19 Exenatide (S24E19)

We often hear about these big medical breakthroughs,
you know, the wonder drugs. But sometimes the
real story, the interesting part, is the journey
a drug takes. Absolutely. Twists and turns, unexpected
discoveries. Exactly. And today we're diving
into one of those journeys, eggs in a tide. You
probably know it better as bieta or bidurion.
And get this, the whole thing kind of started
with lizard spit. It sounds wild, doesn't it?
Gila monster saliva, specifically. It really
shows you how nature can hold these unexpected
medical answers. Totally unexpected. And understanding
exonetide, its story. It gives you a great window
into, well, pharmaceutical innovation for diabetes,
the hurdles of drug development, regulation.
All that stuff. Right. And how something that
starts as like a scientific curiosity actually
ends up helping people manage their health. Precisely.
We want to give you that comprehensive view,
you know, without you having to sift through
mountains of FDA reports or dense scientific
papers. Yeah, we've done the sifting. We looked
at FDA docs, EMA reports over in Europe, clinical
studies, market analyses, even what patients
are saying on forums. Volumix of sources. Definitely.
So our mission here is to pull out the key pieces
of the exenatide story. where it came from, how
it works, its impact, and the sometimes bumpy
road it took. Back to the lizard. Right, the
Gila monster. So scientists discovered this peptide
called Xenden -4 in its saliva. OK. And what
was interesting was how similar it was to a hormone
we naturally produce called GLP -1, glucagon
-like peptide 1. Ah, GLP -1. We hear a lot about
that class of drugs now. We do. And GLP -1 is
really important for regulating blood sugar.
So finding the similar compound in all places,
lizard spit, that was the spark. That's what
kicked off the development of Xenotides. you
wonder what else is out there, you know? Doesn't
it just so much potential in the natural world?
So the first actual drug people could use, that
was bieta, wasn't it? That's right. Bieta was
the first one approved. It's exenatide, but you
inject it twice a day. Twice a day, OK. It got
the FDA approval here in the US, let's see, April
25, 2005. and then Europe followed in November
2006. And patients took what, like five or 10
micrograms? Correct, five or 10 micrograms per
dose. It was a really big step forward at the
time for a type 2 diabetes treatment. But yeah,
twice a day. That sounds like quite a commitment.
I imagine people wanted something. easier. Exactly.
That was the big push behind developing by Durion.
That's the once a week version. Okay, once a
week is much better. How did they manage that?
It required some clever formulation science.
They needed an extended release version. So first
they developed a sort of prolonged release aqueous
suspension. Aqueous suspension, like a liquid.
Yeah, basically. But then they evolved it further
into what's called a microsphere formulation.
Microspheres. Tiny balls, basically. Kind of.
Think of them as tiny biodegradable capsules
holding the exenitide. They're designed to dissolve
slowly over the week, releasing the drug steadily.
Ah, I see. So that gives you the once weekly
dosing. Clever. It really is. The goal was convenience,
you know, helping people stick to their treatment
plan more easily. And was it just one company
behind this or? Well, Amalin Pharmaceuticals
was definitely a key player. Alkermes was also
involved, particularly with some of the formulation
technology. Right. And because you had different
manufacturers, potentially different processes,
maybe different scales of production, they had
to do these comparability studies. To make sure
it was all the same stuff, essentially. Pretty
much. Studies like BCB 108 and 2993 LAR 105,
they were designed to show that the drug exposure
and the patient's response were consistent, regardless
of the exact manufacturing details. That's super
important for regulators and for patient safety.
Makes sense. And later on, they even developed
the Bidurion Auto Injector Pen, which came with
a new suspension that didn't need mixing by the
patient. Just another step towards making it
easier to use. Yeah, premix is always better.
