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here to help . Considering

0:40

that about a month ago the CDC reported

0:43

that just 8% of US children

0:45

and 21% of US adults were

0:47

up to date with the latest COVID-19

0:49

vaccine , which at the time had

0:51

been available for a few months , it's

0:53

no surprise I brought the virus home

0:56

from the JPMorgan Healthcare Conference

0:58

. Between COVID fatigue

1:01

and vaccine hesitancy , getting into

1:03

the COVID vaccine game right now might , at

1:05

face value , seem like a bad business

1:07

move . That is if you're

1:09

coming at the COVID vaccine game from the same

1:11

perspective Moderna and Pfizer BioNTech

1:14

did back in 2020 . But

1:17

maybe if you bring a new vaccine

1:19

paradigm to the population , you'd find that COVID

1:21

fatigue and vaccine hesitancy are actually

1:24

the driving forces behind

1:26

commercial acceptance of your product . I'm

1:28

Matt Pillar , this is the Business of Biotech and

1:30

I'll never knock the incredible result

1:33

of the public-private partnership that we saw

1:35

during Operation Warp Speed . But

1:37

to cut to the chase , there's room for improvement on

1:39

many fronts . We all know the first

1:41

iteration of new technology is never

1:44

the best iteration of a new technology

1:46

. I won't put words in his mouth

1:48

, but Dr Carsten Rudolph , CEO

1:50

at Ethris , agrees with at least

1:52

some of this sentiment . Otherwise he

1:54

wouldn't be taking his company down the path

1:56

of developing intranasally administered

1:59

and inhaled vaccines and therapeutics

2:01

for a number of respiratory indications

2:04

, COVID among them . I

2:06

caught up with Dr Rudolph in San Francisco

2:08

to tape today's episode . Let's

2:10

give it a listen . That's where I want to start . I

2:12

want to start with a little bit of background

2:15

on where you came from and how

2:17

you got into this space . Obviously

2:19

, I did a little bit of research . I

2:21

trolled your crowd up on your

2:23

LinkedIn profile a bit and I learned

2:26

that you have a pharmaceutical degree

2:28

and have , quickly

2:30

on the heels of that

2:33

, you dove into the mRNA space

2:35

, at least it appears that way .

2:37

Yeah , yeah , what does it mean ? Quickly

2:39

, I did my PhD

2:42

exactly at the Department of Epidemiology

2:44

, at Pediatrics , basically in Munich

2:46

, yes , and at the Ludwig-Marsimius

2:49

University . My

2:51

PhD , I was mostly focusing

2:53

on creating

2:56

, developing a gene

2:59

therapy approach for the

3:01

treatment of cystic fibrosis , because

3:04

cystic fibrosis , of course , is in our specialty

3:07

or university

3:09

pediatric hospital . It's

3:11

a quite prominent disease

3:13

. This was always my idea to

3:15

do research

3:19

and providing a new potential

3:22

cure for these patients by delivering

3:24

genes , of course , that replace the missing function

3:26

in the body of these patients . But

3:29

I was mostly working on

3:31

non-biology and delivery . That means

3:33

just using classmates

3:36

and we all know . I

3:38

think you're also a biologist , aren't you ?

3:40

No , no , no , we should have set that record

3:42

straight from

3:46

the outset .

3:47

But then I'll give you a brief biology

3:49

tutorial . You've got to toll

3:51

the line here because I am not

3:54

.

3:54

Listeners of the podcast know I've said

3:56

it many times I dropped out of advanced placement

3:58

biology my senior year of high school

4:00

.

