October 27, 2025 • 31 mins
Novartis’ biggest deal in more than a decade gives the Swiss pharma three programs for muscular dystrophies that are close to the finish line. On the latest BioCentury This Week podcast, BioCentury’s analysts discuss the $12 billion deal for Avidity in the context of Novartis’ recent acquisitions and the antibody-oligonucleotide conjugate platform it is gaining.
The team dives into RNA versus DNA modalities, noting antisense and siRNA approaches appear to be gaining traction with major pharmas as traditional gene therapy and gene editing approaches hit rocky times. Still, they note hopeful progress among base editing therapies given the promising early track records of over a dozen base editors in the clinic. They also discuss BioCentury’s conversation with base editing inventor David Liu; Alkermes’ $2.1 billion acquisition of Avadel; and β-catenin data from Parabilis. This episode of BioCentury This Week is sponsored by Evotec.
View full story: https://www.biocentury.com/article/657412
#AntibodyOligonucleotideConjugates #RNAtherapeutics #BaseEditing #MuscularDystrophy #WntPathway #BetaCatenin #Orexin2Receptor #PrecisionMedicine
00:01 - Sponsor Message: Evotec
02:04 - 12th China Healthcare Summit
08:11 - Novartis' $12B Deal
16:58 - Alkermes M&A
20:01 - David Liu Base Editing
25:02 - Parabilis' Data
To submit a question to BioCentury’s editors, email the BioCentury This Week team at podcasts@biocentury.com.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:00):
[AI-generated transcript.]
Alanna Farro (00:02):
BioCentury This Week is brought
to you by Evotec.
Evotec is a life sciencecompany, pioneering drug
discovery and developmentby integrating deep disease
expertise, AI-driven innovation,and advanced technologies.
Working across modalities,Evotec's, fully integrated
R&D value chain and flexiblepartnering models accelerate the
journey from concept to cure.
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A key area of focus is celltherapy, where Evotec leverages
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solutions for complex diseases.
From discovery through GMPproduction, Evotec supports
the development of cell-basedtherapies, advancing
regenerative medicine andbringing transformative
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treatments closer to patients.
Jeff Cranmer (00:51):
Novartis is getting three late stage
muscular dystrophy therapies viaa $12 billion takeout in what is
the Swiss pharma's biggest dealin a decade and more dealmaking,
a busy week for M&A last week,Alkermes hopes to establish
(01:13):
its commercial presence innarcolepsy via a $2.1 billion
buy of Avadel and takingn-of-1 base editing therapies.
Into broader populations.
Takeaways from BioCentury'sConversation with David Liu
of the Broad Institute of MITand Harvard . Plus promising
(01:35):
data sparks a clinicalopportunity for paralysis.
I'm Jeff Cranmer.
This is the BioCentury'sthis week podcast.
I'm one of the executive editorshere at BioCentury, and joining
me today are my colleagues.
Simone Fishburn (01:51):
Simone Fishburn, editor in chief.
Paul Bonanos (01:54):
Paul Bonanos, director of
Biopharma Intelligence.
Selina Koch (01:56):
Selina Koch, Executive editor.
Lauren Martz (02:00):
And Lauren Martz, executive Director
of Biopharma Intelligence.
Jeff Cranmer (02:04):
All right, Simone.
Uh, like me just offthe plane from Shanghai,
feeling a little, jet lag,but very, very energized.
how was your week in Shanghai?
Simone.
Simone (02:17):
really pretty exciting.
Okay.
so much energy atthis conference.
I think we probably say thatevery time because I feel like,
China Biotech only has sortof two levels, like highly
active and super highly active.
There's no kind of, youknow, slow day there.
but you know, I know there's,a podcast that we did,
(02:39):
especially at the meeting.
to wrap it up.
And I really encouragepeople to listen to that one.
And I'm gonna tell you someof the highlights for me
of that meeting, that mighttell you why you should
go and listen to that one.
obviously, you know, the weekkicked off with this big deal,
between Innovent and Takeda,with a 1.2 billion upfront.
(03:01):
And Paul, you did a greatstory on that last week.
I think putting it as there.
Second biggest ever.
But I, I could even say,although there's a lot of buzz
about it, nobody in China issurprised about this anymore.
The China ecosystem has a lot ofconfidence in what they're doing
in their ability to competeglobally in their ability to
(03:23):
take anything that requiresan antibody and engineer the
heck out of it and do it reallyfast and well and generate
data and, Jeff, you mightallude to this in a minute.
The Hong Kong stockexchanges for biotech is
doing remarkably well.
