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astr60: Dr. Ralph DeFronzo Highlights Biomea [NASDAQ: BMEA] - Menin in Diabetes | astr60 | YouTubeToText
YouTube Transcript: astr60: Dr. Ralph DeFronzo Highlights Biomea [NASDAQ: BMEA] - Menin in Diabetes
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This content discusses Bion's menin inhibitor program, focusing on the drug icovemenib (referred to as "ico" or "icoba men") as a potential treatment for type 2 diabetes, particularly by addressing beta cell mass and function.
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Hey everybody, welcome to uh the Aster
um uh 60 webinar focused on Biomeia and
its men inhibitor program. Uh this is
featuring Dr. Ralph Def Franso live from
the third 23rd World Congress on Insulin
Resistance, Diabetes and Cardiovascular
Disease, WCI RDC. I was there about two
years ago. Loved it. Great place, great
presentation, great vibe. Uh this is in
Los Angeles. This presentation, that's
where he's dialing in from. uh and then
of course I'm here uh this discussion
will center on Bion's positive 52 phase
2 coalent 111 uh data evaluating icen
menib in patients with type two diabetes
I'll call that I'll call it Iiko uh
along with an overview of the mechanism
of action of menin inhibitors as a
potential non-cronic treatment option in
diabetes so Dr. Franzo, uh, welcome. And
I'm just going to read out a quick
presentation for you.
>> Make it quick.
>> No, absolutely.
>> Don't get too carried away.
>> Yeah. Yeah. Absolutely. Um, you know,
um, I want to give everybody here a
sense for why Dr. Def Franzo's
perspective is so valuable. It's really
important. I actually don't do this
often when I uh give a a leadin to to a
key opinion leader, but for more than
half a century, he's been one of the
people who has actually shaped how we
think about diabetes. Many of the ideas
now that we take for granted the role of
insulin resistance, the multiorgan
nature of type two disease, the need to
intervene early and physiologically
trace back to a lot of the work that he
has done of course with many
collaborators. What's remarkable is that
he didn't stop at defining the problem.
He helped bring forward solutions that
change clinical practice guiding the US
development of metformin and later
helping pioneer the SGLT2 inhibitor
class by uncovering how the kidney h
handles glucose. These insights didn't
just advance science. They rewrote
treatment algorithms and improve
outcomes for millions of patients.
Across all of this, he's continued to
mentor investigators, run large clinical
programs, stay deeply engaged in the
biology of the disease. When you talk to
Dr. Defranzo, as I've heard from other
people also, uh he's been getting
selfies, I guess, with people down there
in Los Angeles, you get the sense that
he still approaches diabetes with the
curiosity of someone trying to solve it
for the first time. So we're generally
fortunate to have him today for his
perspective, not just because of his
accomplishments, uh, but because of the
way he connects decades of discovery to
where the field is heading next. So Dr.
Def Franzo, thank you so much for being here.
here.
>> My pleasure. You're very, very kind in
the introduction, but I appreciate it.
>> No, I really appreciate Dr. Franzo. So
you know, to get to the meat of the
matter, people here are dialed in. First
and foremost, I know you did a
presentation on men uh down in Los
Angeles at the present. Could you give
us an overview of that and just sort of
what are your takeaways from your presentation?
presentation?
>> Yeah, the uh presentation actually was
kind of a two-part presentation. One was
to focus on the beta cells and beta cell
failure uh and what we could do to
improve beta cell function and more
importantly uh to increase the number of
beta cells because we know with time
there's a progressive loss of beta cells
and eventually if you don't intervene
with the appropriate therapy you get to
a point where you have a burnt out
pancreas in terms of uh number of beta
cells and beta cell uh function. So
that's one half of the story. uh and the
other half of the story was focusing on
how insulin works and how tissues
respond uh to insulin. So if we think
about diabetes and I would say the
really the largest perspective either
you don't make enough insulin uh or you
don't respond to the insulin. Now that's
a a really simplistic view since uh I'm
the person responsible for the ominous
octet in terms of the pathogenesis of
type 2 diabetes. But I think in terms of
discussion points uh if we just look at
these two big problems okay uh how can I
get people to respond to insulin and
number two how can I improve beta cell
function and at some point in time when
you run out of beta cells how can I
>> now that's fantastic Dr. Franzo um you
know uh the role of men in diabetes has
been coming up more and more when I was
in Los Angeles two years ago uh there
were presentations there um you know if
you can kind of give us uh a historical
context um you know I I know that uh men
was first discovered in pregnant women
and and how it works but if you can give
us a historical context and folks you
know who've also dialed in as to how men
fits in understanding the pathology of
the disease um and why it's a target you
know today versus like 10 or 20 years ago.
ago.
>> Yeah. Well, I think you already hit the
most important thing men in in pregnancy
and women in the world should be
thankful because of men. So uh for a
lady when she becomes pregnant uh during
the second uh month of uh uh gestation
uh what happens is there's an incredible
increase in energy dem of the developing
fetus and the placenta. Uh and uh what
happens is miraculously the number of
beta cells increases quite dramatically.
So that's important to provide
nourishment and energy in terms of
substrates to be utilized uh by the
developing fetus in the placenta. So how
does that happen? So menin is an
inhibitor of beta cell proliferation. It
blocks beta cells from proliferating.
Now during the uh second trimester uh of
uh pregnancy as human placental lactogen
goes up that inhibits menin. So human
placental lactogen up knocks menin down.
