May 19, 2025 • 59 mins
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On this week's episode, Michelle Werner, CEO at Alltrna, talks transfer RNA (tRNA) therapy with host Ben Comer and guest co-host Anna Rose Welch, editorial and community director at Advancing RNA. Werner explains why a single engineered tRNA therapy has the potential to treat "hundreds, if not thousands," of rare genetic diseases, and how her own child's rare disease diagnosis shaped her career and approach to drug development. Werner also discusses Alltrna's use of AI and machine learning for drug optimization, the company's planned use of basket trials, and more.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Ben Comer (00:00):
This episode of the Business of Biotech is brought
to you by Avantor.
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(00:24):
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com for more information.
Welcome back to the Business ofBiotech.
(00:45):
I'm Ben Comer.
Anna Rose Welch (00:47):
And I'm Anna Rose Welch.
Ben Comer (00:48):
And we're both excited to speak today with
Michelle Werner, CEO of Alltrna.
Michelle has worked at some ofthe biggest biopharmaceutical
companies in the world,including Novartis, AstraZeneca
and Bristol-Myers Squibb, buthas now moved into company
leadership at a relatively newtransfer RNA or tRNA
(01:09):
oligonucleotide therapydeveloper, Alltrna, backed by
Flagship Pioneering.
I want to thank Anna Rose,editorial and community director
at Advancing RNA, for bringingMichelle to the Business of
Biotech and for joining us onthe podcast.
Anna Rose Welch (01:25):
On today's show , we're going to get to know
Michelle and find out why shewanted to take a chance with a
tRNA startup, as well as whatmakes tRNA therapies unique and
promising.
We'll also learn about the manychallenges that come along with
working in a new therapeuticspace in terms of attracting
investors, designing trials,manufacturing therapies and
working with patients andregulators.
Ben Comer (01:48):
Michelle, welcome to the show.
Michelle Werner (01:50):
Thank you so much for having me.
I'm really excited to be here.
Anna Rose Welch (01:53):
We're excited to have you.
Ben Comer (01:55):
Yes, we are.
As we alluded to in the intro,you've spent a majority of your
career at Big Pharma, working incommercial functions and as a
country head and franchise head,both in the US and globally.
How did you get connected inwith Flagship Pioneering
initially?
Michelle Werner (02:15):
So I mean, in some cases it was a little bit
of luck, I guess I would saythat I got to a stage in my
career where I was looking to dosomething a little bit
different than I had done withthe previous 20 years in my
career.
So, as you've mentioned, ben,I've been in big pharma for much
of my career 20-ish years.
(02:37):
Most of that has been focusedin the oncology space and I will
say that I had a reallyphenomenal career in big pharma.
I had a you know have reallygreat experiences and memories
of my time at those companiesthat you've referenced and I
found this space to be extremelyrewarding, especially in
(02:58):
oncology, of course, wherethere's huge unmet medical need.
I got into this drugdevelopment business in the
first place because of me havingworked in a cancer clinic, so I
really was working hand in handwith patients and really
understanding what their needsare and what they go through,
and for 20 years that was areally phenomenal place to be
(03:18):
and during that time I got tosee the emergence of some novel
therapies come through.
When I first started it waschemotherapy and maybe chemo
doublets were emerging, but youknow, during my time I saw the
emergence of targeted therapies,I saw the emergence of
immunotherapies, immunotherapycombinations, and that really
(03:41):
changed the overall trajectoryfor patients with a lot of these
different cancers and was areally phenomenal place to spend
much of my career.
But, as happens sometimes inlife, right, different
curveballs get thrown your way,and one such curveball was a
very personal circumstance andit was actually in May of 2020.
(04:03):
So, just about five years agonow, one of my three children
was diagnosed with a raregenetic disease and, in fact, he
was diagnosed with Duchennemuscular dystrophy specifically,
and it happened to be on his10th birthday.
And as a drug developer, right,the first thing that I think of
is okay, well, I know a littlebit about medicine and how to
(04:25):
treat disease and, you know, letme wrap my head around
everything that there is to knowabout treating Duchenne and I
realized that the standard ofcare was, you know, not really
great, with basically high dosesteroids essentially as the
mainstay of treatment, which youknow may be beneficial but also
comes with a lot of sideeffects.
And then so I was treatment,which you know may be beneficial
but also comes with a lot ofside effects.
(04:46):
And then so I was like, well,that standard of care isn't good
enough.
So what else is out there?
And I did what a lot of drugdevelopers would do, and that
would be go to clinicaltrialsgovand see what innovations were
in the works.
And even perusing the few pagesof Duchenne trials on
clintrialsgov, I realized therewas not a single one that my son
(05:09):
was eligible for not a singleone.
And that was heartbreaking,really, really heartbreaking.
And so, basically, you know my,it really cast this spotlight on
the inadequacies right oftreating rare diseases or the
innovations that are availablefor rare diseases versus more
common diseases like cancers.
(05:30):
And I was, you know, I realizedthat it was an appalling
situation and I felt like, aftersome deep reflection of not
just our personal circumstanceshaving changed but my own
professional circumstances, itmade me realize that, okay, in
20 years in oncology we've madea lot of difference maybe not a
(05:52):
self problem, but a lot ofdifference.
I want to spend the next 20years and focus on genetic
diseases, rare genetic diseasesin particular, because I really
personally felt the sheer unmetmedical need and what it was
like to actually feel like youwere a patient that was
completely overlooked by theindustry that I love being in
(06:16):
and that I had been in for thelast couple of decades.
So that was really the sort ofbackdrop to what was happening
at the time, and so to me I wasthinking, okay, maybe big pharma
isn't where I want to be, maybeI need to be in a nimble,
dynamic biotech environment.
But then, honestly, it wasreally when I was first told
(06:38):
about Alltrna specifically thatit made me really realize the
sheer potential of our platformwith our engineered tRNAs,
because the whole idea behindwhat we're doing is one single
engineered tRNA may be used toaddress hundreds, if not
thousands, of different diseases, and as a rare disease parent,
(07:01):
I know that there are somewherearound 10,000 of these.
You know rare genetic diseasesand with today's technology,
even the novel ones like genetherapy, gene editing, mrna all
are taking a one disease at atime strategy, because that's
how those modalities work.
But if you can turn thatparadigm on its head and find a
(07:22):
way to use a single medicine toaddress hundreds of them, you
could clearly appreciate thetransformative potential that
that kind of technology might beable to have on this patient
population, whereby most ofthose diseases do not have an
approved therapy In fact, 95% ofthem do not.
(07:43):
So that's really why I came toAlltrna.
It was also great that it was aflagship, pioneering company.
To be honest with you, that wasan added bonus Because, as a
first time CEO, being part of anecosystem of companies and an
ecosystem of expertise was veryattractive to me.
Ben Comer (08:04):
Yeah, and so it makes sense why you wanted to take
this big swing into geneticmedicines, and I think that you
know the concept of a singlemechanism being able to
potentially solve a whole lot ofdiseases is very exciting.
But, like you said, you're afirst time CEO and I'm curious
now you know you're three yearsinto the job, is it different,
(08:28):
you know, than you expected itto be, kind of on a day to day
level, and how did you preparefor it?
Michelle Werner (08:34):
So, to be honest with you, Ben, I'm not
sure I had this like verypreconceived idea about what
being a biotech CEO would be.
Like my only frame of referencereally were the CEOs of the
various big pharma companiesthat I worked for, I worked at
in my career and I knew it wasgoing to be different than that,
but I didn't really know whatto expect.
(08:55):
I will say that there wasdefinitely a period of time
where, you know, I was reallyexcited about the role and the
opportunity, but I also didn'tknow, like, am I really equipped
to do this job?
Am I ready to be a CEO?
And part of that was, you know,do I have the skills that are
(09:16):
and the capabilities that areneeded to lead a startup
organization number one, a teamof employees who are essentially
all basic science, likescientists, basic scientists
like I've.
I've mostly led, you know, bigteams, but big teams of
commercial people in my career.
(09:38):
So this was a fundamentallydifferent thing.
I'm more of a commercial person.
Do I?
Am I really going to berelatable to the scientists and
to really understand whatthey're doing and for them to
understand me and where?
You know, my vision is?
And so there was definitely aquestion mark about that.
And then there was also, youknow, as with any CEO in a
(09:59):
startup environment, especiallya private company, it's a lot of
focus on fundraising, of course, and it's not something I've
ever done before, right.
So I've had some investorinteractions in my previous
executive roles in pharma, butnot a lot and not where I'd have
, like, the sole responsibilityreally of, you know, making sure
that we can, you know, have acapital formation strategy
(10:23):
that's successful.
So I'd say there were someuncertainties coming into this
role, but there are a few thingsthat I learned and kind of
getting to how I prepared, whichI think you know, honestly,
looking back now, the 20 yearsthat I've been in the industry
actually was the preparationthat I needed for this job.
So, even though I've never hadthe responsibility of raising
(10:45):
capital for a company in thepast, what I did do a lot of in
those different companies is putbusiness cases together to
create a compelling story abouta strategy that we want to
invest in as a company and tosecure the resources within
those companies in order to beable to put behind those ideas.
(11:06):
It's essentially the samecompetency, I'd say, when you're
gearing up for, let's say, aSeries B, as we had to soon
after I joined Alltrna.
So I'd say a lot of that sortof skill was transferable, which
I didn't know at the time, butcertainly was the case.
And then I would just say, morebroadly, around the leadership
(11:29):
skill, I mean, of course Alltrnais a much smaller company than
most of the teams that I've ledbefore in the past and again a
very different phenotype ofemployees than I've led before
in the past.
But there are a lot of thingsfrom a leadership perspective
that are transferable from onegig to the next, from one
employee base to another.
And actually really just tryingto paint a picture for what it
(11:54):
is that we're doing and whatwe're trying to achieve with the
really cool science that we'redeveloping at Alltrna is
something that I feel like I'vehad to do in any number of my
leadership roles in the past.
Paint that picture for a vision.
You know how to make strategicchoices that are going to help
enable that vision to bematerialized.
(12:17):
And I'd say, in particular withthis team and with this company
, the fact that I'm actually arare disease parent as well
resonates with the company andyou know there's not a day that
goes by that I think theAlltrnators, as we call
ourselves, don't love thenicknames.
Anna Rose Welch (12:38):
Yeah, it's great.
Michelle Werner (12:41):
That we don't, that we I mean every single day.
I think we appreciate thatwe're doing cool science, but
we're doing science with apurpose and that purpose is to
really transform the care forpatients across a number of
different rare diseases, and Ithink my personal connection to
this community is uniquelysuited to to help bring that to
life.
Anna Rose Welch (13:02):
You are I mean you.
You expressed really nicely whytRNA right, like why that
molecule itself spoke to you andsort of through your journey
into leadership of a smallbiotech company working with a
tRNA product.
I'm really curious.
You know, outside of themechanism of action of it, what
(13:24):
was the most exciting reason foryou right to sort of jump into
this really novel scientificspace and how had you, or how
have you right continued tolearn more about that scientific
element of this brand newscience, right?
How can you share a little bitmore as well about, about how
you've prepared your leadershipto sort of fit into this more
(13:49):
scientific niche Right and in anew biotech?
Michelle Werner (13:52):
Yeah, so I mean , maybe just you know the like,
the coolest thing I think aboutthe tRNA, like, as I said, is
the ability to transcenddifferent diseases, and when I
was first considering this roleand I met with some of the
founding scientific team, youknow some of the initial like
preclinical data sets that theyshowed me, which showed that a
(14:13):
single engineered tRNA was ableto restore protein across, you
know, almost 25 differentdisease models in cell models
and, and that it was able to dothat regardless of which gene
was affected, which protein wasbeing coded for, and actually
(14:33):
the location of the mutationalso did not matter.
