Latest / The BioHub - by Avetix / Episode 86 - David de Vries - Tr1X

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Episode 86 - David de Vries - Tr1X · The BioHub - by Avetix

0:04
I'm actually re recording this introduction since we did the
0:08
initial recording. The scientists behind the
0:11
discovery of regulatory T cells were awarded a Nobel Prize, and
0:15
on this episode we were joined by David Devries of TL1X.
0:19
They're based in San Diego, and they're utilizing that science
0:22
to explore type 1 regulatory cells and their potential in
0:26
treating a number of autoimmune diseases.
0:28
That includes Crohn's graft versus host disease, and also
0:32
now multiple sclerosis. David was a great guest, so I
0:36
really hope you enjoyed the episode.
0:41
Yeah, David, welcome to the podcast.
0:42
It's great to have you on. Yeah, thanks for having.
0:46
Me awesome. Well, you want to start off
0:49
David, just briefly a wee bit of your background, the guest
0:52
because yeah, you've you've come into TL1X from maybe not
0:57
necessarily the. Yeah, most straightforward.
1:00
The non traditional path in biotypes.
1:03
So prior to to tricks, which is what we call it in in shorthand
1:08
because TR1X takes too long to say, but but prior to tricks, I
1:12
was Co founder of a healthcare AI company called Rene, working
1:16
with colleagues there to scale that from the back of a bar
1:21
napkin in Orlando to now a company that's serving 10s of
1:25
millions of patients in the US and abroad, focusing very
1:29
specifically on how to optimize medications for appropriate use
1:34
and and the best possible outcomes.
1:36
And then before that, I was working at a drug device
1:39
combination company in the Bay Area.
1:42
That was some pretty innovative technology around pairing
1:44
software with the physical act of taking a pharmaceutical
1:49
agent. And by way of background of a
1:52
background in biochemical engineering and yeah, so a
1:56
little bit of an orthogonal path to get into biotech, but started
2:01
tricks in 2022 and it's been a fun journey since then to try to
2:05
prove out some exciting science. And now I'm generating some
2:09
exciting clinical data. Nice and non traditional
2:13
background book. Surely some, yeah, some
2:16
takeaways, some learning from those experiences that you can
2:19
apply to to the new venture, right?
2:22
Yes, hard won lessons. That's I think every
2:24
entrepreneur knows that you, you learn more by by failing in the
2:28
first few tries and hopefully get it right in the next few
2:31
tries. So definitely lessons applied to
2:35
to this venture. Nice, awesome thought.
2:39
There's a bit about tricks. You mentioned 2022, you Co
2:42
founded the business. You want to walk us through the
2:45
sort of this, so you're behind it, the science in, in layman's
2:49
terms, if you don't mind for me. Sure, sure.
2:52
So our work is based on the work of Marie Grazzeron Carollo, who
2:59
discovered the subset of regulatory T cells, which are
3:02
really your immune systems breaks.
3:05
And so when you think of a regulatory T cell, think of of
3:09
the cell whose job it is to prevent, you know, friendly fire
3:12
and then helps shut down inflammation once a threat is
3:15
controlled. And so there's sort of two
3:18
flavors to to regulatory cells, particularly regulatory T cells.
3:23
One is the Fox P3 positive T regs.
3:26
Those are sort of the more famous ones.
3:27
And then there's the type that we work on, which are called
3:29
type 1 regulatory T cells. And these are complementary cell
3:33
subsets, but there's some key differences that that I think
3:36
are important to mention. So Fox P3T regs, which are sort
3:40
of your more canonical when you hear of a regulatory T cell,
3:43
most people think of these Fox P3 positive, which is the marker
3:47
T regs are are programmed from birth.
3:50
It's basically they're hardwired to recognize self and they're
3:56
your built in protection from autoimmunity and and develop
3:59
this thing called central tolerance, right?
4:00
It's the reason our immune system doesn't freak out and
4:03
react to its own, its own chief use, its own systems.
4:07
We're not fully hardwired at birth to deal with everything
4:10
that the world throws at us, right?
4:12
So outside of this developmental process, the immune system needs
4:16
to continually learn, you know, what to attack and what to
4:19
ignore. So when you think about what to
4:22
attack, we think about pathogens or diseases or infectious
4:25
agents, all of all of that. But what to ignore is a large,
4:29
large subset of that when you think of the fact that you have
4:33
meals everyday and your body is encountering all these foreign
4:36
food antigens or the microbiome or environmental antigens, or if
4:40
you're not like me, things like cat dander and, and house dust
4:43
mites. And you don't overreact to those
4:46
and cause an allergic and and continually inflammatory
4:49
process. And that layer is called
4:51
peripheral tolerance. And that's achieved primarily
4:54
through the type 1 regulatory T cells.