When menin goes down, that's the block
that's blocking beta cell proliferation.
So now in the the the mama's uh
pancreas, there's an enormous
proliferation of beta cells. This is a
miracle. Uh there's nothing else that
will do this. Uh and in fact, if this
didn't happen, uh you know, the the the
developing fetus would can would stop
developing. And then what's even more
miraculous because now you have all of
these beta cells, all this insulin is
being secreted.
The mom delivers the baby. Okay, if you
have all of this insulin around, that's
going to make your blood sugar very low
uh and you become hypoglycemic. Well,
now the menin levels come back up and
that in and causes involution of the
beta cells and the insulin levels go
down. It's an incredible physiologic
phenomena and literally every one of us
that's out there should thank their mom
and the changes in men for us being
here. It's an interesting way to think
about it, right?
>> No, absolutely Dr. France. I never
actually thought about that and actually
that kind of leads me to a question
about treat pre-diabetes for example,
right? So in a certain level at least on
a metaphorical level, right? A person
who's pre-diabetic has had a certain
amount of loss of their beta cells,
right? So we need to increase it to get
them to be you know uh to produce more
insulin. So it's sort of metaphorically
analogous to the pregnant woman with uh
you know her baby wanted to have more
beta cells right to produce more
insulin. So and I don't want to get
ahead of ourselves but you know would
pre-diabetes be in the long run an area
that like you know IO could tackle.
Yeah, I I think that's not where we want
to direct our attention because in the
person who has pre-diabetes and we've
published very extensively uh on this uh
they have even though they may have a a
small decrease in the number of beta
cells the amount of insulin they secrete
is very very high and even when you go
into the early diabetic stage they're
secretting lots and lots of insulin. The
problem at this stage is they're not
responding to the insulin. They're
resistant to insulin. But what happens
is now as you become progressively more
and more diabetic, now you start to see
this big drop in beta cell mass. And now
we have a real problem because now we
have a decrease in beta cell mass. We
don't have enough beta cells. We're not
making enough insulin. And the body is
very resistant to insulin. So that's why
my lecture today was really two parts.
Number one, when we look at people who
have significant diabetes, uh they they
now have a deficiency of the number of
beta cells and they have a deficiency of
insulin. But now let's say I could
reproduce their beta cells and now I
give them back more beta cells. They
still fighting against this insulin
resistance and that's going to put a
stress on even these newly generated
beta cells and that stress will cause
them to fail. So even though we give
them back more beta cells which is
critical we got to start there we need
to relieve the insulin resistance that's
why in my talk today as I introduced it
we're looking at two extremes why did
Dr. Yehuda Amman asked me to talk about
both of these things sound very
different but they're they're very
interrelated. You got to make enough
insulin means you have to have enough
beta cells. You have to be able to
respond to the insulin and if either one
is deranged you have a problem.
>> Y and that's you know um Dr. Franzo uh I
diabetes is one of the areas that I'm
less familiar with and I'm not a PhD MD
by training so I have to do a lot of
work you know when I'm focusing on a
disease. So if you don't mind we might
just spend a few moments you know if you
can kind of expound a little bit on
specific um you know let's say uh
terminology that bionas used physicians
diabet diabetists utilize but I think
will be also helpful um you know you
talked about for example as you just did
the you know beta cell function versus
beta cell mass right and just explain to
us again uh what is it with diabetics
you know the the problems they have with
beta cell function and the issues with
beta cell mass and how you men
inhibitors could help.
>> Yeah. So, when you're born, uh you're
not born with your full complement of
beta cells. Uh but within the first two
years of life, your beta cells
proliferate. And by year two of life,
you pretty much close got to your
maximum uh number of beta cells. And
then uh uh very shortly from year two to
childhood uh by the time you're less you
no longer have beta cells that are able
to proliferate. And so when you look at
adults the your beta cells really don't
respond uh as you would when you're you
know one or two years alive into a
number of stimuli.
We'll talk about some of them uh which
would cause your beta cells to
proliferate. So the problem is uh I if
you're a a quote pre-diabetic, this
starts when you screwed up in choosing
your parents, you got some bad genes.
You can't get rid of these genes. So
those genes uh are going to promote two
things. Uh they're going to promote
something that causes beta cell failure
with time and they're also going to
cause insulin resistance. Now I'm a a
believer that in the majority but not
all of people with type 2 diabetes the
earliest defect is insulin resistance.
there clearly a another segment of of
people who present with early beta cell
failure uh in the absence of insulin
resistance but I think the majority of
people present with insulin resistance
and initially in the pre-diabetic stage
uh they maintain normal glucose
tolerance because their beta cells
secrete lots of insulin but then as they
go from the pre-diabetic stage to the
early diabetic stage they're still
secretting a lot of insulin but relative
to the level of insulin resistance, it's
inadequate. And then as you continue to
follow this person in life, their
insulin secretion goes down. And in uh
there are two reasons for this uh
because physiologically the beta cells
that are there are not working normally.
And then the other big problem is you're
losing the number of beta cells. So when
you see people who uh at the end stage
of the their sort of diabetic uh career
they end up on insulin. Why? Because
their beta cells are either severely
dysfunctional or the bigger problem they
don't have enough beta cells. So later
on it's important that we have
treatments. We don't want people to be
on insulin therapy. It's very difficult.
Personally, I think insulin in very very
high doses, particularly in obese
people, is agroenic. Uh so I I would
prefer people not to be on uh insulin.