Yeah. OK, so we've got the Lizard Spit Origin,
the Twice Daily, the Once Weekly. What does Xenotide
actually do for patients? Who is it for? Its
main job, its indication, is for adults 18 and
over with type 2 diabetes. The goal is to improve
their glycemic control. Glycemic control. Basically,
better blood sugar levels. Exactly, lowering
and stabilizing blood sugar. And it's not usually
the only thing they take, right? It's part of
a bigger picture. That's a key point. It's almost
always used in combination with other glucose
-lowering drugs. Like what kind of drugs? Things
like metformin, which is often the first drug
people try. Or sulfanolureas, thiazolid and dines,
even basal insulin sometimes. It fits into a
broader treatment plan tailored to the individual.
OK. And does it actually work well? Like, do
we have proof? I saw mentions of HbA1c. Oh, yes.
Plenty of evidence. HbA1c, as you probably know,
gives you that long -term picture of blood sugar
control over, say, two or three months. Right.
The average level. Exactly. And numerous clinical
trials showed Exenetide, especially Bidurion,
significantly lowers HbA1c. Studies like BCB118
and BCB120 compared it directly against placebo,
but also against the twice -daily Bayetta. and
another drug called Cytogliptin. Definitely.
They provided specific numbers, mean changes
in HBUNC, and showed these were statistically
significant. For example, one trial showed Bidurion
dropping HbA1c by about 1 .44 % compared to Bieta
at 1 .08%. OK, so a clear improvement with the
once weekly. Yes. And another study compared
Bidurion to Cytogliptin and placebo. Bidurion
lowered HbA1c by 1 .12%, Cytogliptin by 0 .87%,
and placebo SIBO only 0 .64%. So meaningful improvements
over other options and definitely overdoing nothing.
That's pretty clear evidence. So just to recap
the dosing, Bayetta is? Bayetta is 5 or 10 micrograms
injected under the skin twice a day, usually
before meals. And Bidurion? Bidurion is a 2 -milligram
injection, also subcutaneous, but just once a
week. OK. And wasn't there something else, a
side benefit some people get, related to weight?
Ah, yes. Weight loss. It's not its primary indication,
but many studies and patient reports show that
exonetide can lead to some weight reduction in
quite a few individuals. Which for many people
with type 2 diabetes is a huge plus, right? Absolutely.
Managing weight is often a really important part
of managing their diabetes overall, so it's a
very welcome potential side effect. Definitely.
Now, I saw a quick mention, something about Parkinson's
disease. Was there a connection? That's important
to clarify. There was some early interest, some
research looking into whether GLP -1 drugs like
exenatide might help with conditions like Parkinson's.
Okay. And Gil. Well, the latest study mentioned
in our sources actually found no benefit for
Parkinson's disease. Ah, okay. So that line of
inquiry didn't pan out for exenatide. It seems
not. It's a good reminder that drugs can be very
specific. Just because it works for one thing
doesn't mean it'll work for something else, even
if the biology seems related somehow. Good point.
Let's get into the mechanism. How does it actually
lower blood sugar? What's the science? OK, so
exonetide is a GLP -1 receptor agonist. That's
the key term. Agonist, meaning it activates the
receptor. Exactly. It basically mimics our natural
GLP -1 hormone. It fits into the same receptor,
like a key and a lock, and triggers the same
downstream effects. What does natural GLP -1
normally do? Well, a major role is signaling
the pancreas to release insulin. But, and this
is crucial, It does this in a glucose -dependent
way. Meaning only when blood sugar is high. Precisely.
So when your sugar levels are normal or low,
it doesn't stimulate much insulin release. This
drastically lowers the risk of hypoglycemia,
dangerously low blood sugar, which can be a problem
with some other diabetes meds. That's a smart
mechanism. Anything else? Yes, it also helps
suppress the release of glucagon. Glucagon is
another hormone, but it does the opposite of
insulin. It tells the liver to release stored
sugar, raising blood glucose. So, exonetide hits
it from both sides. More insulin when needed?
Less glucagon overall. You got it. Helps bring
a high blood sugar back down into a better range.
What about digestion? I think I read something
about that. Yeah, especially the shorter -acting
biota formulation. It's known to slow down gastric
emptying. So food moves out of the stomach more
slowly. Right. Which means glucose from your
meal gets absorbed more gradually, potentially
blunting those big post -meal blood sugar spikes.
