati for inviting me to present to, to all of you

guys and impress upon you. I guess knowledge and wisdom from my

years of experience in the pharmaceutical industry.

a little bit on my background. I've been in the industry, I've been in

multiple pharmaceutical companies for over 25 years now.

I've worked with Schering-Plough, with Johnson and Johnson a number of local

companies here. I'm currently with Arena pharmaceuticals,

I'm the Vice President of Pre-Clinical Development there.

the applications that me and my group support span the research through

development, drug metabolism, pharmacokinetics, bioanalytical,

clinical, and pharmacology aspects. So I'm not going to be talking about all

of these applications to you today. one hour simply wouldn't cover it.

instead, what I'm going to be covering is a, a subset of activities covering

compound selection, the processes that go into that a little bit on the dynamics

and the, the economics, if you will, within the pharmaceutical R&D paradigm.

And then, take you through the pre-clinical studies and some examples of

what is typical, particularly in the small molecule drug development world,

okay? So, my focus will be directed to small

molecules. I won't be touching on a macromolecules,

monoclonal antibodies, or anything like that.

So, to,to cover top to bottom, what I was going to touch on, I'll talk a little bit

about the pharmaceutical research and development paradigm a little bit about

compound selection, what goes into it. there may be a little bit of overlap from

the previous speaker, but that's okay. he's from Pfizer, I come from a multitude

of nine other companies. So, you're going to get a nice

perspective, a good healthy perspective, if you will, okay?

I'll take you through some R&D activities, covering pharmacology, drug

metabolism, drug safety testing and then, round off with a nice case example and

it's interesting because the previous speaker spoke of structural biology.

This happens to be another example of a structural biology-driven process.

So you'll get a, a, a different way of how the, the target was approached and

the, the applications that went into testing and developing this molecule.

Okay. so to start off these are the, the

current general time frames around all the dynamics, within the pharmaceutical

industry. There are three main processes, okay?

There is the discovery stage, the early research stage, the point of identifying

a target, all the way through research and early development, testing, to the

point of filing an initial drug application.

So, this is abbreviated as an IND. That process alone takes anywhere from 1

to 5 years. Traditionally, closer to five years,

okay? at the point of the IND application, and

this is basically a license to transport drug substance across state lines.

Now, it seems bizarre in the context of the pharmaceutical industry but it, it's

basically an application that allows initial clinical testing to proceed.

So, most clinical sites are outside the state where all the R&D had taken place.

So, in effect, this is a license to enable that, okay?

starting at that point and doing all the pre-clinical, clinical chemistry

manufacturing activities generally takes approximately six years in some cases,

even longer. It depends on the complexity of the

program, etc. So, at the end of that, we compile all

the information, send it to the regulatory agency, and then there's a

review process. On average, a little over a year for the

review process. it's a very expensive proposition.

the current costs from start to finish is on the order of $1.3 billion.

This, I would say, is on the conservative side.

having gone through two recent NDA filings and being part of this process of

two separate drugs, two entirely different indications, this is, in one

case, it's spot on, on the other, it's a little bit conservative.

In other words, it cost us even a little bit more than that.

from a success standpoint we don't get it right form the very beginning, okay?

we generally have and, and this is across the industry, very bright talented folks

in the biology side and also in the chemistry side.

But we, we just don't come up with the best molecule that's going to go all the

way to the market. starting out in the research stage, the

chemist will generally come up with, on the order of five to 10,000 molecules.

This is about how many molecules they will have invested time to screen, okay,

and get the right properties, biological, chemical, biopharmaceutical, everything

just right, okay? And, and I'll take you through the

paradigm in the, the funnel, process in a little bit more detail.

So, of all of these, the initial ones that make it through, about 250, actually

shows some level of promise. Or generate enough, enough excitement

among the chemists and the biologists early on to want to proceed into further

testing. Of these 250, only about 10 make it into

human clinical trials, make it actually into an IND.

So, from start to finish, one in a thousand molecules make it all the way.

so when you read in the newspaper that a drug has been approved hopefully this

will give you an appreciation of the, the magnitude of effort that went behind the

whole process. On a linear scale, this is the general

progression of testing and, and validation, if you will, for any given

target regardless of the therapeutic area.

So, starting on from the left-hand side, In Vitro cell or ligand type test tube

applications all the way through to a launched drug.

Now, some companies, what they'll do in the target selection process.

And I suspect you heard this in, you know, from the previous speaker, is

companies will look for variations of approaches for picking the target based

on this validation state. A drug that is on the market has this

absolute validation. It's proven clinically.

It's proven pre-clinically. In other words, they have a molecule.

It hits the target. It does the desired biological or

generates desired biological response. And it works, okay?

That's the lowest level of risk. So this, in addition to the level of

validation state, it's actually a risk reward scenario, too.

some companies choose a balance of targets that fall to the right, highly

validated targets and pursuing those, and they're okay with that.

And then blend that with targets that have no validation, whatsoever.

They know of a target it's out there, no one has even proven that there's any

biological, they have no sense of what it's even going to work towards.

Is this going to work towards diabetes, cancer, inflammation, and CNS disorders,

what have you. So, so, that's the range of spectrum.

What a lot of companies like to do is default because there's a lower risk to

clinically validated targets, okay? so it's a little bit easier and it's

accepting that they're going to come up with, we call them[UNKNOWN] type drugs,

alright? so if they go with that approach then

the, the challenge to them is try to improve upon this timeline.

So, on the very top of the screen, highlights the, the spectrum of

activities going from target identification all the way through the

formal clinical, pre-clinical development type activities.

Now, this is an inner process and I'll give you some more details as, as part of

the research and early development stage, what I mean by that.

But the, the idea is to truncate as, as much as possible, the top time frame to a

time frame that is truncated by four or five years if possible, okay?

So, the pressures are on[COUGH] and all during that, that process, we, we try to

generate the right amount, amount of information that is critical and gives us

some assurance that we've got a decent molecule that's worth investing.

However, we have to be careful not to overdo it on the testing because again

we're challenged by timelines, alright? and we're, we're also in tune with the

rest of the universe in the R&D space or a company that picks target x, for

example, may not be the only company working on target x.

There may be a multitude of companies also working on that so it's a healthy

challenge if you will in the process. So, optimal efficiency is really

important. but at the same time, we have to keep

costs to a minimum. we've got the boys in finance that are

always watching us and always trying us or, or impressing upon us that we need to

cut back and so these are boys in the finance.

They're not always, they look a little bit more presentable than that in a

typical pharmaceutical industry but the general look is not much different than

what is here, okay?

Compound Selection & Preclinical Studies I

Drug Discovery

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