Uh I would prefer them to have their own
beta cells secretreting a normal amount
of insulin and have their tissues
responding to that normally. Well,
unfortunately, uh, when you have people
who are not treated adequately and about
half of people in the in in the United
States and worldwide end up on insulin.
So, that means there are a lot of people
who have gone through this sort of uh
initial okay, I I make too much insulin
to compensate for the insulin
resistance, but now my beta cells are
burned out. I'm not making enough
insulin. And the re real big problem is
now I don't have enough beta cells. Uh,
so I need to restore that. But now at
the same time I need to make their
tissues more responsive to the insulin.
So I got to attack both problems at the
same uh time and uh menin uh is one of
these things which in the adult
is blocking the ability of beta cells to
proliferate. So if I had a way of
knocking down menin, okay, maybe I could
remove that block. I could remove that
inhibition. And now that the beta cells
that are there, they may not be
functioning, uh, but if I can get them
now to proliferate and I can get them
healthy again, I can get people off
insulin, uh, I can get them off their,
you know, anti-diabetic medications,
their oral medications or some of the
injectable medications, uh, because that
makes it easier to treat our diabetic patients.
patients.
>> Yeah, that's fantastic, Dr. Bronzo. I
mean, it's like you've just distilled so
much knowledge. I was I was kind of
staying with you, but there's a lot
there which is fantastic that we're
recording this. Uh I'm sure for a lot of
people there like the transcript and
stuff. So, but you know, uh one other
concept I want to just ask you about um
before we actually dive into the data,
you know, from the coalent one study and
what you thought about that um is this
this uh this difference between insulin
resistant, you know, severe insulin
deficiency. You've kind of explained
about it already, but can you just
explain what is it you know that current
medications it seem like the approved
medications seem to be really focused on
this insulin resistance you know
phenotype GLP1s are making you know beta
cells perform better etc functionality
whereas um insulin deficiency really is
probably where there's a big unmet need
am I correct there
>> yeah uh so uh early in this quote
pre-diabetic stage I I think the big
problem is insulin resistance but as I
said uh there are about 20% of the
people actually who uh present early on
with insulin deficiency so we need to
understand that diabetes is a
heterogeneous disorder but even though I
think the this is my personal opinion
and we've published a lot on this so
it's not sort of you know hearsay or
make make believe uh uh you are insulin
resistant say 80% % of the people. Now,
that puts stress on my beta cells and
I'm those beta cells when they're
stressed, they stop working and
eventually they die off. So, now you're
going to become insulin deficient. And
then there's probably another 20% of
people who start with insulin
deficiency. And when you're insulin
deficient and you don't have enough
insulin, that leads to insulin
resistance. Okay? So, uh, if you
continue to follow diabetics on a
long-term basis, they're all going to be
insulin deficient and they're all going
to be insulin resistant. And at some
point in time, they're going to start to
lose beta cells. And that is why, as I
said, I think it's about 40 to 45% of
people in the US and worldwide are
treated with insulin. Insulin therapy is
difficult. Why? You have to give uh you
know two or three injections of insulin.
Uh you have to what we say carb count.
You need to know how many calories, how
much carbohydrate in the food. So every
time you have a meal, you have to take a
a short acting rapid insulin.
You also have to take a bedtime insulin
that works for 24 hours. You have to
measure your stick your finger three or
four or five times a day because every
time you eat, you need to know where's
your glucose. And then you have to say
based on where my glucose is and how
much carbohydrate, how much insulin do I
have to give? Now, of course, we've had
breakthroughs. We have continuous
glucose uh uh monitoring. So, you can
wear a little patch on your shoulder and
it will read out the glucose and maybe
you don't have to stick your finger so
much. But this is expensive and it's not
available uh to everybody. So, insulin
therapy is not easy and it's expensive.
uh and uh if you look at people who are
treated with insulin, their level of
glucose control and we use the
hemoglobin A1C to assess that is always
about one to one and a half percentage
points above people who are not using
insulin. So why is that? Lots of reasons
but uh the most important one is insulin
therapy is difficult. uh how much
insulin do I need to give these three
shots a day and the long acting insulin
throughout the day to control my
glucose? That's not easy for patients uh
to do. So it would be very nice uh for
these people if we could give them back
a sufficient number of beta cells that
their own beta cells that we've now
regenerated for them would secrete the
insulin and it would take over the job
of having these people to take an
exogenous shot of insulin three four
times a day.
>> Yep. No, that's fantastic Dr. Franzo.
And you know I just want uh our
listeners and everybody to keep an idea
in their minds about this severe insulin
deficiency as Dr. Dr. Fran has talked
about because we'll dive into that a
little bit more uh once we've discussed
the phase 2 results. Um and just on
that, you know, the covealent 111 study
read out the the phase 2 results. Dr.
Franzo, if you can give us an overview
of your thoughts on the results, the you
know, pros and if you saw any cons there also.
also.
>> Yeah. So, I'll try to simplify
[clears throat] this. So, there was a a
very large study several years ago from
Sweden that divided diabetes into five
phenotypes. uh and I don't want to get
very technical about going into the the
five uh phenotypes. Uh I I just want to
focus on two of the phenotypes because
it emphasizes what I've been uh talking
about. There's one of the phenotypes is
the severe insulin deficient diabetes SID.
SID.