4:00

However , our audience will

4:03

appreciate a little bit of flavor

4:05

, but one real problem for using that's plasma DNA then

4:12

, of course , is how to

4:14

get the plasmid

4:16

into the nucleus , Because the gene

4:19

, of course , is active in the nucleus , sarah , and

4:22

the lung tissue is a quite

4:24

post-metonic tissue , so it's not

4:26

fastly

4:30

proliferating when the

4:32

nucleus membrane breaks down , basically

4:35

, so it's really a limitation

4:37

. And then we thought

4:39

, well , and we knew in those

4:41

days basically that our delivery

4:44

systems and model particles that we

4:46

used , we could pretty well shuttle

4:48

the messenger RNA into the

4:50

cytoplasm . Yeah , so that worked

4:52

quite well . And then we thought

4:54

is there a nucleic acid , basically that

4:57

you could make use for the turgis that

4:59

is active in the cytoplasm

5:02

? And of course there's

5:05

the messenger RNA that can be translated

5:08

at the ribosome to produce

5:10

the missing protein . Then this wasn't the

5:12

idea . Well , why shouldn't we use messenger

5:15

RNA ? In those days no one was really doing

5:17

a lot of work in this space here and we

5:19

stuck it on this and we saw

5:21

, well , that works really well . They're

5:23

much , much more efficient than using

5:26

plasmids . But we saw at the

5:28

same time that just

5:30

the standard messenger RNA molecule

5:32

and we know this all now from the pandemic

5:35

vaccine development as well is quite emogenic

5:38

Because we have a lot of sensors

5:40

in our innate immune system that

5:42

is made for detecting these

5:44

foreign RNA molecules , because this could

5:46

signal just invasion of the virus

5:49

, like the coronavirus , which is an RNA

5:51

virus . So we thought , well , it's

5:54

very efficient , but it's also

5:56

quite emogenic , basically . And then

5:59

we thought , how can we navigate around

6:01

this here ? And then we thought about

6:03

modifying the messenger

6:06

RNA and introducing modified

6:09

nucleotides , because we know from you

6:11

, from the SIRNA field and the

6:13

oligonucleotide field in those days , that

6:15

if you do so you can really reduce

6:18

the immune response and recognition

6:20

of the RNA molecules . And then we

6:22

played a little bit of ground and we found really a

6:25

scheme where we can change the pattern

6:27

of the RNA molecules

6:29

so that is not recognized

6:31

any more that well by

6:33

their immune system . And then

6:35

we thought , well , that works quite well , shouldn't

6:38

we exploit

6:40

this potential of such molecules

6:43

? And then we started to find the problem here

6:45

. So that was the idea behind it .

6:47

Yeah , that's why the question I asked

6:49

you is you were talking about this research work

6:51

and we like who was we at the time ? Like pre-athrists

6:54

, who have we ?

6:55

at this . This was my research team basically

6:57

at the Department of Pediatrics and my

6:59

colleagues over there , and I shared the lab

7:02

space with another professor and

7:04

we were running those SIR

7:06

experiments in these days here and then you

7:09

know , I was always because we all know . You

7:11

know that there RNA molecule itself

7:13

, a negative RNA molecule , is not

7:15

taken up by the sample SIR . It does not

7:17

penetrate through the cell membrane and

7:20

so you always have to package this , basically

7:23

or the nanoparticles , and then taken up to

7:25

release the mRNA payload

7:27

in the cytoplasm .

7:28

Yeah , and .

7:29

I was always also intensely collaborating

7:31

with now also

7:33

my micro-founding partner of the company

7:35

, christian Klang , who was running

7:38

and a research group as a professor

7:41

at the Technical University in Munich so

7:43

that's their second large

7:45

university in Munich and he is a

7:47

really expert , well-leading

7:50

expert in designing our

7:52

carrier systems for nucleic

7:54

acids . And then we thought basically

7:56

, yeah , we can put this together , the

7:58

expertise and turn it

8:01

from the company and

8:03

then after we got the first business angels

8:05

convinced that then we were really

8:07

brave .

8:08

Oh , no

8:11

, we have to do it .

8:12

I will always remember this moment , this

8:14

funny moment . So my plan was just

8:18

something I want to become a full-time professor

8:20

, basically , but now I became an entrepreneur

8:25

?

8:25

Yeah , you brought it up , so now I want to dig into it

8:28

. You made that decision . So

8:30

many questions there . What

8:33

was your biggest reservation ? So you thought destined

8:36

for professorship . And

8:38

then you did this work and you realized well

8:40

, there's the foundations of a biotech

8:43

here . What was your biggest reservation

8:45

about making that leap ?

8:48

I would not say reservation , it was more

8:50

a , basically because I

8:52

always thought that if you do research

8:54

here at the university here

8:56

, this also

8:59

should be something where

9:01

you can , because I mean , this is basically the

9:04

both tax money here at France that we

9:06

raised there . That would be something that you

9:08

have to give back also and make

9:10

something useful out of it . So that

9:12

was always my intention of

9:15

my research that I did at the university . So

9:17

we thought , no , we just have to try it now . And

9:21

of course I mean , if we had failed , then there

9:23

would be always the opportunity then go back

9:25

to academia . So . But we

9:28

thought , no , if we don't try it , then

9:30

who will pick up those ideas that we develop

9:33

? No one . So we thought no , we have to restart

9:36

and do it by all .

9:37

That's how we did it . That's great .

9:39

We now have the first program in the clinics . It took

9:41

us some time . It's

9:44

a complex thing to develop

9:46

for a pulmonary messenger RNA

9:48

therapeutic .

9:49

For sure , and we'll talk a little bit about that clinical

9:51

program in a little bit . But

9:54

from the business perspective it

9:56

almost sounds like a bad joke . So two scientists

9:58

are in a bar right Doing

10:02

mRNA research . When

10:05

you decided that you were going to launch

10:07

a company , you said you didn't really have

10:09

reservation because you knew that you wanted to make a contribution

10:12

with what you learned . But

10:14

building a company is a different thing from

10:16

being a research academic , or professor

10:18

, to that matter . So what

10:20

? I guess maybe not reservations

10:23

, but what were some of the early

10:25

steps that you took around learning

10:27

how to be at the helm

10:29

of ?

10:30

a biotech company and the first thing is to

10:32

write a business plan . Basically that

10:34

was the starting point and this was

10:36

basically , I have to say , that was

10:38

a trigger . Then , basically , you know , we had in Germany

10:41

also business plan competitions , basically

10:43

for young startups , and

10:46

then we thought , OK , we try to just

10:48

put down the paper , our

10:50

thoughts , basically , and then you get , of course

10:52

, structured thinking around yeah , so what

10:54

you all need and what kind of

10:56

value proposition , what kind of

10:58

drug , and to start

11:01

or to create a financial plan

11:03

, budget and all these things

11:05

. And there I think we self-trained

11:07

ourselves mostly , I would say . And

11:11

then we thought , yeah , we will try it now and

11:13

we will do it and

11:15

we will learn while we do it . So

11:18

that was the starting point .

