Hey everyone, welcome to the Drive
Podcast. I'm your host, Peter Aia.
[music]
Lloyd, thanks so much for coming out to
Austin. Great to see you again in
person. It's been probably six, seven,
maybe eight years since we were last.
>> It might well be that long. Yes.
>> Yeah. So, um, look, for for folks who
don't know you, um, as as well as as
some of us do, um, tell us just a little
bit about your background. Uh, you're a
physician and a scientist, but talk a
little bit about how those two paths
came together.
>> Right. Uh so my original plan when I
finished college was to go to medical
school following is basically the family
business and um but between college and
medical school I worked in a laboratory
at Brighamin Women's Hospital in Boston
and uh found two things one that I love
doing science and two that I was pretty
good at it and I ended up doing an MD
PhD degree um and that is the training
not required but helpful for becoming a
physician scientist and uh from there I
did medicine training I was a
rheumatology training and I practiced
rheumatology for maybe 10 years and also
had an NIH funded research lab doing
very basic science on um adhesion
molecules in the immune system
>> and that was also at the bighgam did you
stay there after you finished
>> pretty much I have a high activation
energy for moving and doing other
things. Okay.
>> And uh so I stayed there the my whole
academic career.
>> Yeah, that's right. Medical school, MD,
PhD, the whole thing. only job I ever
had uh until I left and went to
industry. Yeah.
>> Which was a little over 20 years ago and
I went to Novartis Institutes
uh which was founded by Mark Fishman
when he was recruited by the then CEO of
Novartis Dan Vella to reimagine how
research and early clinical development
are done in industry. and they basically
brought the whole concept of
translational medicine to industry. Now
that term I think was coined at Oxford
somewhere in the UK for sure
>> and um this was the first industry
manifestation of it. So Lloyd, there are
a lot of specific drugs and indications,
pathways and targets that I want to talk
about today, but I think before I go
there,
there's a there's a black box that
exists that is the world you occupy that
I really think is is just it's unknown
by the public, but I think it would be
very um insightful if people understood
it. And it is the process by which a
drug is discovered. Um, the first person
who I ever uh read articulating this was
Steve Rosenberg. Wrote one of my
favorite books about science called The
Transformed Cell. This book is uh over
30 years old. I probably read it cover
to cover 10 times during the course of
my life. But he starts with a question
which was, hey, he's at a party one day
and someone says, hey, how do you
discover new drugs for cancer? Do you
just go into the kitchen sink and kind
of grab things and experiment? So, so
again, it's it's a a very intelligent
person can still have an enormous blind
spot to what it is people like you do.
So, take that in any way you want, but I
think it might be a great foundation.
>> Let's start from a very broad area of
medicine, not just focus on cancer
because cancer is a special case of a
more general um concept. Um, so I
personally, and this may be different
for different people, but I personally
start with the patients and the clinical
indications. And essentially, you're
looking for what's not there. So you're
looking for um a drug that doesn't exist
or a therapy that doesn't exist but is
needed. Um, and
and then there are two broad categories.
There are incremental improvements and
then there are quantum steps in the
concept of drug discovery. Incremental
improvements are are making a drug that
you have to take less frequently or as
we've seen a lot in the press recently
an oral drug instead of an injectable
drug. Uh or the same kind of drug but
works better and there have been great
examples of that. think avoatin and
ruatin in a mevacor zokor world. Um and
and those have been enormous commercial
successes and there's a strong bias
throughout the drug development
infrastructure to to do those kinds of
things because they're relatively low
risk and there's not so much
uncertainty. on the other hand to see
indications that may not even have been
described yet and don't have ICD10 or 11
codes and um have to deal with the whole
complexity of create
making physicians and patients and
payers and everybody else aware of this
and then creating a regulatory path for
it. It's it's a heavier lift. Uh, but I
think that's where the biggest value
comes to society and individuals and
patients in in creating new therapies.
And that's that's kind of what I do. And
it there's a lot of failure involved in
there. And the things that we can talk
about are um how do you get a new
regulatory pathway established? Um, we
I've been part of that once.
um soup to nuts and um and and then how
do you sort of create new indications?
That's also a a challenge. Maybe it
would be informative to think about how
uh uh my team and I started something
called the new indication discovery unit
at Novartis. So Mark Fishman, who was
the president of Novartis Research at
the time, um had a few of us come into
his office and said, "We need to make
the most needed medicines and um find
out what we're not doing that we should
be doing and get it started and and we
had a budget for that. So super um as I
mentioned, I start with patients and
indications and medical need. So
starting there, uh we made a list of
about 7,000 clinical indications that
were unmet
>> all clinical indications. We just made a
list of all the clinical indications
>> and um it didn't have everything there.
It only had the ones that people had
recognized at the time.
>> But um it gave us a framework in which
we could start thinking and then it
sounds like a lot but surprisingly it
isn't. It's maybe 10 or 20 pages of
paper at the time. [laughter]
And we um we we grouped them into things
that we were already working on, things
that were rare genetic developmental
things that would be difficult to uh
approach
and and the remainder fell into maybe
seven or eight different buckets. And
then we started working on those. One of
them was healthy aging and one of them
was ENT and one of them at the time was
renal diseases and we should talk about
that some more because that's the
regulatory endpoint. Um
Novartis wasn't at the time working on
liver diseases. One of them was those uh
sort of fibrodic diseases in general. Um
and uh and and there were some others
but
and and we started our program and it
eventually grew to have dozens of
projects and became a bit of a monster.
Then we had to sort of whittle it down a
little. Um but some really interesting
studies came out of that. Um
one of them which I know we're going to
get to later is uhab for muscle
diseases.
And uh we can there's a long story there
but but again it came out of a medical
need of frail elderly people. Um and and
I was very mindful as a rheatologist I
saw some of these people. um if you at
the time I'm not I haven't looked at the
data recently but at the time if a
patient had to go to a nursing home not
wanted to go or whatever but had to go
uh the three-year mortality rate
approached 90%.
>> So being a frail elderly person who has
to go to a nursing home was worse than
most cancer. Yep. And there are a lot of
serious diseases in medicine that are
worse than cancer in terms of clinical
outcomes, but we don't treat them the
same way and and I think we should. But
so we we really embraced the concept of
being a frail elderly person. And what
could we do to number one treat it, but
then prevent it down the road?
>> I I didn't know it was that. I didn't
know the three-year mortality for
frailty in that specific indication uh
was so high, but that's a staggering
sit.
>> It was terrible. I I again it might be a
little better now but it's not good.
>> Yeah. Um okay so let's now talk about
that next leap. So let's assume you or
the scientists and the team have decided
we have an indication. There's there's a
target we want to go for an unmet
clinical need and there's not an
incremental opportunity. Right. The
example you gave is a great one. I have
six statins already. I'm going to come
up with the seventh.
>> That's let's put take that one off the
table.
um how do you begin the thinking around
what we're going to do and maybe by the
way for the listener can you explain
some of the different classes of
molecules I also think we talk very
quickly and casually about monoconal
antibodies small molecules biologics but
I I think that that nomenclature might
not be clear to everybody and and
[clears throat] maybe provide a little
bit of that as well
>> sure so so let's start with what we call
small mole molecules which is industry
jargon. It basically means a chemical.
It historically uh the companies that
became our biggest drug companies
started over a hundred years ago as dye
companies because the the chemistry is
very similar for making a dye as for
making a drug. Um so these are just
chemicals.
Um,
the other class are biologicals, which
is pretty much everything that's not a
chemical.
And
within that broader group of
biologicals,
and actually there's a third group,
let's say devices.
Um, so for biologicals, that could be
an antibbody. It could be some other
protein like a peptide or a soluble
receptor. Um, and
I I think we're now creating a separate
category of gene therapies,
uh, which themselves can be complex
based on how they're delivered or
targeted. Um, and then
let's talk about devices because that's
a completely different animal.
and it's regulated by its own group
called CDR at in the FDA.
And that could include things like um a
gadget you make in a workshop. It could
be an app.
It could be uh something simple like a
syringe that you use to inject a drug or
an auto injector which are very common
nowadays.
um or some combination of those things
>> and include all the way up to
implantable.
>> Yes, absolutely.
>> We don't have to go into it, but are
there differences in the IP treatment of
small molecules in biologics? Are there
longer patent lives or anything like
that?
>> Patent law, I think, is the same for
anything, but there are other regulatory
uh con uh conditions that apply to one
kind of treatment or another. For
example, there are different exclusivity
periods for a small molecule versus a
biologic. Um,
and they change periodically. So, um,
and and all of this is something that's
considered as you're working on how do
you protect the drug you're making. This
is a really important point and it's
very topical now with the concern about
expensive new drugs and how do we make
them available for people and I I don't
think it's well understood or adequately
understood um how patent law works about
drugs. May maybe we could take a few
minutes and talk about that.
>> Sure.
>> Um I'm going to preface my remarks by
saying I'm not a lawyer. I don't play
one on TV and I wouldn't if I were asked
to, but
>> But you've been to the rodeo many, many
[laughter] times.
>> Yes. Uh I was the clown. Um
so the way this works is if you think
about at a very high level making a new
a drug that's used by many people
takes longer is more expensive
and takes as many people as building the
biggest skyscraper in the world. Think
you know that the the Burj Khalifa.
Yeah. Um,
just think about that for a minute.
That's thousands of people, many years,
more than a billion dollars.
And unlike a building which can
ultimately pay for itself and pay all
the bond holders and provide a return to
the investors over decades.
Patent law gives a very limited term in
which all of the investment and
potential profit can be recovered and at
the end of the drug's patent life it is
freely available for anybody to make for
the rest of eternity. That's the deal
you make with getting a patent. patent
is essentially a monopoly on being able
to make, use, and sell the drug uh in
exchange for telling everybody how to do
it. That's that's basically what a
patent is. Now, the term of the patent
from the time you file it is 20 years.
And there are a few little things about
extending it for a small further period
based on how much time it took to work
on it. um practically you get 10 to 15
years of exclusivity from the time it
can be launched.
>> So a couple points I'll add just for you
to expand on if you ch if you like.
>> Um some people might also be aware of
the idea that not everything has to be
patented. So for example the classic
example is Coca-Cola, right? Had they
patented the formula for Coca-Cola
hundreds of years ago, I guess I don't
remember when Coke started, but call it
150 years ago or something like that.
Um,
every we wouldn't be drinking the same
thing today. So, they chose a different
route, which is we are never going to
make this secret public and in exchange
for that, we will have no protection.
>> That's correct. That's So, you're
describing a trade secret,
>> correct?
>> That's that's another form of
intellectual property.
>> Now, I assume that is not an option in
pharma. Well, surprisingly it is
interesting.
>> There are some specific drugs where they
were protected by uh trade secrets. So,
um couple of my favorite examples are
armor thyroid,
>> which was thyroid place
>> desiccated thyroid hormone. Yeah.
>> Yep. It was the thyroid hormone for
people who needed replacement therapy
and it was before we could make it
synthetically.
Um and the process by which that was
made was kept secret. Now, it didn't
stop other people from trying, but they
had to copy exactly the
um the
composition of all the peptides as well
as the impurities and the final
preparation in order to be able to use
the clinical and filing package that
Armor used at the FDA to get FDA
approval.
Turned out that was technically really
hard.
Um, another one I really like is Athar
gel. So, this is this was uh it was
purified from pig pituitaries and it was
act basically. That's the act
gel.
>> Um, I used to love it. I used it in the
emergency room a lot because it was a
rheumatology smart missile. Patients
could come in with acute gout and be
miserable. You give them one shot of
that and it gives them indogenous
steroid taper over a period of several
days. It was great.
>> Um
>> totally unaware of that myself.
>> Yeah, it was a funny story behind that
one too. It was um it was cheap and
widely available until um the BSE scare,
the bovine spongform and sephylopathy
scare happened. Um, and then because it
was purified from pig pituitaries, the
company was worried that it was going to
be there's going to be something similar
in pigs. And we know pigs have
endogenous viruses. So, it was pulled
off the market and then it was bought by
a very small company who um eventually
recommercialized it for uh infantile
spat infantile seizures.
And uh and they jacked the price up a
hundred or a thousandfold. And so it
hasn't been available for
rheumatologists to use since then.
>> Um it's stupid bad pharma trick.
>> Well, I'd like to actually talk about a
few more examples of that because there
are several. Um, going back to the
patent in in classic pharma, are patents
primarily issued only for the
composition of matter or are companies
trying to get patents for uh process
manufacturing and other things? Or is
the playbook that hey, if there's a
really complicated process required to
make this drug, I'm going to file my
patent on composition of matter. I'm
going to keep the process as trade
secret. So even when this thing runs off
patent, you might know what the finished
product looks like, you'll never figure
out how to make it. So both of those
things happen depending on the drug.
Exactly.
>> Um so one good example would be um let's
say ABV and Humira.
>> Okay.
>> They patented every single little thing
around that drug that they could. It was
a huge winner for them and they wanted
to keep it um protected as long as they
possibly could.
>> And they would stagger it. So they would
first patent composition of matter, wait
10 years, patent this step in process,
wait five years, and you just keep doing
it, doing it, and you sort of ex
effectively extend the patent life of
the molecule in process.
>> Exactly. And
that that can be abused I I think
personally.
>> Um but Exactly. They'll they'll patent
the the drug. They'll patent the
formulation. They'll patent the salts.
They'll patent the auto injector.
They'll patent the um of course the
indication right at the beginning to the
extent that they can. Um which is sort
of method of use. Um and they'll patent
the dose, they'll patent the route of
administration, everything.
>> Yep. Combining it with something else.
Okay. Going back
>> and the method of manufacturing.
>> Yes. uh going back to the the clinical
team, the scientific team that is
beginning the exploration of what to do.
Are you at the outset completely
agnostic to whether you're looking for
or entertaining small molecules or
biologics as targets? Do certain disease
states lend themsel for you to go
looking in one path versus the other?