I'm not going to use the term SID. I
will continue to to use severe insulin
deficient diabetes so that the listeners
don't get confused. The second other
large group are severe insulin
resistance diabetes the SIDS. Uh and uh
so from a sort of large perspective even
though there are several other groups
that we could talk about I would like to
just focus on these uh two groups. Uh so
uh there is a a molecule called a
coameum which is a menin inhibitor and
so uh in this study they basically
phenotyped uh the individuals and how do
you phenotype them? Okay, you can
measure the fasting insulin and you can
measure the fasting glucose. And if you
know the hemoglobin, A1C and age, you
can predict who are the people who are
the severe insulin deficient type, who
are the people who are the severe
insulin resistant uh type. And their
hypothesis was that if I treat you with
a menin inhibitor, okay, uh a pregnant
lady human placen goes up, it inhibits
menin. Menin goes down, beta cells
proliferate. Okay, so what I want to do
now is I want to take these groups.
Let's just focus on the two groups. Uh
and I'm going to treat them uh with a
menin inhibitor, a coin. And my
postulate is uh behind the study is that
the people who are the severe insulin deficient
deficient
by allowing now the men inhibitor okay
to sort of depress the beta cell
proliferation your beta cells will
proliferate you'll make more insulin and
those people will respond very well the
people who are insulin resistant Okay,
they should also respond. Okay. Uh but
the a covemenum is not an insulin
sensitizing drug. So uh yes, I'm going
to make them make more insulin because
they have more beta cells, but I'm not
correcting the severe insulin
resistance. So I'm going to see a
benefit, but it's not going to be nearly
as good as I see in the insulin
deficient people. So what they did is
they they treated the the people for 12
weeks and then after 12 weeks there's no
treatment and then we follow them up for
26 weeks. So literally for 14 weeks
they're getting no treatment. So what
happened was that in the severe insulin
deficient group they saw a very nice
drop in the hemoglobin A1C which is the
index we use of glycemic control of
about 1.4 4 to 1.5 which is truly outstanding.
outstanding.
Uh so as they predicted you would expect
that this group who has insulin
deficient who's probably don't have
enough beta cells if I give them a drug
that will cause beta cell proliferation.
Now that's of course something you can't
be measuring. You can't be sticking a
needle in the pancreas and measuring the
number of beta cells. But I can look at
the end product which is how much
insulin comes out. Okay? And they did by
measuring ceptide and they saw in this
group there was a nice jump up in
ceptide and that the increase in ceptide
correlated very nicely with the drop in A1C.
A1C.
So now let's take a look at the insulin
resistant uh group. Okay. So I'm going
to give them uh again the coba men. What
that's going to do is the same thing is
in the insulin deficient group. But the
the the problem there, yeah, maybe I I
make them make some more insulin, but
they're so severely insulin resistant
that even though they're making more
insulin, I'm not going to be able to
overcome the insulin resistance. So,
what did they see in that group? They
saw a drop in the A1C was still good 4
to 0.5.
But as I said earlier, if you don't get
rid of the insulin resistance and the
only thing I do is make you make more
insulin, you have a problem. Okay. Uh,
so I'm a big believer in combination
therapy. I've been saying this forever
and ever and ever. In fact, to me, I've
been saying this for 10, 15 years.
Finally, in 2024, the American Diabetes
Association finally made a statement
that you should quote consider, that was
the wrong word. It shouldn't be. You
should consider combination therapy with
an insulin sensitizer, an insulin
secret. you should use combination
therapy. But anyway, that's a step
forward based on a lot of the work uh
that uh we've done. So, it's very clear
that in my opinion anyway that the
severely insulin deficient people are
going to respond very very well to the
menin uh inhibitor. Whereas the insulin
resistant people, they are responding.
They probably are proliferating their
beta cells. They probably are making
more insulin, but you're running it up
against the wall and the wall is the
insulin resistance and I got to knock
down the wall. And if I were to knock
down the wall, like giving an insulin
sensitizing drug such as poglitazone,
which I like, then you'll be able to now
see even in that group the benefit of
the men inhibition.
>> Y Dr. Franzo. Okay, fantastic stuff. I
mean, that's so much information and you
you sort of uh condense it so well. very
few wasted words. Uh really fantastic.
Um you know uh there are a couple of
questions that seem to have come out of
the call that Biomia did uh you know
with with on on sort of um their
covealent 111. I was wondering if I
could ask you that on the efficacy side.
Well one is the patient population. So
they're going to go off this you know
severe insulin deficient patient. I
imagine that the phase 2 they're going
to have to start running you know the
inclusion exclusion criteria will be set
up in such a way in the protocols to be
able to find these patients right. How
confident are you that they can find,
you know, quote unquote, find the
patients that did well in the study, you
know, reliably well and consistently in
a in a phase two study over many centers.
centers.