It was able to restore proteinor read through these mutations
in each one of those settings ina very universal way, which is
not something I've ever seenachieved with really any other
modality that at least I wasfamiliar with, and so I found
that to be like, truly, you know, like I said, could be very
(14:56):
transformative, Because thatreally said to me like, even if
I just take Duchenne, forexample, which is a disease I
know very well because that'sthe one that my son happens to
have In Duchenne, now there's agene therapy that can be used
across, you know, all patienttypes, or most patient types,
not all but most.
But before that there wereactually exon skipping
(15:17):
technologies, which meant thatyou had to have a mutation in a
certain place that would beamenable for those types of
technologies.
And guess what?
My kid did not have thatmutation.
So there were many approachesthat just were not possible for
my own son and gene therapy isthe same way, by the way, it's
(15:37):
not depending on the mutationlocation or depending on
baseline antibodies or a lot ofother different reasons right,
May not be an appropriatetherapy.
So having a drug that might, orhaving a modality that might be
able to transcend some of thosenuances, I thought would be like
truly, truly interesting.
And so that to me was like I'mhooked.
I was really hooked on thatgeneral idea from the outset.
(16:01):
And then, how did I reallyprepare?
I mean, I will tell you, youknow other than my biology 101,
you know class right back fromcollege books.
Yeah, I mean I don't think Iever said tRNA in my lifetime, I
mean.
So there was a lot that I reallyhad to learn.
So the thing to me was the bigpicture idea I got, and then to
(16:25):
me it was really about likedigging into the science and
understanding the science.
And and that's where I would sayis, you know, I got really
invested in it, and so I feltlike the basic thing that I
really needed to do was reallyjust listen actively, listen to
all the incredible scientiststhat we have here at Alltrna to
(16:47):
really understand.
This is the opportunity, theseare the challenges, this is how
we think we need to translatethis modality, or translate the
science, into a new therapeuticmodality for patients.
And it was really a lot oflistening and learning and that,
to me, I'd say, was, I mean,that's where I spent most of my
(17:07):
time in the first few months,listening and learning, asking a
ton of questions and reallygetting up to speed.
And then, once I sort of gotthe basic fundamentals of the
tRNA biology that sort of kindof, I'd say, positioned with the
(17:28):
drug development experiencethat I acquired in my, you know,
couple of decades of being inthe business, I was able to
start making some connectionsbetween the biology and you know
, ultimately, at the end of theday, what we're trying to do for
patients.
Anna Rose Welch (17:42):
There are a lot of connections right between
all the different modalitiesthat you can definitely make.
Ben Comer (17:47):
I want to.
Oh sorry, anna Rose, I cut youoff there.
No, I just I wanted to pick up.
I'm curious about theinvestment piece and you've
talked about some of thoseskills being transferable from
previous work you've done in bigpharma.
But I have to imagine that whenit's a brand new modality,
never been a drug approved therehas to be.
(18:08):
Well, correct me if I'm wrong.
There must be some bit ofeducation that you have to do
with investors and I'm just sortof curious about this.
The story obviously is soimportant for an investor and I
just wonder, you know if youmight share kind of how that
experience has gone.
Have you had to explain notonly how the mechanism works but
(18:29):
kind of make it real forinvestors and say this is why we
think this is possible?
Michelle Werner (18:34):
A hundred percent Right.
So that's exactly how we'vereally teed things up for
investors.
I mean, honestly, I alwaysreally start a lot of these
conversations with you know,let's just talk about the unmet
need, right.
The numbers of diseases thereare 95% don't have an approved
therapy.
We're trying to tackle it oneby one, kind of just like the
conversation we've just had alittle bit, to really sort of
(18:56):
like appreciate the sort of whatseems like an insurmountable
challenge that we have in theworld of genetic diseases.
That's basically where I start.
And then, yes, just like Ineeded a foundational
understanding of what is a tRNA,what's its function and why do
we think it has this kind ofuniversal ability.
(19:18):
We then talk about the specifictypes of mutations that we're
tackling in the first instance.
So we think a tRNA can addressa number of different types of
mutations, but we have to startsomewhere and we are starting
with nonsense mutations.
So with a tRNA we're takingthis approach of identifying
those common nonsense mutationsacross a number of different
(19:40):
diseases and why you know why wesee the same nonsense mutations
from one disease to the nextand why the sort of conserved
biology of a tRNA should be ableto address all of those.
And then it is about, like,giving a reason to believe.
Right, we all need reasons tobelieve, just like I needed a
reason to believe to joinAlltrna.
(20:01):
Investors need a reason tobelieve that you know that this
isn't just a crazy idea, thatthis crazy idea actually might
have legs to it, and that comeswith data.
And so, with our Series B,which we announced raising 109
million in August of 2023, whichyou know, we're really very
proud and excited about, thatwas really based off of mostly I
(20:24):
mean a preclinical data setthat was mostly based on in
vitro data, with one small pieceof in vivo data, our very first
piece of in vivo data.
And now, you know, we've beenable to progress the platform as
such to now have multiple invivo data sets across multiple
different disease models, andnow we're demonstrating that
(20:47):
what we saw in in vitroenvironments across multiple
diseases now is similar in thein vivo or mouse setting, which
is also super exciting.
So, if you see translation fromcell to mouse, the likelihood
of seeing a translation fromanimal to human is much, much
higher.
So that's what we're reallyexcited about.
So yeah, you have to tell thatstory, but then I would say also
(21:10):
, in addition to telling thatstory from the basic kind of
biology, is also how we'replanning to develop our tRNAs,
because this is also a littlebit, you know, I'm going to call
it somewhat unconventional,although it's been used before
in the past.
So certainly some investorswho've been around the block,
especially in the oncology space, would be familiar with this,
(21:32):
because this is what we callbasket trials.
You may be familiar with thembut it's been used very commonly
in oncology.
In fact, I'm going to say sevenor eight different drugs got
approved using a basket trialstrategy.
And what a basket design is isbasically patients have
technically different diseases.
So in oncology it could be lungcancer or breast cancer or, you
(21:55):
know, ovarian or anything youkind of put.
You know, fill in the blank,but each patient is selected by
having a common mutation.
So, again in oncology, it couldbe the EGFR mutation, for
example.
In rare diseases it could be aspecific nonsense mutation.
So patients technically have adifferent disease, but they're
all selected by having that samecommon mutation.
(22:18):
Across those different diseases.
They're given the same drug inthe clinical trial and then
they're monitored right, maybefor the same things, maybe for
different things, and that'swhat we're doing in rare
diseases.
So a common development strategyin oncology is now going to be
applied in rare diseases.
It has before in the past, butto a lesser extent in oncology,
(22:41):
but now we have a modality likea tRNA that actually is uniquely
suited to take advantage of thebasket trial design.
And what's great about that isis that not only in this
clinical trial can you includethe more common of these rare
diseases, you get to alsoinclude the ultra rare diseases
(23:01):
as well, and that, honestly, isreally the most exciting thing,
because those ultra rarediseases will likely have, maybe
never a clinical trial or aninterventional clinical trial in
a patient's lifetime.
That's the reality, which isreally really, you know,
heartbreaking when you thinkabout it.
So I really love this strategybecause of this idea about
(23:24):
bringing all these patientstogether and unlocking not only
what we hope will be aninnovation that will be
beneficial to these patientpopulations where there are
essentially no effectivetreatments, but actually, from
an investor perspective, itreally unlocks a value pool that
is currently completely lockedright now, because there are no
(23:49):
drugs that you know or nocompany that is specifically
going to focus on these ultrarare conditions really mostly
because those individual patientpopulations in and of
themselves are too small If youhave to take one disease at a
time strategy.
Ben Comer (24:10):
So now we all of a sudden you know, and that's how
we sort of paint the picture ofthe opportunity to investors.
So with you will be kind of outof the gate, pursue a basket
trial, multiple disease armsfrom the very beginning.
Or will you do some initialearly stage like safety stuff
before you start?
You know, go into a baskettrial.
Michelle Werner (24:26):
Well, that will definitely be a decision that
we make in in combination withinput from health authorities,
and you know we are workingthrough that right now.
So some of those details arestill remaining to be seen, but
the idea for us is to get into abasket trial as quickly as
possible, right?
So maybe we do need to do asmall first step just to be able
(24:49):
to demonstrate a quick clinicalproof of concept or a quick
safety data set in humans.
You know that matches thepreclinical data package that
we've already developed, but theidea is for us to be able to
get to a basket trial as soon ashumanly possible.
And so, because that's where wethink we have the most
(25:10):
potential to be able to addvalue to the patient-
populations and really todemonstrate what a tRNA can do
across a number of differentdiseases.
Anna Rose Welch (25:28):
Well, I think, as the parent of a patient with
a rare disease, right to thescientists, the people working
within your company, and evenjust some of the work you're
doing now, thinking about thestrategy for delivering and
developing a rare diseaseproduct, right, I'm curious if
you can share a little bit moreabout some of the?
(25:49):
You know new skills you've hadto develop, right, you've been
able to carry a lot of the workyou've done as a leader.
You know new skills you've hadto develop, right, you've been
able to carry a lot of the workyou've done as a leader.
You know into the work you'redoing at Alltrna, but in what
ways has working with tRNA youknow, kind of differed, you know
, and what new skills have youhad to develop in order to best?
Michelle Werner (26:08):
Yeah, I mean, first of all, I will say that
it's been a really, really,really long time.
I mean I did some basic scienceresearch at the very, my very
first job outside, like once Igraduated with my university
degree.
But I mean to go back to basicsreally like to really
understand the cell models andcell cultures and you know what
(26:31):
is a Western blot and you knowlike all kinds of things that
honestly, I just really not hadto think about in the last 20
years.
So a lot of it was really kindof getting back to what actually
happens in the lab and what arewe really trying to achieve and
and and really I'm going to saybrushing some of that off but
then developing a completely newvocabulary there that I
(26:54):
probably didn't have even, youknow, given my time there.
So that was definitelysomething new for me.
But then also, you know what Iwould say is I spend a lot of
time in my current jobinteracting with patient
advocacy groups.
Now, I did a little bit of thatin my previous life or my
previous professional life, butnot so much actually.
(27:16):
I've done a lot of it as apatient caregiver, right, so
I've had that experience, but Ireally haven't had the
experience of really developingthose relationships and those
connections and really you knowusing those interactions with
across a number of differentpatient advocacy groups because,
(27:38):
as you can imagine, with thetechnology that can go across
many different diseases, I speakto many different patient
advocacy groups or who arealmost exclusively organized by
disease and you know to reallylike learn how to like be a deep
, deep, deep listener tounderstand their point of view
(27:59):
on, you know, differentendpoints that are really
important and relevant to them,different ways of designing a
study, even just like pickingtheir brains about, you know,
like are patients getting testedfor different mutations?
Where are they actually gettingseen?
Like, really like asking a tonof questions of them.
(28:19):
I haven't had to have thatlevel of engagement with patient
advocacy groups, probably everin my lifetime, and so that was
definitely something that wasnew for me, but I will say,
fortunately, something that camepretty naturally.
I'd say probably, because I wason the other side of the table
and have been for the past fewyears since my son's diagnosis,
(28:43):
not only as a member of one ofthese rare disease communities,
but actually my family startedour own nonprofit after he was
diagnosed.
So I've had some of that youknow experience as well.
So but those are things likefor me, like really we've taken
very seriously, really tried todo as much of that as humanly
(29:04):
possible, even for an earlystage company like us, where
we're not even in the clinic yet, but really being able to bring
different stakeholders along onthis journey with us.
Because one thing that I'vereally learned a lot in the rare
disease setting is there's noone person or no one company or
no one team that has all theanswers to addressing these
(29:29):
complex medical situations.
A lot of it has to come throughreally a partnership
perspective leveraging theknowledge base that exists,
working together to try to fillthe gaps on where those you know
the knowledge gaps currentlyare, and then coming with a
unified approach on how we'regoing to tackle data generation
(29:52):
or interactions with regulatorsand things like that, which has
all been, you know, I'd say,mostly pretty new for me.
Anna Rose Welch (30:01):
Yeah, I would say so.