>> I think there's two considerations. one
one is that um there are some conditions
that might um
suggest one one route or the other. Uh
but there are also sometimes companies
or um or infrastructure that would make
it better to use one format or the
other. I think big companies are format
agnostic because the all the big drug
companies are now doing small molecules
and biologics and some many gene
therapies and and even some now cell
therapies which are sort of the
>> the the frontier of complex medical
therapeutics. Um
for example, if if you're treating a
childhood disease, then you need to make
something that is oral and tastes good.
Um, you know, all the parents out there
are going to remember um, you know, the
the grape and the cherry flavored um,
>> Tylenol like grape septra was was a
particular favorite of mine when I was
given my kids drugs.
>> Yeah. So, that's one example. Uh, others
are there are inhaled drugs for specific
lung conditions and so some formats will
will make sense and and there's a
medical rationale for that.
>> So then how do you begin the screening
process? How do you begin to identify
molecules? And um again, I think we
should assume that our listeners um who
are otherwise well informed won't know
the details of what an IND is,
>> what we use phase 1, 2, 3, 4, and what
has to happen prior to the IND. Like
let's just start from the very
beginning,
>> right? So um with the with the preamble
that this this would be about a
year-long course.
>> Yes. If we did this as a seminar at
Harvard, this would take [laughter] you
a year. Yeah.
>> Um but but to cover it at a high level,
um starting from the idea and the
medical indication and it might be
useful to think about
um one specific example and we can let's
let's think about muscle weakness and
which can be described as sarcopenia or
um and the definition of that is still
evolving frankly. Um I I've gone to some
of these uh specialty meetings like the
Gexia consensus conference and it's a
topic of discussion every year. Um but I
think one we seem to be converging on
the concept of uh decreased muscle mass
with impaired muscle function as as a
good definition of sarcopenia
and and whether the function is grip
strength or gate speed or stair climb or
people use different ones. Um
okay so we'll we'll talk about that as a
specific indication. So, um, impaired
muscle function with low muscle volume,
>> which to your point, by the way, nobody
listening to this doesn't care about
this. So, this is [laughter] this is a
very topical consideration. It's not
>> esoteric. It's something I I've
personally been working on for 20 years,
as you know. [snorts] Um, so what should
be the drug format? Well, the patient
population are likely to be older
adults. So, we need to it needs to be a
drug format that'll be suitable to them.
and
shouldn't underestimate the importance
of this. It's what's most likely to work
because in a in a drug development
program, especially with a new target
and a new indication, there are so many
unknowns and all of the risks multiply
across a drug development program. So if
you have if you have say 20 risks you're
taking in a drug development program
whether it's target and format and
bioavailability
>> toxicity the whole thing
>> everything and you and all of them have
have maybe a 90% chance of success. You
multiply all that out 10 or 20 times
it's zero.
>> It's a huge failure.
>> Yes.
>> Yeah.
>> So so you have to minimize risks at
every step
other than the ones that you sort of
identify and accept. This is the big
question that that that we don't know
and we have to answer early. Um so we
want
>> you want to fail fast
>> if you can. Yes. Yeah. Absolutely. The
the the worst outcome in drug
development is failing in phase three.
>> Oh yeah.
>> Actually that's probably not true. The
worst outcome is succeeding in phase
three and failing commercially. Failing
early. Super important.
>> Now let me just ask a question about
this specific indication. So you've
already made a decision which is we're
going after sarcopenia
and you've decided to do that as opposed
to say we're going to go after
musculardrophe.
>> Mhm.
>> Is so tell me the the are you doing that
because sarcopenia is a much much much
bigger market which is the obvious
choice or are you saying it's easier to
get approval there and then ultimately
we can also demonstrate that this will
work in Duchaine's muscular distrophe. H
how would you think about those two ways
to proceed?
>> My personal bias is I have a limited
amount of time on this earth to
um develop medicines and help people. I
want to help as many people as I can. So
I mostly do large indications and and
and that's that's my personal choice.
Now in that situation Lloyd sorry to
interrupt
>> regulatory pathway might be harder for
sarcopenia if it is not yet identified
clearly as a disease.
>> Question no question whereas Duchain's
muscular droy that's an orphan disease
you would probably get a quicker
regulatory pathway to approval.
>> Yes. Yes. And so a different strategy
might be we go after Duchainees because
we can get there faster and then once we
have demonstrated a drug that works in
that category we then chase the approval
pathway to help as many people as
possible. Would those just be two
different strategies?
>> Yes. And and frankly I've done both.
Okay. Depending on the on the
circumstance and the mechanism of the
drug and so forth and and frankly I'm
doing that right now with one of the two
companies that I work with.
>> Okay. Um
let's so
>> so let's go back to your example then
>> let's get back to sarcopenia and um the
very first thing that I tried to do in
sarcopenia
was prevent falls
now
how do you measure a fall Peter
>> well I was going to ask a harder
question which is which are the muscles
that are most responsible for a fall and
maybe that's part of what you could test
Um, it turns out I think it's very
complicated. Right? I've had a guest on
this podcast who um presented data that
suggested something that's seemingly as
innocuous as great toe strength is an
enormous predictor of falls. Now,
there's a very objective way to measure
the force that a person can generate
with their great toe. And as that force
gets below certain thresholds relative
to their body weight, the probability of
falls just starts to go straight up.
>> Balance obviously. I would argue that
they don't really know that. Um because
I asked the question, you know, what
first what causes falls? There's about
11 different things that cause falls and
people can think think through them
themselves. They're the obvious ones
like weakness and dizziness. Um which
dizziness itself is very complicated. Um
but also vision, also attention. Um lots
of things can cause falls.
>> Yeah. Yeah. I mean, I I think another
big one that we see clinically, Lloyd,
is um
loss of reactivity. So, foot speed and
reactivity. So, you and I, if we went
for a walk today around Lake Austin, so
there's a 10mi beautiful loop around
Lake Austin, the probability that on
that 10 mile loop, you and I wouldn't
stumble once, at least once, and miss
our footing is zero.
>> But I would venture that neither of us
would fall. And so the question is why?
Why wouldn't we fall despite being
challenged at a great level? You know,
stepping on a twig, missing a branch or
a root or something like that. And the
reason is we have the reactive speed of
our feet to catch ourselves. And that to
me is one of the things that's missing
and that tends to come down to the type
2A muscle fiber, right? Like that's a
very explosive
>> but also propriception.
>> Yes, absolutely. Vision, all the things
that we're talking about. May maybe the
broader point is this is multiaceted.
There is an atrophy that is beginning of
various systems in the body and it's
creating this perfect storm where when
you watch an elderly person fall,
>> you realize that that's a situation
where they would have saved that fall.
It's not the insult that's the problem.
Whatever caused the perturbation in the
step, it's the inability to catch it
that
>> No, I I think that's exactly right. So
let's get back to the issue of
>> but that's hard. I mean if you're
tryings Yeah. that that this is becomes
a very hard problem.
>> So I tried to do that because in a in in
a clinical environment the only falls
that are ascertained are those that
cause injury.
>> Right? From from our perspective as
physicians those are the patients we
see. Um, and patients are reticent about
reporting falls because they know they
could potentially be taken out of their
home environment if they were felt to be
unsafe. And frankly, I would do exactly
the same thing if I were in that
circumstance. I want to stay home.
>> Yeah.
>> So,
we developed uh a study to try to
measure falls. And so we worked with a
with a large company that manufactures
triacial accelerometers
and we made a we made a research device
for this for this effort and and I
designed a wonderful study. So the study
was we were first going to put the
device on bad ice skaters in Boston in
the winter and uh videotape the rink.
And so the videotape results are the
positive controls for actual falls. And
then we would look at the device
telemetry and look at the sensitivity
and specificity of the device for as
>> it's worn on the ankle, the wrist, where
would
>> this was going to be a pendant.
>> Okay.
>> Um and then the second part of the study
is if the first part worked and the
device worked on falls that were real,
we were going to put it on elderly
nursing home residents. And there and
there the positive control was um little
old lady found on the floor because the
people were old and frail and unable to
get up themselves. So when the nurses or
the staff found them on the floor that
was a that was a fall however they got
there and then we look at the device
telemetry and see. And sorry, was the
purpose of that exercise, Lloyd, to see
if the ice skating uh telemetry could
predict a fall on ice? And was it
offering the same insight that you were
seeing in the actual field with the
elderly people?
>> Well, it's a little bit that falls are
falls are like the Supreme Court and
pornography. You know, you say you know
it when you see it. And so we wanted to
see it on the ice skating rink and then
look at the device telemetry and see was
it reporting falls when they actually
happened? Was it reporting falls when
they didn't?
>> Yeah.
>> No. Was it missing things?
>> Um, basically to see if the device
worked.
>> So, I I put that through the the the
institutional processes for funding and
I was told cut the first part out and so
just put it on the older adults. So, I
worked with a really good geriatrician
named Lou Lipitz
um and uh we did that study
Uh Kieran Dole was the operation
clinical operations person and it it it
was really it was really a good study
execution because working with patients
and research subjects participants in
their 80s to up to a little over a
hundred
>> is is challenging
>> and these were all individuals in one
living environment or across
>> they're in one living environment. We
wanted to make it as we wanted to
minimize the variables. And
>> how many subjects were?
>> We had 60 subjects.
>> And you follow them for how many months?
>> We follow them for six months. And these
these were people who had fallen at
least once in the prior six months. So
we we knew they were at high risk for
more falls. And remember, this
institution has
a lot of protocols and procedures in
place to try to prevent falls and
they're still falling now and then.
>> So Lloyd, 60 subjects followed by six
months. How many falls did you capture?
>> Well, it we ended up 117 I think was the
number of events that actually happened
based on someone found on the floor.
However, the device was awful
in that I think it had about
it it detected 17% of the real falls
and only 17% of the device actuations
where it said somebody fell were false.
So it was just not useful and it was the
best we could come up with for um
>> and just to be clear you weren't asking
it to predict antecedent movement
pattern of fall you were just asking
once a person has fallen do you know
>> yes very simple
>> I would have guessed that you would have
been higher
>> so did I but we were wrong um this study
is actually published now um but but we
but then we couldn't use it for
measuring falls.
>> We tried one more thing. U there was a
Massachusetts Institute of Technology
professor named Dina Katabi
>> uh who was using um Wifi type devices to
measure people's movements in their
homes and it's it is a little scary. It
could it could measure wherever you were
and whatever you were doing. And so we
thought that would be a great way to
assess falls. But ultimately there I I
don't remember the issue but we could
ended up not being able to use it. So we
had to stop our whole program for making
drugs to prevent falls because we
couldn't measure them.
>> Now let me play devil's advocate for a
moment.
>> Couldn't you have just said
we want everyone involved in a study to
report if they fell because it's going
to help us get better data for the
study. And I [clears throat] mean given
that you're you're going to capture all
the reported falls and really all you're
trying to do is capture the signal of
unreported falls. But if you ask the
people say look we're not taking away
your driver's light you know whatever it
is that you're afraid of losing that we
are just trying to report this as an AE
or as an outcome. I mean it seems to me
you'd have a much higher chance of
capturing it than any sort of device at
this point.
>> That would be true. Um, we were just
worried about the data quality because
people, you know, again, remember these
are older adults who were frail and we
were worried about the, you know,
recall.
>> Yeah.
>> Bias and we were worried about whether
they would have something to write it
down with and people generally weren't
device savvy at the time. I think that
that might be better now. Anyway, we we
elect you
>> have to think there's some AI way to do
like you there must be
>> I mean were these accelerometers using
any AI?
>> This was a long time ago. This was 10
years ago.
>> Got it. Okay.
>> Or more. So there was no AI in those
days. Well, some people would take issue
with that way. Not the way we see it
today. Y
>> um so anyway it was a it was a an
interesting example of a lot of ideas
are conceptualized and we have to be
able to objectively measure things
ideally in drug development and we tried
and we couldn't and we we moved on. So
um this this kind of brings us to
sarcopenia and muscle mass and strength
which was the genesis of bagram
um and active and receptor antagonists
in general. Um now we knew at the time
about myastatin. So sin Lee is sort of
the father of myastatin. He discovered
the biology. Um, and
in rodents, myastatin is,
you know, kind of amazing. You can you
can turn a mouse into an Arnold
Schwarzenegger mouse by by blocking
myastatin.
>> This was in the mid 90s, right?
>> Oh, I think so. Yeah.
>> Yeah. I mean, I this was when I was in
medical school. I remember in 97 seeing
the images of the mice, the chickens,
>> the dogs,
>> cows. I mean, we we couldn't get enough
of these myostatin knockout animals. We
thought it was the greatest thing we'd
ever seen as students.
>> There were no people who had that
though.
>> No.
So,
so at the time um the the the the people
who led the discovery project, so this
is the laboratory research were so Chris
Louu and his team and uh David Glass and
his team
um and and and that's where the the
original code of the was BYM338 and
that's where that's where that VAT came
from. Um, I was part of that team on the
clinical side.
Um, and
if they made the drug, how would we test
it?
>> I sort of interrupted you, but do you
want to explain how myostatin inhibition
would lead to enormous muscles?
>> Yes. So,
the the broader question is what governs
the size of your muscles?
um and we know its nutrition and we know
its use and then there are biochemical
things that regulate it and um myastatin
is an inhibitor of muscle growth. So if
you block so if you inhibit the
inhibitor or block myatin muscles get
larger up to another point where there's
something that regulates them and we
don't know what that is. Um
and that's and that's most of the
inhibitory effect biochemically in
animal species. In humans it turns out
that it's more complex. It's myastatin
plus activants mostly active in a
um and this is the
advantage of inhibiting
myostatin
and active together or blocking the
receptor which is what bagram does. So
>> what was the evolutionary I mean I'm
asking you as though you were there
during the design phase but uh
[laughter] what is your best guess for
what the evolutionary reason was to
limit muscle growth? Was it simply a
nutrient management system which was
like hey we grew up in a nutrient uh
sparse environment. We can't just have
muscles demanding all of this protein. I
I would I would have to guess that based
on everything else about people, there
were times during our evolution when
resources were very scarce and we had to
conserve.