>> Yeah. Well, I think you hit on a very
important uh question and this is at the
heart of uh the therapy. Uh obviously,
if you want to get the maximum benefit,
we need to identify the group who are
insulin deficient. Now, remember that
the group are insulin resistant. they're
also going to respond, okay, in terms of
making more insulin and maybe having
beta cell proliferation, but I'm not
attacking the insulin resistance in that
group. Uh, so that's a problem. But in
the insulin deficient group, well,
that's the major problem. That's the
group where I expect to see the biggest
benefit. Now we have very sophisticated
ways of measuring how well your beta
cells are working uh and how much
insulin you're making. Uh and one simple
way is to do an oral glucose tolerance
test and to measure how much insulin
ceptide you make during the oral glucose
tolerance test. Now in general uh people
everywhere in the world uh endocrine
diabetes societies have gone away from
the oral glucose tolerance test and uh
that is also quite frankly cumbersome
for doctors in practice. Doctors who
seeing patients every 10 to 15 minutes
they can't be doing O GTTS and measuring
insulin and ceptide. Uh it's cumbersome
it's expensive etc. uh but if you could
it would be very easy to identify the
people who are the insulin deficient
versus the insulin resistant but it's
not practical. So can we come up with a
simple way of identifying who are the insulin
insulin
deficient people? Well uh from the
studies that they've done now
[clears throat] in the initial covealent
studies uh you can get a pretty good
idea who are the people who are insulin
deficient. Okay, these are the people
who are younger in age. These are the
people who are lean. Uh these are the
people who have higher A1C. So you can
use some relatively simple uh you know
uh phenotypic and laboratory features
that we have in all of our patients and
then uh those are the people uh that uh
are going to respond in uh the best and
in fact in the studies that they've
already carried out where they actually
have made measures of sophisticated
measures of insulin secretion
uh they know these are the insulin
deficient people and And they say, "Who
are they?" Well, they're look, they're
much younger. Okay, look, uh, these are
people very poorly controlled. They have
very high a A1C's. So, we can come up
with some pretty simple criteria. These
are the lean people. All right? And so
uh the hope is that as they go forward
uh that in the larger studies that
they'll be carrying out using these
criteria they can differentiate who's
likely to be the insulin deficient
people versus who are likely to be the
insulin resistant uh people uh and that
uh they I think can they I think they'll
be able to do it. uh but you know we'll
see for sure as we go forward uh how
predictive these simple phenotypic and
laboratory measures are in in
identifying the insulin uh deficient
versus the insulin resistant people. Now
I want to point out that even though you
are insulin resistant and I said this
before I say it again uh you are going
to get some response it's just not going
to be as dramatic as in the insulin
deficient but here is even more
important even those insulin resistant
people with time because their beta
cells are stressed they're going to
become insulin deficient so maybe today
they're not in the insulin deficient
category wait three or four or five
years, they will be in the insulin
deficient category and then now they'll
have a much better response, okay? But
you're still going to have to have a a
drug uh in those people uh that
ameliorates the insulin resistance.
People need to understand two big things
with diabetes. You don't make enough
insulin, you don't respond. I'm not
going into the ominous octet and discuss
about the other six factors. I'd like to
keep this in the most simplistic way as
we go forward.
>> No, that's great. Dr. Danzo, you know,
and then just going, it seems like when
the company focused on uh the insulin
deficient uh you know, patients, they
had a pretty good uh you know, size
effect of of therapy, right? Uh I think
1.2 1.4 1.6 uh you know, percent
decrease. Um and this is with patients
that are on background therapy, which I
always found impressive. So these
patients are already on you know taking
taking drugs that are that are pretty uh
approved drug that are pretty potent to
begin with. Um my what one other
question you know would be that uh still
you know these are small numbers uh
you've done a lot of clinical trials
you've been involved with a lot of drug
development you know in diabetes space
how confident are you that these small
numbers of patients in this well-run
trial the co 111 can be replicated in a
larger trial consistently assuming they
find those insulin insulin deficient
patients reliably.
>> Well that's why we do like these large
trials. So we're going to answer that
question. So uh in in in their studies
they found that about 20 to 25% of the
total population were these severely
insulin resistant individuals and uh
they as I said using some very simple uh
laboratory phenotypic values were able
to uh identify these people. Uh I think
this will bear out in the large
prospective studies. I mean, uh, we're hypothesizing,
hypothesizing,
uh, but I'm pretty positive that it's
going to work out. The good thing is
we're doing a really well-designed study
or the company is doing a really
well-designed study that will, I think,
give a definitive answer uh to this
question. And if it turns out that they
are correct, that you can identify these
people easily, that makes it very easy
for physicians. They don't have to do an
oral glucose tolerance test and measure
the insulin and c peptide. They just
need to know look what's the BMI that's
simple. We have that in everybody.
What's your A1C? Is it markedly
elevated? What's your age? Etc., etc.,
etc. And then we can say these are the
people who should be really be placed on
the drug. But then I would say if you're
really smart as you go forward, there
should be another study in which now I'm
going to give the men an inhibitor plus
an insulin sensitizer poglyone. I'm
going to attack those people who are
insulin resistant. And now even though I
may not have seen the men and inhibitor
alone working in that group, now when I
get rid of the insulin resistance,
believe me, their beta cells are still
not working. Okay? And they got a
deficiency of beta cells. Now I I can
see the benefit of my my my therapy. So
I'm not giving up on the insulin
resistant part of the people. But if you
don't understand the pathophysiology, if
you have a wall, okay, why you run
against the wall? You're gonna hit your
head. All right? And then you're gonna
get a bruise. So let's let me knock down
the wall and now I can run right through
it with the uh in inhibitor. So if you
understand the pathophysiology,
uh it goes beyond just identifying uh
those insulin severely insulin deficient
uh people.
