168 - Advances in Biotechnology & Gene Therapy (S12E3)

Welcome to the Deep Dive. Today we're jumping
into, well, a really exciting area, biotechnology
and gene therapy. Absolutely. It feels like...
more than just science advancing. It's almost
a revolution in how we can treat diseases, right?
Tackling them at the source. It really is. We're
seeing decades of research finally turning into
actual therapies. So yeah, in this deep dive,
we'll look at some of these breakthrough treatments,
try to unravel how they actually work, the science
bit. And the journey they take, because it's
not simple. Not at all. That whole complex path
to actually getting them to patients, we'll be
drawing on quite a range of materials to piece
that together. OK, so These amazing therapies,
they don't just pop up fully formed. Where does
that first glimmer of an idea come from? Is it
like a lightning bolt moment or something else?
It's usually much more methodical than a lightning
bolt, I'd say. It often starts by really understanding
unmet medical needs, meaning looking at diseases
where the current options just aren't good enough,
or maybe there are no options at all. That deep
understanding, plus what we're constantly learning
about the biology of these diseases. That's what
points towards potential ways to intervene. Right.
So identify a gap, a need, then dig into the
biology, what's actually going wrong inside the
body. And once you have a handle on that, you
start looking for a place to step in. Exactly
that. Once you've got to clear a picture of the
disease mechanism, the next really critical step
is target selection. Target selection. Yeah,
finding that specific molecule could be a protein,
maybe an enzyme, sometimes even a gene that's
playing a key role in driving the disease. Yeah.
The aim is to find what we call a druggable target.
Druggable. Okay, so not just any molecule involved,
but one we can actually affect with a drug. Like,
it's not enough to know a wheel is broken, you
need to find a wheel you can actually reach and
fix. Perfect analogy. And it's not just about
finding a keyhole. You want the right keyhole.
Sometimes you find a target that when you tweak
it, it influences a whole network of disease
pathways. That can be much more powerful. Ah,
like hitting a master switch instead of just
one light bulb. Precisely. And this ability to
actually change the target's activity, we call
it modulability. That's also key. You need a
lever you can actually pull or push to get the
result you want. Makes sense. So, okay, we found
this promising lever. How do you know pulling
it will actually help, that it'll have a therapeutic
effect? Good question. That's where target validation
comes in. Researchers use different models, could
be cells in a dish, could be quite sophisticated
animal models, to basically simulate what happens
when you hit that target. Trying it out on a
smaller scale first. Exactly. It gives you that
initial evidence. Does messing with this target
actually do what we think it will? It's like
running simulations before you commit to building
the whole thing. That sounds way more efficient.
Sort of testing the blueprint before construction.
It is. And it's getting even more sophisticated
now with big data and bioinformatics. We can
analyze huge data sets, gene activity, protein
interactions to help spot potential targets.
How does that work? Well, you might look for
genes that are always switched on too high in
disease tissues, for example, or proteins that
aren't interacting the way they should be. It's
like using data mining to find the most likely
suspects. OK, so we've used data models. We've
got a target. We think hitting it will work.
Now the actual drug development part starts,
right? Which sounds long and complicated. Where
do you begin the testing? The development journey
kicks off with pre -clinical evaluation. This
is absolutely crucial. It's where we get the
first real safety data before anything goes near
a human. A huge part of this is toxicology studies
in animals. Testing for potential risks. Side
effects. You mentioned relevant animal species
before. Why relevant? Why not just say mice for
everything? Ah, well, especially for biopharmaceuticals.
Things like antibodies or protein therapies.
The international guidelines, like from ICH,
say you need a relevant species. That means the
animal's biology has to be similar enough to
humans in the key area. Meaning the drug actually
works in that animal. Yes. The animal has to
have the biological target, the receptor, the
molecule that the drug is designed to hit. If
the drug can't interact with its target in that
species, then testing it for safety might not
tell you much about human risk. Okay, that makes
sense. These studies also help check if the drug
hits unintended targets in the body. Very important
for predicting human safety. So, find an animal
where the drug does its thing, see what happens
good and bad. If that preclinical data looks
okay, what's the next barrier? Once you have
enough preclinical safety data, and hopefully
some hint that it might actually work, the next
big step is getting permission to test in humans.
The regulators step in. Exactly. In the U .S.,
you submit an investigational new drug application,
an IND, to the FDA. Think of it as a big package
of all your preclinical findings and your detailed
plan for the human trials. The protocol. Right,
the clinical trial protocol. In the EU, it's
a similar thing called a clinical trial application,
or CTA. There's a huge amount of ethical review
and regulatory scrutiny before any human testing
can start. So the FDA and others are gatekeepers
right from the start. OK, you get the green light.