11:19

Yeah , did you have support resources

11:22

? So like here in the States ? You know I'm not

11:24

sure what the biotech scene looks like in Munich

11:26

, but here in the States you know oftentimes

11:29

startups will take advantage of communities

11:31

, incubators . You know even parent

11:34

companies that spend biotechs on . So

11:37

I'm just curious , like , to what degree did you have

11:39

the opportunity to lean into

11:41

folks who had founded

11:43

biotech companies ?

11:45

Yeah , so there was definitely some exposure

11:47

, you know , because our first business angel who

11:50

helped us also to

11:52

move this forward and

11:55

look

11:57

into the right things that you have to

11:59

basically consider yeah , so that

12:01

was . And then there is , of course , I mean , also

12:04

in Munich . You know we have a kind

12:06

of small biotech hub there

12:08

with their kind of infrastructure and

12:10

this was also good when we got some

12:13

exposure here to this

12:15

sort of creating business .

12:16

Yeah , yeah , getting back to the

12:19

science that you founded the company

12:21

on , you said it started

12:23

out with research and cystic fibrosis

12:25

. Right Was the by the

12:27

time you realized that you had something

12:30

that was really building a biotech

12:32

around . What was sort of your

12:36

therapeutic intention at that

12:38

time , like in terms of indications

12:41

and targets , did you think , well , we can move

12:43

this well beyond where it ?

12:44

started . Yeah , it was always this

12:46

. Focusing to the pulmonary space , you know

12:48

, because that's where I have

12:50

my home , my scientific home , so to

12:52

speak , and where

12:55

I knew this field very good

12:57

, the biology and , of

12:59

course , the exposure to our

13:01

thinking of what you have to consider for

13:03

delivery , etc . So

13:06

and with I mean there are

13:08

really a few severe diseases

13:11

, therapeutic

13:13

diseases , where there's not

13:16

a good cure available . Yeah , so

13:18

we thought , no , that's a good place to

13:20

go . Basically , I mean , we did also some

13:22

work in those days in bone

13:24

regeneration , you know , to locally

13:28

translate our proteins

13:31

that are in grafted oncology and sponges

13:33

to induce

13:35

bone healing and non-critical

13:37

defects , you know where bones are

13:40

broken and they don't

13:42

know anymore that they've been all

13:44

together . So you have

13:46

the help there with biology that we

13:48

did also some work in this space . Basically

13:51

, but mostly we decided

13:53

to look and go into the lung space .

13:56

Yeah , okay , remind me what timeframe

13:58

this was . What was after this ?

14:01

So we started to look into using messenger

14:04

RNA . That was roughly around the

14:06

2006-2007 timeframe

14:08

, yeah , and we

14:10

followed the initial most important

14:13

patterns of our technology in 2009,

14:16

. Yeah , and then we started

14:18

the company towards

14:22

2011, . Yeah , basically

14:24

and really truly operational

14:26

we became in 2012, . Yeah , it's

14:28

pretty much 10 years from now , yeah

14:30

.

14:31

That's , I mean relative

14:33

to the recent , I

14:36

guess , advance in awareness and

14:40

even growth , just in terms of the industry and the number

14:42

of companies who are playing in this space . Those

14:44

were early days .

14:46

Yeah , those were the very early days and also

14:48

, you know , in the academic setting , basically

14:51

there was pretty I mean , I

14:53

think , pretty much a lot

14:55

of the birth of the messenger RNA

14:57

drug modality . I think

14:59

this was came really from Germany

15:01

, yeah , so we had the longest

15:04

there . I think that were our colleagues from QVAC

15:06

, basically , I think more , who were the first

15:08

one who tried to develop

15:10

messenger RNA for cancer vaccines . Then

15:13

we had Hugo Schahe in the same time

15:15

, the founder of BioNTech

15:17

, who you were thinking of , developing

15:20

messenger RNA for the cancer treatment

15:22

, and it was us basically , I

15:25

think , to develop our pulmonary therapeutics

15:28

. So this is all roughly in

15:30

that timeframe , basically , yeah .

15:32

Yeah , what's fascinating in

15:34

those early days . You mentioned your business

15:37

angel your angel investor From

15:41

there to sustain the company and

15:44

to grow the company . What was the

15:46

investment scene like

15:48

in this therapeutic modality

15:50

in those alley days ?

15:53

It was tough , basically because

15:55

there was not this awareness

15:58

of messenger RNA . Now everyone

16:00

knows what messenger RNA is . Of course , in

16:02

those days they were rather not

16:04

. There

16:07

was also a time where the SIR RNA

16:09

therapeutics there were waves . It goes

16:12

up and down . There

16:15

were sometimes some into the SM

16:17

and then I remember

16:19

a time when Roche stepped

16:21

out of their SIR RNA . Then

16:23

there was again less

16:25

appetite . Then it took a little bit

16:28

again to create the awareness

16:30

. But this was early . It was really

16:32

entirely new in those days .