>> Yeah, you know, great Dr. Franzo and I
think that you know Ramse's and the team
are also hoping that you know investors
in the biotech space are going to be um
you know get jazzed uh you know over
time they already are I believe about
biia but even more so so they have the
ability to run these uh you know more of
these trials know fantastic front so
going through uh the combination therapy
uh it was so fascinating to me uh you
know I followed this company previously
when I worked for a bank uh as a
sellside analyst and I thought their
approach uh was really really
intriguing. Um, and you know, an oral
therapy for people with diabetes, you
know, that could help the beta cell
mass, like increase in beta cell mass,
and so therefore, you know, helping them
control their A1C. Uh, but like this
GLP1 data and comment, you know, with
the 10 patients, I thought was really
fascinating. Um, I think that their
chief scientific officers previously
said that if you give or you
downregulate men, you see increases
trans, you know, from transcription
basis, mRNA goes up, you know, for GLP1
and GLP receptor. the protein goes up.
So it seems that the you know uh
scientific rationale is there. What are
your thoughts on the data? I know it's
small number of patients. What are your
thoughts on the data in the combination
with GLP-1?
>> Yeah. So this is a a nice uh novel
observation and potentially very uh
exciting. So GLP-1 receptor agonist
people forgot the original reason why
they were developed because they're a
powerful effect on the beta cell. Now,
we've gotten sort of lost in the dark
because now everybody's concerned about
obesity and these drugs are wonderful
for making you lose weight. Now, in the
United States, if you listen to TV, you
see Oprah in the morning. So, Oprah
started this big and in front of our
eyes. She she shrunk down and of course,
what is Oprah doing? She's taking one of
these GLP1 receptor agonists. So
everybody now is focused on GLP-1 and
weight loss which is believe me very
important okay but we've lost track
track of the fact that the reason why
GLP-1 receptor agnus would were
developed is because they have
incredibly powerful effect to improve
beta cell function. So now if these many
inhibitors upregulate the GLP-1
receptor, okay, this means that the
combination uh of uh a GLP1
uh uh with uh you know a men inhibitor
would be a potentially a very very
powerful combination and uh I I know
that they do have plans to do a study uh
in humans to look at this combination uh
in uh more uh detail. So, uh, you using
the men inhibitor alone can turn out to
be very good, but maybe putting it with,
uh, you know, a GLP1 would be even
better. And if they're really smart,
then they put it with poglitazone. And
that's like a grand slam home run in the
ninth inning. For those of you who
follow baseball, it's walk off. You made it.
it.
>> That's great. Dr. Franzo, hopefully
you're a fan of the Los Angeles Donners,
Dodgers, and you've made it twice in a
row now. So, I have to say I'm actually
a fan of the Boston Red Sox and I could
I could have signed with the Red Sox
coming out of high school in 1960 and my
father has never forgiven me for not
doing that.
>> But I'm very happy what I'm doing.
>> Yeah. You know, Dr. Defrono, I think
that there's probably tens of thousands
of diabetic patients that have probably
thanked you uh both to you uh directly
and in their prayers uh and and just
their thoughts. Uh so I think the the
the bargain probably worked out. Um you
know uh one one question I have is um
you know uh just um on the GLP1
combination use uh what is your idea Dr.
Franzo off like like what kind of
patients like there's so many patients
taking GLP-1 now right that come and see
you how would you be able to identify
those patients that would be a good
candidate for combination with icoba men
>> easy everybody [laughter]
so I'm a big believer in combination
therapy so if you at the Texas Diabetes
Institute which I direct we see 10,000
unduplicated diabetic patients every
year and initial therapy in these people
Doesn't make any difference if your A1C
is 6 1/2 or 15. Uh right now uh you get
triple therapy from the beginning. You
get a GLP1, you get Pitazone. We use an
SGLT2 uh inhibitor. That's our triple
therapy combination from the beginning.
We have lots of data showing that this
is great therapy for lowering your A1C,
protecting your heart, protecting your
kidneys, liver, etc. But now if we had
you know the men inhibitors uh you know
that would be part I would of this
combination therapy particularly in
those people who come to us who have
really high A1C levels uh because those
people really have burnt out their
pancreas either dysfunctional or some
combination of dysfunction and loss of
ASL mass.
>> Yeah. And is there Dr. fronts are just
because I think investors you know will
probably want to be uh they get a little
bit um you know pnicity for lack of a
better term and I don't mean that I mean
they you know they've got their
investments to protect um the the thing
is that I I think you know until the
protocol is written up and we find out
what exactly like when you say all the
GLP-1 patients would you initially just
want the patients you've just put on a
GLP-1 and so therefore put them as a
candidate into the study or would it be
patients who've been on GLP-1 for a
while and you see their A1C starting
creep up where where would you be
initially in that in that phase two?
>> So I would like to see the prospective
data as they go forward what kind of
results they're going to get. But let
let's assume they do the appropriate
study and we see uh we'll be able to
define what groups are going to respond
best to this kind of combination
therapy. But if I saw a very robust
response uh by putting the GLP1 now
remember if I give you a GLP1 you're
going to see a good response
particularly the new ones. But now if I
saw that an even better response in the
group uh that has the IOA men have added
uh it may well be that you ought to be
thinking about putting these two drugs
together right at the very beginning.
Now obviously where we go and uh who are
the people who are going to use the drug
in in combination therapy we need to see
what's going to happen as we go forward
with the studies that are already uh
designed. But I think that the studies
will give us the insight that we need as
to who are the people uh who should be
uh being thinking about uh for the GLP1
combination with the co medbid. But
let's see the results first and then
when we see the results we'll have a
better idea where to go.
>> Yeah. And Dr. Franzo, you know, to go
down your path of pierlitazone, I mean,
I think that's just such a u such a cool
idea, you know, and and I believe
pierone is generic, too, right? If I'm
not mistaken,
>> in te state of Texas is $5 a month.