>> Yeah.
>> But but I don't know your guess is as
good as
>> but it is interesting because the other
way that nature could have solved that
problem was just to make it completely
uh supply limited and just say yeah but
anyway okay so we don't really have a
great te theological
>> that's kind of the way it works with
atapost tissue.
>> Yeah. Yeah. Exactly.
>> Um, that's right. So, we don't have a
great explanation for why, but
regardless, in humans, myastatin
plays a smaller role than it does in
these uh less presumably slightly less
complex mammals. Um, and what is the
actual mechanism by which myostatin is
inhibiting? Is it does it something in
actin meosin filaments? What is what is
it doing to prevent hypertrophy?
complicated, but uh to to summarize it
briefly, the receptors are part of this
larger TGF beta super family of
receptors and there's dozens of them. Um
there's type one, type two, type threes.
Um and they all signal via mostly a
common pathway of called SMADS
which was named by those whimsical
drosophila geneticists. It stands to um
it stands for similar to mothers against
decapentlegic
which people don't need to know but um
and those are transcription factors and
they govern a whole lot of gene
programs. Um some of the more important
ones are muscle. So muscle size is
regulated by
nutritional availability and then um
muscle protein synthesis versus muscle
protein turnover.
And the proteins that turn over muscle
are um
are Murf one and Mathbox or atrogen. And
David Glass was one of the discoverers
of of this pathway uh who I mentioned
earlier. And um
myastatin signaling via the actin
receptors uh suppresses
the proteins that are involved in
targeting muscle proteins for
degradation.
>> Before we leave myastatin to talk about
beimma, do you want to say anything
about falstatin? And I don't even know
if you're aware, but Fistaten became a
very popular recreational sort of gray
market uh agent that was sold for
research purposes only in quotes. Um and
the the the the marketing material
suggested, look, if you take fistatin,
uh folstatin inhibits myastatin, you're
going to get really big muscles. And so
people were pumping themselves full of
folstatin. Um actually that's not really
true. I think the folstatin was so
expensive they weren't doing that. They
were doing some attempt at fostatin gene
therapy.
>> Um so do you want to just explain what
folstatin is or or why it may not be as
uh as as holy grail as it was made out
to be?
>> So folatin and then there's folstatin
like proteins um are endogenous
inhibitors of this pathway we've been
talking about. Um,
and
it it it does if you do a gene therapy
in rodents result in larger muscles. Um,
but it's a small protein with a
relatively short half-life and I don't
think dosing it systemically now and
then. We we did the math on this and you
would need to give it several times a
day and given the price of fallstaten
you'd be spending above I don't know
you'd be spending a million dollars a
month on fallstatin um but also it
wasn't clear that it would do anything
in an adult in other words it seemed
that there might have been a critical
window during which administration of
folstatin or fistatin gene therapy would
have an impact but it had to be pretty
young it had to beuring ing the
development of the muscle more so than a
mature phase of the muscle.
>> I I think it would work in adults if you
could solve the half-life and I know
there are companies working on this with
FC fusion proteins and other half-life
extended versions.
>> Can you tell people I I that's a good
point. Can you tell people why an FC
fusion I mean I think we have to talk
about some of this technical stuff
unfortunately. I was I almost caught
myself as I was asking the question, but
but explain what an FC fusion protein is
and why that might be able to like keep
it in place longer.
>> Sure. You can you can edit this out
later if it gets too technical. I'll try
to make it uh try to speak in in plain
English.
>> Well, yeah, just think about it through
the lens of like how you manipulate
drugs. Like I think of this as part of
the story. If I remember correctly, the
technology that we use now for FC fusion
proteins was originally developed by
Brian Seed at the Mass General. And the
very first drug that used it was
Emerald,
>> which is Etannercept. It's um which is
itself a really interesting story
because t it's this is a TNF inhibitor
that's now approved in rheumatoid
arthritis and psoriasis and some other
things but it was first tested in
sepsis.
>> I didn't know that.
>> Um and it made people worse. Well,
because I think physicians and
scientists at the time knew that sepsis
was um
was an exuberant inflammatory reaction
to an infectious stimulus and but
thought by tamping down the inflammatory
component you might be able to have
better outcomes. And it turned out it
made people worse. But ultimately it was
then tested in rheumatoid arthritis and
it was amazing
>> and and you know the story after that. Y
>> but a company called Immunex at the time
licensed the technology from Mass
General to make a Tannercept and
essentially what it does it does two
things. So the soluble receptor which
was the which was the low affinity
regulatory TNF receptor I think at the
time got to double check that I haven't
thought about a tannercept in like 20
years um
had a relatively short halflife just as
a as a protein injected all by itself
and um doing the recumbent DNA
technology to attach it to this part of
an antibbody called the FC region did
two things. One is it extended the
half-life of the protein in the
circulation by allowing it to
recirculate the way some blood proteins
are recirculated normally. So you're
sort of hijacking an endogenous
mechanism to preserve proteins in the
bloodstream and doing it the same way.
And the second thing it did is it put a
hook on the protein to allow you to
purify it easily because the protein G
and protein A columns were well
established at the time and easy to use
to purify proteins. So so that's that's
what it did for the drug developers.
>> Yeah.
>> And and since then people the techn this
is a great example going back to our
patent discussion. Originally that was
patented technology and only immunex
could use it or some other lency of the
mass general but the patents expired and
now it's the technologies freely
available to the rest of the world for
the rest of the eternity and many many
many companies use this technology to
make drugs and and we're all better off
for it.
>> So how did you guys discover BEMA? How
did you create it?
>> Yep. So again, the original the the
earliest biology was done by Chris Lu's
team in the pathways group at Novartis
Institutes. Jeff Porter was the leader
of that group. Um and
the the the idea was we wanted to
inhibit the receptors, not go after all
the possible lians because we knew that
myastatin wasn't the whole story in
humans. um we didn't know which act
which activins it was um thought it was
probably active but it could have been
others too and and that story and that
thinking has panned out subsequently as
we can get into later um and
at the time
therapeutic antibodies were the were the
best technology to do this. Um remember
the affinity of the lians myostatin and
activins for the receptors was um
nanomolar low nanomolar maybe high
peeker. So we needed an inhibitor that
could bind down in the low peakar range
in order to effectively prevent lians
from binding. Can't really do that
easily with small molecules. Okay, this
is a great example of the importance of
understanding that distinction. Yes.
>> Um I'm going to explain what you just
said and then I want to have you state
that last point again. So
>> people when they're talking about
pharmacocinetics and they're talking
about affinity and you have to talk
about a concentration. So what
concentration of this uh hormone or this
liand is necessary to get into this and
the when you start talking about you
know we could talk about millim moles
micro moles nanomles as we get smaller
and smaller and smaller as those numbers
get smaller and smaller and smaller it
means you don't need very much of the
thing to get in the receptor and
therefore if you're trying to develop
something to block that it becomes a
harder problem because you better figure
out a way to usurp this guy getting in
and this guy gets in very easily.
>> Yes. Exactly. Exactly. So,
>> and you're saying to get a small
molecule to have that degree of
sensitivity is very challenging.
>> Yes.
>> And therefore something that's biologic
makes more sense.
>> Yes.
>> And is that due to just the physics of
the confirmational fit?
>> Yeah, I think you could describe it that
way. It's essentially this. It's more
complicated than this, but think about
it as the surface of interaction of the
of the two molecules binding together.
Essentially, we need if the if the lian
myostatin and actin for the receptor is
sticky, you need an inhibitor that's
even stickier.
>> Stickier.
>> Yeah.
>> And and that [clears throat] would be
very challenging to do with a small
molecule. So in this case we went with
the biologic route um and
sort of ran a therapeutic antibbody um
project uh in collaboration with
Morphosis which with whom we had a
collaboration at the time um and had a
bunch of candidate antibodies and then
ran through the usual developability,
maturation, improvement of what we get
in the screen until we have what we
think could be a therapeutic utic drug.
>> How many molecules enter the top of that
funnel?
>> Oh, there might be thousands of
antibodies that get tested initially.
This is done with something called fagee
display technology. So
I would say for the past 15 to 20 years,
we don't make antibodies in mice
anymore.
>> It's all done in by recumbent
>> reccomant DNA using these viruses. Okay.
>> Yeah. And I think back, I've been in the
business long enough, you know, I' I've
made antibodies by immunizing mice and
fusing cells and growing them up and
putting them back into mice as a sites
tumors to get enough antibbody to to do
experiments with. I mean, it was
terrible. It's it's much better now.
>> So, you're literally running a screen
with all of these antibodies and you're
screening for two things, but well,
basically one thing. what is going to
give me the lowest concentration that
binds to this lian binds sorry to this
receptor.
>> Yes. So
>> knowing that you have to be below a
certain concentration
>> we knew we needed really high affinity
antibodies
um there were some things we didn't
know. So
in the laboratory most of the time you
can measure a cell surface receptor on
the surface of the cell pretty easily
using things like flowcytometry.
uh the active and type two receptors are
actually expressed at such low levels
you can't see them by flowcytometry
unless you somehow very artificially
manipulate the cell.
>> So we had to create a screening assay
that was essentially a reporter assay.
So we couldn't measure the receptor on
the surface of the cell. Um
we we could have developed an assay to
do that but it would have been very
laborious radioactivity
not necessary. So we put in a reporter
gene which is and basically made the
cells glow with firefly uh luciferase
um if the lian bound myostatin or
activate and then we were looking for
decrease in the in the glowing
>> y
>> um with with therapeutic intervention
and we also didn't know whether we
needed to inhibit active in receptor
type 2 a or b or both most of the work
in vitro suggested for muscle
hypertrophy,
most of it was driven by 2B.
Um, but we weren't sure
and and we ended up getting a a 2B
preferential
um drug, but it also hits 2A.
>> And this has nothing to do with muscle
fiber type.
>> No, this works on all fiber types.
>> Okay. And then we looked for antibodies
that worked in that cellular assay where
we wanted to prevent cells from glowing
when we added myostatin and actin. It
had to work on both of them. Other
words, it shouldn't matter which lian
you put in. The antibodies should block
their activity. Um and and the affinity
of the antibodies had to be really good.
So it had it had to be much stickier
than the lians for the receptor. And so
we had that. And then the the real
important experiment is could we block
the activity in an animal
and
>> but just that first steploid until you
could identify candidates. How many
months was that?
>> Years.
>> That was years. So again just going back
to the analogy of building a skyscraper.
Um that's the planning phase of the
skyscraper. That's the excavation of the
whole. That's probably the laying the
foundation. You haven't actually put any
of the big pillars up yet.
>> It's it's the permitting, it's securing
the funding, it's the it's sort of the
site planning, it's all of that from
your building perspective.
>> And by the way, I assume that the the
standard estimate 20 years ago was every
approved drug is approximately 10 years
and a billion dollars. That's got to be
pretty low today. What's the Do you have
a sense of what the more accurate dollar
figure is? It's got to be more than a
billion today per approved drug.
>> Oh yeah, there's a there's a Tufts
organization for the study of drug
development and they think it's I don't
know two, three, four billion something
like that.
>> The part you're doing now is
timeconuming. Luckily, it's not that
expensive. Correct. You're you're
spending millions of dollars but not
necessarily you know tens of millions at
this point. Okay.
>> Yes. So you you finally identify a
candidate or several candidates that you
now want to take to the next step which
is hey in vivo does this thing work?
>> Yeah. So we would typically have
two to 10.
>> Okay.
>> At this stage um and and it's taken
years because we have to we have to work
through the biology and make sure that
we understand what's going to happen.
Not because we want to save the cells in
the petri dish, but because we don't
want to start something unless we have
confidence it'll succeed if we pass each
step. So, um, we have to work through
the biology. We have to make all the
tools we need, which are these glowing
cells in response to myastatin, for
example. And there's plenty of other
tools that we need too. Um, we need to
make the reagents. we need to make the
myastatin and the active NA and um all
the tools we need to do these
experiments.
So, and then run the experiments and
then we have to make the antibodies and
that takes quite a bit of time as well
as um developability on the antibodies
which means we need to at the very
earliest stage have high confidence that
we're going to make an antibody that we
could give to people and it'll be stable
and it'll have predictable physical fun
physical properties and it'll have a
shelf life and it'll all these things
are what we build into the antibodies to
this at this very early stage.
>> How confident are you at that stage,
Lloyd, that the antibbody won't elicit
an immune response in a human?
>> It's still one of the biggest unknowns.
Um and and the best way to do it is to
use fully human antibbody. Not
humanized, fully human, straight up
human.
>> Yeah.
>> Can you explain to folks the distinction
there?
>> Yeah. Well, there's
um humanized is used to describe taking
a mouse or other species antibbody and
replacing as much of it as you can with
human sequences based on what we know
about human human antibbody codon usage
and amino acid preference and so forth.
Whereas um fully human means you're
starting with human genetic material
antibodies,
>> but ultimately it still has something in
it that's foreign
>> as little as part of the sequence. I
mean as little as well there's there's
going to be something new because
antibodies
in in intrinsic ability to recombine and
create new sequences.
>> Yeah. Now in in vivo in people so if you
make some brand new antibbody and it's
not suitable for some reason it gets
selected out whereas when we do this in
vitro in a test tube that doesn't happen
we do the best we can and try to end up
with sort of common codon usages common
antibbody sequences even pair-wise and
so forth. Um but you don't really know
until you um put it into people. There
there there are some in there are some
incilico screens you can do by looking
at what peptides are likely to be
generated in a loome and are they going
to have high affinity b binding to an
MHC molecule and so forth and we do all
that stuff but you still don't know
until you do it.
>> Yeah.