Do you have like any helpfulpractical best practices for
other early stage companies likeyours, right that?
Are you know, from the top downright embracing that
patient-first mindset?
Do you you know what would youencourage other CEOs in your
position right working in thisrare disease space?
(30:22):
How can they continue to get toknow their patient advocacy
communities?
Michelle Werner (30:27):
Yeah, I mean.
So to me, I would say, firstand foremost, it's start early,
right.
I'd say.
Oftentimes people don't engageuntil you are right at that
stage of having a clinical trialand, quite honestly, I felt
like that was going to be waytoo late.
So, you know, I started when Ifirst joined, you know, three
years ago.
So I probably had my firstengagement with a patient group,
you know, within the first fewmonths of me being in this role.
(30:51):
So I'd say, start early, early,early right, it's never too
early to to engage with apatient advocacy group.
However, right at the same timeand I say this also now as a, as
a parent it's also reallyimportant to not try to oversell
something and to be verypragmatic about what the
(31:13):
expectations are, because thelast thing you want to do is to
make a promise that you can'tkeep.
So I think there's a realbalance of like, how do you make
a connection, get the insightsthat you need that are going to
be really important to shape aprogram moving forward, and that
you can start developing arelationship, but also in a way
(31:33):
where you, you know, aren'tsaying that you're going to cure
these diseases, that they'revery focused on.
When you don't we don'tnecessarily have those data yet
to be able to say that.
And so, to be very, very kindof practical about what those
expectations are, kind ofpractical about what those
(31:54):
expectations are, We've seenmany times, you know, companies
come into a disease area andthen, unfortunately, something
happens, whether it's, you know,data driven or funding driven,
and you know those programscan't continue, and it's really
heartbreaking, right as apatient or as a family.
And so I think, really beingsensitive and in tune to that is
something that I think is soimportant, so important.
(32:16):
So, start early, establishthose relationships, build it
over time, but bring people on ajourney with you.
That's also, you know, based onin reality.
Anna Rose Welch (32:28):
That's great advice greater place.
Ben Comer (32:38):
Michelle, can you explain the concept and
implications of reclassifyingpatients with genetic diseases
into a stop codon disease"category?
Michelle Werner (32:43):
Yeah, so right, we call it stop codon disease.
So again, you heard me referencethe 10,000 different you know
different genetic diseases outthere, and that's the equivalent
of hundreds of millions ofpatients around the world would
have one of these types ofgenetic diagnoses.
(33:03):
Now about 10% of all thosegenetic diagnoses are diseases
that stem from a prematuretermination codon or a nonsense
mutation.
As we've been talking about anonsense mutation, and just for
reference, if people areunfamiliar with what a nonsense
mutation is, this is where acode for an amino acid in the
(33:24):
protein translation processunfortunately codes for a stop
instead, and that means thatinstead of translation
continuing from beginning to end, the translation stops where it
has this mutation, and that'stoo early.
So the result then is atruncated or a dysfunctional or
sometimes even an absent protein, and that's what causes disease
(33:46):
.
So about 10% of all of thesegenetic diagnoses come from a
premature termination codon andcollectively we would call that
as a premature termination codonand collectively we would call
that as a patient having stoppedcodon disease.
Now roughly about 30 or 35million people around the world
would have, you know, fall intothe category of having stopped
codon disease.
Now I'd say the idea aboutreclassifying those patients is
(34:13):
really important because what'shappening today, with all the
other technologies and all thedifferent modalities that exist,
like I mentioned, whether it'sgene therapy, gene editing, mrna
, most small molecules, asos,for example all of them are very
specific to a disease or aprotein.
And so when you are one of thesestop codon disease patients and
(34:35):
let's say the stop codondisease is in phenylketonuria,
or the stop codon disease is inmethylmalonic acidemia, these
just happen to be rare geneticliver diseases where we're
focusing first, but it couldalso be stop codon disease in
Duchenne muscular dystrophy.
It could also be stop codondisease in Rett syndrome, for
(34:55):
example.
Right, these, you know, thesestop codons exist across almost
every single disease and rightnow, what patients need to do is
wait for individual treatmentsfor each and every one of those
diseases.
Now, again, coming back to10,000 different diseases,
unfortunately, most of thosediseases will never have an FDA
(35:18):
approved drug as they do today.
Most of them I mean only 5% doso instead of when you treat
patients by stop codon disease.
That means that, instead of apatient needing to wait for an
individual treatment for eachand every disease within that
category, perhaps a singleengineered tRNA may be able to
address patients acrossthousands of different
(35:40):
life-threatening conditions.
That's the real potential ofwhat we're aiming to do at
Alltrna.
Now that sounds easy.
It's not easy, of course, butthat's really the idea behind.
You know the reclassificationof so many different patients
across so many differentdiseases into, let's say, a few
(36:01):
universal diseases that can betreated by addressing those
common mutations that existacross all of them sound very
easy at all to me.
Ben Comer (36:18):
I you know, I know that that Alltrna is is
leveraging AI and machinelearning and I wonder if you
could just discover how thosetools factor into your discovery
and drug development.
I mean, is that how you landedon nonsense mutations for your
kind of initial look?
Michelle Werner (36:31):
It wasn't how we landed on non-sense mutations
, but it definitely has helpedus land on our development
candidate AP003, which is movingforward, and all of the other
kind of best tRNA designs thatwe're advancing.
So let me just share with youabout how we're leveraging that.
So, just taking a step back,how we design tRNAs is by using
(36:57):
two-pronged approach.
First we optimize for thesequence of the roughly 75
nucleotide structureoligonucleotide right that makes
up the tRNA.
That's one way.
And then the second thing thatwe do is actually then optimize
those tRNA structures withdifferent chemical modifications
, essentially decorating thosestructures with different
(37:18):
modifications that we think arereally important to enhance
different properties of the tRNA, such as how well they read
through these nonsense mutationsand what their potency is, for
example, maybe even theirmetabolic stability.
Those are things that can beengineered for.
So the tRNA sort ofcombinatorial space is actually
massive.
So there are more tRNA patternsthan there are atoms in the
(37:41):
universe, right?
That's a lot right.
I don't know exactly what thatnumber is, but it's a lot, and
so, of course, even thebrilliant scientists that we
have at Alltrna cannot wraptheir heads around.
You know one tRNA design versusanother, not to mention trying
to really understand and holdthe knowledge of.
(38:01):
You know more atoms in theuniverse, tRNA designs right
they can't.
Come on, they can't.
I mean, we're really good butnot that good, really good but
not that good.
So you need a machine learningengine that really underpins the
platform that we have atAlltrna, that is really
understanding the design rulesof our tRNAs in ways that are
(38:25):
well beyond any brilliant humanbrain can achieve, and so what
it is helping us to do is reallyto understand in a very
predictive and generative way,that certain tRNA designs are
going to have a certain outcome.
Like you know, they're going tobe more active, they're going
to be more potent.
They, you know, may be able toprotect the tRNA that can create
(38:48):
it to be a more stablestructure.
And then we take all of thesesort of like learnings from the
machine and our scientists thenapply those learnings in a
rational way into our tRNAdesign process.
So I'd say it's a very it's avery sort of comprehensive way
of designing these tRNAs, thatit's not just built on machines,
(39:10):
it's not just built on humanbrains, it's really the
combination of the two.
That's our secret sauce, thatmakes the magic happen.
Anna Rose Welch (39:18):
That's what I've heard.
Right, it's you can't just relyon the technology, you can't
just rely on the human, it's yougot to have both.
And I'm curious you knowthere's AI and machine learning
are obviously huge buzzwordsright in the in the industry
today, and so there's, I'm sure,a lot of different technology
platforms out there right thatyou can pick from and work with.
(39:41):
You know how are you and yourteam kind of deciding what's the
best right fit for your uses,for your for tRNA right To help
you conquer the giant universeof tRNAs?
Michelle Werner (39:57):
Yeah, I mean, I'd say for us, right, like all
of the like, the machinelearning engine that we're using
is generally data that we'regenerating ourselves.
Right, it's not like we'reaccessing or buying or right.
But the good news is is that,in addition to what we're doing
at Alltrna, of course, there's agazillion things happening in
(40:18):
the environment around us, andone of the beautiful things
about being in the flagshippioneering ecosystem is that
there are capabilities withinflagship pioneering that we
don't necessarily need to beexperts in at Alltrna, but we
can tap into.
So, for example, when it comesto AI and and ML, there's a
group within flagship that'scalled pioneering intelligence,
(40:40):
and this is like what they do,right?
This is their bread and butter,so, and they know about Alltrna
, of course.
So the great thing about thatis, like, with all of the work
and the explorations thatthey're doing, if they see that
there's, you know, a tool or anasset or a fit for our platform,
you know it would come to ourattention.
Some like one way or another,without us necessarily trying to
(41:02):
stay on top of all of thatadvancement that's happening in
the field.
So that's one of the beautifulthings about the ecosystem, for
sure.
Anna Rose Welch (41:11):
I was going to say, do you have to do a lot of
other types of investments aswell?
Obviously there's.
There's this help right throughthis ecosystem, but have you
had to hire different types ofpersonnel or purchase different
types of technologies, establishnew internal departments, Like,
what kind of investments havebeen really required to to help
build these, these capabilitiesand this know-how internally?
Michelle Werner (41:32):
Yeah, I mean I would say you know computational
biology and computationalchemistry are definitely
capabilities that we've broughtin-house and are developing
in-house.
So that absolutely is veryconsistent with you know us to
be able to continue to leveragethe machine learning well, to
make the machine learning evenbetter than it is today, but
(41:53):
then also to make sure thatwe're leveraging it in the best
ways possible.
And it's actually brilliant tosee how these groups come
together with.
You know our biology teams andour chemistry teams and you know
the computational teamstogether in the tRNA design
process.
It's super cool actually.
So all those differentcompetencies have a seat at the
(42:14):
table.
Ben Comer (42:16):
Let's talk for a minute about Alltrna's progress
so far.
Your lead candidate uses alipid nanoparticle for delivery
to the liver and you'recurrently, I think, doing
IND-enabling studies.
What can you say about thereasons behind choosing lipid
nanoparticles as the initialdelivery mechanism?
As the initial deliverymechanism?
Michelle Werner (42:38):
Yeah.
So I would say, Ben, honestly,this was a pure strategic choice
, right?
You know, whenever you have anew technology, you have to make
a lot of decisions, especiallyin early stage.
And because we are very focusedon, you know, as I mentioned,
you know, a couple of years agoit was translation from cell to
animal.
Now it's about translation fromanimal to humans, and so we're
(43:01):
planning for an entry intoclinic.
So for us, it was a realstrategic choice to use an LNP,
a lipid nanoparticle, and thatwas because LNPs now, as you
know, have been in millions ofpeople around the world because
of them having been used in theCOVID mRNA vaccines.
So, and not to mention othertherapeutics as well, it's used
(43:23):
in.
So it's a delivery technologythat, I will say, is very well
characterized, very wellunderstood, certainly
commercially available.
So it's accessible for anemerging company like Alltrna.
And so for us, we really wantedto try to mitigate or minimize
delivery risk as much aspossible, and every
(43:44):
oligonucleotide needs to thinkabout delivery, not just the
payload.
So we wanted to say, okay, howdo we take care of delivery risk
and mitigate as much aspossible so we can focus on the
tRNA, knowing that a tRNA hasnever been in humans before and
this is, you know, going to beone of the you know, maybe the
(44:06):
first time it's ever been inhumans.
And so to really focus on whatthe tRNA payload can do, its
safety profile, its efficacyprofile, knowing that a lipid
nanoparticle is very effectiveat getting to the hepatocytes,
which is the cells that we needto target for our initial basket
of diseases that we're aimingto enter into, it was a
strategic choice, so it wasabout not having two novel
(44:29):
technologies at the same time,but really focusing on one novel
technology with one de-riskedtechnology, and that seemed to
be like the best strategy sothat we can get that clinical
proof of concept, which is goingto be critical for us to unlock
the potential of our platformmuch more broadly, have you
started to think about amanufacturing scale up?