16:36

So how did you , as an academic and founding

16:38

the company with an academic beyond that

16:40

angel investor , how

16:42

did you learn to navigate

16:45

the biotech fundraising

16:47

scene ? What did you do in those early days to maintain

16:49

Speak with a lot of ?

16:51

people yes , speak with a lot of people . Basically

16:53

they are going to

16:55

meetings , to conferences to

16:59

find investors . That's what

17:01

we then also found , basically our

17:03

first investors

17:05

. We then basically

17:07

invested with the company so that we could really

17:09

do the first steps .

17:12

Did you see a spike

17:17

in interest from the investment

17:19

community during COVID ?

17:22

Yes , I think so Because

17:26

of the awareness that

17:29

we got from the mRNA

17:31

space . I think it's very

17:33

important for the theater . In

17:35

the end of the COVID pandemic there was a

17:37

nightmare for the world , but

17:40

for mRNA it's

17:42

a great success . It

17:46

could be shown that the full potential of

17:48

messenger RNA that you can develop really

17:51

fast drug products

17:53

. Most important , we have

17:55

approved our mRNA

17:57

vaccines . It's also now clear

18:00

that this is a new drug

18:02

modality that can

18:06

achieve a proof of that . I think that's very

18:08

important for the entire field . Now we

18:11

have so many new great

18:13

areas where people

18:16

now

18:19

explore the potential of messenger

18:21

RNA . It's a new drug modality

18:23

that's fantastic to see .

18:27

Events like that obviously a

18:31

global pandemic is going to have an impact

18:33

on biotech

18:35

, not

18:38

just in terms of the repercussions

18:40

that we saw accessibility of

18:42

raw materials and

18:45

outsourced capacity , that kind of thing . But it can also

18:47

alter the course

18:49

of the company's

18:52

pipeline ambitions . We saw it in COVID

18:54

. There were hundreds

18:56

of biotechs that didn't have

18:58

COVID therapeutics .

19:02

Suddenly we had a little bit of the same policy

19:04

. We embarked

19:06

on one program at the beginning of the pandemic

19:09

. We're with a partner

19:11

, a company in Switzerland , nurengun

19:13

, which are incredibly

19:17

knowledgeable in identifying

19:20

human antibodies . We

19:24

teamed up , basically , and then

19:26

, from the first patients that were accessible

19:29

to them , they isolated and

19:31

identified a really super potent

19:34

human , a patient-derived

19:36

antibodies . The idea

19:38

was that we translate

19:41

the protein code into an mRNA

19:44

code which can then

19:46

be inhaled and you produce

19:48

the antibody in the lung directly

19:50

at the site of virus infections

19:53

, so that you have , to speak , a protective

19:55

level , a level

19:57

of layer of antibodies covering

19:59

the lung tissue . We

20:03

could nicely in

20:05

those days hamsters were used

20:08

as a model and we could nicely

20:10

reduce and avoid this

20:13

weight loss that

20:15

you experience after infection with SARS-CoV-2

20:17

. We moved this

20:20

pretty far . But then what happened

20:22

? All in the sun , and that's what we also know

20:24

, this virus changes

20:26

its face quite rapidly

20:28

and then

20:30

, when we reached the

20:33

Omicron level

20:35

, basically , of mutation , we then unfortunately

20:38

saw that the antibody

20:40

was not neutralizing

20:43

the virus anymore . So

20:45

we unfortunately had to terminate

20:48

that program . So

20:50

that's for one , and the second one

20:52

is basically , you know , the program

20:54

that is now moving in

20:56

. The ball is in the clinics now . We just

20:59

started the first phase one trial

21:01

just before Christmas . This

21:03

also a little bit goes back basically to

21:05

the pandemic time because you know that's

21:07

the concept , eth 47

21:09

, where we have

21:12

a method , rna that encodes

21:14

for a type III interferometer , and

21:17

these type III interferons in the

21:19

lung are called , yeah , it is capable

21:21

of programming the epithelium

21:23

in a very broad antiviral state

21:26

which interferes with

21:28

replication basically of any respiratory

21:31

virus . That's a very broad activity

21:34

, this molecule . And this basically

21:36

goes also back to the pandemic

21:38

time because we've got a

21:40

big

21:43

funding for this program from the Bavarian

21:45

state , yeah , so who were looking

21:47

in those days not only to put

21:50

the bet on only vaccines

21:52

, because no one knew in those days will

21:54

the vaccine make it , but we also

21:56

need therapeutics basically . So

21:59

in the end the pandemic

22:02

had an influence on what we did .

22:04

Yeah , it sounds like a win and a loss . Maybe

22:06

A

22:08

bigger win than loss . Yeah , absolutely

22:10

, biger win , definitely . What was

22:12

your pipeline structure before

22:15

those two opportunities presented ?

22:18

Yeah , just mostly centered only on

22:20

rare pulmonary diseases

22:22

. So that's still a focus

22:24

of our company , because for

22:26

a program here , what I just mentioned , eth

22:28

47 , this is

22:30

a program where you need really

22:33

a partner with the Global Footprint

22:35

app to develop this drug basically

22:38

, but it's a small biotech company

22:40

. We really want to become

22:43

a fully integrated biotech company

22:45

that develops manufacturers

22:48

and sells its own drugs , and

22:50

that , of course , is something you

22:52

can achieve in a space where

22:57

you have a very decidable

22:59

patient population that

23:01

you can serve by yourself , the

23:03

biotech company , and that's , of course , the

23:06

rare disease space . So this

23:08

was always our goal and that's why we've

23:11

looked at our major focus

23:13

is on rare

23:15

genetic pulmonary diseases .