>> Um now it's it's an interesting
historical perspective because I'm
getting old enough to be interested in
history now. [laughter]
Um the very first antibodies tested in
humans were mouse antibodies
and there's still one that's used to
this day as a therapeutic. So it's OKT3.
So this is this is an antibbody used to
prevent transplant rejection.
Uh it's an anti- T- cell antibbody,
human T- cell antibody and we still use
it to this day.
>> And what is it targeting? Is it
literally targeting CD3?
>> Yep.
>> Wow. So it's it's broad.
>> Yes. It's going after every T- cell.
>> Yes. Right. And there's and there's
there's there's rabbit anti-thyocy
globulin too that's still used
clinically.
>> Um
>> that's a blast from the past.
>> It's still used. Yeah. And these were
the first antibodies used in people. And
of course uh the other antibiot the
other foreign antibodies that are still
used are antivenenoms. Most of them are
horse serum. M
>> as you can imagine, you only want to get
bitten by a snake once and need that
because when you need it the second
time, you have kind of a ferocious um
serum sickness response.
>> Great point. So you identify Beimma plus
a few others and you start now running
these into the mice.
>> Yes. Is there another chance that
because you've gone to all the trouble
to make sure you have a human antibbody,
it won't work in the mice when it
otherwise would have worked in humans.
We test that beforehand.
>> Okay, got it. So this is this is again
part there's an enormous amount of
detail in drug development and
one of the things is that your drug has
to crossreact I mean work also in at
least one of the two species we're going
to use later for toxicology
um and it has to work in a species we're
going to use for pharmarmacology
if it doesn't then you need to make
surrogate drugs y
>> to do that. But in our case,
we we made one that worked in um
rodents.
Now, it turns out that Bagramab is is
pretty immunogenic in mice, but not in
rats.
>> How common is that?
>> It's kind of idiosyncratic.
Um, so the
construct we ended up using in mouse
experiments was something called
CDDH866,
which was we you you talked about
humanizing antibodies. We murinized
Bagramab so that we could use it in
>> we could go back and use it. Yeah, that
makes sense.
>> And
and and to make a long story short, we
were able to give these antibodies to
mice and see if it caused muscle
hypertrophy or not. And how much did it
do so relative to the pure myostatin
knockouts that were enormous?
>> Probably more so than the myostatin
knockouts. It was really impressive.
>> Again, we're we're going to link in the
show notes to what these images look
like. Um, but it is it is truly a
caricature.
>> It's impressive in the mice. Look at
also the whippet dogs, the the Belgian
blue cattle that are double muscled.
It's uh it's impressive.
>> Did you do anything else Lloyd at that
time? So when you demonstrate that
Beimma is making bodybuilding mice, was
there any assessment of muscle function?
>> Yes.
>> Okay. And what did you find?
>> Uh the the mice were stronger and can
run faster.
>> Okay. But remember, they had perhaps a
30% increase in their muscle mass.
I mean, which is which is a huge
Um, and people can look at the pictures
online and see it's it's quite obvious.
So, it it doesn't work this well in
humans because just just skipping all
the way ahead and we'll come back. Um,
humans get about
4 to 8% increase in muscle mass. Most of
the people we've tested have been older
people. Uh, which is one caveat.
Whereas,
>> did you do it in old mice?
>> Not in old mice. I think David Glass did
some experiments in older rats and it
still worked, but not quite not as well
as in younger ones. And remember, when
people do these muscle experiments in
rodents, they almost always do males
because it works better in males than
females.
>> Fool thyself.
[laughter] Um, it would be interesting
to know as you ran it across a continuum
of of escalating age, what the what what
accounts for the reduction in efficacy,
right? Is it is it substrate limited? Is
it a muscle protein synthesis problem? I
mean, what what is you know,
>> I don't I don't I don't think that's
been studied formally by scientists.
>> Um [clears throat]
I might it might be known in the in the
bodybuilding community.
Um, and just just a heads up to the to
the listeners who might be bodybuilders,
the first thing that any company does
when they're working on a drug that has
the potential for abuse is we work with
the um with with Wada, the World
Anti-Doping Agency to make sure that
they can screen for these things.
>> So, where in the pathway of BEMA did you
begin
notifying Wada that we're working on
this thing? soon as we had a the soon as
we worked in the mice antibody
>> we started that process
>> I think I would
>> and um
>> and and and basically they've they've
had an assay for more than 10 years.
>> Have they ever caught it? Have they ever
screened?
>> I have no idea.
>> That's funny. Um okay, so after the you
get the home run in mice, do you want to
go into a primate? Where do you
typically go from mice?
>> So for therapeutic antibodies, often it
includes a primate simply because
we we we want to have one of the two
toxicology species in whom the antibbody
has the expected pharmarmacology. So we
can look at sort of on pathway and off
pathway toxicity of the therapeutic. And
since the the
anyway, so we we we we typically use
non-human primates for this.
>> When you're at the mouse stage, Lloyd,
is how how are you screening for to
talks besides the most obvious, right?
Obviously mortality or something
catastrophic is obvious, but um for non
apparent or nonmortality based toxicity,
what are you looking for? And is any
toxicity at the mouse level
disqualifying to go forward? Or are you
evaluating it case by case and saying,
"Look, okay, this ended up being pretty
bad for the mice despite the efficacy.
We don't think that's going to be an
issue or we think we got the dose
wrong." or do you basically keep going
back and perfecting it in the mice until
you get the dose response right before
you move up or do you just sometimes say
no we're going to go to the primate or
whatever other model we're going to look
at and reassess talks as we get closer
to our species of interest.
>> Yeah. So with with the with the uh
caveat that I'm not a toxicologist
um the fundamental principles are you
use a weight of evidence approach based
on all the all the data that
accumulates. Um from a clinical
perspective
we try to balance risk and benefit with
new medicines in general. So if if it
turned out that pimagraab had some and
pimagraab has some talks that we that
we'll get into. Um but if it were
unsuitable for use on a big population
that we then think about higher medical
need patients
>> that's when you would go from maybe
sarcopenia to duchain muscular. Yes. If
we Yep.
>> Um and where whatever the the adverse
effects are would be outmatched by the
potential benefits. Yep.
>> Um but secondly, we want to know
precisely what the toxicology is. And
the two big things we look for are
whether it's moniable, whether it's
reversible.
So if we have irreversible cardiac
toxicity with a therapeutic, that's
yeah, that's usually the end. for
example, or neurologic.
Um, if it's if it's serious organ
toxicity,
but there's enough of a prorum. So, for
example, if it's
>> well, you look at a drug like um
Lamicil, right? Something as supposedly
benign as Lamicil. I mean,
>> that can destroy your liver. But if
you're checking liver function tests,
transaminases, the warn the writing's on
the wall, long before you get there, you
can stop the drug. So that's your point.
It's monitable. Moneratable and
reversible if you stop it and you get a
long enough warning.
>> Yeah.
>> Because otherwise, if it would just
automatically destroy a person's liver
at a frequency of one in a hundred
people using it, you could never justify
it. So, you're describing um
idiosyncratic liver toxicity, which is
the most common reason drugs get pulled
off the market still.
>> Yeah.
>> Um and I personally have killed drug
programs for that. Um and it's hard to
can't predict it pre-clinically.
>> Yeah. So, you get bema into the
primates.
>> Yes.
>> And how does it how does it perform?
Well,
in order to do toxicology studies, you
have to know how much to give them and
how long it's going to last and what
it's doing. And so there are there are
preliminary studies in a small number of
animals. And so we did those, but we did
them long enough so that we could see
the muscle hypertrophy if it were going
to happen. And it did work. Not as well
as in the rodents,
um, but it did work. So it it gave us
confidence that we could move ahead with
the rest of the activities. Now
manufacturing enough antibodies for use
in larger animals is you know is is an
is time and expense and so all of that
was going on in parallel and each of
these decisions. So you're doing this
all inside of Novartis. Um is there an
IC is there an investment committee that
basically revisits every time there is a
new you know allocation of capital to
move from one thing to the other where
everybody presents and h how does that
typically work in a large company? All
big drug companies work kind of the same
way and that there are there are
typically two or three or four depending
on the company major checkpoints where
all the data are assembled and you know
and made into a slide decks and
presented and feedback's obtained and
programs course is adjusted and um and
and so that happens and and I think it's
it's more frequent but faster at small
companies.
>> Um but it's the things are constantly
being re-evaluated and reassessed.
>> Yeah. And what's interesting for for
folks listening to us is we're talking
about this in the context of um a large
company that doesn't have to go out and
raise capital every time it does this.
But the exact same idea that you just
described, everything you just said
could have been done by a startup, but
now it would have a totally different
look and feel in that, hey, we're going
to go raise some seed funding to go test
this idea. Okay, guess what? We were
able to find the antibbody. we're going
to have to go raise another, you know,
$20 million and boom. And now they'd be
at the stage where they'd be probably
raising a series B or no, probably this
would be still be an A, I think, as they
go into the primate.
>> What? Whatever you call it, you
>> but give folks a sense of how much you'd
have to raise for this next stage, which
is basically your pre-IND.
So if it includes many so you have to
manufacture
>> it's going to include the primateology
and clinical material you have to run
the IND enabling studies which is
toxicology and and some other things um
and and and and frankly investors want
value creation for their money and
reasonably so. So
I would think for Bagramab if this were
in a small company the value creation
step would be showing muscle hypertrophy
in the very first clinical study. So I
so the funding that I would raise would
be IND enabling
>> plus phase one
>> plus phase one plus a runway to raise
the next round.
>> Yep. And you would structure your phase
one to demonstrate efficacy even though
technically you only need to do talks.
Yes.
>> You would have it long enough, big
enough,
>> not not talks, but safety
intolerability.
>> Yeah. Yeah. So, okay. And then just for
using BEMA as an example, how many
dollars would that be from where we are
now to give you that runway into 2A?
>> In today's dollars, probably $20
million.
>> Okay. Yeah. So, series A
>> thereabout.
>> Yeah. Okay.
>> Um maybe
>> that's lower than I would have guessed,
by the way.
>> May maybe a little more.
>> Okay. It it it it depends on where you
do the manufacturing and
>> um
>> so for for Novartis this is nothing for
a startup this is everything they're
betting the farm
>> well
>> I don't want to make light of it inside
of Novartis but the point is Novartis
doesn't have to go back to the public
market to say I need to raise another
$25 million to fund this they're doing a
lot of these in parallel
>> big companies though have
their resources are stretched too it
it's kind of funny thinking about it
looking from the outside but having been
inside a big
people are competing for a fixed amount
of research dollars, the the people
within the company and resources are
allocated based on company strategy and
um
ironically sometimes there's more
project capital available in a small
company than in a big company because
the comp the small company's got one or
two or three projects fewer shots on all
the money's going there. Yeah. whereas
there are hundreds in the big companies.
So, and I've seen it both ways. I've
seen some big company projects get high
high um highprofile, high importance,
well funded. Um [clears throat]
so, yeah, so let's we'll say 20 to $30
million maybe at at this stage. And
yeah, so Bagramab at that point made it
through rodent and non-rodent toxicology
studies and
um what we call DMPK which is
distribution metabolism
pharmaccoinetics. It's um knowing that
when you give a a participant or a
patient a subject a medicine,
does it get into their body? Does it go
to where you want it to be? Does it do
what you expect it to do? And you have
to you have to know all that stuff
before you go into patients for the
first time. And we assess that uh in
animals. Um you asked earlier, what do
you actually do to measure the toxic
effects of a medicine? And um animals
receive courses of therapy. And we do
blood tests just like we do in people.
Sometimes we would do X-rays if it was
warranted. And then they get autopsied
to look at all the organs and look for
microscopic changes that you might not
perceive clinically. And we know we have
to know all of that before we give
people an in experimental medicine for
the first time.
>> Any red flags whatsoever as you
um or anything that is of concern, not
necessarily a red flag, but anything
that's that's still an unknown as you're
going into the phase one.
>> Lots lots of unknowns going in. And
there are always things of concern. I've
never seen a drug development program
that couldn't be stopped for some
reason. And you you have to balance the
unknowns and the uncertainties and the
risks with the potential benefits and
make a make a decision about whether you
move forward or not. It it's it's kind
of a joke in the industry that every
really successful program has been
almost killed or killed several times
before it eventually makes it out into
into humans and then eventually
commercialization.
>> What's the approximate attrition from
that first candidate drug discovery to
the IND filing? That's a a winnowing
down of what to what to one. It's it
it's hard to put it in aggregate because
it depends based on the format of the
drug
>> and then [clears throat] there's other
factors like strategy and funding and
everything else but for for biologics
like bimagro and a therapeutic antibbody
it's it's pretty low actually
>> 5 to one six to one
>> I would say maybe 30% of them actually
get into humans
>> okay um Yeah, more than I would have
thought.
>> Yeah, it's simply because there are no
offtarget adverse effects with
antibodies in general. There are some
specific specific counterexamples to
that, but in general, an antibbody is
not like a small molecule that could
have liver tox or some other talks that
you can't predict for reasons that you
don't understand.
>> That's a great point. Yeah. So maybe
I'll yeah I'll I'll restate that so
folks get it because because the
antibbody is so specific by definition
it can't bind to many other things
>> and in fact we screen to make sure it
doesn't.
>> Yeah. Whereas the chemical
>> can do lots of things off target. You
know, I had on uh recently we had a
podcast talking about uh CEP inhibition
>> and you know, the very first version of
that drug lowered uh LDL cholesterol but
raised blood pressure and that was a
completely offtarget complication of the
drug. Yeah,
>> exactly. Um so that doesn't generally
happen with biologics.
>> Got it. So that's why you have the
higher throughput.
>> Yeah.
>> Okay.
>> Um
>> so now you're let's skip. So you file
the IND and you're now ready to start a
phase one.
>> So an IND is tell what it is. Regulatory
permission to uh administer the drug to
people
>> and you've already filed your patent at
this point.
>> Yes.
>> Yeah. Where in that process did you
file?