Ben Comer (44:53):
I mean, I assume that you're probably manufacturing
enough for these early stagedefinitely preclinical, but
early stage clinical trials.
Well, I guess my question iswill you manufacture that
internally?
Are there partners availablefor a brand new modality like
this that you know that can helpyou scale up eventually?
(45:14):
What's your?
What's your approach?
Michelle Werner (45:16):
So the answer is yes and yes right.
I mean we are planning topartner, right, and so actually
we do have a couple of CDMOsthat have been onboarded.
We spend a lot of time as acompany talking about the
scaling up of drug substance anddrug product and you know all
of that is underway in order tomake sure that we have the
(45:38):
materials that we need forGLP-TOX and our initial phase
one clinical trials.
So, yes, that is moving forwardas planned.
We do have the possibility ofmanufacturing these ourselves,
right.
So even in the small labs thatwe have at Alltrna, we can do
small batch sizes of our tRNAsand actually formulate them
(45:58):
in-house, our of our tRNAs, andactually formulate them in-house
.
And that work is actuallyreally critical to make sure
that we understand, you know,the methods that are really
required from a manufacturingperspective.
So, as we are partnering withour CDMOs, that we can work with
them on you know those methods,those you know that technology
that scale up all of thosethings purification, et cetera,
(46:18):
et cetera, that scale up all ofthose things purification, et
cetera, et cetera.
That is a critical component ofthe scaling for clinical
readiness.
We have to be experts on it sothat we can be best partners
with our partners to help themas we move forward.
So, yeah, so we do some of themanufacturing ourselves, but
(46:39):
really the CDMOs are going to domost of it for us.
And what I would say is the goodnews is is that, yes, these
partners do exist.
So, even though a tRNAtechnology is very, very new,
the good news is is that siRNAshave been around for a decade.
Mrnas now have been around foryou know, about a decade.
(47:00):
Been around for a decade.
Mrnas now have been around foryou know, about a decade, and a
lot of those manufacturingcompetencies for those types of
RNAs have been reallyinstrumental for the sort of
readiness of tRNA manufacturing.
So I always say that we standon the shoulders of giants,
right, companies like Alnylam,companies like Moderna, who have
(47:21):
come before us and have reallypaved the way.
Yes, of course we have to dothings that are specific for
tRNAs, but we're not startingfrom ground zero, right?
We're really able to have anaccelerated pace from a
manufacturing perspectivebecause of all the hard work
that's been done from othercompanies ahead of us.
Ben Comer (47:39):
Have those companies similarly paved the way, would
you say, with regulators?
And I'm curious, you know, ifyou how much you could share
about any kind of preliminarydiscussions that you've had with
FDA, for example?
Anna Rose Welch (47:54):
So I would say yes and no to this question.
Cmc is a tricky one.
Michelle Werner (47:59):
Yeah, it definitely is a tricky one,
right.
Yeah, cnc is a tricky one.
Yeah, it definitely is a trickyone, right.
So now, when it comes to thebasket trial strategy, right,
those other technologies, as wealready talked about, cannot
leverage that Right, so they'renot doing the heavy lifting on.
You know what the preclinicaldata package needs to be to
support a basket trial strategy,especially getting into,
hopefully, pediatric patientpopulations, which is where the
(48:20):
bulk of these patients are.
So that's work that, I'd say,bespokely, we're figuring out
Now, granted, we're also takingcues from the oncology space, so
trying to leverage as much aspossible there.
But then also in certain rarediseases there have been basket
trials before.
Let's say, for example, the ureacycle disorders, where, you
(48:43):
know, other types oftechnologies have been able to
be used across a number of thosedifferent diseases, and so
there is precedence, I'd sayalready in the rare disease
space have helped before isreally, you know, thinking
through clinical trial design inrare diseases, for example, and
(49:07):
not just them but othercompanies as well, even big
companies like Sanofi or Alexionor you know other companies
like that, who have had, youknow, historical roots in the
rare genetic disease space.
They've sort of already workedwith regulators to understand
okay, maybe you don't havevalidated biomarkers from the
outset, but maybe you validatethose biomarkers as part of a
clinical trial.
How do you, you know, thinkabout different clinical
(49:29):
endpoints for some of thesediseases or in any of these
diseases and sort of you know,thinking through what you're
going to measure as part ofthose designs?
So I would say, absolutelythere is some progress that we
can latch on to, but otherthings that we definitely need
to tackle that are specific tothe work that we're doing in
Alltrna.
Ben Comer (49:50):
Do you get a sense that?
I mean, do you have a kind of Idon't know, I'll let you
describe it.
What kind of relationship doyou have with FDA?
Have you had thoseconversations?
Are they open and excited, asyou are, about this new modality
coming forward?
Michelle Werner (50:06):
Yeah, so I would say those engagements are
beginning.
But what's actually super coolis, even, if you just like,
listen closely to the way thathealth authorities and not just
the FDA, but the MHRA, ema, forexample the narrative that's
coming from the healthauthorities themselves is
(50:26):
actually very, you know, laysthe foundation for this basket
trial strategy and this reallymany diseases at a time strategy
.
That's how they describe it.
Right, they understand thesheer problem of so many rare
and ultra rare diseases.
They know it.
They know that they seeclinical trials for a handful of
those diseases and they neversee a clinical trial for most of
(50:47):
them.
So they're even talking aboutwhat is the approach that can be
taken.
That's a many diseases at atime strategy that could be
beneficial for patients in amuch different way than we've
been able to do before.
So so that's like what'shappening in the back background
with the regulators, which youknow.
So then, hearing about a tRNAthat may be able to address so
(51:11):
many different diseases andmight be able to do so in a much
faster and more efficient way,yeah, of course there are
questions, because there's.
It's a brand new modality.
No one knows how a tRNA isgoing to behave in humans, and
so, yes, there's a lot ofcuriosity and, you know,
discussion that is related tothat, but the whole concept of
(51:31):
like taking a single drug andusing across many different
diseases is exactly what they'vebeen almost asking the industry
to figure out a way to makehappen.
And so now it is that we'recoming with a potential solution
to that problem, and you knowso, yeah, so I'd say that I'm
feeling good about like us beingable to achieve it, but, of
(51:52):
course, everything will have tobe done in partnership with
regulators, but I do think thatthe there's reason to be
optimistic here.
Anna Rose Welch (52:00):
I'm getting this like image of tRNA as a
really like kick-ass superherolike in a comic book series for
some reason, I don't know, Ilove that.
Anna Rose, I love it.
Ben Comer (52:09):
Thousands of enemies at once.
Anna Rose Welch (52:13):
Do you need any materials for patient advocacy?
Michelle Werner (52:17):
Absolutely.
I'm going to call you on thatone.
Anna Rose Welch (52:18):
We're going to work on it, please do.
I'm excited I've got some ideas, all right.
Ben Comer (52:23):
Michelle, I noticed on your LinkedIn profile that
you are a member of Chief, anorganization that supports
senior women executives.
Can you tell us a little bitabout that organization and and
what you've gotten out of thatmembership?
Michelle Werner (52:38):
Yeah.
So I had the opportunity to joinChief I'm going to say around
four years ago now or so, maybefive.
I have found it to be a greatresource of other executive
women leaders who are oftentimes, I'd say, you know tackling,
you know certain professionalchallenges or thinking about a
(53:00):
you know tackling, you knowcertain professional challenges
or thinking about a.
You know making a change intheir career.
And one of the best things,that when you first join chief,
you're assigned to a group ofaround I'm going to say, six or
seven other female executiveswho somehow are all connected to
each other, although you don'tknow how, when you're first
(53:22):
assigned to that group and youbasically just become a resource
for each other, almost like asupport group for each other.
So you get really real in theseconversations.
The first experience I had wasfacilitated by a moderator who
helped engage a conversationacross all of us, and then you
(53:43):
start really building theserelationships yourselves and
become a support system for eachother, even independent of the
moderator, actually sometimeseven independent of Chief, and
but I have found it to be supergreat.
I loved, you know, when I firstjoined Chief.
It was when I was making thistransition from big pharma to
biotech.
(54:03):
So I and my son's diagnosis wasactually super fresh also.
So a lot of what I got out ofChief was how to navigate this
transition and to sort of couplethat with this kind of personal
crisis that my family was goingthrough, and I found it to be
an incredible resource and whatI actually learned is, even
(54:24):
though my story seems veryunique and perhaps probably
doesn't happen to most people intheir lives, actually all these
women go through stuff that isdifferent, but equally as sort
of impactful or equally aschallenging, right, just in a
different way, and the strugglesthat I have might be helpful
(54:46):
for somebody else to kind ofunderstand how to navigate the
struggles that they have andvice versa, and I have loved
being part of a group of womenlike that.
Ben Comer (54:58):
For our female biotech leaders and aspiring
leaders out there.
I'm curious is Chief aninvitation only organization?
Can anyone join after you reacha certain level?
Do you have a sense of that?
Michelle Werner (55:12):
I know that I had to be nominated.
I'm not sure if that's changedin the last few years.
So, yeah, somebody had tonominate me and then I had to be
vetted and accepted.
I think they are trying to makesure that you know the, the,
the seniority, the level ofseniority is at a stage where it
can be relatable amongst themembers, and so I think that's
(55:35):
something that they'redefinitely looking for.
But I think if you want to be amember, there are ways to
become a member.
Anna Rose Welch (55:41):
You're going to become a member, Ben.
Ben Comer (55:44):
I don't think I'd be eligible but Anna Rose.
I would nominate you.
Anna Rose Welch (55:47):
Hey, hey, you should join.
It's great, you'd love it.
Hey, I've followed Chief for awhile.
I've been kind of entranced bytheir business model.
It's really awesome.
I'm curious, you know, as we'rekind of approaching here, you
know we're in a new year, I'mjust curious how you're
(56:08):
envisioning this upcoming yearprogressing for Alltrna, right,
what are some of the biggestchallenges you think you're
going to be tackling for thecompany moving forward, as well
as maybe some of the challengesas a leader you're going to be
taking to chief for some help,right?
Yeah, your network.
Michelle Werner (56:23):
Well, it's, it's true, right.
So what I would say is I mean,first and foremost, we're at a
pivotal stage as a company,right, we have our development
candidates in the IND enablingphase.
So of course that means thatwe're going to be, you know,
making that transition from apure research stage company to a
research and development almostequally weighted kind of
(56:44):
company.
And that's a big thing for anorganization, especially when
you're a group of you know,essentially basic scientists
that have been working on theplatform for the last few years
to really sort of wrap our headaround, well, what happens when
you know you get to the clinic.
So building that clinicalcapability is, is, is one of the
(57:04):
things that we're working onright now.
So that's like for us as acompany.
But then, yeah, of coursethere's a lot of things
happening in the macroenvironment, micro environment
and, and, and certainly what Iwould say about that is you know
we're tackling diseases thathave incredible unmet medical
need.
You know we are everything thatwe do is going to transcend,
(57:30):
you know, all of those differentchallenges that are happening
in the macro environment,because guess what?
Patients are still going to getdiagnosed with these conditions
and, unless we do somethingabout it.
Patients are still going to diewith these conditions.
So we got to focus on whatwe're doing.
We've got to make sure that wehave the capital in order to
enable that to be possible, andthen we really need to bring
this technology forward.
So those are the things that Iwould say is just trying to
(57:52):
focus on the things that can becontrolled right now and to, you
know, focus on the needs of thepeople that we're aiming to
serve, and that's what I wake upevery single day looking to do.
Anna Rose Welch (58:02):
Keep making medicines.
Yeah, that's right.
Ben Comer (58:05):
That is Michelle Werner, CEO at Alltrna.
I'm Ben Comer.
Anna Rose Welch (58:10):
And I'm Anna Rose Welch.
Ben Comer (58:11):
And you've just listened to the Business of
Biotech.