23:21

So it's interesting . It seems the exception to the rule

23:23

of late . Like most of

23:25

the companies that I've talked , most of the CEOs that

23:27

I've talked to are very clear about their intentions

23:30

, and it's decidedly not to build their own

23:32

manufacturing facilities and become an integrated

23:34

biopharmaceutical company .

23:36

Okay , if you , in the end , fully manufacture

23:38

everything in-house , that's a different question

23:40

. You can use , of course , wonderful CDMLs

23:43

that's what we do right now but we

23:45

established all the manufacturing processes

23:48

in-house . And that's also important

23:50

, you know , because we have

23:52

for pulmonary drugs you have rather

23:55

higher doses than for vaccines

23:57

. So we always looked very

23:59

early on in creating

24:02

and developing our easily scalable

24:05

manufacturing process . So

24:07

we have our narrow process developed

24:09

that is not

24:12

based on HPLC , so

24:14

it's just built on tangential flow filtration

24:17

, which is easily scalable Now , and

24:19

also the advantage that it's purely

24:21

APS , no solvents involved

24:23

, and

24:26

this is what we transferred to CDML . We worked

24:28

with a fantastic CDML there together manufacturers

24:31

, our drug product

24:33

.

24:33

Yeah , I'm interested

24:36

in your perspective on the

24:38

explosion of the RNA

24:40

, anything RNA space . We'll stick with

24:42

mRNA , but I mean you can put any letter you want

24:44

in front of it , right ? Yeah , yeah

24:46

, in a COVID and post-COVID

24:49

world , and I

24:52

mean , I think about it like you've been working

24:54

on this . You know science and this technology

24:57

since you know the mid-2000s

25:00

and before , and

25:02

for years and years . I'm

25:05

not going to say it's going unnoticed , but it's not

25:07

necessarily , you

25:09

know , in the media cycle

25:11

, and then all of a sudden this pandemic happens

25:14

. And then , on the heels of the pandemic , it's

25:16

like being the only person in the world who thinks

25:19

the color blue is cool , or even knows

25:21

about the color blue , and then , all of a sudden

25:23

, overnight , like everyone's- like blue is awesome . We

25:25

love blue , right I

25:27

? mean there had to be . That had to be kind of a

25:29

you had to be aware of

25:31

it , right , and like the explosion

25:34

of interest and explosion

25:36

of companies . I mean , there's so many companies in

25:38

this space right now , so

25:40

what's your take on that Like .

25:43

It's great for the field . I

25:46

mean , it's fantastic . So the

25:48

more approaches

25:51

we see , the better we get

25:53

here . And there are so many diseases

25:55

that can be potentially

25:58

treated with messenger in A . This

26:00

can't be done by only one party

26:03

basically . So that's great

26:05

that we have so many different approaches here

26:07

, not only for the vaccines . So

26:10

I think we will see

26:12

some new

26:14

potential approvals rather shortly

26:16

, also for additional vaccines or in

26:18

infectious disease space . But

26:21

also look into the cancer

26:23

space here . I think we see really very

26:25

nice good signals in this space where

26:27

people use messenger RNA as

26:30

a drug fidelity . But

26:32

then look into genome

26:35

editing . There is a great potential

26:37

for messenger RNA to

26:39

be used here . And I mean we have

26:42

the first success now for CRISPR

26:45

being approved , crispr

26:47

technology . So that's a huge

26:49

step basically and I think

26:52

a huge stimulus

26:56

also for moving this

26:58

forward with using messenger RNA

27:00

. Basically . And then , of course , there is

27:02

this field of rare genetic diseases

27:05

where we see , I

27:07

think , pretty good programs

27:10

also for liver genetic

27:13

diseases and of course we want

27:15

to achieve the thing with our pulmonary programs

27:17

there and to really offer

27:20

hopefully as soon as possible

27:22

some help for

27:25

the patients suffering from these diseases

27:27

. So I think there's not

27:29

really moving forward right

27:31

now .

27:31

Yeah , in

27:34

the context of your pulmonary

27:36

focus , what do you

27:38

see as the

27:41

biggest potential risk to progress

27:44

? But whether

27:46

it's a technical risk or a market risk

27:48

or a scientific risk , what's

27:50

the rate limiting factor or big risk that

27:53

could stand in the way of progress ?