4:57
So there's an interplay between sort of what you're primed with
4:59
at birth and what you encounter in everyday life, you know, in
5:04
your experiences. And so over the past 30 years,
5:08
our scientific founder who identified both these type 1
5:12
regulatory T cells was actually the first person to describe the
5:15
human Fox. P3T regs as well has worked to
5:19
develop additional knowledge about what these cells do, how
5:23
they work. And eventually, as technology
5:26
slowly caught up, trying to figure out a way to make these a
5:30
therapeutic agents so that you can give them to patients who
5:33
are suffering from autoimmunity to sort of restore their ability
5:37
to put the brakes on that process.
5:39
And so this is a story when it comes to tricks of technology,
5:42
really catching up to basic signs.
5:44
A lot of this work was done in the academic setting to describe
5:48
these cells, what they do, how they work, how they don't work
5:51
when you have an autoimmune disease.
5:53
And then as you think of the all the incredible technology that
5:56
that has advanced over the last 20-30 years in terms of being
6:00
able to make now what we call living drugs like cell therapies
6:04
with gene editing and with, you know, vector science and in a
6:08
lot of different methods to sort of generate a living drug.
6:15
This was really IN2022A marriage of technology catching up to the
6:19
sides. And so that's when we started
6:21
the company. The idea being that we wanted to
6:23
make a scalable, safe, really powerful version of these cells
6:29
to then apply to a number of autoimmune diseases, including
6:34
things like inflammatory bowel disease and particularly
6:37
Crohn's, but also graft versus host disease, autoimmune uveitis
6:41
and a number of other conditions.
6:43
So Long story short, it's been, it's been a labor of love in the
6:46
academic setting for for 30 years.
6:48
And then we finally felt like it was time to spin that out once
6:52
the technology caught up and and try to, you know, build a
6:55
company around it. Yeah.
6:57
A life's work essentially, right?
6:59
Let's go into it predicted. You talk about the potential
7:04
uses in autoimmune diseases, like obviously there's a lot of
7:09
focus on that etcetera at the minute, right?
7:12
And there's a lot of other product modalities, bispecifics,
7:17
monoclonals. Where do you see your platform
7:22
as as being different? What is the differentiator for
7:25
you guys? Yeah, it's a great question and
7:28
it's something we think about a lot, right?
7:29
I think we have strong opinions on this and we're obviously
7:32
biased, but I think, you know, in the field, we can largely
7:36
agree that the, the traditional biologics and small molecules
7:41
leave a lot to be desired in terms of both their efficacy as
7:45
well as some of the complexities around really requiring lifelong
7:48
administration, right? So when you think of a
7:50
traditional biologic or small molecule, not only are you
7:53
dealing with a therapeutic ceiling, you know, 2/3 of
7:56
patients either don't respond in the 1st place or lose response
8:01
over time because their immune system catches up and generates
8:03
these anti drug antibodies. And then you have to take it for
8:06
life. And, and frankly, that's,
8:08
that's, you know, something that we should aspire to do better
8:12
around, you know, we always think of, of trying to do long
8:14
term remission or cure. Some of the newer modalities are
8:17
really exciting. You mentioned the bispecifics,
8:20
the T cell engagers, even, you know, car T cells in, in, in, in
8:24
autoimmunity have now gained some traction.
8:27
And I think there there's a real trade off, right?
8:30
There's, there's an efficacy for sure, but these are
8:32
fundamentally repurposed oncology assets.
8:35
And So what you're seeing is, yes, I get, you know, tremendous
8:39
efficacy, but the costs you pay are really high, whether it be
8:43
in terms of cytokine delise syndrome or neurotoxicity or
8:47
even, you know, grade 3 infections, because you're
8:51
really massively depleting the immune system.
8:53
It's it's not a free ride. And particularly in the case of
8:57
autologous cell therapies, you've got an overhang of
8:59
tremendously complex logistics and the associated costs, right?
9:03
So there's still a big trade off there between efficacy and sort
9:08
of safety and tolerability. And I think, you know, where
9:11
something might be acceptable to a patient and a provider and
9:16
physician, a community in oncology where patients are
9:20
really staring down a a survival outcome that is rapidly, rapidly
9:24
deteriorating. In autoimmunity, it's a little
9:27
bit different. These are crippling conditions
9:29
that lead to tremendous bird disease burden and tremendous
9:33
quality of life issues. But they're certainly not as
9:36
acute as some of these oncology indications where these
9:40
modalities have been traditionally applied.