So are sort of, I would sayquite a lot of buzz there,
(03:45):
and various threads that arecoming out that we are seeing
how that ecosystem is maturing.
seeing a next generation ofbiotech leaders coming up
who don't necessarily feelthat they need to gain their
chops outside of China,for example, in the U.S.
there's a lot of going ondomestically where they
(04:05):
can hone their skills.
That's just, you know, oneof several things now that
we'll tap into is, you know,RNA, the next frontier, what
they've done for antibodies,can they do for RNA?
So Jeff, what wereyour thoughts?
Jeff Cranmer (04:19):
Yeah, I mean, speed, like my trip started
with, uh, a ride into townon the maglev train at
301 kilometers per hour.
And I think that
Simone Fishburn (04:31):
Well, mine was terrible.
I took like an hour and a halfto go very little distance,
Jeff Cranmer (04:34):
you got the one New York cabbie,
uh, in, in Shanghai.
I, I actually hada, a terrifying.
cab ride or two, I, I actually,uh, screamed in my cab as,
uh, he, uh, launched hiselectric vehicle within one
inch of another car that wasattempting a, multi-point turn.
(04:56):
And, uh, when we got outof the cab, I, I, I said,
man, you're ready for F1?
And, and he understoodme and laughed.
but yeah, I think it'sjust the speed, The
ability to turn over thingsquickly, like back to cars.
Literally every car in Shanghaiis a brand new electric car.
(05:16):
suffice to say, therewas a McLaren parked
in front of the hotel.
but yeah, a lot of first timefolks, we went out to, uh, the
Zhangjiang life Sciences Park.
And for me it was surprisingto see so many Western
companies with theirincubators set up there.
I think we saw Bayer, wesaw a whole bunch, and
(05:40):
indeed, uh, Western companiesare all over the place.
as our CEO just said on oureditorial call or shared a
picture rather, Shanghai's,tallest building illuminated
in blue, with Pfizer'sname written down the side.
So, western companies,uh, are, are waking up.
Lot of folks at our conferencethere for the first time
wanted to see it with theirown eyes, but even they, they,
(06:02):
they're like, I'm gonna haveto like, convince people in
my home office that, thisShanghai thing is for real.
And one way they could dothat is pointing to what
you said earlier, Simone,the, the Innovent deal.
Uh, I just wanted to clarifywhen you said it was second
biggest, uh, that's the secondlargest upfront payment in a
(06:25):
licensing deal at 1.2 billion.
That's just on the heels of thePfizer 3SBio upfront payment
that we saw earlier this year.
Selina Koch (06:38):
Jeff, when you started talking about speed
and cars, I thought for sureyou were gonna pivot to CAR Ts.
Jeff Cranmer (06:43):
Yes.
Well, uh,
Selina Koch (06:45):
great precedent of Esobiotec showing
like China speed through,through InVivo CAR T, um,
early clinicaldevelopment there.
Simone Fishburn (06:54):
Selina, it's interesting that you
say that because, and I thinkwe should stop 'cause we'll
send people to the other pod.
But that inside China isconsidered probably one of the
seminal deals, like there arecertain nodes on the pathway.
I'm not sure that everybodyin the West understood the
significance of it, but theidea of a company in Europe
(07:15):
deciding it's got only so muchmoney and how's it gonna get
data and going to China to dothose early clinical trials.
The ecosystem there like lordsthat and thinks that that is,
that is the way things will go.
So really good callout by you on that one.
Yeah.
Jeff Cranmer (07:31):
Yeah, uh, I was, you know, uh, it's sort of like
a Stockton to Malone thing.
Uh, Selina, I was justsort of setting you up
for your slam dunk there.
I will say that, uh, JP,the CEO of Esobiotec, was
a very, very popular person.
At the meeting.
And with that, look outfor, BioCentury this week.
(07:53):
live on tape from Shanghai.
it's a good one.
Uh, we had, the CEO of Duality.
Uh, we had the CFO of a Akeso,and we had, one of the top
guys, from, Charles River.
on the podcast.
all right, I'd liketo bring in Paul now.
(08:14):
Paul has been busy.
He, he, wrote about Innovent,last week, uh, yesterday.
He, uh, took a littlebreak from, uh, playing
baseball in the yard orwatching football, whatever
he gets up to down in, uh.
Florida to, uh, write aboutNovartis, uh, Novartis
getting three late stage RNAtherapeutics for muscular
dystrophies via a $12 billionacquisition of Avidity.
(08:40):
Paul.
Paul Bonanos (08:41):
Yeah, so it's a big deal even for a
company of Novartis's size.