27:55

I mean , in the end it's

27:58

always the basic concept

28:01

of developing a drug and

28:04

this all centers around right

28:07

biology you have to really

28:09

understand your biology then

28:12

right exposure

28:14

, so that you have the right

28:17

PK , you know that your drug gets

28:19

there where it needs to be for

28:22

the right time basically . Then

28:25

, of course , pretty good , the right safety . That's

28:28

all the basis of a

28:30

successful drug in the end . And

28:32

then and that's what you mentioned is

28:34

there the right patient ? You have to

28:36

understand your patient , basically and

28:39

then the right commercial . So I think it's

28:41

a kind of umbrella , basically

28:43

, that you have to look at and

28:46

go into very detail for each of

28:48

these elements basically and

28:51

we did this for PCD , for

28:53

primary sedatives , canisia we

28:56

believe that we

28:58

hit those boxes

29:01

basically . So we tackle

29:03

very interesting biology because

29:06

in those patients who suffer from the

29:08

disease , they

29:11

are miscellaneous proteins

29:13

that drive the motility of the tiny

29:15

airs and our lungs and our airways

29:18

that are responsible for moving

29:20

the mucus out of the lung

29:22

. Yes , that's called mucosilir

29:24

escalator and it's made

29:26

to remove any dust that we inhaled

29:29

from the lungs so that we have a fully

29:31

particle-free surface of the lung

29:33

. But what is important to understand

29:36

here is that these CDR

29:38

, they are just made by

29:41

the airway cells , once

29:43

in the cell life and

29:45

in the half-life of the airway

29:48

. You said something

29:50

like four to eight weeks and that

29:52

means you can imagine if

29:54

you're delivering a messenger RNA

29:57

during the cediation process

29:59

, quite persistent effect

30:01

. So if you translate

30:03

a quite short lift

30:06

drug itself the mRNA is gone

30:09

in the lung after two and a half

30:11

days , something like this , into a quite

30:13

persistent effect . And

30:16

so we believe that's a

30:18

good starting point from the biology

30:21

and that's why we

30:23

, for instance , picked the PCD

30:25

the patients . It's a very

30:27

clearly defined because it's a genetic

30:30

mutation . So you take this

30:32

risk out of it , basically of the explosion

30:34

. We know that we

30:36

need to potentially

30:39

restore the CDR

30:41

function in about 20%

30:43

of the CD8 cells . We believe that's

30:45

doable on what we see in our

30:47

preclinical studies and

30:51

there is a commercial potential because

30:54

it's a life-limiting

30:56

disease basically , and it's

30:59

a high unmet need because there are no drugs on

31:01

the market . So that's why

31:03

we believe that's

31:06

a good spot for messenger

31:08

RNA computing .

31:11

I mean I could go down a rabbit hole here . Am

31:14

I hearing you correctly ? You talk about this cellular

31:17

regeneration like

31:20

a cycle and you're saying

31:23

that there's

31:25

an efficacy opportunity

31:28

at a specific point in that cycle

31:30

.

31:31

No , you just have to restore the function

31:33

. Basically once the CDR

31:36

are restored , you have a quite persistent

31:38

effect Because the cell

31:40

does not change the CDIA , so it's once

31:42

built and then they

31:44

work until the cell

31:47

is removed

31:49

from the body and replaced by a new cell . For

31:53

the lifetime of the cell Gotcha

31:55

.

31:55

OK , see , these are the questions I should have been asking

31:58

in AP biology before I

32:00

dropped the class .

32:01

My senior year .

32:03

Not long ago I had

32:05

your senior director of formulation and

32:07

aerosol research done on

32:09

a live event that I hosted

32:11

for Bio Process Online , christian Domen

32:13

.

32:16

Great guy , by the way . He is fantastic

32:18

.

32:18

I tell you , yeah , absolutely yeah

32:21

he was super valuable , just

32:24

brought a whole lot of wealth and wealth

32:27

of information to that conversation . But one of

32:29

the things that we talked about quite a bit on

32:31

that during that conversation was LNP

32:34

stability and some of the challenges around there . So

32:37

is that , do you see that as potentially

32:39

a rate limiting factor ?