>> Patents typically get filed
again there's a
>> you want to do it as late as possible
but while still protect
>> Exactly. So typically around the point
where you have a group of a group of
candidates from which your final drug
will be selected, that's typically when
we would do it.
>> Okay. Wow.
>> Because you want the patent to last as
long as possible. But once once
information about what you're doing is
getting out, you you want to have it
protected. So from the time you file the
IND with the FDA until and you have to
show them everything that you we've
talked about do you also have to at the
IND show them that you can manufacture
in GMP?
>> Yes. So the manufacturing is a core
element of the of the uh common
application that you do for an IND and
and this this is USP specific
nomenclature. IND stands for
investigational new drug. In Europe,
it's called a clinical trial application
um CTA. Um there are other countries
that have different nomenclature and you
companies can do the first in human
study
anywhere in the world that's got a
proper regulatory environment and
suitable investigators and clinical
sites and with with adequate quality and
so forth. Um
but
maybe maybe we'll be US- ccentric for
this discussion.
>> Sure. Can you explain to folks what the
hurdle is to to GMP or good
manufacturing processes and why it's so
important? And again, I'll I I call this
out to listeners because we live in an
era now where these peptide therapeutics
are very prevalent, these sort of gray
market peptides, and there are people
out there that think, "Hey, I'm buying
reatride."
>> Yeah. No, they're not. Yeah, exactly.
Maybe use the GMP uh process as a way to
explain why when you think you're buying
retatride peptide for research purposes
only, you are definitely not buying what
Eli Liy is going to eventually sell if
they get FDA approval.
>> Right? So, GMP stands for good
manufacturing process
and it's
basically a commitment by the
manufacturer to to use high quality
standards with extensive documentation
to be able to prove what they've made.
Um, and so that everybody can have
confidence that this is this is a good
quality material and they know that
what's on the label is what's in the
bottle basically.
>> And that there's nothing in the bottle
that's not on the label.
>> Exactly. It's it's it's purity, its
activity, its contamination or lack
thereof, its uh sterility, if you will.
Um, it's all of those things. It's that
the material that's being purchased
eventually commercially is the same
material as what was tested clinically
and and and we can have confidence in
it. It mean basically the factories are
inspected and the factories that make it
have the and and typically there are
many manufacturers involved when when
you buy a um you know with the exception
of saying buying a bottle of um tears
from Eli Liy but typically when you buy
a drug from somebody the drug's
substance the chemical is manufactured
by one company and then it is formulated
or put into a
um a mixture that makes it predictably
absorbed or administered is done by
another company and then it's put into a
package by a third company and then it's
distributed by a fourth company. So
there's a lot of people involved and
this this whole manufacturing uh
infrastructure and pipeline is the is is
well controlled and well documented and
um you can buy online peptides that may
be the same as reatrite they might not
you have no way in knowing yeah and in
many ways that's the premium you're
paying when you're buying the drug from
Nova Nordisk or Eli Liy or Novartis or
whatever is the the part of the premium
is it's very expensive to manufacture
under GMP conditions.
>> Yes.
>> Um so it's a it's a bit of a buyer
beware when you decide not
>> I think it's a big mistake to buy these
peptides from from you know from fly by
night manufacturers.
Conceptually it's no different than
going and than than a drug user going
and buying some opioid from a street
corner drug dealer. You have no idea
what's in that. Could it have fentinyl
in it? Could it have carfentinyl in it,
which is even worse than fentinyl? Um,
you know, baking soda. You have no idea
what's in there. It's the same thing
with these peptides. You have no idea.
>> Yeah.
>> I think it's I think it's a mistake. And
and plus, even if you were to have
confidence that those peptides were what
they're saying they were, the data to
support what they do are almost
non-existent.
Um
I I've been reading in the popular
literature about this one that's I think
it's called BP 197. Is that right?
>> BPC57.
>> 157. Yeah. Um
all of the data for that peptide come
from one investigator who's the only
person published on it. And remember the
fundamental tenate of science is if it's
real, it's reproducible. This has not
been reproduced.
What the hell is it? It's not encoded in
the human genome. So, it's not a human
peptide.
>> It It has no known receptor.
>> We have So, it Yes. So, we don't even
know how it works. There's so many red
flags for this.
>> No, it's the It's the poster child for
what I would argue is the absolute
greatest grift of the entire health and
wellness industry.
>> There's a lot of I'm sorry if I'm
insulting you, Peter. There's a lot of
grift in the health and wellness
industry. Ah, you're not insulting me.
>> Um,
>> but but that's my point. Despite how
much grift there is in the health and
wellness industry,
>> I'm I'm putting BPC 157 on the podium at
least.
>> I would too. Yeah, I would too. Um,
okay. So, we we've made Bagramab and
it's made it through all of the um IND
enabling study activities and we're
ready to give it to people. Who do we
give it to?
And this depends on
what we need to measure and what the
expected safety and tolerability issues
are in people. Again, we talk about tox
toxicology in animal species. We talk
about safety and tolerability in humans.
And
again, most antibodies,
including bagramab, won't have um safety
intolerability issues that are off the
pathway that it's working on.
>> Um and didn't really see any safety into
any toxicology to speak of in the
animals. The only thing that I was a
little worried about that we saw was in
the rats. they had um cardiac
hypertrophy.
However, remember the animals had
enormous change in their body size
because of the muscle hypertrophy. And
if you normalize the heart size to the
body size,
it was normal. So does that mean that
you didn't know if the cardiac
hypertrophy was in response to more you
know SVR you know uh more resistance
that the heart had to work against or
whether the antibbody was working
directly on the cardiac myasytes and
increasing hypertrophy there as it was
in skeletal muscle.
>> Exactly. We didn't know, but we could
make an argument that rats of the size
that they became
>> should have bigger hearts.
>> Should have bigger hearts.
And and that was the argument we made to
regulators. And so we didn't think there
was any specific cardiac toxicity. And
and typically in toxicology studies, you
have something we call a recovery period
where the the drug is withdrawn and some
of the animals are followed to look and
see whether any toxic effects that did
occur are reversible. And in fact, when
you stop giving the animals vagramab,
the muscles got smaller and the heart
got a little smaller.
>> How often was it dosed? Is it a
>> So the way you dose in the toxicology
studies is you want the exposure which
means the amount of drug in the blood to
be
ideally higher than what we ever expect
to get in humans.
>> And then when you got to the humans
>> so we we do so the so that was that was
the preamble to the answer to your
question which was weekly. So we gave
the animals the drug weekly
>> and the um the halflife of the drug
presumably is short but
>> it's shorter in animals but again you
you drive the dosing in the toxicology
studies to make the amount of drug in
their blood
>> ideally higher than we will get in
people so that we have what we call a a
safety margin of exposure. Now how do
you know at that point Loy Lloyd if
toxicology is driven by peak or trough
because some drugs are
>> you don't you don't
>> you don't you you make a best judge
judgment but
>> is there a general rule of thumb
>> you measure both and you want both of
them to be higher in the animals than
what you get in people.
>> Okay. Now this is in in general medicine
therapeutic indications in in some nasty
oncology drugs
tox you know toxic effects and
therapeutic effects are at the same
exposure or even lower sometimes.
>> Yeah.
>> Um but the medical need is so great that
you accept the toxicity.
>> Well, I was going to actually use that
as an example. We we sort of skipped
ahead a little bit on the phase one
patient selection. We we rushed through
that but um or actually we we didn't
answer it. We got we we we went off
topic. We're going to come back to which
patients do you select for the phase one
and that really depends on the drug
because in an oncology drug you're going
to test it on
>> the most recalcitrin cancer patient,
right? You're going to test it on a
patient who's progressed through every
therapeutic. They have stage four
version of whatever cancer you're
testing. And this is the Hail Mary. And
you're not just testing for tolerance
and side effects. You're hoping to get a
sliver of efficacy through dose
escalation.
>> That's the most common scenario in
cancer.
>> But here, what are you doing? Are you
going out to the most frail sarcopenic
elderly person or are you going to test
it in? So, so what I do personally and
uh and a very experienced drug developer
named Bob Schmouter taught me this and I
I think he's right is
ideally you'd like to test this a new
medicine in in the cleanest population
you possibly can where anything you
measure is related to the drug and not
some underlying disease or or other
thing. However, we do not want to expose
healthy volunteers
to risks if we possibly can.
>> Right?
>> So, we use our best clinical judgment to
say that I don't want to expose people
to a risk greater than that of a
lightning strike in a year.
>> Is that literally a probabilistic uh
form formula?
>> That's what I use. Interesting.
>> Yeah. So the risk of being struck by
lightning in the US in a year is about
one in a 100 thousand.
>> It's actually that's actually higher
than I would have thought.
>> Me too.
>> That's a little scary,
>> but that's what it is.
>> Okay.
>> And so I don't want the risk of
something bad happening to one of my
volunteers to be greater than that. And
and that's frankly how I explain it to
him.
Um,
so if I can have some confidence that
that's true, I I would we will test
drugs in healthy volunteers.
Um,
if we're worried about a toxicity or a
risk, then we will go into people who
have a potential benefit from the
therapy. So you can make a risk benefit
argument. And this is all laid out in
plain English in the consent forms. But
is I mean so first of all that's a great
framework Lloyd which is if the if the
risk of adverse event is greater than
one in a 100 thousand we must move to a
population that is going to potentially
get benefit to justify
>> serious
>> adverse is that a Lloydism or is that a
truism across the entire industry? Is
that is that something that every is
that is that something the FDA would ask
of every company?
>> It's a schmutterism but Bob if you're
listening thank you. Um but in in
>> but the FDA doesn't force that.
>> The FDA doesn't force that but the it
the principle is still there.
>> Okay.
>> Um
>> but it's a great standard.
>> Yeah. I again and and if you think about
the industry as a whole, how do we do in
bringing new medicines into
healthy volunteer populations?
I've I've been in this business
partially in academia wholly in industry
for maybe 30 years total where I've been
watching this and about once every 10
years we see
something serious happen to healthy
volunteers once every 10 years in a
study. So that's pretty good and we
learn something when those happen. Um so
we're talking about therapeutic
antibodies. The one that um comes to my
mind and maybe to others is the toenro
incident.
>> Say more about that. I don't remember
that.
>> This was a therapeutic antibbody that
was directed against CD28. It was an
agonist antibody. Now CD28 is an
inhibitory receptor on TE- cells and the
idea was um
um I'm sorry is is an activating
receptor on TE- cells and I forget the
actual
therapeutic indication they were going
for but they tested the antibbody
preclinally everything was fine and then
they started at a very low dose in
humans and what we think happened is
they cross-lin the CD28 receptor and
they had extremely strong T- cell
activation and an acute cytoine release
syndrome in healthy volunteers. Some of
them died. I mean, it was terrible.
>> I mean, why did more than one of them
die? In other words, why didn't they
figure this out the very first time they
>> administer? That's super important. So
that study which that happened boy more
than 20 years ago
um
that that experience is why ever since
we typically have sentinel patients and
dosing cohorts when we're bringing
something brand new into people. So they
do I think six people at once with the
active drug.
>> Oh my god.
>> Um we don't do that anymore. The other
one there was a example with a small
molecule uh bial I think was the was the
example B I P people can look it up but
it's it's extremely uncommon to have
healthy volunteers have anything bad
happen to them in a in a drug study um
extremely uncommon if you think of the
>> I remember there was one at Hopkins when
I was there um
it was
it was an inha oh no no no you know what
it was I'm sorry that was not a it was a
woman that a healthy volunteer that
underwent a broncoscopy and I think had
a horrible bronco spasm
>> um
>> that
>> so it was I don't if I'm remembering
correctly it wasn't a drug that caused
the issue but it was a horrible adverse
event to
>> uh but anyway but she she died
>> procedures can have yeah
>> um adverse consequences which which are
known and disclosed in the in the uh in
the consumer.
>> This gave me a lot of when I was in
medical school. I was I mean I was so
broke and doing anything I could to
generate a buck. I vol I was probably
one of the most volunteered people for
studies at Stanford. And I mean it like
if if there was a study that paid
$1,000, it didn't matter what it asked
of me, I would do it. Um and I I
remember coming away from I mean, I had
radial lines in my I had, you know, as
you know what a radial line is, but
arterial lines into my radial arteries
that to this day I still have scars over
my wrists.
>> Can you can you imagine that I subjected
myself to that?
>> That that seems a little much. My I
think many of us as medical students
volunteered for this stuff. My personal
favorite was there was there was a study
called brain electrical activity mapping
that children's hospital was running
when I was a medical student and
essentially they um they attach
electrodes to your head and then you go
sleep in the lab and they monitor that
and video video you while while you're
sleeping. Um they loved me as a subject
because I was bald as a medical student
and it was really easy to put electrodes
on and off. I loved it because all I had
to do is go in and go to sleep. But
there were there were some others like
inhaling radioactive microspheres.
>> I once I used to do I used to donate
plasma via plasma feresis as often as I
could when I was at the NIH. And um on
one occasion I was in there and this was
like a lymphosy plasma feresis. It's a
4-hour procedure
>> and again it probably paid 200 bucks
which seemed like
>> it was a lot of money. when you're a
medical student, that is that's infinite
money. Um,
>> and then at one point, somehow the nurse
stepped out and the lab locked and I was
stuck in there locked and they could not
find a key. So, they couldn't [laughter]
get back in. They were losing their
minds, but I didn't know it. I was just
in there watching whatever movie was on
the thing. It turned out to be like one
of the most stressful moments in the in
the NCI history, you know, trying to
figure out a way to get a spare key to
get into the lab and and take and I was
completely oblivious to it.
>> Oh,
>> okay. So, back to patient selection. So,
ultimately for BEMA,
>> ultimately for BEMA, a healthy volunteer
study,
>> you did go with healthy volunteers.
>> Um, older volunteers.
>> Okay. So people,
>> what was your criteria specifically in
terms of muscle mass?
>> So I actually didn't run these studies.