Find us and subscribe anywhereyou listen to podcasts and be
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Welcome back to the Business ofBiotech.
(00:45):
I'm Ben Comer.
Anna Rose Welch (00:47):
And I'm Anna Rose Welch.
Ben Comer (00:48):
And we're both excited to speak today with
Michelle Werner, CEO of Alltrna.
Michelle has worked at some ofthe biggest biopharmaceutical
companies in the world,including Novartis, AstraZeneca
and Bristol-Myers Squibb, buthas now moved into company
leadership at a relatively newtransfer RNA or tRNA
(01:09):
oligonucleotide therapydeveloper, Alltrna, backed by
Flagship Pioneering.
I want to thank Anna Rose,editorial and community director
at Advancing RNA, for bringingMichelle to the Business of
Biotech and for joining us onthe podcast.
Anna Rose Welch (01:25):
On today's show , we're going to get to know
Michelle and find out why shewanted to take a chance with a
tRNA startup, as well as whatmakes tRNA therapies unique and
promising.
We'll also learn about the manychallenges that come along with
working in a new therapeuticspace in terms of attracting
investors, designing trials,manufacturing therapies and
working with patients andregulators.
Ben Comer (01:48):
Michelle, welcome to the show.
Michelle Werner (01:50):
Thank you so much for having me.
I'm really excited to be here.
Anna Rose Welch (01:53):
We're excited to have you.
Ben Comer (01:55):
Yes, we are.
As we alluded to in the intro,you've spent a majority of your
career at Big Pharma, working incommercial functions and as a
country head and franchise head,both in the US and globally.
How did you get connected inwith Flagship Pioneering
initially?
Michelle Werner (02:15):
So I mean, in some cases it was a little bit
of luck, I guess I would saythat I got to a stage in my
career where I was looking to dosomething a little bit
different than I had done withthe previous 20 years in my
career.
So, as you've mentioned, ben,I've been in big pharma for much
of my career 20-ish years.
(02:37):
Most of that has been focusedin the oncology space and I will
say that I had a reallyphenomenal career in big pharma.
I had a you know have reallygreat experiences and memories
of my time at those companiesthat you've referenced and I
found this space to be extremelyrewarding, especially in
(02:58):
oncology, of course, wherethere's huge unmet medical need.
I got into this drugdevelopment business in the
first place because of me havingworked in a cancer clinic, so I
really was working hand in handwith patients and really
understanding what their needsare and what they go through,
and for 20 years that was areally phenomenal place to be
(03:18):
and during that time I got tosee the emergence of some novel
therapies come through.
When I first started it waschemotherapy and maybe chemo
doublets were emerging, but youknow, during my time I saw the
emergence of targeted therapies,I saw the emergence of
immunotherapies, immunotherapycombinations, and that really
(03:41):
changed the overall trajectoryfor patients with a lot of these
different cancers and was areally phenomenal place to spend
much of my career.
But, as happens sometimes inlife, right, different
curveballs get thrown your way,and one such curveball was a
very personal circumstance andit was actually in May of 2020.
(04:03):
So, just about five years agonow, one of my three children
was diagnosed with a raregenetic disease and, in fact, he
was diagnosed with Duchennemuscular dystrophy specifically,
and it happened to be on his10th birthday.
And as a drug developer, right,the first thing that I think of
is okay, well, I know a littlebit about medicine and how to
(04:25):
treat disease and, you know, letme wrap my head around
everything that there is to knowabout treating Duchenne and I
realized that the standard ofcare was, you know, not really
great, with basically high dosesteroids essentially as the
mainstay of treatment, which youknow may be beneficial but also
comes with a lot of sideeffects.
And then so I was treatment,which you know may be beneficial
but also comes with a lot ofside effects.
(04:46):
And then so I was like, well,that standard of care isn't good
enough.
So what else is out there?
And I did what a lot of drugdevelopers would do, and that
would be go to clinicaltrialsgovand see what innovations were
in the works.
And even perusing the few pagesof Duchenne trials on
clintrialsgov, I realized therewas not a single one that my son
(05:09):
was eligible for not a singleone.
And that was heartbreaking,really, really heartbreaking.
And so, basically, you know my,it really cast this spotlight on
the inadequacies right oftreating rare diseases or the
innovations that are availablefor rare diseases versus more
common diseases like cancers.
(05:30):
And I was, you know, I realizedthat it was an appalling
situation and I felt like, aftersome deep reflection of not
just our personal circumstanceshaving changed but my own
professional circumstances, itmade me realize that, okay, in
20 years in oncology we've madea lot of difference maybe not a
(05:52):
self problem, but a lot ofdifference.
I want to spend the next 20years and focus on genetic
diseases, rare genetic diseasesin particular, because I really
personally felt the sheer unmetmedical need and what it was
like to actually feel like youwere a patient that was
completely overlooked by theindustry that I love being in
(06:16):
and that I had been in for thelast couple of decades.
So that was really the sort ofbackdrop to what was happening
at the time, and so to me I wasthinking, okay, maybe big pharma
isn't where I want to be, maybeI need to be in a nimble,
dynamic biotech environment.
But then, honestly, it wasreally when I was first told
(06:38):
about Alltrna specifically thatit made me really realize the
sheer potential of our platformwith our engineered tRNAs,
because the whole idea behindwhat we're doing is one single
engineered tRNA may be used toaddress hundreds, if not
thousands, of different diseases, and as a rare disease parent,
(07:01):
I know that there are somewherearound 10,000 of these.
You know rare genetic diseasesand with today's technology,
even the novel ones like genetherapy, gene editing, mrna all
are taking a one disease at atime strategy, because that's
how those modalities work.
But if you can turn thatparadigm on its head and find a
(07:22):
way to use a single medicine toaddress hundreds of them, you
could clearly appreciate thetransformative potential that
that kind of technology might beable to have on this patient
population, whereby most ofthose diseases do not have an
approved therapy In fact, 95% ofthem do not.
(07:43):
So that's really why I came toAlltrna.
It was also great that it was aflagship, pioneering company.
To be honest with you, that wasan added bonus Because, as a
first time CEO, being part of anecosystem of companies and an
ecosystem of expertise was veryattractive to me.
Ben Comer (08:04):
Yeah, and so it makes sense why you wanted to take
this big swing into geneticmedicines, and I think that you
know the concept of a singlemechanism being able to
potentially solve a whole lot ofdiseases is very exciting.
But, like you said, you're afirst time CEO and I'm curious
now you know you're three yearsinto the job, is it different,
(08:28):
you know, than you expected itto be, kind of on a day to day
level, and how did you preparefor it?
Michelle Werner (08:34):
So, to be honest with you, Ben, I'm not
sure I had this like verypreconceived idea about what
being a biotech CEO would be.
Like my only frame of referencereally were the CEOs of the
various big pharma companiesthat I worked for, I worked at
in my career and I knew it wasgoing to be different than that,
but I didn't really know whatto expect.
(08:55):
I will say that there wasdefinitely a period of time
where, you know, I was reallyexcited about the role and the
opportunity, but I also didn'tknow, like, am I really equipped
to do this job?
Am I ready to be a CEO?
And part of that was, you know,do I have the skills that are
(09:16):
and the capabilities that areneeded to lead a startup
organization number one, a teamof employees who are essentially
all basic science, likescientists, basic scientists
like I've.
I've mostly led, you know, bigteams, but big teams of
commercial people in my career.
(09:38):
So this was a fundamentallydifferent thing.
I'm more of a commercial person.
Do I?
Am I really going to berelatable to the scientists and
to really understand whatthey're doing and for them to
understand me and where?
You know, my vision is?
And so there was definitely aquestion mark about that.
And then there was also, youknow, as with any CEO in a
(09:59):
startup environment, especiallya private company, it's a lot of
focus on fundraising, of course, and it's not something I've
ever done before, right.
So I've had some investorinteractions in my previous
executive roles in pharma, butnot a lot and not where I'd have
, like, the sole responsibilityreally of, you know, making sure
that we can, you know, have acapital formation strategy
(10:23):
that's successful.
So I'd say there were someuncertainties coming into this
role, but there are a few thingsthat I learned and kind of
getting to how I prepared, whichI think you know, honestly,
looking back now, the 20 yearsthat I've been in the industry
actually was the preparationthat I needed for this job.
So, even though I've never hadthe responsibility of raising
(10:45):
capital for a company in thepast, what I did do a lot of in
those different companies is putbusiness cases together to
create a compelling story abouta strategy that we want to
invest in as a company and tosecure the resources within
those companies in order to beable to put behind those ideas.
(11:06):
It's essentially the samecompetency, I'd say, when you're
gearing up for, let's say, aSeries B, as we had to soon
after I joined Alltrna.
So I'd say a lot of that sortof skill was transferable, which
I didn't know at the time, butcertainly was the case.
And then I would just say, morebroadly, around the leadership
(11:29):
skill, I mean, of course Alltrnais a much smaller company than
most of the teams that I've ledbefore in the past and again a
very different phenotype ofemployees than I've led before
in the past.
But there are a lot of thingsfrom a leadership perspective
that are transferable from onegig to the next, from one
employee base to another.
And actually really just tryingto paint a picture for what it
(11:54):
is that we're doing and whatwe're trying to achieve with the
really cool science that we'redeveloping at Alltrna is
something that I feel like I'vehad to do in any number of my
leadership roles in the past.
Paint that picture for a vision.
You know how to make strategicchoices that are going to help
enable that vision to bematerialized.
(12:17):
And I'd say, in particular withthis team and with this company
, the fact that I'm actually arare disease parent as well
resonates with the company andyou know there's not a day that
goes by that I think theAlltrnators, as we call
ourselves, don't love thenicknames.
Anna Rose Welch (12:38):
Yeah, it's great.
Michelle Werner (12:41):
That we don't, that we I mean every single day.
I think we appreciate thatwe're doing cool science, but
we're doing science with apurpose and that purpose is to
really transform the care forpatients across a number of
different rare diseases, and Ithink my personal connection to
this community is uniquelysuited to to help bring that to
life.
Anna Rose Welch (13:02):
You are I mean you.
You expressed really nicely whytRNA right, like why that
molecule itself spoke to you andsort of through your journey
into leadership of a smallbiotech company working with a
tRNA product.
I'm really curious.
You know, outside of themechanism of action of it, what
(13:24):
was the most exciting reason foryou right to sort of jump into
this really novel scientificspace and how had you, or how
have you right continued tolearn more about that scientific
element of this brand newscience, right?
How can you share a little bitmore as well about, about how
you've prepared your leadershipto sort of fit into this more
(13:49):
scientific niche Right and in anew biotech?
Michelle Werner (13:52):
Yeah, so I mean , maybe just you know the like,
the coolest thing I think aboutthe tRNA, like, as I said, is
the ability to transcenddifferent diseases, and when I
was first considering this roleand I met with some of the
founding scientific team, youknow some of the initial like
preclinical data sets that theyshowed me, which showed that a
(14:13):
single engineered tRNA was ableto restore protein across, you
know, almost 25 differentdisease models in cell models
and, and that it was able to dothat regardless of which gene
was affected, which protein wasbeing coded for, and actually
(14:33):
the location of the mutationalso did not matter.
It was able to restore proteinor read through these mutations
in each one of those settings ina very universal way, which is
not something I've ever seenachieved with really any other
modality that at least I wasfamiliar with, and so I found
that to be like, truly, you know, like I said, could be very
(14:56):
transformative, Because thatreally said to me like, even if
I just take Duchenne, forexample, which is a disease I
know very well because that'sthe one that my son happens to
have In Duchenne, now there's agene therapy that can be used
across, you know, all patienttypes, or most patient types,
not all but most.
But before that there wereactually exon skipping
(15:17):
technologies, which meant thatyou had to have a mutation in a
certain place that would beamenable for those types of
technologies.
And guess what?
My kid did not have thatmutation.
So there were many approachesthat just were not possible for
my own son and gene therapy isthe same way, by the way, it's
(15:37):
not depending on the mutationlocation or depending on
baseline antibodies or a lot ofother different reasons right,
May not be an appropriatetherapy.