Does the once -weekly bidurion do that too? It
might, but possibly less so over the long term.
There's this phenomenon called tachyphylaxis.
Tachy what? Tachyphylaxis. It basically means
the body's response to a specific effect of a
drug can lessen with continuous exposure. So
that slowing of gastric emptying might not be
as pronounced with long -term bidurion use compared
to bieta. Interesting. And does it affect appetite?
You mentioned weight loss earlier. It can. GLP
-1 receptor agonists generally seem to increase
feelings of satiety or fullness. That could definitely
contribute to the weight loss effect by helping
people feel satisfied with less food. Okay, that
whole mechanism makes a lot of sense. Now, what
about how the body handles it? Once it's injected,
how quickly is it absorbed? How long does it
stick around? Pharmacokinetics, right. Right,
pharmacokinetics and pharmacodynamics PKPD. So
it's injected so cutaneously under the skin.
For Bidurion, the once weekly one, it takes a
little while to see the full effect on blood
sugar. Maximum HbA1c reduction usually happens
around week 14 or so. 14 weeks? Wow, okay. Yeah,
it reflects that slow, sustained release from
the microspheres and the time it takes to reach
what we call steady state concentration in the
blood. Steady state. Yeah. Like a consistent
level. Exactly. With the weekly bidurion shots,
the level stays around 300 picograms per milliliter,
maintained over the week. And what about half
-life? How quickly does the body clear it? For
bieta, the twice -daily one, it's quite short,
about two hours. That's why you need two doses
a day. Makes sense. And Bidurion? Bidurion is
different because of the slow release. It doesn't
have a simple half -life like Biata, but it takes
about six to seven weeks of weekly injections
to reach that stable, steady state level in the
body. OK. And you mentioned different manufacturers
earlier. Did the drug behave the same way regardless
of who made it? That was checked carefully in
those comparability studies. They looked at the
exposure -response relationship, basically, how
much drug in the blood leads to how much effect
on HbA1c. And they found it was comparable between
the different manufacturers, like Amalin and
Alkermes. The potency seemed consistent. They
even calculated the EC50. Yeah, the concentration
needed to get half the maximum effect. For Bidurian's
effect on HbA1C, it was around 83 .5 picograms
per milliliter. And that number held up across
the different manufacturing sources. Consistency
is key. Definitely. Now, this next part sounds
really interesting. Antibodies. the body can
fight the drug. Yes, this is a fascinating and
important aspect. Some patients develop antibodies
to exenitide. Their immune system recognizes
it as foreign and creates antibodies against
it. Does that matter? Does it stop the drug working?
It can. If the antibody levels or titers get
high enough the threshold mentioned was a titer
of 625 or more, they can actually interfere with
measuring the drug in the blood and, more importantly,
potentially reduce its effectiveness. So your
own body could make the diabetes drug less effective?
Potentially, yes, at those higher antibody levels.
The pharmacokinetic models even predict that
the drug concentration might increase if antibody
titers go up or if kidney function goes down.
It's complex. Wow. Doctors need to be aware of
that possibility. They do. Although it's worth
noting, the studies didn't find a clear link
between having antibodies and having more side
effects, just potentially less effect at high
titers. Okay. And you mentioned kidneys just
now. How does kidney function affect xenotide?
For patients with mild or moderate kidney problems,
exposure to the drug seems pretty similar to
people with normal function. But what about severe
kidney issues? Ah, well, for Bayetta, the twice
-daily one, it's specifically not recommended
for people with severe renal impairment or end
-stage kidney disease. The risk of side effects
might be higher because the kidneys play a role
in clearing the drug. Got it. Okay, let's shift
to the physical product itself. Bidurion. with
the microspheres. How is it actually made and
put together? It's not just a simple liquid,
right? No, definitely not. It uses that sustain
-release microsphere technology. The egg -zenotide
drug is encapsulated inside these tiny biodegradable
polymerspheres. So the product usually comes
as a kit. You get a vial with the dry microsphere
powder, a syringe pre -filled with the liquid
diluent to mix it with, plus needles and a connector
piece. So the patient has to mix it? Traditionally,
yes, for the original vial formulation. You have
to carefully transfer the diluent into the powder
vial, mix it gently to create a suspension. It
looks kind of cloudy. And then draw it up and
inject it. It's a bit of a process. Each kit
delivers that two milligram dose. Sounds like
something you wouldn't want to mess up. Precision
is definitely required. That's why the pre -filled
pen, the Biodurion B -Cise, was a welcome development,
no mixing needed. Right. And what else is in
there besides the drug and the polymer? Any key...