Clinical trials begin. Can you give us the quick
flyby of the phases? Sure. It typically starts
with phase one. Small group, often healthy volunteers.
The main goal here is safety. What dose is safe?
How does the body handle the drug? Absorption,
metabolism, excretion, all that. Just basic safety
and processing. Yeah. Then phase two, now you're
usually testing in patients who actually have
the disease. Still looking closely at safety,
but also starting to get the first signals of
efficacy doesn't seem to be working. Okay. First
hint of whether it helps. Then phase three, that's
the big one, right? That's the big one. Phase
three trials are much larger. involving potentially
hundreds or thousands of patients with the disease,
often across many different locations. Why so
big? Well, the main goals are to really confirm
if the drug is effective compared to maybe a
placebo or the current standard treatment and
to keep monitoring safety in a larger, more diverse
group of people. You need that diversity to see
how it works in different subgroups. Makes sense.
You want to know what works for, well, everyone
who might eventually take it. How do they measure
if it's working in phase three? What are they
looking for? They use predefined endpoints. These
are specific things they measure to see if the
treatment worked. There's usually a primary endpoint,
the main outcome the study is designed to assess.
Could be survival, could be reducing tumor size,
could be improving a specific symptom score.
Something concrete. Exactly. Measurable. Then
there might be secondary endpoints looking at
other benefits or aspects. You need solid data
showing a real clinical benefit. And you mentioned
comparing it often to the existing treatment.
Yes, very often. Many trials aim for superiority,
showing the new drug is definitely better than
what's currently used, or better than nothing
if there's no treatment. Better is good. Better
is good. But sometimes the goal is non -inferiority.
This means showing the new drug is at least as
good as the current standard. That might be valuable
if the new drug is, say, easier to take, or has
fewer side effects. Ah. OK, so maybe not a home
run, but still a valuable improvement in some
way. These trials must be incredibly carefully
planned. Oh, absolutely. The clinical trial protocol
is the rule book. It details everything. Who
gets into the study, how the drug is given, how
data is collected, how it's analyzed. Everything
has to be standardized to minimize bias and make
sure the results are trustworthy. And how they
analyze the data matters, too. You mentioned
ITT and PER protocol. Right. Intention to treat
or ITT analysis includes everyone who was randomized
into the trial, even if they dropped out or didn't
follow the instructions perfectly. It gives a
more real -world picture, maybe. PER protocol
analysis only looks at the patients who stuck
to the plan exactly. Comparing those results
helps give a fuller picture of the drug's effects.
Sounds incredibly thorough. But we hear about
phase three trials failing pretty often, right?
It's not a guaranteed win, even at that stage.
That's absolutely true. It's a tough reality,
a lot of investment, a lot of hope. But many
phase three trials just don't meet their primary
endpoint. The drug doesn't prove effective enough
or maybe safety issues emerge. And even for drugs
that do get approved, sometimes problems crop
up later after they're on the market. Ongoing
monitoring is essential. A sobering reminder.
OK, but let's say a drug makes it through phase
three. Looks good. Then it's back to the FDA
for the final decision. Yes. The sponsor submits
all the data, preclinical, clinical manufacturing
details, and what's called a new drug application,
NDA, or biologics license application, BLA, for
biologics. The FDA reviews everything meticulously.
Safety, efficacy. And the manufacturing part
is key, too. Hugely important. They look very
closely at the manufacturing process and the
control strategy. How do you ensure every batch
is the same quality, the same safety? This is
where quality by design or QBD comes in. QBD,
like designing quality from the start. Exactly.
Instead of just testing quality at the end, you
understand how different steps in manufacturing
affect the final product. You control those critical
steps to build quality and consistency into the
process, like knowing exactly how oven temperature
affects your cake, not just tasting it afterwards.
Got it. So the FDA is looking at the whole picture,
product, and process. Definitely. And they have
real teeth. They could put a clinical hold on
a study if safety worries arise during trials.
Sponsors also have to report serious side effects
very quickly. And the rules keep changing. They
do. Science evolves, technology evolves, so the
regulatory standards adapt, too. We see it with
things like AI in medical devices now. And even
which part of the FDA reviews what can shift.
CBER has traditionally handled biologics, but
some now go through CDER, the drug center. It's
dynamic. Definitely complex. Okay, let's shift
focus a bit. Let's talk about some of the really
exciting stuff, the breakthroughs themselves.
What mechanisms are driving these new therapies?
Any examples from the sources? Oh, absolutely.
There's some great examples. One is about using
orally delivered serenade, small interfering
RNA. RNA interference, right. Silencing genes.