So having a drug that might, orhaving a modality that might be
able to transcend some of thosenuances, I thought would be like
truly, truly interesting.
And so that to me was like I'mhooked.
I was really hooked on thatgeneral idea from the outset.
(16:01):
And then, how did I reallyprepare?
I mean, I will tell you, youknow other than my biology 101,
you know class right back fromcollege books.
Yeah, I mean I don't think Iever said tRNA in my lifetime, I
mean.
So there was a lot that I reallyhad to learn.
So the thing to me was the bigpicture idea I got, and then to
(16:25):
me it was really about likedigging into the science and
understanding the science.
And and that's where I would sayis, you know, I got really
invested in it, and so I feltlike the basic thing that I
really needed to do was reallyjust listen actively, listen to
all the incredible scientiststhat we have here at Alltrna to
(16:47):
really understand.
This is the opportunity, theseare the challenges, this is how
we think we need to translatethis modality, or translate the
science, into a new therapeuticmodality for patients.
And it was really a lot oflistening and learning and that,
to me, I'd say, was, I mean,that's where I spent most of my
(17:07):
time in the first few months,listening and learning, asking a
ton of questions and reallygetting up to speed.
And then, once I sort of gotthe basic fundamentals of the
tRNA biology that sort of kindof, I'd say, positioned with the
(17:28):
drug development experiencethat I acquired in my, you know,
couple of decades of being inthe business, I was able to
start making some connectionsbetween the biology and you know
, ultimately, at the end of theday, what we're trying to do for
patients.
Anna Rose Welch (17:42):
There are a lot of connections right between
all the different modalitiesthat you can definitely make.
Ben Comer (17:47):
I want to.
Oh sorry, anna Rose, I cut youoff there.
No, I just I wanted to pick up.
I'm curious about theinvestment piece and you've
talked about some of thoseskills being transferable from
previous work you've done in bigpharma.
But I have to imagine that whenit's a brand new modality,
never been a drug approved therehas to be.
(18:08):
Well, correct me if I'm wrong.
There must be some bit ofeducation that you have to do
with investors and I'm just sortof curious about this.
The story obviously is soimportant for an investor and I
just wonder, you know if youmight share kind of how that
experience has gone.
Have you had to explain notonly how the mechanism works but
(18:29):
kind of make it real forinvestors and say this is why we
think this is possible?
Michelle Werner (18:34):
A hundred percent Right.
So that's exactly how we'vereally teed things up for
investors.
I mean, honestly, I alwaysreally start a lot of these
conversations with you know,let's just talk about the unmet
need, right.
The numbers of diseases thereare 95% don't have an approved
therapy.
We're trying to tackle it oneby one, kind of just like the
conversation we've just had alittle bit, to really sort of
(18:56):
like appreciate the sort of whatseems like an insurmountable
challenge that we have in theworld of genetic diseases.
That's basically where I start.
And then, yes, just like Ineeded a foundational
understanding of what is a tRNA,what's its function and why do
we think it has this kind ofuniversal ability.
(19:18):
We then talk about the specifictypes of mutations that we're
tackling in the first instance.
So we think a tRNA can addressa number of different types of
mutations, but we have to startsomewhere and we are starting
with nonsense mutations.
So with a tRNA we're takingthis approach of identifying
those common nonsense mutationsacross a number of different
(19:40):
diseases and why you know why wesee the same nonsense mutations
from one disease to the nextand why the sort of conserved
biology of a tRNA should be ableto address all of those.
And then it is about, like,giving a reason to believe.
Right, we all need reasons tobelieve, just like I needed a
reason to believe to joinAlltrna.
(20:01):
Investors need a reason tobelieve that you know that this
isn't just a crazy idea, thatthis crazy idea actually might
have legs to it, and that comeswith data.
And so, with our Series B,which we announced raising 109
million in August of 2023, whichyou know, we're really very
proud and excited about, thatwas really based off of mostly I
(20:24):
mean a preclinical data setthat was mostly based on in
vitro data, with one small pieceof in vivo data, our very first
piece of in vivo data.
And now, you know, we've beenable to progress the platform as
such to now have multiple invivo data sets across multiple
different disease models, andnow we're demonstrating that
(20:47):
what we saw in in vitroenvironments across multiple
diseases now is similar in thein vivo or mouse setting, which
is also super exciting.
So, if you see translation fromcell to mouse, the likelihood
of seeing a translation fromanimal to human is much, much
higher.
So that's what we're reallyexcited about.
So yeah, you have to tell thatstory, but then I would say also
(21:10):
, in addition to telling thatstory from the basic kind of
biology, is also how we'replanning to develop our tRNAs,
because this is also a littlebit, you know, I'm going to call
it somewhat unconventional,although it's been used before
in the past.
So certainly some investorswho've been around the block,
especially in the oncology space, would be familiar with this,
(21:32):
because this is what we callbasket trials.
You may be familiar with thembut it's been used very commonly
in oncology.
In fact, I'm going to say sevenor eight different drugs got
approved using a basket trialstrategy.
And what a basket design is isbasically patients have
technically different diseases.
So in oncology it could be lungcancer or breast cancer or, you
(21:55):
know, ovarian or anything youkind of put.
You know, fill in the blank,but each patient is selected by
having a common mutation.
So, again in oncology, it couldbe the EGFR mutation, for
example.
In rare diseases it could be aspecific nonsense mutation.
So patients technically have adifferent disease, but they're
all selected by having that samecommon mutation.
(22:18):
Across those different diseases.
They're given the same drug inthe clinical trial and then
they're monitored right, maybefor the same things, maybe for
different things, and that'swhat we're doing in rare
diseases.
So a common development strategyin oncology is now going to be
applied in rare diseases.
It has before in the past, butto a lesser extent in oncology,
(22:41):
but now we have a modality likea tRNA that actually is uniquely
suited to take advantage of thebasket trial design.
And what's great about that isis that not only in this
clinical trial can you includethe more common of these rare
diseases, you get to alsoinclude the ultra rare diseases
(23:01):
as well, and that, honestly, isreally the most exciting thing,
because those ultra rarediseases will likely have, maybe
never a clinical trial or aninterventional clinical trial in
a patient's lifetime.
That's the reality, which isreally really, you know,
heartbreaking when you thinkabout it.
So I really love this strategybecause of this idea about
(23:24):
bringing all these patientstogether and unlocking not only
what we hope will be aninnovation that will be
beneficial to these patientpopulations where there are
essentially no effectivetreatments, but actually, from
an investor perspective, itreally unlocks a value pool that
is currently completely lockedright now, because there are no
(23:49):
drugs that you know or nocompany that is specifically
going to focus on these ultrarare conditions really mostly
because those individual patientpopulations in and of
themselves are too small If youhave to take one disease at a
time strategy.
Ben Comer (24:10):
So now we all of a sudden you know, and that's how
we sort of paint the picture ofthe opportunity to investors.
So with you will be kind of outof the gate, pursue a basket
trial, multiple disease armsfrom the very beginning.
Or will you do some initialearly stage like safety stuff
before you start?
You know, go into a baskettrial.
Michelle Werner (24:26):
Well, that will definitely be a decision that
we make in in combination withinput from health authorities,
and you know we are workingthrough that right now.
So some of those details arestill remaining to be seen, but
the idea for us is to get into abasket trial as quickly as
possible, right?
So maybe we do need to do asmall first step just to be able
(24:49):
to demonstrate a quick clinicalproof of concept or a quick
safety data set in humans.
You know that matches thepreclinical data package that
we've already developed, but theidea is for us to be able to
get to a basket trial as soon ashumanly possible.
And so, because that's where wethink we have the most
(25:10):
potential to be able to addvalue to the patient-
populations and really todemonstrate what a tRNA can do
across a number of differentdiseases.
Anna Rose Welch (25:28):
Well, I think, as the parent of a patient with
a rare disease, right to thescientists, the people working
within your company, and evenjust some of the work you're
doing now, thinking about thestrategy for delivering and
developing a rare diseaseproduct, right, I'm curious if
you can share a little bit moreabout some of the?
(25:49):
You know new skills you've hadto develop, right, you've been
able to carry a lot of the workyou've done as a leader.
You know new skills you've hadto develop, right, you've been
able to carry a lot of the workyou've done as a leader.
You know into the work you'redoing at Alltrna, but in what
ways has working with tRNA youknow, kind of differed, you know
, and what new skills have youhad to develop in order to best?
Michelle Werner (26:08):
Yeah, I mean, first of all, I will say that
it's been a really, really,really long time.
I mean I did some basic scienceresearch at the very, my very
first job outside, like once Igraduated with my university
degree.
But I mean to go back to basicsreally like to really
understand the cell models andcell cultures and you know what
(26:31):
is a Western blot and you knowlike all kinds of things that
honestly, I just really not hadto think about in the last 20
years.
So a lot of it was really kindof getting back to what actually
happens in the lab and what arewe really trying to achieve and
and and really I'm going to saybrushing some of that off but
then developing a completely newvocabulary there that I
(26:54):
probably didn't have even, youknow, given my time there.
So that was definitelysomething new for me.
But then also, you know what Iwould say is I spend a lot of
time in my current jobinteracting with patient
advocacy groups.
Now, I did a little bit of thatin my previous life or my
previous professional life, butnot so much actually.
(27:16):
I've done a lot of it as apatient caregiver, right, so
I've had that experience, but Ireally haven't had the
experience of really developingthose relationships and those
connections and really you knowusing those interactions with
across a number of differentpatient advocacy groups because,
(27:38):
as you can imagine, with thetechnology that can go across
many different diseases, I speakto many different patient
advocacy groups or who arealmost exclusively organized by
disease and you know to reallylike learn how to like be a deep
, deep, deep listener tounderstand their point of view
(27:59):
on, you know, differentendpoints that are really
important and relevant to them,different ways of designing a
study, even just like pickingtheir brains about, you know,
like are patients getting testedfor different mutations?
Where are they actually gettingseen?
Like, really like asking a tonof questions of them.
(28:19):
I haven't had to have thatlevel of engagement with patient
advocacy groups, probably everin my lifetime, and so that was
definitely something that wasnew for me, but I will say,
fortunately, something that camepretty naturally.
I'd say probably, because I wason the other side of the table
and have been for the past fewyears since my son's diagnosis,
(28:43):
not only as a member of one ofthese rare disease communities,
but actually my family startedour own nonprofit after he was
diagnosed.
So I've had some of that youknow experience as well.
So but those are things likefor me, like really we've taken
very seriously, really tried todo as much of that as humanly
(29:04):
possible, even for an earlystage company like us, where
we're not even in the clinic yet, but really being able to bring
different stakeholders along onthis journey with us.
Because one thing that I'vereally learned a lot in the rare
disease setting is there's noone person or no one company or
no one team that has all theanswers to addressing these
(29:29):
complex medical situations.
A lot of it has to come throughreally a partnership
perspective leveraging theknowledge base that exists,
working together to try to fillthe gaps on where those you know
the knowledge gaps currentlyare, and then coming with a
unified approach on how we'regoing to tackle data generation
(29:52):
or interactions with regulatorsand things like that, which has
all been, you know, I'd say,mostly pretty new for me.
Anna Rose Welch (30:01):
Yeah, I would say so.
Do you have like any helpfulpractical best practices for
other early stage companies likeyours, right that?
Are you know, from the top downright embracing that
patient-first mindset?
Do you you know what would youencourage other CEOs in your
position right working in thisrare disease space?
(30:22):
How can they continue to get toknow their patient advocacy
communities?
Michelle Werner (30:27):
Yeah, I mean.
So to me, I would say, firstand foremost, it's start early,
right.
I'd say.
Oftentimes people don't engageuntil you are right at that
stage of having a clinical trialand, quite honestly, I felt
like that was going to be waytoo late.
So, you know, I started when Ifirst joined, you know, three
years ago.