Uh, we've written about how,Vas Narasimhan, the CEO.
He said he prefers smallerdeals with, big potential.
so presumably Novartis believesthe assets it's getting from
Avidity are, um, potentialmulti-billion dollar sellers.
That's what Vas says.
He's always looking forhigh value programs.
(09:01):
and just to clarify, when wetalk about getting assets,
yes, Novartis is buying thewhole company Avidity, but
it's also planning a spin out.
So we'll get tothat in a second.
Um, they're doing the dealto get three late stage
programs all for differenttypes of muscular dystrophy.
They could all be on themarket in the next few years.
Uh, avidity had been liningup submissions for 2026.
(09:22):
all three areantibody-oligonucleotide
conjugates.
We talk about ADCs antibodydrug conjugates all the time.
These have an oligo linked to anantibody for specific delivery
into, Cell types or tissues.
and in this case, all threehave del in their names short
for delpacibart, that's onecomponent of the therapies.
So Del-zota is for Duchennemuscular dystrophy,
(09:44):
specifically for Exon 44skipping, that has shown
both biomarker and functionalimprovements in the clinic.
And Avidity thinks it cansubmit for accelerated
approval next quarter.
There's Del-desiran, that'sfor myotonic dystrophy.
Type one, DM1, and then there'sDel-brax for, and this is a
mouthful, fascioscapulohumeralmuscular dystrophy.
(10:06):
I hope I said that right.
Uh, those latter two programshave both generated clinical
data already more due by thesecond quarter of 2026, and
um, they could go to regulatorsby year end next year.
Simone Fishburn (10:18):
Paul.
So, you know, we'reseeing a fair number
of deals at Novartis.
Some of them sinceRonny Gal joined as.
Chief Strategy Officer.
and then this one in theantisense space sort of
comes on the heels ofthey've got Leqvio right
Paul Bonanos (10:38):
That's via a very large deal with
the medicines Co. Uh, toobtain the medicines co to
acquire it in, I think 2019.
And that's before Ronniegal's time, but um,
that was 9.7 billion.
This is even bigger.
Yes.
Simone Fishburn (10:50):
And they have one against Lp(a)
Both of those are sortof in the cardiovascular
space, it feels like this.
modality is one thatthey're moving into, they're
putting more money into.
They obviously, feel thatthey've got good traction there.
It's probably been commerciallyde-risked and maybe even
scientifically de-risked or.
If that's the right word.
(11:12):
Um, so I don't know Selina,Lauren, how do you look at this
technology in what Novartisis doing and maybe even other
companies, do you think?
Selina Koch (11:21):
I was gonna
Simone Fishburn (11:22):
things to come.
Selina Koch (11:23):
yeah, I was gonna say we should bring
it in Lauren, because sherecently spoke to Tony Wood
at GSK, they've really, theystopped their sort of AAV
development, but they're kindof really doubling down on
RNA modalities, so maybe shewants to talk about that.
Lauren Martz (11:37):
I think just the fact that we're seeing
multiple large pharma companiesexiting gene therapies or
gene editing therapies, orat least deprioritizing some
of these and, looking moreinto the oligos, the siRNAs,
the, you know, uh, all ofthe RNA based modalities.
I think that's just a testamentto where this modality stands.
(11:58):
You know, it'srelatively de-risk.
There are multiple programson the market that, you
know, commercially arerelatively de-risked too.
And you've also got thefact that, with a CRISPR
based therapy for multipleindications, you're not
actually seeing necessarilymore knockdown of whatever the
target is than you might seewith an RNA therapy like this.
(12:20):
it's opening the world oftargets to something that
you can't address rightnow with, with more of the
traditional modalities.
And it seems to have a morede-risked path than some of
the even newer modalities,than, than what we have for
potentially comparable efficacyand long term efficacy,
just not one and done.
yeah, I, I think moreto, more to come from
(12:41):
the pharmacist probably.
Selina Koch (12:42):
I think that comparison to gene editing
is really interesting becausethere was a time, a moment in
time where we're like, is geneediting just gonna supplant
all of these RA modalities?
And that just hasn'tbeen the case at all.
Simone Fishburn (12:53):
I mean, I think we also have to give some credit
to Alnylam who really did theheavy lifting on a lot of this.
It was not a short journey,you know, one of the 20
year overnight successstories that we talk about.
And they as a company havereally dominated this space.
And now there areother companies,
obviously with products.
Many of those, you know,came from that technology.
(13:15):
And I think it's, we don't knowyet whether gene editing is
sort of just partway throughits journey and gonna make it,
there seems to be a, I dunnoif I would call it cyclical,
but certainly something likea sine wave going up and down
there on, on gene therapies.