Exactly. This specific example targeted a gene
called MAP4K4 inside macrophages, which are immune
cells. MAP4K4 is involved in inflammation. So
the idea is deliver this serin A orally. It gets
to the macrophages, silences that gene, and helps
suppress systemic inflammation. Very targeted.
Orally delivered serin A is pretty cool. Much
easier for patients. Potentially, yes. Another
fascinating one involves microRNAs. Specifically,
microRNA -92 influencing something called KCC2
in certain brain cells, cerebellar, or granule
neurons. MicroRNAs are tiny regulators. Yeah,
they fine -tune gene expression. This just shows
how we're drilling down to these really intricate
molecular controls, even within specific cell
types in the nervous system. Amazing precision.
What else? Well, there's the development of HIV
protease inhibitors, like nelfinavir and darunavir.
That story really shows how understanding the
exact shape and interactions between the drug
and its target, the HIV protease enzyme, led
to better drugs. How so? They figured out exactly
how the drugs fit into a little pocket on the
enzyme. the S2 pocket. Drunivir, for instance,
was designed with a specific structure to fit
really snugly in that pocket and make strong
bonds, making it much harder for the virus to
mutate and become resistant. It's like designing
a key that fits even if the lock changes a bit.
Great analogy. And then there are the therapies
that have really made headlines recently. Absolutely.
Chi -R T -cell therapy has to be mentioned. Chimeric
antigen receptor T -cell therapy. Taking a patient's
own immune cells and reprogramming them. Essentially,
yes. You engineer their T -cells to recognize
and attack their cancer cells. It turns the patient's
own immune system into a targeted weapon. It's
been truly revolutionary for some blood cancers,
and regulators have definitely recognized it
as a breakthrough. And gene therapy, too. Yes,
like Luxterna. That's a gene therapy approved
to treat a rare inherited eye disease that causes
blindness. It delivers a working copy of the
faulty gene directly into the eye. Another huge
step forward acknowledged by regulators. Sarah
T. Gene therapy. It feels like we're really getting
into futuristic medicine, but making these complex
things must be incredibly challenging. Quality
control sounds vital. You hit the nail on the
head. Manufacturing these advanced therapies
is incredibly complex and needs extremely tight
control. For many drugs, especially biologics,
just controlling how the drug substance crystallizes
is critical. Crystallizes? Like salt or sugar?
Sort of, but on a molecular level. How the molecules
arrange themselves into a solid structure. This
affects stability will it degrade and bioavailability
will the body absorb it properly. Things like
polymorphism. Different crystal forms. Right.
The same molecule packing in different ways.
That plus particle size, purity, it all has to
be controlled meticulously. Getting the crystal
form wrong can actually lead to recalls. Regulators
watch this very closely. Wow. So the tiny physical
structure makes a massive difference. Massive.
And even the inactive ingredients, the excipients,
play a role. They can be used to help control
the crystal size and shape, which then affects
how the drug dissolves and gets absorbed. OK.
and then you need sophisticated tools to check
you've made the right thing. Techniques like
IR spectroscopy, infrared spectroscopy, act like
a molecular fingerprint to confirm the structure,
it's exactly correct. So lots of checks and balances.
Constantly. And new manufacturing approaches
are coming online too, like continuous manufacturing.
Instead of making drugs and batches, it's a constant
flow. That can potentially improve quality and
safety. Interesting. And it all ties back to
that quality by design idea we mentioned, understanding
the process, controlling it, building quality
in from the start. Right. It keeps coming back
to ensuring every single dose is safe, effective,
and exactly what it's supposed to be. That's
the goal, always. From that very first idea about
an unmet need, through all the research, the
trials, the regulatory hurdles, right down to
the details of making it consistently. It's quite
a journey for these biotech and gene therapies.
It really showcases scientific ingenuity, but
also the absolute need for careful processes
and oversight. Well, this has been incredibly
insightful, a real deep dive into biotechnology
and gene therapy, definitely dynamic fields.
We've gone from the spark of an idea through
the maze of development and trials, looked at
the regulators, and touched on some genuinely
transformative therapies. It's been great to
talk through. These fields really do hold immense
promise for diseases that seemed untouchable
not long ago. But as we've seen, getting these
breakthroughs from the lab bench to the patient's
bedside is, well, it's a huge challenge. Complex,
expensive. and with plenty of hurdles. Yeah,
it's clear that progress is constant, but the
hard work in research, development, manufacturing,
it all has to continue to actually deliver on
that promise and improve treatments for people.
It really makes you think about what's next,
doesn't it? And the importance of doing the science
rigorously and ethically. Absolutely. Hopefully
this deep dive gives you a solid foundation.
There's so much more to explore in specific areas
if your curiosity has been sparked. It's a field
that's constantly evolving. Thanks for joining
us on the Deep Dive.