So I probably had my firstengagement with a patient group,
you know, within the first fewmonths of me being in this role.
(30:51):
So I'd say, start early, early,early right, it's never too
early to to engage with apatient advocacy group.
However, right at the same timeand I say this also now as a, as
a parent it's also reallyimportant to not try to oversell
something and to be verypragmatic about what the
(31:13):
expectations are, because thelast thing you want to do is to
make a promise that you can'tkeep.
So I think there's a realbalance of like, how do you make
a connection, get the insightsthat you need that are going to
be really important to shape aprogram moving forward, and that
you can start developing arelationship, but also in a way
(31:33):
where you, you know, aren'tsaying that you're going to cure
these diseases, that they'revery focused on.
When you don't we don'tnecessarily have those data yet
to be able to say that.
And so, to be very, very kindof practical about what those
expectations are, kind ofpractical about what those
(31:54):
expectations are, We've seenmany times, you know, companies
come into a disease area andthen, unfortunately, something
happens, whether it's, you know,data driven or funding driven,
and you know those programscan't continue, and it's really
heartbreaking, right as apatient or as a family.
And so I think, really beingsensitive and in tune to that is
something that I think is soimportant, so important.
(32:16):
So, start early, establishthose relationships, build it
over time, but bring people on ajourney with you.
That's also, you know, based onin reality.
Anna Rose Welch (32:28):
That's great advice greater place.
Ben Comer (32:38):
Michelle, can you explain the concept and
implications of reclassifyingpatients with genetic diseases
into a stop codon disease"category?
Michelle Werner (32:43):
Yeah, so right, we call it stop codon disease.
So again, you heard me referencethe 10,000 different you know
different genetic diseases outthere, and that's the equivalent
of hundreds of millions ofpatients around the world would
have one of these types ofgenetic diagnoses.
(33:03):
Now about 10% of all thosegenetic diagnoses are diseases
that stem from a prematuretermination codon or a nonsense
mutation.
As we've been talking about anonsense mutation, and just for
reference, if people areunfamiliar with what a nonsense
mutation is, this is where acode for an amino acid in the
(33:24):
protein translation processunfortunately codes for a stop
instead, and that means thatinstead of translation
continuing from beginning to end, the translation stops where it
has this mutation, and that'stoo early.
So the result then is atruncated or a dysfunctional or
sometimes even an absent protein, and that's what causes disease
(33:46):
.
So about 10% of all of thesegenetic diagnoses come from a
premature termination codon andcollectively we would call that
as a premature termination codonand collectively we would call
that as a patient having stoppedcodon disease.
Now roughly about 30 or 35million people around the world
would have, you know, fall intothe category of having stopped
codon disease.
Now I'd say the idea aboutreclassifying those patients is
(34:13):
really important because what'shappening today, with all the
other technologies and all thedifferent modalities that exist,
like I mentioned, whether it'sgene therapy, gene editing, mrna
, most small molecules, asos,for example all of them are very
specific to a disease or aprotein.
And so when you are one of thesestop codon disease patients and
(34:35):
let's say the stop codondisease is in phenylketonuria,
or the stop codon disease is inmethylmalonic acidemia, these
just happen to be rare geneticliver diseases where we're
focusing first, but it couldalso be stop codon disease in
Duchenne muscular dystrophy.
It could also be stop codondisease in Rett syndrome, for
(34:55):
example.
Right, these, you know, thesestop codons exist across almost
every single disease and rightnow, what patients need to do is
wait for individual treatmentsfor each and every one of those
diseases.
Now, again, coming back to10,000 different diseases,
unfortunately, most of thosediseases will never have an FDA
(35:18):
approved drug as they do today.
Most of them I mean only 5% doso instead of when you treat
patients by stop codon disease.
That means that, instead of apatient needing to wait for an
individual treatment for eachand every disease within that
category, perhaps a singleengineered tRNA may be able to
address patients acrossthousands of different
(35:40):
life-threatening conditions.
That's the real potential ofwhat we're aiming to do at
Alltrna.
Now that sounds easy.
It's not easy, of course, butthat's really the idea behind.
You know the reclassificationof so many different patients
across so many differentdiseases into, let's say, a few
(36:01):
universal diseases that can betreated by addressing those
common mutations that existacross all of them sound very
easy at all to me.
Ben Comer (36:18):
I you know, I know that that Alltrna is is
leveraging AI and machinelearning and I wonder if you
could just discover how thosetools factor into your discovery
and drug development.
I mean, is that how you landedon nonsense mutations for your
kind of initial look?
Michelle Werner (36:31):
It wasn't how we landed on non-sense mutations
, but it definitely has helpedus land on our development
candidate AP003, which is movingforward, and all of the other
kind of best tRNA designs thatwe're advancing.
So let me just share with youabout how we're leveraging that.
So, just taking a step back,how we design tRNAs is by using
(36:57):
two-pronged approach.
First we optimize for thesequence of the roughly 75
nucleotide structureoligonucleotide right that makes
up the tRNA.
That's one way.
And then the second thing thatwe do is actually then optimize
those tRNA structures withdifferent chemical modifications
, essentially decorating thosestructures with different
(37:18):
modifications that we think arereally important to enhance
different properties of the tRNA, such as how well they read
through these nonsense mutationsand what their potency is, for
example, maybe even theirmetabolic stability.
Those are things that can beengineered for.
So the tRNA sort ofcombinatorial space is actually
massive.
So there are more tRNA patternsthan there are atoms in the
(37:41):
universe, right?
That's a lot right.
I don't know exactly what thatnumber is, but it's a lot, and
so, of course, even thebrilliant scientists that we
have at Alltrna cannot wraptheir heads around.
You know one tRNA design versusanother, not to mention trying
to really understand and holdthe knowledge of.
(38:01):
You know more atoms in theuniverse, tRNA designs right
they can't.
Come on, they can't.
I mean, we're really good butnot that good, really good but
not that good.
So you need a machine learningengine that really underpins the
platform that we have atAlltrna, that is really
understanding the design rulesof our tRNAs in ways that are
(38:25):
well beyond any brilliant humanbrain can achieve, and so what
it is helping us to do is reallyto understand in a very
predictive and generative way,that certain tRNA designs are
going to have a certain outcome.
Like you know, they're going tobe more active, they're going
to be more potent.
They, you know, may be able toprotect the tRNA that can create
(38:48):
it to be a more stablestructure.
And then we take all of thesesort of like learnings from the
machine and our scientists thenapply those learnings in a
rational way into our tRNAdesign process.
So I'd say it's a very it's avery sort of comprehensive way
of designing these tRNAs, thatit's not just built on machines,
(39:10):
it's not just built on humanbrains, it's really the
combination of the two.
That's our secret sauce, thatmakes the magic happen.
Anna Rose Welch (39:18):
That's what I've heard.
Right, it's you can't just relyon the technology, you can't
just rely on the human, it's yougot to have both.
And I'm curious you knowthere's AI and machine learning
are obviously huge buzzwordsright in the in the industry
today, and so there's, I'm sure,a lot of different technology
platforms out there right thatyou can pick from and work with.
(39:41):
You know how are you and yourteam kind of deciding what's the
best right fit for your uses,for your for tRNA right To help
you conquer the giant universeof tRNAs?
Michelle Werner (39:57):
Yeah, I mean, I'd say for us, right, like all
of the like, the machinelearning engine that we're using
is generally data that we'regenerating ourselves.
Right, it's not like we'reaccessing or buying or right.
But the good news is is that,in addition to what we're doing
at Alltrna, of course, there's agazillion things happening in
(40:18):
the environment around us, andone of the beautiful things
about being in the flagshippioneering ecosystem is that
there are capabilities withinflagship pioneering that we
don't necessarily need to beexperts in at Alltrna, but we
can tap into.
So, for example, when it comesto AI and and ML, there's a
group within flagship that'scalled pioneering intelligence,
(40:40):
and this is like what they do,right?
This is their bread and butter,so, and they know about Alltrna
, of course.
So the great thing about thatis, like, with all of the work
and the explorations thatthey're doing, if they see that
there's, you know, a tool or anasset or a fit for our platform,
you know it would come to ourattention.
Some like one way or another,without us necessarily trying to
(41:02):
stay on top of all of thatadvancement that's happening in
the field.
So that's one of the beautifulthings about the ecosystem, for
sure.
Anna Rose Welch (41:11):
I was going to say, do you have to do a lot of
other types of investments aswell?
Obviously there's.
There's this help right throughthis ecosystem, but have you
had to hire different types ofpersonnel or purchase different
types of technologies, establishnew internal departments, Like,
what kind of investments havebeen really required to to help
build these, these capabilitiesand this know-how internally?
Michelle Werner (41:32):
Yeah, I mean I would say you know computational
biology and computationalchemistry are definitely
capabilities that we've broughtin-house and are developing
in-house.
So that absolutely is veryconsistent with you know us to
be able to continue to leveragethe machine learning well, to
make the machine learning evenbetter than it is today, but
(41:53):
then also to make sure thatwe're leveraging it in the best
ways possible.
And it's actually brilliant tosee how these groups come
together with.
You know our biology teams andour chemistry teams and you know
the computational teamstogether in the tRNA design
process.
It's super cool actually.
So all those differentcompetencies have a seat at the
(42:14):
table.
Ben Comer (42:16):
Let's talk for a minute about Alltrna's progress
so far.
Your lead candidate uses alipid nanoparticle for delivery
to the liver and you'recurrently, I think, doing
IND-enabling studies.
What can you say about thereasons behind choosing lipid
nanoparticles as the initialdelivery mechanism?
As the initial deliverymechanism?
Michelle Werner (42:38):
Yeah.
So I would say, Ben, honestly,this was a pure strategic choice
, right?
You know, whenever you have anew technology, you have to make
a lot of decisions, especiallyin early stage.
And because we are very focusedon, you know, as I mentioned,
you know, a couple of years agoit was translation from cell to
animal.
Now it's about translation fromanimal to humans, and so we're
(43:01):
planning for an entry intoclinic.
So for us, it was a realstrategic choice to use an LNP,
a lipid nanoparticle, and thatwas because LNPs now, as you
know, have been in millions ofpeople around the world because
of them having been used in theCOVID mRNA vaccines.
So, and not to mention othertherapeutics as well, it's used
(43:23):
in.
So it's a delivery technologythat, I will say, is very well
characterized, very wellunderstood, certainly
commercially available.
So it's accessible for anemerging company like Alltrna.
And so for us, we really wantedto try to mitigate or minimize
delivery risk as much aspossible, and every
(43:44):
oligonucleotide needs to thinkabout delivery, not just the
payload.
So we wanted to say, okay, howdo we take care of delivery risk
and mitigate as much aspossible so we can focus on the
tRNA, knowing that a tRNA hasnever been in humans before and
this is, you know, going to beone of the you know, maybe the
(44:06):
first time it's ever been inhumans.
And so to really focus on whatthe tRNA payload can do, its
safety profile, its efficacyprofile, knowing that a lipid
nanoparticle is very effectiveat getting to the hepatocytes,
which is the cells that we needto target for our initial basket
of diseases that we're aimingto enter into, it was a
strategic choice, so it wasabout not having two novel
(44:29):
technologies at the same time,but really focusing on one novel
technology with one de-riskedtechnology, and that seemed to
be like the best strategy sothat we can get that clinical
proof of concept, which is goingto be critical for us to unlock
the potential of our platformmuch more broadly, have you
started to think about amanufacturing scale up?
Ben Comer (44:53):
I mean, I assume that you're probably manufacturing
enough for these early stagedefinitely preclinical, but
early stage clinical trials.
Well, I guess my question iswill you manufacture that
internally?
Are there partners availablefor a brand new modality like
this that you know that can helpyou scale up eventually?
(45:14):
What's your?
What's your approach?
Michelle Werner (45:16):
So the answer is yes and yes right.
I mean we are planning topartner, right, and so actually
we do have a couple of CDMOsthat have been onboarded.