32:41

I see that this limitation

32:43

in the field , because I mean just

32:46

look into the commercialized

32:49

vaccines , mrna

32:51

vaccines there . So first

32:54

we see that they need very

32:56

cold temperatures to be stored

32:58

and that was OK

33:00

during the pandemic basically . But

33:02

now we move into the post-pandemic

33:04

phase and we really want to have

33:07

temperatures that

33:09

the pharmaceutical

33:11

industry is used to use and also for

33:13

the patient . So that means

33:16

this overall cold chain needs

33:19

to be improved and need to be overcome

33:21

, and I think we have done a lot here with our

33:23

technology where we can contribute

33:26

to this and achieve this . But

33:28

with our technology we have , for instance

33:30

, the livalization process in place

33:32

where we see that we can store

33:35

the drug product already for

33:38

a year in the fridge , two to eight

33:40

degrees , and the studies are ongoing

33:43

, but we don't see any change here . And

33:45

even at room temperature you

33:47

see this already for more

33:50

than half a year . So that's , I

33:52

think , a huge step forward . And

33:56

then also you have to see and look into

33:59

the stability of the

34:02

drug product itself . Look

34:05

, the commercialized vaccines are

34:08

ready to use drug product so

34:10

it can be used for chemo-laws

34:12

basically . And we have with

34:14

our SNAPs what we call

34:16

our LNP . So we have already

34:19

achieved six days at

34:21

room temperature . That means doctors

34:23

can now really plan for

34:26

using the drug for an entire week . So

34:29

I think that's a large improvement . And

34:31

on top we have developed

34:34

our recall and stabilizing XEPian

34:36

technology here . Those

34:39

are a certain class of excipients from

34:41

the inactive ingredient list

34:44

from the FDA . That's what you can add

34:46

to the LMPs

34:49

and you make them mechanical

34:51

stable . And why do I

34:53

mention it ? Because on the label of

34:55

the commercial vaccines that's mentioned

34:57

don't check them because they are very

34:59

prone to aggregation , basically . So

35:02

and we can really now stabilize these

35:05

nanoparticles so that you

35:07

can even vortex them and shape

35:09

them at full speed and

35:11

we don't see any changes in

35:13

the particles . And of course this

35:15

gives you confidence to also

35:18

the doctors and pharmacists

35:20

to use the drug , because they don't

35:22

have any concerns anymore

35:24

that might potentially aggregate , and

35:27

also for manufacturing . You know

35:29

, when , in particular , the philipinibus

35:32

step , these nanoparticles

35:35

flow through little tubings

35:37

to basically go into

35:39

the bile , then

35:42

of course you have to avoid aggregation

35:44

, to avoid any batch

35:46

failures . So I think that's

35:49

really important , what we have achieved

35:51

here . And

35:54

then I think another I mean , when

35:56

we speak about limitations , I

35:59

think another limitation maybe and I think

36:01

that's a little bit unspoken also in the field is

36:03

that there are . You

36:06

know the pronunciations from the commercialized

36:08

vaccines they biotip

36:10

, distribute to the entire body . Yeah

36:14

, from the documents , from

36:16

their authorization

36:18

, you see that 30% goes

36:20

into the liver , it goes into

36:22

the heart even if you just locally

36:24

inject the muscle . Yeah , and

36:26

even 2 to 4% of

36:28

what's found in the plazas found

36:30

in the brain , basically , and

36:33

we think if you don't need it in the brain , one

36:36

should not deliver it to the brain , basically , and

36:38

you know our SNAPs that are Seems

36:40

logical . Yeah , okay , and

36:44

you know our SNAPs that

36:46

are made from catechonic

36:48

lipidoids , not

36:50

catechonic lipids . They are a little

36:53

bit more positively charged so

36:55

they can package the messenger RNA

36:57

more tightly , so you need just

37:00

half of the formulation but they

37:03

lead to a full retention

37:05

of the mRNA

37:08

drug at the site where you

37:10

deliver it . And that's of course so

37:12

you can avoid this biotip distribution . And

37:14

this is you know for us for our pulmonary

37:16

drugs that we develop . We want to

37:18

have the full activity of

37:21

the messenger RNA , of course at

37:24

the site where it's needed , that means in the

37:26

lung , and avoid any biotip

37:28

distribution . It's also safety aspect of

37:30

that . So that's why we

37:33

think really we have achieved pretty

37:36

much here to

37:38

move the field

37:40

in our products also really

37:42

forward with

37:45

the advantages and

37:48

to try to overcome those limitations

37:50

that we just spoke about before .

37:52

Yeah , what's been

37:54

your experience with the ? I

37:57

guess on the regulatory scene . So

37:59

I have conversations with my colleague

38:01

, anna Rose Welch , who's leading a

38:03

new project that's going

38:05

to be called Advancing RNA right now and

38:07

we often talk about , you know , some of the uncharted

38:10

regulatory waters in

38:12

this space , so what's been your perception

38:14

there ? I ?

38:14

mean , I think overall all the regulators

38:17

are really very

38:19

, very educated now from

38:21

the commercialized vaccines . I think that's

38:24

a great step , but you

38:26

know what I think for the field

38:28

it would

38:30

be very helpful , but that's ongoing

38:33

already . The other is to

38:35

consider a kind of platform approach

38:37

, so where you can more

38:39

easily , if you leave everything

38:41

the same and your drug formulation , the mRNA

38:44

formulation , but just then replace

38:46

this with another messenger RNA

38:49

, so that you get there certain

38:56

efficiencies . Exactly , exactly , so

38:59

this is for us also very important this approach

39:01

, because these primary

39:04

cellar dyskinesias they are

39:06

not caused by a lack

39:08

of acidic fibrosis , by only a

39:10

mutation in one gene , but

39:13

there are more than 50 genes

39:15

known , when mutated , that

39:18

can lead to primary cellar dyskinesia

39:20

, because you can imagine this is a very complex

39:22

proteinaceous apparatus

39:25

. To get this beating

39:27

ongoing , and

39:33

for us it would be very helpful

39:35

to swap out one

39:37

messenger RNA for another messenger

39:39

RNA to then serve

39:42

another genetic mutation that

39:44

causes the disease . So

39:46

those things that would be really

39:49

helpful , but I think that's a lot

39:51

of thinking into this direction already

39:53

.

39:53

Yeah , yeah

39:56

. When I look at the ATMP , space

39:58

, cell and gene therapies

40:02

, there's a lot of bad news

40:05

. I mean there's a

40:07

lot of consternation about

40:10

accessibility and cost

40:12

and

40:14

even commercialization . I mean there have been some not

40:17

so smooth approvals

40:19

in terms of commercial access how

40:22

does the mRNA field collectively

40:24

ensure ? I mean , obviously with the

40:27

COVID vaccine it was sort of a non-issue , right , we all

40:29

got our shots . But

40:32

how does the mRNA world , as it

40:34

addresses more complex

40:36

indications and perhaps charts

40:39

some complex manufacturing waters , how

40:41

do you make sure that you're not making some

40:44

of those same ? I don't even want to say

40:46

mistakes , but trying to maintain an

40:48

efficiency that

40:51

results in patient accessibility

40:53

at the end of the day , I

40:56

think you're referring to those gene therapies

40:58

that were upfront .