>> Yeah. Yeah. So, actually those companies
from a patient perspective, it would be
even more compelling, right? Because
you're combining a branded drug with a
generic drug. >> Yeah.
>> Yeah.
>> Correct. Got it. Got it. Got it. Uh no,
that would be fantastic. It'll be great
to see by go down that path. Um you
know, Dr. Franzo, u I guess my my other
just questions I'm sort of uh now
starting to run out of questions. So,
I'm going to ask you like sort of, you
know, final Jeopardy, but these are more
relaxed, easygoing questions. Um, you
know, let's just say we're a year or two
years from now. We're back at this
conference. Uh, I really enjoyed the
conference, so hopefully I'll be there
in person the next time we talk and
we'll be doing this uh via, you know,
via live conference call. Uh, but, uh,
what what clinical results would you
like to see in the monotherapy, you
know, severe insulin deficient? Um, you
know, that would be okay versus great.
And then I'll ask you the same question.
What would you like to see in the
combinational GLP1? But let's tackle,
you know, what kind of results would you
would you like to see two years from now
that would be okay that you think it's
great to move forward to phase three and
what kind of results combination you
know of variables would just you just
like wow her this is actually pretty amazing.
amazing.
>> Yeah. So I would like to see them
reproduce what they've seen in the early
covealent studies. So I'd like to see
that uh using their criteria to identify
the insulin deficient people. I'd like
to see a nice drop in A1C of of 1.5,
which is, you know, pretty similar. If
it's better than 1.5, hallelujah. And
that's that's in people who starting
with an A1C in the 8 to 8 and a half
range, which means that I'm going to get
you to an A1C of seven or less, which is
the treatment goal from the American
Diabetes Association. Uh, so that would
be a fantastic uh response. As I said,
uh the the the problem is identifying
the benefit in the insulin resistant
people because they are so insulin
resistant. uh now [clears throat] I know
as they go forward uh they're thinking
about combining GLP1
uh with uh a covenantum uh and that is a
study that really needs to be done and
so we'll see what the results are uh and
my my guess is that we'll see an even
better response uh in the insulin
deficient group uh how much better
response in the insulin resistant group
I don't know but what I'd also like to
see done is the study where now they're
combining uh you know the menin
inhibitor with an insulin sensitizer and
then when they do that then I think
they'll see a blockbuster response in
the insulin resistant group because once
I knock down the wall and get rid of the
insulin resistant then they're going to
see all of the benefit. Now, one of the
big things that's holding back, I I call
it the big un sort of known in type 2
diabetes is that we do not have a way of
measuring beta cell mass in people, real
life people walking around. Uh and uh
that is really unfortunate. There is no
pet isotope uh technology uh that allows
us to quantitate beta cell mass. But if
we had such a technology then we
wouldn't have to be worrying about you
know using A1C and body mass index and
other things to identify who are the
people who are going to respond. We we
be able to tell you definitively these
people have you know lost the great
majority of the beta cells. These people
have not these are the people who you
should go after. Unfortunately we don't
have that. So from the research
standpoint, it would be very nice if
someone would come up with such a tool
and then a lot of the things that we're
kind of quote speculating on which we
will get an answer to in these studies.
We could a priority uh feel much more
comfortable knowing look I give the drug
here I I could forget about measuring
insulin I can do that but now I said
look I doubled my beta cell mass I just
hit a home run.
>> Yeah. No Dr. Franzo, that's great. Um,
you know, one very specific technical
question I have now that we're getting
to the end was just in in your thoughts
there is that, you know, one of the in
the study there was some variability
that was dependent on the PK, you know,
off the drug, right, in the area
underneath the curb. And so here we're
going to have to just get a little
technical. And so, you know, it seems
like R&B, which was the the 100
milligram um you know, 12 weeks QD u you
know, did better than other dosing
regimens and and the company, you know,
figured out that it was because of the
the the area underneath the curve, the
PK. Um how confident are you that in the
future phase 2s, you know, this PK
variability is not something that will,
you know, come to sort of bite, you
know, uh icon of IO vmened. I know
they're doing a food study etc. and
you've done a lot of diabetes trials
again but just what are your thoughts
there? Does that raise any concern for
you or not really?
>> I mean of course it raises a concern
because uh there is some variability. So
we need to be uh objective about this
and one of the things that you mentioned
is that uh the interaction with food may
be playing some important role here. So
yes am I a little bit concerned? Yes. uh
why am I less concerned is because
they're doing the appropriate studies to
look at what's causing the variability.
So eventually they'll get a better
handle on this and then uh they'll have
a better idea about going forward use
with food without uh food. So although
all I'm although I am concerned about
the variability uh I'm feel very
comfortable that they have the
appropriate you know studies that are
being done actually as we speak uh to
define uh what is causing this
variability uh and then once they have
identified this I think they'll be able
to marketly reduce uh this variability.