We spend a lot of time as acompany talking about the
scaling up of drug substance anddrug product and you know all
of that is underway in order tomake sure that we have the
(45:38):
materials that we need forGLP-TOX and our initial phase
one clinical trials.
So, yes, that is moving forwardas planned.
We do have the possibility ofmanufacturing these ourselves,
right.
So even in the small labs thatwe have at Alltrna, we can do
small batch sizes of our tRNAsand actually formulate them
(45:58):
in-house, our of our tRNAs, andactually formulate them in-house
.
And that work is actuallyreally critical to make sure
that we understand, you know,the methods that are really
required from a manufacturingperspective.
So, as we are partnering withour CDMOs, that we can work with
them on you know those methods,those you know that technology
that scale up all of thosethings purification, et cetera,
(46:18):
et cetera, that scale up all ofthose things purification, et
cetera, et cetera.
That is a critical component ofthe scaling for clinical
readiness.
We have to be experts on it sothat we can be best partners
with our partners to help themas we move forward.
So, yeah, so we do some of themanufacturing ourselves, but
(46:39):
really the CDMOs are going to domost of it for us.
And what I would say is the goodnews is is that, yes, these
partners do exist.
So, even though a tRNAtechnology is very, very new,
the good news is is that siRNAshave been around for a decade.
Mrnas now have been around foryou know, about a decade.
(47:00):
Been around for a decade.
Mrnas now have been around foryou know, about a decade, and a
lot of those manufacturingcompetencies for those types of
RNAs have been reallyinstrumental for the sort of
readiness of tRNA manufacturing.
So I always say that we standon the shoulders of giants,
right, companies like Alnylam,companies like Moderna, who have
(47:21):
come before us and have reallypaved the way.
Yes, of course we have to dothings that are specific for
tRNAs, but we're not startingfrom ground zero, right?
We're really able to have anaccelerated pace from a
manufacturing perspectivebecause of all the hard work
that's been done from othercompanies ahead of us.
Ben Comer (47:39):
Have those companies similarly paved the way, would
you say, with regulators?
And I'm curious, you know, ifyou how much you could share
about any kind of preliminarydiscussions that you've had with
FDA, for example?
Anna Rose Welch (47:54):
So I would say yes and no to this question.
Cmc is a tricky one.
Michelle Werner (47:59):
Yeah, it definitely is a tricky one,
right.
Yeah, cnc is a tricky one.
Yeah, it definitely is a trickyone, right.
So now, when it comes to thebasket trial strategy, right,
those other technologies, as wealready talked about, cannot
leverage that Right, so they'renot doing the heavy lifting on.
You know what the preclinicaldata package needs to be to
support a basket trial strategy,especially getting into,
hopefully, pediatric patientpopulations, which is where the
(48:20):
bulk of these patients are.
So that's work that, I'd say,bespokely, we're figuring out
Now, granted, we're also takingcues from the oncology space, so
trying to leverage as much aspossible there.
But then also in certain rarediseases there have been basket
trials before.
Let's say, for example, the ureacycle disorders, where, you
(48:43):
know, other types oftechnologies have been able to
be used across a number of thosedifferent diseases, and so
there is precedence, I'd sayalready in the rare disease
space have helped before isreally, you know, thinking
through clinical trial design inrare diseases, for example, and
(49:07):
not just them but othercompanies as well, even big
companies like Sanofi or Alexionor you know other companies
like that, who have had, youknow, historical roots in the
rare genetic disease space.
They've sort of already workedwith regulators to understand
okay, maybe you don't havevalidated biomarkers from the
outset, but maybe you validatethose biomarkers as part of a
clinical trial.
How do you, you know, thinkabout different clinical
(49:29):
endpoints for some of thesediseases or in any of these
diseases and sort of you know,thinking through what you're
going to measure as part ofthose designs?
So I would say, absolutelythere is some progress that we
can latch on to, but otherthings that we definitely need
to tackle that are specific tothe work that we're doing in
Alltrna.
Ben Comer (49:50):
Do you get a sense that?
I mean, do you have a kind of Idon't know, I'll let you
describe it.
What kind of relationship doyou have with FDA?
Have you had thoseconversations?
Are they open and excited, asyou are, about this new modality
coming forward?
Michelle Werner (50:06):
Yeah, so I would say those engagements are
beginning.
But what's actually super coolis, even, if you just like,
listen closely to the way thathealth authorities and not just
the FDA, but the MHRA, ema, forexample the narrative that's
coming from the healthauthorities themselves is
(50:26):
actually very, you know, laysthe foundation for this basket
trial strategy and this reallymany diseases at a time strategy
.
That's how they describe it.
Right, they understand thesheer problem of so many rare
and ultra rare diseases.
They know it.
They know that they seeclinical trials for a handful of
those diseases and they neversee a clinical trial for most of
(50:47):
them.
So they're even talking aboutwhat is the approach that can be
taken.
That's a many diseases at atime strategy that could be
beneficial for patients in amuch different way than we've
been able to do before.
So so that's like what'shappening in the back background
with the regulators, which youknow.
So then, hearing about a tRNAthat may be able to address so
(51:11):
many different diseases andmight be able to do so in a much
faster and more efficient way,yeah, of course there are
questions, because there's.
It's a brand new modality.
No one knows how a tRNA isgoing to behave in humans, and
so, yes, there's a lot ofcuriosity and, you know,
discussion that is related tothat, but the whole concept of
(51:31):
like taking a single drug andusing across many different
diseases is exactly what they'vebeen almost asking the industry
to figure out a way to makehappen.
And so now it is that we'recoming with a potential solution
to that problem, and you knowso, yeah, so I'd say that I'm
feeling good about like us beingable to achieve it, but, of
(51:52):
course, everything will have tobe done in partnership with
regulators, but I do think thatthe there's reason to be
optimistic here.
Anna Rose Welch (52:00):
I'm getting this like image of tRNA as a
really like kick-ass superherolike in a comic book series for
some reason, I don't know, Ilove that.
Anna Rose, I love it.
Ben Comer (52:09):
Thousands of enemies at once.
Anna Rose Welch (52:13):
Do you need any materials for patient advocacy?
Michelle Werner (52:17):
Absolutely.
I'm going to call you on thatone.
Anna Rose Welch (52:18):
We're going to work on it, please do.
I'm excited I've got some ideas, all right.
Ben Comer (52:23):
Michelle, I noticed on your LinkedIn profile that
you are a member of Chief, anorganization that supports
senior women executives.
Can you tell us a little bitabout that organization and and
what you've gotten out of thatmembership?
Michelle Werner (52:38):
Yeah.
So I had the opportunity to joinChief I'm going to say around
four years ago now or so, maybefive.
I have found it to be a greatresource of other executive
women leaders who are oftentimes, I'd say, you know tackling,
you know certain professionalchallenges or thinking about a
(53:00):
you know tackling, you knowcertain professional challenges
or thinking about a.
You know making a change intheir career.
And one of the best things,that when you first join chief,
you're assigned to a group ofaround I'm going to say, six or
seven other female executiveswho somehow are all connected to
each other, although you don'tknow how, when you're first
(53:22):
assigned to that group and youbasically just become a resource
for each other, almost like asupport group for each other.
So you get really real in theseconversations.
The first experience I had wasfacilitated by a moderator who
helped engage a conversationacross all of us, and then you
(53:43):
start really building theserelationships yourselves and
become a support system for eachother, even independent of the
moderator, actually sometimeseven independent of Chief, and
but I have found it to be supergreat.
I loved, you know, when I firstjoined Chief.
It was when I was making thistransition from big pharma to
biotech.
(54:03):
So I and my son's diagnosis wasactually super fresh also.
So a lot of what I got out ofChief was how to navigate this
transition and to sort of couplethat with this kind of personal
crisis that my family was goingthrough, and I found it to be
an incredible resource and whatI actually learned is, even
(54:24):
though my story seems veryunique and perhaps probably
doesn't happen to most people intheir lives, actually all these
women go through stuff that isdifferent, but equally as sort
of impactful or equally aschallenging, right, just in a
different way, and the strugglesthat I have might be helpful
(54:46):
for somebody else to kind ofunderstand how to navigate the
struggles that they have andvice versa, and I have loved
being part of a group of womenlike that.
Ben Comer (54:58):
For our female biotech leaders and aspiring
leaders out there.
I'm curious is Chief aninvitation only organization?
Can anyone join after you reacha certain level?
Do you have a sense of that?
Michelle Werner (55:12):
I know that I had to be nominated.
I'm not sure if that's changedin the last few years.
So, yeah, somebody had tonominate me and then I had to be
vetted and accepted.
I think they are trying to makesure that you know the, the,
the seniority, the level ofseniority is at a stage where it
can be relatable amongst themembers, and so I think that's
(55:35):
something that they'redefinitely looking for.
But I think if you want to be amember, there are ways to
become a member.
Anna Rose Welch (55:41):
You're going to become a member, Ben.
Ben Comer (55:44):
I don't think I'd be eligible but Anna Rose.
I would nominate you.
Anna Rose Welch (55:47):
Hey, hey, you should join.
It's great, you'd love it.
Hey, I've followed Chief for awhile.
I've been kind of entranced bytheir business model.
It's really awesome.
I'm curious, you know, as we'rekind of approaching here, you
know we're in a new year, I'mjust curious how you're
(56:08):
envisioning this upcoming yearprogressing for Alltrna, right,
what are some of the biggestchallenges you think you're
going to be tackling for thecompany moving forward, as well
as maybe some of the challengesas a leader you're going to be
taking to chief for some help,right?
Yeah, your network.
Michelle Werner (56:23):
Well, it's, it's true, right.
So what I would say is I mean,first and foremost, we're at a
pivotal stage as a company,right, we have our development
candidates in the IND enablingphase.
So of course that means thatwe're going to be, you know,
making that transition from apure research stage company to a
research and development almostequally weighted kind of
(56:44):
company.
And that's a big thing for anorganization, especially when
you're a group of you know,essentially basic scientists
that have been working on theplatform for the last few years
to really sort of wrap our headaround, well, what happens when
you know you get to the clinic.
So building that clinicalcapability is, is, is one of the
(57:04):
things that we're working onright now.
So that's like for us as acompany.
But then, yeah, of coursethere's a lot of things
happening in the macroenvironment, micro environment
and, and, and certainly what Iwould say about that is you know
we're tackling diseases thathave incredible unmet medical
need.
You know we are everything thatwe do is going to transcend,
(57:30):
you know, all of those differentchallenges that are happening
in the macro environment,because guess what?
Patients are still going to getdiagnosed with these conditions
and, unless we do somethingabout it.
Patients are still going to diewith these conditions.
So we got to focus on whatwe're doing.
We've got to make sure that wehave the capital in order to
enable that to be possible, andthen we really need to bring
this technology forward.
So those are the things that Iwould say is just trying to
(57:52):
focus on the things that can becontrolled right now and to, you
know, focus on the needs of thepeople that we're aiming to
serve, and that's what I wake upevery single day looking to do.
Anna Rose Welch (58:02):
Keep making medicines.
Yeah, that's right.
Ben Comer (58:05):
That is Michelle Werner, CEO at Alltrna.
I'm Ben Comer.
Anna Rose Welch (58:10):
And I'm Anna Rose Welch.
Ben Comer (58:11):
And you've just listened to the Business of
Biotech.
Find us and subscribe anywhereyou listen to podcasts and be
sure to check out new weeklyvideo casts of these
conversations every Monday underthe Business of Biotech tab at
Life Science Leader.
We'll see you next week andthank you for listening.
Avantor is a leading lifescience tools company and global
(58:32):
provider of mission-criticalproducts and services to the
life sciences and advancedtechnology industries.
Avantor works side-by-side withcustomers at every step of the
scientific journey to enablebreakthroughs in medicine,
healthcare and technology.
Avantor's portfolio is used invirtually every stage of the
(58:52):
most important research,development and production
activities at more than 300,000customer locations in 180
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For more information, visitavantor s Sciences.
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