But there are lots of reasonsand there are people who,
even in the heyday, whichis just a few years ago, if
Gene therapies were sayinglogically these antisense,
(13:40):
even mRNA or you know, sRNAmodalities carry lower risk
and can do the same thing,there's still genetic medicines.
They're still givingyou the same kind of.
Biological risk profile orlower biological risk profile,
say small molecules ever will.
So there's still a lot of thethings that gene therapies do,
(14:04):
these modalities do withoutperhaps some of the drawbacks.
Lauren Martz (14:08):
Tony Wood made a really interesting comment,
which is that, you know, it'sall about the durability.
I don't think anyoneexpected these oligo
therapies to be as durable.
As they are when we set out,you know, RNA inherently is
unstable, and so there's beena lot of work going into making
these more stable and the factthat you could treat someone
(14:29):
and have it last for six monthsmakes a huge difference when
you're comparing it with withother modalities as well.
Selina Koch (14:35):
We are at our Bio€quity conference.
I talked to somebody at Alnylamabout that who said it's
really like they get trappedin the endozome but then they
can like leak out slowly.
So actually you turn that intoto your advantage 'cause you
get a bit of a time releaseand an extended activity, which
is kind of neat and yeah, Idon't think that was expected.
Paul Bonanos (14:55):
Simone, you mentioned the Novartis's
experience with inclisiranUm, Leqvio, you know, in this
modality, uh, you know, alot of their deals are, into
adjacent areas or other areasthat they have experience with,
and I thought I'd just mentionalso, This takeout, builds in
musculoskeletal disease and, andyou know, Novartis has had a lot
of success in spinal muscularatrophy with that gene therapy.
(15:17):
So this is adjacent to that.
And Novartis also saidit's complimentary to
its neuro offerings.
So, it's also adjacent totheir MS drugs, and that's
another area that they'rebuilding in with their deals.
they've done deals,successive deals in, um,
in kidney disease as well.
they've done a really a, awhole lot of deals this year.
This is the fourth prettybig one with Tourmaline,
(15:38):
Regulus, and Anthos comingin last year was MorphoSys
and a couple others as well.
they've done a lot of dealssince bringing in Ronny Gal
as the gatekeeper, lookingfor high value products.
So I just thought I'dmention all of that.
Jeff Cranmer (15:50):
And the, the Regulus deal brought
in, earlier this year, amicro RNA, technology.
Paul, um, there was aspin out in this deal.
Paul Bonanos (16:01):
Yes, I did mention that.
so Avidity has some morepreclinical programs
that a couple of r sorry,mRNA, DEGRADERS for
Cardiology indications.
And those are going into thespin out, two rare cardio
diseases, uh, associatedwith specific genetic causes.
Avidity also has partnerships,two partnerships of note BMS,
in cardiovascular indicationsand with Lilly in immunology.
(16:25):
The deals also go intothe spin out, and although
Novartis gets the existing,AOC platform that's, um,
antibody-oligonucleotideconjugate platform.
That it makes the conjugatesfrom, Avidity says the spin
out will be able to iterate onit in, cardio disease to make
technological modifications andmaybe next generation products.
(16:46):
So there's still someroom to innovate there.
And the, the chief programsofficer at Avidity will become
the CEO and the CEO will becomethe chair of the spin out.
So retainingleadership continuity.
Jeff Cranmer (16:58):
All right, so the other big deal last
week, Alkermes , Lauren,you just, wrote a story a
couple of weeks ago about.
Some really interestingnarcolepsy data, from
Alkermes as well as Takeda.
both leaders in the space andnow we see Alkermes, making
a play for, Dublin Irelandbased Avadel Pharmaceuticals.
(17:24):
Tell us.
a little bit about that.
Lauren Martz (17:26):
Thanks, Jeff.
through this deal, they gain anapproved drug for, some of the
symptoms of narcolepsy, whichis LUMRYZ (sodium oxybate).
I think this deal reallydoes two things for
Alkermes, uh, maybe more.
It gives them this commercialstage product, which may be
complimentary to the internalprograms that they have.
(17:47):
It also gives them a commercialinfrastructure in the sleep
space, which is somethingthat they didn't have.
So the story that we wroterecently was about Phase II data
for, um, the orexin 2 receptoragonists that Alkermes has.
this is a new classin narcolepsy.
they're slightly behind Takeda,which just released Phase
III data for their program.
(18:08):
as a new class, this worksto replace the functionality
that's lost specifically, intype 1 narcolepsy when these
patients don't have the ligandfor high enough expression
ligand for this receptor.