>> Yeah. And Dr. Frana I want to ask you
another question which just a much more
bigger picture question. and get your
thoughts there and again I don't know
this space um you know as well as as
well as maybe some others but you know
you had mentioned earlier about how beta
cell mass you know we can't stick
something into the pancreas to like
measure beta cells right the amount of
beta cells but you also mentioned at
another time that we have ways to tell
where patients beta cell mass is and how
well they're functioning right we're
sort of surrogate measures for for lack
of another term right we've got various
diagnostics and tools that that in
diabetes that you can have. How
confident are you that in the future,
you know, there's a possibility of some
of these tools becoming or these
endpoints becoming I know H1 is like a
surrogate marker that could, you know,
help speed development along, right? I
know that H1 um A1C is already a sort of
a surrogate marker, right? But could
there for BICO va which specifically is
impacting beta cell mass, right? um are
there surrogate markers that you think
could speed the development not just for
the initial studies but maybe for
studies down the road?
>> Yeah, this is a big problem as I said
it's the big unidentified question. We
don't have a good measure of beta cell
mass uh and uh it would be very nice to
the people who are working as I said
with these PET technologies
that they [clears throat] could come up
with such a technique uh that would then
simplify everything. uh and there are a
lot of people uh there there are some
people in Sweden who have some uh I
think interesting leads. See you have to
have a a molecule a peptide that is only
present on the beta cell. So now I can
make a radio label tag that will
interact only with that molecule and
that molecule is only present on the
beta cell. So now I can give the uh
antibbody it will bind to that protein
on the beta cell and then because it's
radio label I can pick it up with PET.
So there are people who are working on
this technology but I have to say it's
not been an easy nut to crack or we
would have had it by now. Uh so uh yes I
think we will get this technology in
these tools. uh when uh um I can't give
you a a definitive uh answer uh to that,
but you can rest assure we'll be one of
the first groups that are using the
technology uh uh to to really look at
this question of beta cell mass versus
function in much more detail.
>> Yep. Great. Great. Dr. Franzo, and then
you know uh I guess uh last couple of
questions here. um you know one is that
uh are you going to be one of the sites
in the phase two that is participating
that that they're going to be running?
>> Well, I I already told them that I would
be delighted to participate
uh in these studies. uh uh uh and we
have a a unique sort of advantage as I
told you we see 10,000 unduplicated
patients every year and I just did an
analysis u at the Texas Diabetes
Institute uh 78% of our people are on
GLP1 receptor agonist
>> for their GLP-1 study they don't need to
go to any other sites we can do the
whole study in San Antonio okay
so I'm hopeful that we will be uh one of
the sites particularly in the GLP1 study
uh that uh uh they are uh planning.
>> Yep. And then you know just another
thought on just again thinking a little
bit you know out of the box and big
picture um you know assuming um you know
uh investors uh who are interested in
diabetes you know give uh biome you know
the ability to to fund more studies I
mean could a investigative sponsored
trial be done for example with Iikova
men and pagzone
would that be a study that you know for
example your site would be willing to
entertain if if the financing was
available I
>> I would start the study tomorrow. To me,
this should be done at the top of the
list and I give you the answer in a year
and we wouldn't be sitting here
speculating because I think this study
would show that even in the insulin
resistant group who are not they have
the you know they have a good response
which is not as good as the other group.
We would give you the answer very quickly.
quickly.
>> Yep. And then last question just on type
1 diabetes Dr. Def Franzo any thoughts
on icoba men in type 1 diabetes or you
think that's still over the horizon and
maybe something you know to to think
about down the road?
>> No, I I I think of course the the
jackpot is type two because it's right
here but I think type one is a huge
unmet need. Uh and so as part of my
present presentation today I talked
about other molecules uh that would also
cause beta cell proliferation. So in
type one there are two problems. Uh
problem uh number one is these people
have no beta cells. So we got to find
some beta cells. We don't have enough
people in in terms of who pass away
they're going to donate their pancreas.
We're never going to that's never going
to work. Uh so now uh with things like a
coat and several of the other molecules
I talked about today in a test tube we
can actually cause these uh uh beta
cells to proliferate. So now the
availability of beta cells is not going
to be a problem. I'm quite concerned
about this. All right. But in type ones
now you have the immune response. So now
yes, I have the beta cells and I can
give them, but I'm still going to have
to suppress the immune uh response. So I
would say that these molecules uh and
there are a number of different totally
different classes than men and
inhibitors that can expand beta cell
mass. That will be a way to get around
step number one. I have enough beta
cells. Step number two, we still have
this big problem of immunosuppression
and you know uh uh technubab we have
some new drugs that uh look promising
anti-thyocy lymphoy globbulin uh maybe
giving uh the beta cells with GLP1 uh
with the imunosuppressive therapy right
from the beginning. Uh so I I think that
this is not so far off. I think it's on
the horizon quite quite frankly and
needs to be uh pursued as type 1
diabetes is a big problem and even
though you know there all these you know
I call them gadgets and you know
artificial pancreas etc. Uh it would be
very nice if people had their own beta
cells and they didn't have to wear a
pump and they didn't have to worry about
constantly measuring uh the glucose and
they could just go on and do their
everyday life and be really normal and
not have to be thinking about this.
>> Yeah. No, no, absolutely well said, Dr.
Danzo. I can tell you I've done hundreds
of these. Uh this was a real pleasure.
Thank you so much for taking your time.
I know you're very busy there for having
this amazing energy. Ramsey's told me
about it. uh and he uh it is absolutely
you're you're spot on. Your energy is
amazing and u your insights are great
and the amount of care you have for your
patients also shines through. So really
thank you so very much Dr. Danzo really
a pleasure and look forward to many more conversations.
conversations.
>> Okay, anytime you want. It was great
talking with you. You have a good rest
of your day.
>> Thanks. You too Dr. Franzo. Have a good
one everyone. Bye
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