inactive ingredients. Yes, excipients are crucial.
They often use medium chain triglycerides, MCTs,
which help control how the exanatide gets released
over the week. And sucrose, basically sugar,
is used in the newer formulation as a stabilizer
to keep the product stable over its shelf life.
And I assume there's rigorous testing to make
sure every batch is right. Oh, absolutely. A
quality control is intense. They test everything.
The exact amount of drug, its purity, the size
of the microsphere particles because size affects
release rate, how much drug bursts out initially,
the release rate over time, and lab tests, moisture
content, any leftover solvents. You name it.
Sounds thorough. It has to be. These comparability
tests ensure consistency and quality from batch
to batch. OK, complex manufacturing. Now let's
talk regulations. Getting these drugs approved.
Was it smooth sailing for eggs in a tide? Uh,
not entirely, especially for Bidurian, the once
weekly version. The first application, the NDA
was submitted to the FDA back in 2009. Approved.
Nope. They got what's called a complete response
letter. Basically, the FDA said not yet. Oof,
why? What were the issues? The FDA wanted more
information. Specifically, they had concerns
about the drug's potential effect on the heart's
rhythm, the QT interval, and they wanted more
safety and efficacy data from one of the key
clinical trials, study 2993LAR105. So back to
the drawing board essentially. Pretty much. The
company had to gather the extra data, address
the concerns, and then resubmit the application.
And eventually got approved. Yes, Bidurion did
eventually get the green light from the FDA.
Bayetta, the twice -daily one, had its own process
and was approved earlier, back in 2005, as we
mentioned. What about after approval? Does the
monitoring stop? No way. Post -marketing surveillance
is crucial. And with Bayetta, after it launched,
reports started coming in about some potentially
serious issues. Like what? Things like acute
pancreatitis, some cases of acute kidney failure,
and even some concerns about thyroid growths,
specifically thyroid C -cell neoplasms. Wow,
okay. So what did the regulators do? Well, these
reports led the FDO to require a REM for Beata.
A REMS risk evaluation and mitigation strategy.
Exactly. It's a safety program to make sure the
drug's benefits still outweigh its risk, given
the new information. It could involve extra patient
education, special guides, things like that.
Any other requirements? Yes. There was also a
deferred pediatric study required under PREA,
the Pediatric Research Equity Act, to look at
its use in kids, though it was initially approved
only for adults. And how did things go in Europe
with the EMA? Similar process, different timeline.
The EMA authorized Bayetta in the EU in June
2009, and Bidurion followed in June 2011 based
on their own review of the data. OK. Shifting
from regulators to lawyers. What about patents?
Are these drugs heavily protected? Oh, definitely.
The patent landscape for GLP -1 agonists like
exenatide is really complex. Sources suggest
companies often get a lot of patents for each
drug. How many are we talking? Like an average
of maybe 19 or 20 patents per product in this
class. 20 patents for one drug. What are they
all for? Interestingly, a big chunk, often more
than half, aren't just for the drug molecule
itself, but for the delivery device, the pens,
the microsphere technology. Why? How you get
the drug into the body. Ah, so protecting the
pen. is as important as protecting the pill,
so to speak. Exactly. And on top of patents,
they get regulatory exclusivities, like NCE,
new chemical entity exclusivity for the first
approval of a totally new drug, or sometimes
NPP, new patient population exclusivity if it
gets approved for a new group. Do generics ever
challenge these? They can try under the Hatch
Wax Men Act, but our sources indicate that so
far no generic company has successfully challenged
the patents and gotten a generic GLP -1 agonist
approved by the FDA. Which means? Which means
these drugs stay branded and generally quite
expensive for a long time. Lack of generic competition
is a big factor in the cost. Right, the cost.