9:42
So our point and again we're biased is that you know, the
9:46
future of I and I treatment is something that you can do safely
9:50
at scale with minimal complexity and ideally with a single dose,
9:54
maybe a couple doses to really induce long term symptomatic and
9:59
fundamental biologic improvement.
10:02
Gotcha. So that is the standout point,
10:05
right? Rather than it being a
10:06
continuous treatment, it's a one or two and you're done?
10:10
Well, that's the theory I guess. Yeah, that's the ambition is to
10:14
sort of induce this immune reset and and sort of make sure that
10:17
you get set back to baseline in a way that is durable.
10:24
Great. It's and you mentioned obviously
10:28
where you're applying it briefly earlier, it is in pretty tough
10:33
patient populations, right. You're going after some, yeah,
10:37
pretty severely affected patients, particularly in
10:40
Crohn's. You mentioned also as well as
10:44
the potential for other indications as well.
10:46
Where were you sort of looking in the near term?
10:49
Yeah. So we're developing 2 products.
10:51
Our first one which is called Trix One O 3 is primarily
10:54
focused on T cell mediated autoimmunity.
10:56
That's your IBD, that's your Ubi, this your graft versus host
11:00
disease. And you're right, we're going
11:02
into patient populations that are staring down an otherwise
11:06
very unpalatable course of rescue therapy, whether it be
11:10
having massive sections of their gut resected in in surgery, in
11:14
the case of refractory Crohn's disease, or even a stem cell
11:18
transplant to try to ameliorate symptoms.
11:22
It's really sort of being that last line of therapy.
11:25
And obviously we have the ambition to move upstream.
11:27
But I think one of the the premise and promise of cell
11:30
therapy is that you can take these patients who have no other
11:33
solutions and really provide an alternative option that
11:37
hopefully has some durable efficacy.
11:39
Our second product takes advantage of a unique feature of
11:44
the biology of TR1T regs in our engineered TR1 T Rex, which we
11:49
call trick cells, which is that if you add a chimeric antigen
11:52
receptor, you can actually make these work both ways.
11:56
You can make them work like the regulatory T cells which are
11:58
putting on the brakes, but you can also take advantage of some
12:01
machinery that these cells have to really target specific cell
12:06
subsets and deplete those much like an effector cell therapy
12:09
would do. So our second product, which we
12:11
call Trix 319 tries to take advantage of both of these
12:15
things with the T Reg chassis and then ACD 19 chimeric antigen
12:20
receptor on top. And for that, for that product,
12:24
we're trying to position it in diseases where there's a known
12:26
dual B&T cell component. So first effort there will be in
12:31
progressive forms of multiple sclerosis, which as you know has
12:34
basically zero options that significantly all disease
12:38
progression today. And we have a number of other
12:41
indications that we haven't disclosed yet that we are
12:43
pursuing with with that modality as well.
12:47
Super interesting for sure. Where are you at with things at
12:51
the minute? Obviously we, we talked about
12:53
the first portion you're in phase one for Crohn's and graft
12:56
versus health disease, how close to I was getting into the clinic
13:00
for the for the second portion. Yeah.
13:02
So we were in Phase 12A for the Tricks 103 program across those
13:08
two indications you mentioned our plan is to complete the dose
13:11
escalation portion of both of those trial by the end of this
13:14
year. So that we're really in the
13:16
Phase 2A portion and reading out some meaningful clinical data in
13:20
the early part of next year. Trix 319 is an Ind enabling
13:24
studies. We expect to launch the the
13:26
multiple sclerosis study in the first quarter of next year and
13:30
to start reading out at least some biomarker data in the
13:33
second-half of next year. So it's all happening pretty
13:35
fast. We'll have some announcements
13:37
soon, but it but it's an exciting time.
13:40
Yeah, 100% for sure. Cool.
13:42
Awesome. No, sounds like some really good
13:45
progress. I mean, you've thought about the
13:48
the positives behind the platform and and the product,
13:52
right? But cell therapy has had its
13:54
challenges over the years as well.
13:57
Yeah. What are the key ones you've
13:59
faced so far? And yeah, how have you overcome
14:02
them? You know, I think cell therapy
14:05
right now is a little bit out of fashion unless you're talking
14:09
about in in vivo induction of cell therapy.
14:12
But yeah, it's certainly having a skinny gene moment.
14:17
However, I think there's there's a lot of promise that remains in
14:21
the field. It's just to prove it story at
14:23
this point. I think there's there's three
14:25
things that really go on in the world of cell therapy.
14:28
The 1st is that the manufacturing has to be unlocked
14:32
to a place where you can treat 10s of thousands of patients to
14:35
really make these drugs compelling for large pharma
14:38
players. So you need to be able to
14:41
access, you know, 10s of thousands of patients.