Uh it was it was the the the clinicians
involved were Dan Rrook and Ronan
Rubinoff at the time. Um but the the
principle here is healthy volunteers
doesn't necessarily mean you're 20some
year old with no problems. It means
people without
um typically diagnosible disease or
concominant medications that could
confuse yeah any any assessments
>> in the case of BEMA because we were
thinking older adults. These were older
healthy volunteers
um and people in whom we would be able
to measure some of the effects of BEMA.
We hope so. Um, and again, what you what
you measure in a healthy volunteer study
depends on what the drug is expected to
do and what and what adverse effects you
might expect. So, there's some things
you always do like a set of standard
blood tests. Um, but in in the case of
Beimma, we were assessing people's
muscle mass
>> via DEXA
>> and strength.
I so you this this is almost archaeology
at this point thinking of what you know
what's what what we measured but um we
we would have measured muscle mass and
at different times we used MRI and we
used DEXA okay
>> I don't remember what that study had
>> got it
>> um but we would have measured muscle
mass measure soluble muscle proteins in
the blood like CK and Aldase and LDH and
um
um and so forth.
>> Did you see any adverse effects in the
phase one?
>> So yes, so the the the three adverse
effects that are evident with beimma
that we think are on target
um and that were assessed in that study
were muscle spasms
or cramps.
Um
acne is rare in older adults and it was
rare in this study because those were
older adults. But when skipping ahead,
when we've tested younger people, acne
is more common. We don't understand why.
And then there are GI symptoms of
diarrhea that happen. Um they tend to be
first dose related and less common
subsequently, but they they're
reproducible and we think they're real
and we saw that stuff.
>> And how many steps of dose escalation
did you do in that study? Or and by the
way, if that's too much detail to
remember, don't worry about it. But just
I'm wondering if you remember how high
you got relative to what was an
efficacious dose.
>> So there's some principles here. Um
I personally like to dose as high as we
can in the first in human study to
understand if there is going to be any
uh safety or tolerability issues in
people while at the same time never
exceeding the exposures we've tested in
animals.
Um so we would have so the study designs
include the opportunity to go as high as
we can. Um typically in antibodies that
ends up being as as high as is feasible.
Um, and there are a lot of technical
details here we don't need to get into,
but when your antibodies are made from
cell culture and they're highly
purified, but there's still some
measurable contaminants in them and the
amount of contaminants,
of course, they're also tested as part
of the toxicology studies because
they're in the drug we give the animals.
Um, but we can't exceed the exposure to
the contaminants either in the clinical
studies. So sometimes that sometimes
it's the volume we can administer, the
mass we can administer and so forth. So
um
so I think the highest dose that we
ended up doing in bagramab was something
like 50 to 100 milligrams per kilogram
but you know I don't remember
>> and in that study in humans you're
administering once a month. Uh initially
you'd administer once
and then based on the emerging results
for how long that lasts.
>> I see.
>> Um and and we knew what exposures we
needed to reach in order to get maximal
efficacy based on the culture data. Um
there were a lot of um cell culture
experiments we did that we haven't
talked about like we you can culture
muscle cells in a dish and we did that
and looked at the ability of the drug to
cause hypertrophy of those cells. So we
we we knew what exposures we needed to
get to and how long we we wanted to do
it. Um but again we don't exceed the
exposures that we get in animals. So I
think after the single dose study we
probably did um three doses
um
and and that was it for the first in
human study
>> and and and typically you need multiple
doses in order to be able to see the
the technical term is pharmacodnamic
effect. So the the effects on the body
that the drug causes. So the end point
for the phase one before you move to
phase two where you're really going to
actually look as your primary and you're
always looking obviously for safety but
now you're really pivoting to efficacy
being the thing that you're you're
trying to chase.
>> Yes.
>> Um
what what did you need to submit to the
FBA the FDA to say okay we have we
checked our phase one box? So typically
you're in reasonable communication with
regulators whether it's the FDA or
whether you're overseas elsewhere and
you you provide them with a report
>> and Novartis is a European company right
they're based in Switzerland
>> but this work was being done in the US
>> I think we did do the first in human
study in the US yeah
>> any reason for that is it are Europe uh
European and US regulators so comparable
on this point that it's really just a
question of where your teams are or
>> so Every country is a little different.
Um,
Europe is
somewhat homogeneous, but not completely
so. Every country is a little different.
Um,
and I think it's true both for large
companies and small companies that you
go wherever makes the most sense. It's
where you can remember that the three
biggest challenges of any clinical study
are recruitment, recruitment, and
recruitment. So you have to be able to
get the subjects or the patients or the
participants. You need qualified,
experienced, reliable clinical
investigators. You need a regulatory
environment that's supportive for what
you're trying to do. Um,
and then you think about cost of the
study. They're different in different
countries. Um, and so you integrate all
of that stuff and that chooses where, at
least personally, where I would go to do
a first in human study. Um,
countries that are often used nowadays
are
Germany, uh, US,
>> Australia is pretty popular,
>> Australia, New Zealand is very popular
now. Um things have really changed I
guess maybe in the past year or two
about China being really popular because
China has um a regulatory environment
that's become more favorable and they
can do investigator initiated studies
with um um less supporting data than we
require for a typical IND.
So it can often be a faster way to test
something.
Um and of course China has a lot of
patience.
Um so that's something that's being done
now too. Um
I personally
love doing studies in the US and Taiwan.
Um Taiwan has you know they they they
have wonderful investigators. They speak
English better than we do. They have a
very centralized clinical environment.
So they have many patients at a limited
number of uh clinical sites. The
regulatory environment uh is very
similar to the US. Um Australia, New
Zealand is is favorable because they
have a especially this is Australia now
they have a different regulatory
construct where safety is assessed by
the ethics committee and um and CM drug
quality is assessed by the regulators.
So they have a clinical trial
notification process rather than a
approval process. Um and plus the the
exchange rate's favorable now. So too.
So if we get back to what is the trial
going to cost, that's useful. And how
much reciprocity is there between
agencies? So if you
um
well I should clarify the question. You
can conduct the trial in Australia but
under the opices of the FDA where
they're issuing or does it have to be in
the US if the FDA is overseeing?
>> If the FDA is overseeing the study's
done in the US.
>> Okay. So if you do a study in Europe and
get European approval or you do a study
in Australia and get Australian
approval,
how much of an additional hurdle is
there for the FDA to typically approve a
drug?
>> Let's talk about running a study versus
marketing approval. Very different. So
for running a study, if you're doing it
in say Australia, you apply to the
Australian regul regulatory authorities
and the ethics committee for the study
and they do the review and uh request
modifications and eventually approve and
then the studies run in Australia. Um,
if you want to then do a study in the
US, you have to apply for an IND just as
you would if you were doing it any other
time, but you include all the data that
you got in Australia as well. And if you
were doing it the other way around, it
would be the same thing. And it's true
for any two countries.
>> Meaning, if you had a drug that went all
the way to the equivalent of a phase
three ready for approval in Australia
and you come back to the US from scratch
and say, "We want to do we want to be
able to sell this drug in the United
States." They're going to say submit an
IND.
>> The FDA,
>> I think. So, yes.
>> Yeah. Wow. And but how much do you get
to shortcut? Would they still make you
do a phase one and a phase two or would
they let you go straight to phase three?
>> I would think you could go right to a
regulatory study. I mean to right to a
registration study.
>> Okay. Um
and and in fact this kind of thing is
often done if because typically you do
the you you do the uh phase one study
somewhere but rarely in more than one
two or three countries.
>> Yeah.
>> And then you can use that data to go to
many countries for a phase two and then
use that data to go globally. There are
a few specific examples um
where you do have to run a phase one
study before you go into that country.
um best examples
well the the the
best defined examples are Japan. So to
run a to run a large study in Japan you
need to have run a phase one study in
Japanese people and there is a formal
regulatory definition of who is Japanese
from the Japanese regulators and you
have to provide that data before you can
do a larger study in Japan. um they're
called ethnic sensitivity studies. And
the scientific rationale for this is
that the the the genetic background of
Japanese people can be a little
different. Um average body size is often
different from people in the west and
you want to make sure that the the
dosing and exposure will be safe and
tolerable. Um,
but because the Japanese are so well
organized and specific about what a
Japanese person is, you can do these
ethnic sensitivity studies in uh in
Hawaii, for example, or or even uh uh
California or you can do them in Japan.
Um,
and I like to do them in in Hawaii.
Um,
China generally requires an ethnic
sensitivity study also for the same
reasons and and there are some specific
examples of where there's toxicity of
drugs in people of Honchinese ethnicity.
Um,
but they have a less specific definition
of who's Chinese. Easiest way to do it
is in is in China.
>> All right. So, let's go back to Beimma.
Bema
>> we've um you go into phase two now by
the way at some point doesn't Novartis
sell this asset.
>> Yes. So, Novartis had strong confidence
in Bagramab. It was first in class, had
really obvious biology in humans and
basically
[clears throat] Novartis ran maybe
I think 16 phase 2 studies
of one sort or another. Wow.
>> Phase one, phase two study and different
indications.
tried very hard. So the drug reliably
and predictably increases muscle size
but not
performance assessments
in a in a major way and and I think
that's because remember in the rodents
in whom we saw both size increase and
performance increase the mass increase
was large 20 to 30%. Or more in humans
it's 4 to 8%. And eight is the absolute
max.
>> And were those differences based on dose
or starting mass?
>> Biology people are just not mice.
>> Oh, sorry. Um I mean the difference
between the four and the eight. How much
of that is dose dependent versus other
demographic dependent on the p like you
know do you get more muscle mass in
younger people, more muscle mass in
people starting with more muscle mass?
Yeah, there's a trend to more in in in
males versus females, a trend to more in
uh younger versus older, but there's a
lot of variability.
>> Do we know if
other variables such as resistance
training, nutrition, protein consumption
would have augmented these findings and
how much were those variables controlled
in these studies?
>> So, we know some of that. We try to
control as much as we can. Um there was
one study
that has not been published in
peer-reviewed form yet but there is an
abstract for it. If people want to find
it they can look at so the the believe
study of bagramab in um in obesity was
just published a few months ago in
nature medicine. If you look in there
this this nutrition study is referenced
but there was
>> we'll link to it in the show notes.
Yeah, there was a
there was a study of
Bagramab in patients who were dosed at
three different levels of protein
calorie nutrition.
>> And the bottom line is the more pro and
and it was the recommended daily amount
half of that
>> or one and a half times that I think.
>> Um and basically within those boundaries
the more protein you ate the more muscle
you built. which probably shouldn't
surprise anybody. The other really
interesting finding,
>> and by the way, twice the RDA is only
1.2 grams per kilogram.
>> Yeah, maybe that's what we used. It was
1.2.
>> Yeah, I I would argue had you gone to
1.6 or two, you probably would have seen
more hypertrophy.
>> It's not been tested. I think you're
probably right, but it hasn't been
tested.
>> It's interesting. So, it it suggests
that in humans, you might have been
substrate limited,
>> amino acid limited or protein synthesis
limited. It's it's a possibility
>> and not drug limited.
>> I'll tell you a funny story about that
in just a minute. But let's but just to
finish that study, the other very cool
thing we found is that as you would
expect, if you have half the recommended
daily amount of protein, calorie,
nutrients, you lost muscle mass, but
prevented that.
>> So there was there was some some biology
working there for sure.
>> No question. No question. So the really
interesting story is that when when um
the Bagramab project when it was still
in the research stage moved from Chris
Lou's lab to David Glass's department
um and which I was part of as the
clinical side of that. One of the things
we really wanted to do was co-develop a
nutritional component to this therapy
for the exact reasons that you brought
up.
>> Yeah. And at the time, Novartis had a
nutrition uh arm.
And so we were working with them to
develop a specific nutritional
supplement for Bagram for what became
Bamagram. At the time it didn't even
have a code yet. And
but then Noardis sold their nutrition
unit, I think, to Nestle.
>> And so got the rug pulled out from under
us on that side. And we were never able
to fully pursue that. But in retrospect,
I really wish we had.
>> Do you think this is a blind spot for
big pharma? Just the the role of
nutrition and other behaviors that can
potentiate drugs.
>> Big pharma tries to control it, but they
don't see that as their core mission.
>> Yeah. But I'm I'm saying a blind spot. I
appreciate that they want to control it.
Um, and that makes sense, but I'm saying
like it's an opportunity lost, right?
Probably.
>> Like here's a great example, right? Like
Beimma could have been more of a hit if
maybe and maybe not, but but a drug like
that could have been a hit had it been
appreciated that oh by the way like you
actually have to kind of do something to
reap the benefits.
>> We would have figured this out many
years sooner if we had kept that
nutrition element. But again, one of the
challenges of big companies is there's
so many people involved. They don't all
know what the others are doing. Yeah.
>> Despite everyone's best efforts. So
basically
>> it was a missed opportunity
>> and and so did Novartis then spin it out
after the less than expected findings in
humans.
>> Yeah. So so what happened was we saw
muscle mass get larger but not stronger.
And parenthetically that's the same as
was seen with IGF-1 agonists and with
androgen agonists. Remember the SARMs
were extensively studied is that you can
make muscles larger. They don't get
stronger in the absence of resistance
training. So it's not unique to the
active and receptor antagonist pathway.
Um and in a metaanalysis of the Novarta
studies
where they looked at muscle hypertrophy
in sarcopenia
um
the metaanalysis showed an increased six
minute walk distance
six me uh 9 meters. So, a small effect.
>> That's my least favorite test in the
world.
>> It's surprisingly hard to standardize.
Um,
>> why wouldn't they just do something like
uh, you know, a wall sit or you know,
something that really tests strength?
>> Many other things were done, the the
timed upandgo test, the short physical
performance batteries.
>> Um, but six-minute walk was included in
multiple studies. So, you were able to
do a meta analysis of that. Got it. Um,
and
so the an academic group did this and
they published it and so the the
four to I don't know 8% increase in
muscle mass that these older adults got
>> yielded a 9minut in 9 meter increase in
six minute walk distance.