Let's talk economics. How big is the market for
exenatide? It's pretty substantial. For 2024,
the global market for exenatide injections is
estimated around $2 .97 billion. Yearly $3 billion.
And is it growing? Oh, yeah. It's projected to
grow at a rate of over 8 % per year, hitting
something like $5 .6 billion by 2032. significant
growth. What's driving that growth? More people
getting diabetes. That's a huge part of it. Yes.
The rising prevalence of diabetes globally is
a key driver, plus greater acceptance of injectable
therapies. You know, people getting more comfortable
with them. And the technology helps, right? Better
pens and stuff. Absolutely. Advancements in drug
delivery like the easier to use auto injectors
make a difference. And sometimes government initiatives
supporting diabetes care play a role, too. Where's
the biggest market geographically? Still North
America. Yes, North America is dominant currently.
Strong pharma presence, high diabetes rates,
established healthcare systems. Europe is second.
Any regions growing particularly fast? The Asia
-Pacific region is projected to have the fastest
growth. Think rising healthcare spending, more
disposable income, greater awareness about diabetes
treatment options in countries there. With all
this growth, are the drugs actually affordable?
You mentioned they're expensive. That remains
a major issue. GLP -1s, including exenitide,
are costly. Net prices have generally been rising,
and that translates into significant out -of
-pocket costs for many patients, which can be
a real barrier to access. Yeah, that's the tough
part. Effective, but potentially hard to afford.
OK, lastly, what about the sort of cultural side?
Patient experiences, public awareness. Looking
at patient forums and discussions online, you
see a mix, as you'd expect. Many people report
good results, better blood sugar. The weight
loss benefit is often mentioned. But downsides,
too. Yes, side effects are definitely discussed.
Gastrointestinal issues like nausea seem pretty
common, especially initially. And injection site
reactions, redness, itching. It highlights that
individual experiences really vary. And does
exenatide get caught up in all the recent buzz
about GLP -1s for weight loss generally? Well,
while the newer drugs like semaglutide and terzepotide
are getting most of the headlines for weight
management specifically, exenatide, as one of
the pioneers in the GLP -1 class for diabetes,
certainly helped pave the way. So it laid some
groundwork for public understanding. I think
so. It helps introduce the concept of GLP -1
agonists for diabetes treatment, even if newer
agents are more in the spotlight right now. It's
part of that evolving story. Okay, so as we kind
of wrap up this deep dive, what are the absolute
key takeaways people should remember about eggs
in a tide? Well, first, that amazing origin from
Gila monster saliva showing where science can
find inspiration. Then it's evolution, you know,
from twice daily biota to the more convenient
once weekly by durian using that microsphere
tech. Right. It's important role in managing
type 2 diabetes by mimicking GLP -1, improving
blood sugar, often with that weight loss kicker,
but also the complexities how it works, the potential
for antibodies to affect it, the careful manufacturing.
And the journey it took. Exactly. The regulatory
hurdles, the safety monitoring that led to the
REM -S, the whole patent situation, keeping generics
at bay, and ultimately the significant economic
impact, but also the challenge of cost and access
for patients. It's a really packed story. It
absolutely is. molecule with quite the biography.
So maybe a final thought for you, our listener,
to chew on. Considering this whole journey, the
innovation, the careful regulation, but also
the high cost and patent walls we see with drugs
like Xenotide. How do we strike the right balance?
How can we keep encouraging these kinds of breakthroughs
while making sure the resulting treatments are
actually affordable and accessible for everyone
who stands to benefit? That is the multi -billion
dollar question, isn't it? Something critical
for us all to think about. And hey, if this dive
into XNHAD got you interested, definitely dig
deeper into the sources or related research.
For sure. There's always more to uncover. Thanks
so much for joining us on this deep dive. See
you next time.