41:00

You paid a few millions basically

41:02

for a treatment . And

41:05

I mean the situation , I think

41:07

, with messenger RNA drugs is a little bit different

41:09

because it's more like a standard

41:11

drug that you repeatedly

41:14

administer to

41:16

the patient . So I mean

41:18

for our PCD programs

41:21

. Basically , we believe that's a little bit

41:23

into the direction that you

41:25

see for cystic fibrosis

41:27

, where you have already the

41:29

pricing then here on the market .

41:31

So you don't anticipate any indications

41:33

where that cost

41:36

control might become

41:38

a factor .

41:39

If you use messenger RNA or possible

41:41

genome editing , that means a one-time

41:43

treatment and then you are done . Basically

41:46

you face the same problems . But I think also

41:48

the people start to think creatively

41:50

how to solve this . What you mentioned , yeah

41:53

, how can we find financial models

41:55

basically that we

41:57

can also serve those

42:00

patients suffering from these

42:03

rare diseases ? Because

42:06

in the end , for one rare disease just

42:09

a few patients , but if we sum up

42:11

, all patients that

42:14

suffer from all the genetic , no

42:16

rare diseases that we have , those are

42:18

many patients basically , and

42:21

I agree with you . But I

42:23

believe that the field is looking into

42:25

creative reimbursement models

42:27

because we have

42:29

to find a solution there , because we want to provide

42:33

medicine to these patients as well

42:35

. But for the mRNA I

42:37

think it's a little bit different because it's not a one-time

42:41

treatment , or at least what we do , and

42:44

then you fix it , but it's those like

42:46

standard drug basically .

42:48

Yeah , very good . Just a couple

42:50

more questions that I will need to wrap up , but

42:52

I'd start with what

42:55

? Give us a clinical update , what the next big steps

42:57

for atherists are . What's

43:00

on your immediate ?

43:01

horizon ? Yeah , exactly so . For us important

43:03

and I mentioned this already for the first program

43:05

we just started our

43:07

first phase one

43:09

study just before Christmas

43:11

. So this

43:14

is our study

43:16

that has three arms basically

43:18

One arm is where we deliver it into the

43:20

nose and one arm is

43:22

where we deliver it into the lung and

43:25

then we will have , after defining

43:27

their highest dose , basically

43:30

a combined arm . And

43:32

we do , of course , safety . That's

43:34

their major clinical

43:37

endpoint . But we look into

43:40

also targeted engagement , which is very important

43:42

so that we can measure in nasal

43:44

swabs and in sputum from

43:47

these treated healthy volunteers , the

43:51

production of their recombinant

43:53

protein produced by the messenger RNA

43:55

. And , more important , you know that we

43:57

also see the downstream activation

43:59

of the genes that are induced by

44:02

the interferonamda , which gives us

44:04

the indication it works , it

44:06

is really doing what it is expected

44:09

to do . And this is the

44:11

study we will have completed

44:14

towards springtime

44:16

. So we think we will

44:18

plan an interim readout towards

44:22

early spring basically . So that's the

44:24

first very important news that

44:27

we expect then in

44:29

2024

44:32

. And then afterwards we

44:34

are also in the midst of putting

44:37

the preclinical package together

44:39

for finding

44:41

a CTA towards autumn

44:44

this year for

44:47

our first PCD candidate , and

44:50

so it's exciting time For sure , yeah

44:54

, very good .

44:55

And then , just to wrap things up , when you come

44:57

to an environment like a giant

45:00

investor conference at this stage

45:02

and atheroses sort of continual

45:05

non-clinical bath

45:07

, what's your MO here ? What's your

45:09

goal ? What are you looking to make happen ? Raise money

45:11

?

45:13

No , seriously . I mean now we enter into

45:15

the sort of clinical scene , basically , and

45:17

then we need many

45:20

more financial resources than before and

45:22

that's our goal here at JPMorgan and

45:24

also to fund partners , because we have

45:26

a really powerful we

45:29

believe best industry platform

45:31

technology and of course this

45:33

can also enable and help

45:36

other potential partners to develop

45:38

new drugs with our technology

45:40

. So it would be great to leverage on

45:43

top our technology also outside

45:45

our focus area .

45:47

Basically , yeah , excellent

45:49

. Well , I wish you well the rest of your

45:51

time here and I appreciate you coming all

45:54

the way from Munich solely

45:56

for this opportunity to be on the business , of course

45:58

, math yeah . Absolutely

46:01

my pleasure . I enjoyed conversing

46:03

with you and learning more about what Ethris is doing . Same

46:06

here , Matt .

46:07

Many thanks for having me . Thank you All , right

46:09

Very good .

46:11

I'm Matt Pillar and you just listened to the business

46:13

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46:38

. Backslash B-O-B . If

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you have feedback or topic and guest suggestions

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, hit me up on LinkedIn and let's chat and

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, as always , thanks for listening .