>> Yeah, I not I'm not convinced that's
going to help anybody not fall.
>> No, I don't think it will either. And
and and Novartis didn't think so either.
I guess I don't I wasn't an insider at
the time. I don't know why they
outlicicensed it. I was the recipient of
that.
>> Yeah,
>> we were on the outside pulling. Um but
[clears throat] no, the very last study
Novartis did was a study in type two
diabetics
and
because we we had we had had data that
um hemoglobin A1C's
decreased in patients given Bagram.
Um and
that study which ran for 48 weeks. So it
was it was 10 migs per kig monthly for
12 doses.
>> Okay. So a lower dose than you were
giving for hypertrophy.
>> No, this this maximized the
>> Oh, why did I think you said earlier 50
migs per
>> in phase one? We went up higher.
>> We went up that high. Got it.
>> We went up as high as we could because
we wanted to know what would happen if
people were overdosed later.
>> Okay.
>> Um and the answer was nothing.
>> So at 10 migs per kick monthly over 48
weeks
>> Yeah. was was was a was a maximal dose
in terms of effect size and they saw the
expected muscle mass increase.
Interestingly, they saw a substantial
fat mass decrease
and hemoglobin A1C and these type 2
diabetics decreased by about 7 or8%.
Absolute, which is pretty good effect.
>> Yeah. And do you think that that was on
account of just more insulin sensitivity
or was it a larger reservoir for glucose
disposal?
>> Both of those things,
>> I think.
>> And these patients didn't have to do
anything else. It wasn't like in
addition to that, they changed the way
they ate or they exercised more. You
gave them a drug that added muscle mass,
took off fat mass, and lowered A1C by
7%.
>> Yep. and and they had standardized
dietary advice to
>> try both the 500.
>> So who did Novartis run that study?
>> Nois did the whole study and then they
made a strategic decision that the
effect size wasn't big enough. I
actually I don't know what their
strategic decision was but they decided
>> the output was we're going to spin it
out.
>> The output was to spin it out. And at
the time I was working with Joe Gimenez
and Mark Fishman and Pina Kendullo at
Adid Bio as as an adviser
and we really wanted Bagram.
>> What year is this approximately
>> that it spun out was 20 21.
>> Okay.
>> I think it was 2021. 20.
Yeah. Um, discussions had been ongoing
in 2020, but I think it finally happened
in 2021.
>> Okay. So, you guys acquired the asset
obviously for a lot less than you could
have produced it.
>> Yeah. Still wasn't cheap because it was
a phase two ready program.
>> Yep.
>> Um,
and
but anyway, we acquired
>> you guys raised money for that
acquisition.
>> Dedum did it all themselves. Okay.
And
to their credit, um, but and and the
plan was we were going to develop it in
older adults with low muscle mass and,
um, impaired muscle function. Uh,
because we thought who were also obese
because we thought this was the patient
population most likely to benefit.
losing fat and building muscle and
maintaining muscle in the in the context
of of weight loss we thought would be
super important for those people. And
remember all of this happened in the
context of nobody being interested in
obesity.
Everybody thought it was a wasteland for
drug development. Every drug that had
been developed in obesity had failed um
commercially. I mean people there are
some that had been registered, right?
But by 21, you're saying pre21.
>> This was before Nova's semiglutide data
came out.
>> Okay, that's right. Yep.
>> And and I'll tell you I
>> because that was 21, wasn't it?
>> Later in 21.
>> Okay. So it's November of 21.
>> Yeah. I think February 21 we started
Versuspio which is the company that
licensed
>> um Bagramram from the Vartis. So at at
that point um so I was the founding CEO
and I was working with Elon Zipkin and
we went out to uh raise money from
investors because now all right great we
had this assay this asset we needed to
run a big phase two study and we went
out to raise money. I think we talked to
53 investors. Almost none were
interested
>> because you told them indication
sarcopenia still.
>> Well, it was it was sarcopenic obesity.
>> Yep.
>> And obesity was just not a successful
area for drug development. So, people
weren't interested.
>> How much did you need to raise?
>> We ended up How much did we need versus
how much we got are different issues.
>> Yeah, I know. That's [laughter] why I
asked. But we ended up raising 70
million.
>> And what was your w if you could have
had your wish list, what would you have
raised?
>> About 100.
>> Okay. However, um uh Atlas Venture and
Medici
liked the story and and I had worked
with Atlas before and um Michael
Gladstone was the partner um and it was
uh Vonnie Marie and uh and uh and Nick
at um Medici Nick Williams and
we then built a a um investment syndic
and they funded the company and
then everything everything changed when
Novo's data came out with semiglutide
which was amazing. It was the first
really effective obesity medical
therapeutic
and
but then you know when you're doing drug
development you skate to where the puck
is going to be. It's Jay Bradner's
favorite saying. Um, but the puck was
going someplace else now, right?
Semaglutide was going to become the
standard of CLA or some increet agonist.
We knew it. So, so what we did is we
quickly repositioned the company to
think about what is Bagramab going to do
on top of that because that's going to
be the standard of care. So I I quickly
ran a bunch of mouse studies and the
efficacy was additive when you when you
took pomeagramab in the with semiglutide
or tzepatide or luraglutide. It did them
all. Um and and the efficacy was sort of
unprecedented. Never seen
>> for both fat loss and obviously for
preservation of lean mass.
>> Exactly. for for for for weight loss,
fat especially fat loss and preservation
of lean mass. It was it was amazing. Um
so the opportunity became much larger
and and the board then br and I was part
of the board. The board then brought in
a super experienced CEO. this was Mark
Bzanski
um to
to lead the company then because we we
had a really big opportunity and we knew
it.
So, um, and we brought in a CMO, Ken
Addi, because I I had been serving as
the CMO also and and then I stepped into
president and cso role just in terms of
company organization. But we all kept
working on the program and we ultimately
ran what became the belief study and the
the story here. We spent a lot of time
thinking about what we would name our
studies. The plan was believe was going
to be phase two, become was going to be
phase three, and behold was going to be
post-registration studies.
>> And then you actually have to come up
with what those things stand for,
knowing only what the B stands for when
you start. I mean, this is so funny how
drug name studies work.
>> Yeah, you you know how it goes. I know
the drill.
>> But it was all they all became with B
for Bagram.
>> Yeah.
>> Now, you haven't asked me where Bagramap
came from. So this is this is another
interesting wonky drug development
thing. So the
the generic name is called the IN name
for I think international nomenclature.
I'm not sure what it's an acronym for,
>> which is why it ends in MAB, obviously.
>> So the suffix of a drug generic name is
prespecified based on the class. Um, if
you're the first in class, they'll pick
a new one, but the company gets to
recommend the prefix and sometimes the
infix.
So, Beimma is the Indian god who's as
strong as 10,000 elephants.
>> And that's why Bagramab is Bagramab
>> and that ends in Mab monoconal
antibbody. The groomab is a monoconal
antibbody suffix and beimma.
>> Yep. So any other drug that comes along
in that class, what would be the
nomenclature naming options?
>> Antibodies are just complicated. There's
a lot of different um criteria for
naming antibodies and you have options
for infixes and suffixes.
>> And what was the what was the GLP1
before lautide? Um
>> there's there's eccent
right. So the tide became the thing that
everybody had to link to going forward.
>> Tide is a peptide. There's a
>> so any but they they were they forced
into semiglut laglutide semiglutide
tzepatide
>> that tide is the is used for that class
but there are other peptides that end in
tide.
>> Yeah. Okay. So you guys ran believe.
>> Yes. So, so believe
it was originally planned to be a
24-week study in patients with
sarcopenic obesity. That was what we
were going to do. But then when Novo's
data came out and we got super excited
about obesity, we said, "Oh my god, we
got to do a bigger study. We're going to
do it in combination with semiglutide."
And this was during the pandemic.
So there was a lot of complexity and
supply chain disruptions but um and
remember with semiglutide
it was a proprietary drug of novo we
couldn't get the drug substance
and so we had to use the commercial
presentation of semiglut
>> expensive
>> which was expensive and it's an auto
injector we couldn't make a placebo for
that so the study design included
semiglutide is open label
But we did a we did placeboc controlled
beamagramab because we had control of
that. Um we used bagramab intravenously
uh just because it was the fastest most
straightforward way to get into the
clinic. Um
not public was that we were working hard
on an auto injector and we would have
been ready in the next study for an auto
injector.
Um
but it was it was introvenous for
bumagra.
Um and then what combination should we
use? We ended up doing something called
a full factorial design. So we did all
possible combinations of lowd dose
semaglutide highdosese semaglutide lowd
dose bagramab highdosese beragramab and
placebo. So it's a nine arm study.
>> Why? because we didn't know in humans
what would happen with those different
combinations. We didn't know if there
would be adverse effects of the drug
combinations or not. They did have a
couple of adverse effects in common.
Diarrhea in for example
>> and
>> and this is in part why I did that
pharmarmacology study in rodents because
if there was anything unexpected that
would happen with the drug combination I
wanted to know about it. Um
technically
actually we and we had to do this
because we weren't using the semiglutide
in its intended population. I think it
it wasn't registered yet I guess was the
issue. We had the data but it wasn't
registered. So it wasn't indicated in
obesity. So if you're using an
>> and so yeah you were using OMIC not WGO.
You were still using
>> We used them both actually did whatever
we could get. Remember they were in
short supply.
>> Yeah.
and and to the regulators credit
uh they recognized all of this and
were um willing to allow us to
substitute
interchangeably and go.
>> Yeah.
>> So what were the findings of this
six-month ninearm study? So it was
originally going to be six months but we
changed it from the original plan with
bagramab alone to the combination and it
eventually became 72 weeks of treatment.
48 weeks was the primary endpoint and
then we had a six-month follow-up
period. So 104 weeks total study two
years.
>> Did you have to raise more money?
>> We did. I was
>> going to say that's that's a hard study
to do for 70 million bucks. Yes, we we
did and it was 500 people enrolled
roughly. 507 was the exact number. Um,
so
we found, so I guess number one, and one
of the things I'm kind of proud of is I
got the doses right because you wanted
to see a partial response with the low
dose, a full response with the high dose
for both of the drugs, and see those
kinds of dose responses in the
combination arms. Remember, there's four
combination arms. Yep.
>> Right. There's there's low dose beema,
high dosema, low dose, sema, high
dosema, four combinations, and then
placebo. Um, and we saw the dose effects
in all the arms. So, that was good. And
the primary endpoint was body weight.
Wasn't what I wanted for a primary
endpoint. I wanted waist circumference.
>> Why couldn't you get DEXA? Too
expensive. We thought that since the
registration
decision is made on the basis of body
weight loss, we wanted that as the
primary endpoint. We included DEXA in
every single patient.
>> Yeah. It's crazy to me when you're that
that you would be held to the standard
of weight loss when in reality a better
outcome might be less weight loss
>> if you're if you're preserving muscle.
>> We were acutely aware of that.
>> Yeah. This awful. But it is not what
it's not what the field was was
thinking.
>> No, I I know. But it's just I mean it's
actually good biology abuts uh
regulatory
um simplicity for
>> Yeah. Yeah. Yeah.
>> I personally wanted waist circumference
and and I I wrote a long white paper
about this
>> because
waist circumference is more closely
linked to important clinical outcomes
than is BMI or body. Yeah.
>> So body mass index is
if you're following longitudinally is
essentially the same as body weight
because height doesn't change over a
short term
>> just for listeners. Um
>> so
>> we ended up using body weight as the
primary endpoint and it wasn't just
regulatory intrigence. It was also what
do investors and potential acquirers
think? Everybody cares about what the
approval endpoint's going to be. We
wanted that to be the primary endpoint.
But we measured all these other things.
And and to to sort of zip ahead to the
end in the highdose combination group,
the body weight lost at 72 weeks was 22
23% of starting body weight.
>> High high.
>> Yeah. Double posit the high combination.
>> And what was the high?
>> But the fat loss was 45.7% of starting
body fat. Now that's what you get with
beriatric surgery. So this to me this is
the first medical therapy that gives
fat loss equivalent to or superior than
um beriatric surgery. That's amazing.
>> Did you do any functional testing in
that study?
>> We did. Uh we did um and and we even did
a preliminary
observational study in overweight adults
at different age cohorts and we tested a
few different things.
Um we tested um
essentially
uh timed up and go for short physical
performance battery. We tested the 302
chairstand test which is my personal
favorite. And we tested grip strength,
but ultimately we went with grip
strength in the belief study because it
was the one most closely linked to
clinical outcomes.
>> And did you see an improvement in
strength?
>> Small and but also it was a variable
assessment.
>> Okay.
>> It's and it's in the published study
that came out a few months ago.
>> Now, Novo bought this asset from you
guys, right?
>> No, Lily did.
>> Oh, Lily did. Yeah.
>> Okay.
>> So, we were super excited about the
study. It was ongoing. We were
enthusiastic.
We closed a series B in two tranches and
we'd called the first trunch
and then the company got bought by Ela
Lily
and so they have Magraab now.
>> What are they doing with it?
>> You have to ask Lily. But they made some
noise last fall that they were pausing
the program or
>> No, they just they they paused one
study, but they still have other studies
in clinical trials.gov.
>> Okay.
>> Um but you got to ask them.
>> I see. So publicly, the only thing we
know is they're still doing something
with it presumably testing it with
Tzepatide, I'm guessing, or reatr.
>> Yeah, the the study that's in clinical
trials.gov of is a is a is a complex
combination study with tearsite.
Um
I I I do think it's fair to mention the
one adverse adverse outcome that
happened in the believe study that we
weren't really expecting uh which is an
increase in LDL.
>> Yeah. How much I remember that now I
thought and I thought that was actually
something that Lily saw but that was in
your study. Yeah. And how how much of an
increase was it?
>> It's about 20%. Why do you think that
was biologically?