14:43
And if you're doing this one by one in an autologous situation,
14:46
despite all the optimization that's going on, it remains
14:50
really challenging. The second challenge then is as
14:53
people move from autologous to allogeneic cell therapies,
14:57
meaning off the shelf generated from third party donors or
15:01
generated from the patients themselves, but stored for a
15:03
period of time. The efficacy story hasn't been
15:07
proved out and some early talk signals, particularly in the
15:10
oncology setting really, really generated some some headwinds
15:15
for the field more broadly. And So what you saw was really
15:18
two approaches take place. There's one school of thought
15:21
that says, OK, if I'm developing an allogeneic cell therapy and
15:25
obviating all the manufacturing and cost challenges associated
15:28
with autologous, I need to make sure that these cells can last
15:32
long enough to do their job in in patients.
15:36
And So what happened there in the setting of effector cell
15:38
therapies in particular is a lot of genetic engineering, a lot of
15:42
really interesting science using CRISPR, using other
15:45
methodologies to knock out or knock down those molecules on
15:49
the surface of the cell that the immune system would then
15:51
recognize and and eliminate to try to engender a little bit
15:55
more persistence of the product. The flip side is that there were
15:59
also some talk signals related to recognition of a foreign cell
16:03
entering the body. So that's one school of thought
16:05
and that's still ongoing. And there's a lot of clinical
16:07
trials with what we call gene edited cells in the algae
16:10
setting. The other school of thought
16:12
said, what if, what if we turn the patient's own body into the
16:16
manufacturing center and drove basically the creation of these
16:21
cell therapies in vivo? And there's two main methods
16:25
that are being used for that. One is a lentiviral vector
16:28
method, which I have some earns around the toxicities applied to
16:32
autoimmunity specifically and the other one is using targeted
16:35
lipid nanoparticles. So again, you're trying to take
16:37
care of a lot of the the challenges which include the
16:40
fact that you need to give chemotherapy before you give
16:43
these therapies. They cost a lot to make.
16:45
If they're allogeneic and you don't engineer them
16:47
specifically, they don't last long enough to do their job.
16:51
And so I think, you know, the field is catching up.
16:54
I think we've learned a lot of the last 5-10 years in the
16:56
clinic, our approach has always been that if you hook into
17:00
nature, you're, you're bound to have a better outcome.
17:02
So we've taken the approach that, you know, reprogramming
17:06
our cells basically mimic this regulatory T cell phenotype
17:11
where you are by definition shielded from immune clearance.
17:15
And we sort of call it our, our stealth reprogramming the cells
17:19
will last long enough to do their job.
17:21
And then you're not counting necessarily just on your product
17:24
to have the efficacy. The way our product works is it
17:27
hooks into your biology and your immune system to really drive
17:31
what we hope is a long tail, right.
17:32
So we don't need our cells to stick around for months and
17:35
months and months. We just need them to be there to
17:38
teach your immune system to do its job again.
17:41
Oh. I get you it.
17:44
It's almost like more of a natural treatment in some form.
17:49
Funny way got you. You mentioned execution on the
17:54
first part. I think manufacturability and
17:58
reaching huge patient populations is a key thing
18:00
across cell and gene therapy. You've built in pretty solid CMC
18:05
and tech OPS power in the organization from a very early
18:10
phase, right? Yeah, I mean, it's been front
18:12
and centre for us from the beginning.
18:14
I think we've got a wonderful group of people that leads our
18:17
tech OPS everywhere from from process development to
18:21
manufacturing to supply chain, and then ultimately also
18:24
analytical development, which is critical for making sure that
18:27
we're generating, you know, consistent product.
18:30
And, you know, we started from a point of view that if we really
18:34
want to treat and hopefully cure autoimmune diseases that are
18:37
affecting millions of patients, you better have a solution
18:40
that's scalable. And So what we've built out from
18:43
the beginning is, is a model and a mentality that we have to
18:46
design for scale. And our, our clinical
18:49
manufacturing process happens in a closed system.
18:53
It takes about 3 weeks for us to generate 1 clinical batch of our
18:57
cells across both products. And the output there is 10s of
19:02
billions of cells. And what that means for us is
19:05
that today with our first generation process and the guys
19:08
and gals are always mad at me that I don't let them yet go to
19:11
the second generation process, but I promise I will, is, is, is
19:17
that we have a commercial cost of goods today.