>> It's a direct effect of the drug in the
liver.
>> So interesting. Again, you wouldn't
expect this offtarget, would you?
>> This is on target,
but because remember there's active in
receptors everywhere including
>> Oh, I didn't realize that.
>> Yeah.
>> Ah.
>> Um,
>> so it's doing something to interfere
with LDL clearance presumably,
>> I guess. But I I don't know what the
biology is. It hasn't been studied to
>> or No, maybe. I mean, what would be a
more plot? I mean, that would be
studyable, right? Is is it is it
impeding LDL clearance or is it
increasing LDL synthesis?
>> I know who knows the answer to this. So,
so Chris Lou when he left Noartis
eventually founded a biotech called
Lakna in uh in China and he's made
therapeutic antibodies to active
receptor type 2 A, type 2B and the
combination and he studied them. So, he
knows the answer to this. Um
but I and I assume he'll publish it at
some point.
>> And Lloyd, were there any adverse
effects on glucose in the other
direction? Did glucose ever go up?
>> No.
>> Okay. So, and did you continue in the
belief to see glucose go down the way
you did in the diabetic studies?
>> Yes.
>> Independent of what you would have seen
from Sema? I mean,
>> yes. Well, so we have all of that data
and it's published in the Nature
Medicine paper and um at EASD in
September, which is a European meeting,
uh we're we're going to publish the
results of the sixmonth off drug
results. Um so that's
>> that's off all both drugs.
>> Yes.
>> Okay.
>> And and so the real issue is what's
going to happen when you withdraw the
drugs.
Um, and we know what happens when you
withdraw semaglutide, right? Everything
goes back towards where it was. Doesn't
quite get there. Um, and we're going to
find out with pagramap.
I I expect some things are going to
reverse like we we know that muscle mass
with every muscle anabolic agent reverts
towards baseline when you withdraw the
therapy. I expect that's going to happen
in the humans. It happens in the
rodents. Um in in believe we
deliberately included uh patients with
metabolic syndrome.
So these are people who are pre-diabetic
uh so we can measure diabetic endpoints
in these people and it's going to be
super interesting to see what happens
there.
Personally if we had kept vagrammab in
Branis and been a standalone entity we
would be
we we would be well advanced into phase
three by now. Um and and the reason is
because I believe even with those LDL
effects which which which are not
favorable LDL predicts cardio adverse
cardiovascular endpoints um but I
believe that
>> you can monitor it and you can treat it.
>> Yes.
>> Yeah. Um which as an aside
since my my personal interest is making
drugs to prevent
um the most common causes of morbidity
and mortality in older adults. Side
effect of that is healthy longevity.
That's what I do. I am not making
cardiovascular drugs even though it is
the most it is the number one cause of
morbidity and mortality in in adults in
the US and in many developed countries
around the world. The reason is we've
already got a lot of good drugs. We're
just not using them for primary
prevention which we need to be doing
more of.
>> So with that aside, I would be well
advanced in developing Bagram in phase
three. But I would I think the paradigm
for managing obesity is going to be
induction and maintenance of remission.
Um so
probably combination and injectable
therapies to get people to their you
know to move them categorically from
obese to non-obese
and then they need something for
maintenance which might be something
like or forgrron or some oral GLP1
agonist to maintain u appetite and
satiety
>> and you don't think just a lower dose of
the injectable could do?
>> Absolutely it could.
>> Yeah. You're just saying economically it
might be easier to make it orally.
>> Exactly. Yeah. Exactly.
>> Um, okay. I want to pivot and talk about
one other thing. Um,
which is also an area where you know a
lot about it, which is selective mTor
inhibition. [laughter]
Um, we're not going to spend as much
time on it of course, but again talk to
me about where your head is at these
days on that pathway in general. Um, do
you believe that there are
that this is geroprotective in in
humans? I mean, it's it's been well
established how geroprotective this is
in mice. Um, almost assuredly, I think
it'll end up being geroprotective in
dogs. Um, so it might be safe to say
that inhibiting mTor in everything from
yeast to dogs and maybe even primates
extends life. We don't have a clue if
it's going to in humans. You'll never
probably get to directly test it. Um
there are really good compelling
arguments on both sides of why it may or
may not be the case in humans,
>> uh including the uh longevity quotient
argument and things like that. What are
your thoughts?
>> I think it probably will. It's highly
conserved biology across evolution. Um
so I
I I think so if if if
reductively. If you envision
MTOR one as a master regulator of
um
sensing sort of integrating nutritional
inputs and then deciding to grow or not
grow um or and not grow means circling
the wagon upregulating autophagy and
recycling pathways. Um I I think it
probably would. I think the effect size
is going to be modest is just as it has
been preclinally.
Um
and I think it's torque one.
>> Um
haven't seen a lot of new data on that.
>> Well, there was that study somewhat
recently suggesting that rapamy impaired
I don't know if it was impairing MPS or
um some other metric of physical
performance or something. Um,
obviously you're familiar with the
agents you've tested. Um,
you know, we're still at sort of the
infancy of these drugs, right? What what
do you think is standing in the way of
more drug development on more and more
selective
potentially higher efficacy but
potentially lower side effect burden
versions of drugs that can um inhibit
mTor complex one? the the the
selectivity is the is the big challenge
because with
rapal logs as you know there's they're
they're torque one's selective but
there's a down regggulation of torque 2
with sustained exposure and I don't know
that we you know so in in restore bio we
tried to manage that by a combination of
a catalytic and an alossteric inhibitor
um which seemed [clears throat] to do it
Um
and and I know there are other companies
that are working on other ways to get
torque one selective inhibition and I
think that's what we need is a real
torque one selective inhibitor and then
we can we can test the biology
>> and do you think that just intermittent
dosing of everolamus or cerolamus gets
that
>> maybe again it's hard to tell in healthy
people because
you know in cancer when you study mTor
inhibitors the the cancers have a highly
upregulated path pathway and it's easy
to see the biology. You can't really see
the active biology in humans measuring
blood and it's not necessarily the
tissue you want anyway. When we do this
in rodents, we measure their liver
activity. Um, and I think we mentioned
you and I discussed this before that in
in um in young rodents with fasting they
um they downregulate mTor as you would
expect.
>> In old rodents they didn't.
So, it it makes me call into question
the whole concept of intermittent
fasting in older people because I don't
know if it'll do the same thing.
>> Yeah. Again, imminently testable.
>> Nobody's lining up for liver biopsies,
though. And and and there's
>> and we can't get [clears throat] that
with MRS or anything else.
>> I don't think so. It's just
>> Yeah. Again, the price of admission is
so great on that.
>> Okay. Final question, topic.
As you think about drug discovery over
the next decade, I'm not going to ask
you the question everybody's thinking is
how is AI going to help? We'll punt that
for now.
>> Thank you.
>> Yeah. What are you most optimistic about
in terms of
pathway disease?
Uh
where are you most excited? Where do you
think we're going to be in 10 years
where there's been a step function
change? I think we're starting to wake
up to the concept of real medicine pre
real medical prevention. I mean, this is
something I've been saying for years.
You've talked about it a lot is that we
need to get away from being a sick care
system to a health care system. And the
way you do that is with preventive
medicine. Um, and the way to implement
it is you need better primary care and
you need codes for preventive visits
because right now they're If if I wanted
to see a patient for prevention of
cancer, for example. So my new company
is cancer prevention,
there's not codes for that.
So you can't build for it. So there's
there's a lot of institutional
hurdles that we need to get through. But
I I think people are waking up to the
concept of I want to stay healthy rather
than get sick and get treated. say a bit
more about your current company and how
how could one develop a drug for cancer
prevention.
>> Yeah. So this is this is conceptually
difficult to wrap your head around. Um
but again where do new drugs come from?
They come from reading the literature
and thinking which is sort of what I did
after um after Versus ended for me. It's
still ongoing in Lily. Um, and there is
there are some papers published over the
past 5 to 10 years about drugs that
cause cancer.
So if a drug causes cancer, it must be
most likely inhibiting a cancer
protective pathway. Most drugs are
inhibitors of things.
Um the the prototype for this is
saraphanib which is a multicinase
inhibitor that's used to treat renal
cell carcinoma and hpatic cellular
carcinoma primarily. Um you if you give
that drug to people about 10% of the
patients of the of the older patients
get skin cancers.
>> Why is that?
>> And are these melanomas or are these
squamus or basil cells? the the cancers
they get seem to be the prevalence
that's reflected in the normal
population. So almost everything that's
ascertained
>> is basilc cell and squamous cell.
So and and and more recently we
understand the pathway biology of that.
These are saraphanib is a is a
multicinase inhibitor. It inhibits a lot
of kinases, but one of the ones that it
inhibits is the sensing kynise that
triggers something called ribbotoxic
stress. And this is a pathway that
causes cell death.
Um,
and that pathway if you turn it on
irreversibly and coalently is the target
of some of the nastiest toxins that you
know about like dtheria toxin, sarsen,
ryson. It's a very very potent pathway.
My innovation is putting together
different parts of the literature. I I
came up with a way to turn it on in a
gentle and controlled fashion. Remember,
it's on constitutively in people because
if you turn it off with these
multicinase inhibitors, you get cancer.
So
the hypothesis of the company is if we
turn that pathway on a little more,
we'll prevent cancers. Not all of them,
but maybe 50% is what I'm hoping. And
since skin cancer is almost as common as
all other cancers put together, we got
to start there. But in a phase two study
of older adults, and older adults in
this context means 50 and up. Sorry,
Peter.
>> I'm I'm in that category squarely,
[laughter] don't worry.
>> I have been for a while. And um and who
have had at least five skin cancers in
the past. Those people have a 50% chance
of having another skin cancer within a
year. So if we recruit a cohort of 100
or 120 of those, we would be able to
test a low dose highdose placebo and
actually measure cancer prevention in a
phase 2 study. Now is there a risk that
it will only work in preventing squamous
cell and basilc cell carcinoma but will
not progress an epithelial tumor or
prevent I'm sorry that's that's possible
because the only data we have are for
skin cancer but even if it only
prevented skin cancer that's a really
big medical need but I think it will
work on multiple cancers
but it's going to be almost impossible
to test that before approval just
because
cancer incidence is a really rare event.
>> I guess the next thing
that would be an interesting question
Lloyd would be you take a bunch of
patients who have successfully undergone
adgiuvenant therapy for a stage three
epithelial cancer. So I would think
colon cancer or breast cancer.
um they're NE no evidence of disease for
the listener but there's a 50% chance
they're going to have a recurrence uh
you you know you stratify it in a way
that you you basically find people who
have a very high risk of a cancer
recurrence and then you you treat them
>> I I think that's one way to do the other
study what what I've done in co-l
therapeutics is um a collaboration with
the broad institute where we took our
tool compound Now we don't quite have a
development candidate yet
but the we took the tool compound which
is good enough and run it through their
panel of a thousand cancer cell lines to
see what tumors are sensitive to it. So
this would be a treatment mode rather
than a prevention mode
>> and um
>> and you think it could have efficacy and
treatment as well.
>> That's the question we were asking.
>> Okay. um and melanomas emerged as by far
the most sensitive tumor. Now I'm not
sure why because my my hypothesis the
thing about skin cancer is it's got a
heavy mutational burden because of all
the UV exposure.
>> Y
>> it's the highest mutational burden organ
we have in normal people
>> and I thought that was going to be it.
And there and there was a correlation
between mutational burden of the cell
lines and susceptibility to this
mechanism, but it wasn't great enough to
explain the tumor susceptibility. So,
it's something else.
>> Good news.
>> Yeah. So, it it's there, but it's not
good enough. So, I don't know why
melanomas are so sensitive, but they're
enormously sensitive. So, I'm very
confident this will be a therapeutic for
melanoma as well. Um and it it augers
well to the idea of preventing melanoma
which which is also testable and has
been proven with a therapeutic
intervention in a wonderful study
conducted in Australia.
The intervention was intensive sunscreen
use compared to usual practice. Um so
it's going to be testable in a in a
large phase three study but not not
before that. Um,
so yeah, so that's what I'm doing and I
think preventing
>> that's a that's a very interesting idea.
I mean that talk about a new
a whole new playing field, right?
>> Pharmacologically.
>> Yep. Nobody's nobody's made a drug for
this mechanism
>> because we usually think avoiding cancer
or preventing cancer comes down to
avoiding carcinogens
>> which is which we should definitely do.
>> Yes. Yes. Absolutely. So, don't drink
alcohol much
>> or, you know, don't smoke. Uh, be be as
insulin sensitive as possible. Yes.
Yeah. All All of these things.
>> All of those things. Lose weight if
you're overweight. We we know that
successfully treating obesity prevents a
bunch of cancers. Y
>> and we know that from the Swedish
obesity study, which is an observational
cohort of Swedish patients who've
undergone buriatric surgery. And um
these these people are being followed
for decades.
It's doing all the good things you'd
expect of successfully managing obesity.
>> Well, Lloyd, this has been great. This
has been kind of a um a wonderful
education on drug discovery using I
think a very interesting drug in Beimma
as a as a case study for the complexity
and the nuance of the process. Um and by
the way, I don't think I realize that
the Beimma story is still ongoing. So
that's great. So, we're going to
continue to follow this biology and
it'll be interesting to see um where
Lili goes, where Eli Liy goes with this
drug. Um, but it sounds like based on
what's showing up on clinical
trials.gov, they're following in your
footsteps in that they're probably
testing this in parallel with uh the
newer generation GLP1 agonists and the
>> as best I can tell, that's what they're
doing. And it's not now just Eli Liy
because many other companies, you know,
who have seen the believe data because
we've been presenting it at national
meetings are um and international
meetings for that matter. Um there's a
lot of other pathway inhibitors that are
uh that are under development.
>> Well, really appreciate your time,
Lloyd, and it's been a pleasure to chat
again. Great efforts. Yeah. Thank you.
>> Thank you.
>> [music]
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