19:19
We have something that can stand up to the TC ES in the
19:21
biologics, certainly is much more compelling than the
19:25
autologous cell therapies and can really drive broad adoption
19:29
of this at scale. That's all and it's coming up in
19:34
conversation so much more even conversations we're having with
19:38
leaders in the space building in that capacity earlier.
19:43
I think CMC, it's something that was maybe, yeah, not always
19:48
front and centre of everyone's mind throughout the past 20
19:51
years, but it it should have been and it hopefully will be
19:55
moving forward. Cool.
19:57
Awesome. Long term, like really long
20:00
term. David, where do you see the
20:02
business going? And like, Sky's the limit, by
20:05
the sounds of things. Yeah.
20:08
I mean, I think we're learning a lot, right.
20:09
And as you mentioned, we're tackling really tough patient
20:12
populations. And in areas of large unmet
20:14
medical need, I think we always build the company for the long
20:18
term. Everything we do has an eye
20:20
towards taking these products all the way to market so that we
20:22
can get them to the patients that need them.
20:24
And that's how we think very thoughtfully about our
20:28
development plan. And so you know, the idea is
20:30
that 2026 will really be a year for us to understand how this
20:34
product is working across multiple modalities, multiple
20:37
settings and hopefully preparing them for pivotal trial.
20:41
Our ambition is obviously, you know, if I, if I talk to you
20:44
about our vision, it's that you get a one time, 15 to 20 minute
20:48
infusion of our cells and your immune system is restored for a
20:53
long period of time so that you can go by about living your
20:57
daily life. You know, I think that's, that's
20:59
where we hope to end up. Obviously there's a long road to
21:01
get there, but but that's the long term vision is really to
21:04
build a company that can make these, distribute these, sell
21:08
these incredibly powerful agents that hopefully really shift the
21:12
paradigm of how these diseases are treated today.
21:16
I mean it sounds awesome, right? I think we talked about before
21:21
we when we were doing this little prep for this, that,
21:24
yeah, my old brother has, yeah, a colostomy value.
21:28
It'd be awesome to have tuticorin and so that, but yeah,
21:33
it'd be awesome to have a an option like that for really
21:37
severely affected patients so they don't have to get literally
21:40
meters that are out of their intestine, Right.
21:43
So yeah, awesome. For sure.
21:45
And you know this better than I do, right.
21:47
The patients that we are seeing and treating in our trials are
21:50
patients that have failed multiple, multiple options
21:52
available to them. And they're not fifty, 60-70
21:56
years old, you know, they're in their 20s and 30s and they've
21:59
got their whole life ahead of them.
22:00
And I'm sure that they're staring down a future that seems
22:04
very unappealing, right? So if we can do something to
22:07
help people live healthier lives, particularly young
22:10
people, we were, you know, it's a, it's an easy way to get up in
22:15
the morning and go to work. 100% I think you hit the nail on the
22:19
head with that right. The patients have such a lot to
22:22
look forward to in life. It's not like some other disease
22:25
areas, not what I'm saying they're less worthy or anything
22:28
like that. But yeah, all the patient
22:29
populations, they'd live the life up to a certain point.
22:32
But this particularly Crohn's, from first hand experience, it
22:36
doesn't discriminate. It's.
22:38
Yeah, it's really affecting the young.
22:39
Sure. Oh, awesome.
22:41
It's been great to have you on and learn a bit more, David.
22:45
We'll finish with the final Biohub question, I guess, and we
22:49
were on it through beforehand. But yeah, one person, past or
22:54
present, can be a scientist, can be an entrepreneur who'd like to
22:57
invite for dinner. Who would it be and why?
23:01
Oh, I think for me, it goes back to sort of, you know, who I
23:07
admire in terms of what, what they've done and what they've
23:09
done for the world. I think there's there's a person
23:12
who was very instrumental in the field in which we work.
23:16
His name is Paul Berg. And my family actually had a
23:19
chance to meet him. I only met him when I was very,
23:22
very small. But you know, he's simply who
23:24
really changed the the world of medicine and the world of
23:26
science in particular. And he was a teacher and a
23:29
mentor to a lot of tremendous people.
23:32
And I think just having a chance to sit down with them would be,
23:35
would be fantastic. So for anyone who hasn't heard
23:38
of him, I, I urge you to look him up and look at his work.
23:40
You know, he's won a Nobel Prize.
23:42
You should be. What is it?
23:44
Family Meeting. Stanford many, many moons ago.
23:49
But yeah, he was, he was a biochemist by by training and
23:54
just an incredible human being by the sounds of it.
23:56
So that would that would be my wish.
23:59
Nice, Good choice. Awesome.
24:01
Well, look, great to have you on.
24:03
Thanks again for the time. Really appreciate it.
24:06
It's good to see you, John.