So these drugs aretaken during the day to
help people stay awake.
Alkermes think they may have anadvantage there as a once daily,
(18:28):
once in the morning therapy.
the sodium oxybate class oftherapies is used at nighttime
to help patients stay asleep.
this particular one is alsodosed once when patients go to
bed, um, which, you know, may bea differentiation in that space.
So there are these two programsin the narcolepsy space.
Both could potentiallyhave a dosing advantage.
(18:50):
And, you know, as thiscompany's preparing to advance
this in this new class in theorexin 2 receptor agonist.
they now are inheritingthis, commercial team,
commercial structure that,that's capable of, of working
within the narcolepsy space.
Jeff Cranmer (19:06):
All right.
We are gonna take a quickbreak and we'll come back
to talk base editing.
Alanna Farro (19:14):
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Jeff Cranmer (20:01):
And we're back.
And I just wanted to giveyou a little shout out.
Simone will be takingBioCentury's this
week on the road toCambridge, Massachusetts.
So just wanted to give a shoutout to our Boston listeners.
we will be on the road, November6th in the Boston, Cambridge
area for K Blockbuster Night.
(20:25):
I'm sure it will be golden.
join us at Venture CafeCambridge and watch a live
recording of the podcast withspecial guests joining Simone
to discuss Korea biotech.
Register for free atventurecafecambridge.org.
or you can hit up our buddyJosh Berlin, our head of bd.
(20:48):
On LinkedIn, you can hit meup as well to learn more and
we hope to see you there.
well, David Liu joined ourcolleague Danielle Golovin in
conversation, recently and weran a q and A in BioCentury
and here with some takeaways.
Uh, Selina.
Selina Koch (21:09):
thanks Jeff.
I guess there were two thingsthat really struck me about
what he, um, said to Danielle.
first is that his lab is workingon a technology that could.
Kind of overcome one ofthe big issues with base
editing that makes it hardto, build a business on it.
one of the great thingsabout base editing is it
goes after causal biology,pretty much by definition,
(21:32):
It corrects a specific pointmutation in a specific gene.
And, often that's used forn-of-1 type bespoke therapies
or n of a few, right?
So super ultra rare indications,where the economics are
hard to work out from abusiness kind of perspective.
Um, so now they're workingon something over there
(21:53):
where you're still changinga specific, base, but instead
of doing it in, in a gene thatcauses, you know, a specific
disease or trying to do it in agene that causes many diseases.
So for example, there'sa kind of wide range of
diseases that are causedby premature stop codons.
And so they now have atechnology that can recognize
(22:14):
this premature stop codonacross many different genes,
and therefore across manydifferent rare diseases.
And so once you startaggregating up these ultra
rare diseases, maybe theeconomics can change.
So I thought that waskind of interesting future
direction of a technology.
Jeff Cranmer (22:30):
good stuff.
Selina, what wasyour second takeaway?
I.
Selina Koch (22:33):
So he mentioned in this interview that there
are now 23 base editors in theclinic, um, which I had not
realized there quite that manyhad advanced to the clinic.
Um, so Danielle thenwent in a second story.
She rounded all of those up.
kind of assess theirearly track record.
So, 13 of them have producedinitial data and all 13 of them
(22:55):
have made the intended changeto the, the base, the base edit.
And all of them have movedbiomarkers in a direction that
indicates clinical activitywith, except for one case.
mild manageable, safety.
So when I think of like justearly clinical track records
for say, gene therapy, othernew modalities, um, you'd
(23:18):
be hard pressed to find oneas looking as promising.
I think.
Simone Fishburn (23:22):
So Selina, I think for many people he's a
very known name, but some peopleprobably know less about him.
So just for context, He'sfounded some pretty big
companies in this space, Iimagine we expect to see more.
You wanna just fill in anythingon, uh, on the background of
David Liu for our listeners?
Selina Koch (23:40):
Well, base editing that technology, led
him to found a company calledBeam Therapeutics, which is
still a leader in that space.
after, Base editing, which heinvented around 2016 and 2019.
there's a next generationtechnology called prime editing
that can do some things.
Base editing can't, that healso invented base editing can
(24:02):
change something like 4 of the12 possible base pair changes.
Prime editing can hit themall and it can do some small
in insertions and deletions.
So that's an excitingdevelopment off of base editing.
And that led to a companycalled Prime Medicine.
which is so far the first andstill only biotech to bring a
prime editor into the clinic.
(24:23):
that's an area towatch in the future.
but then a lot of the, thework, those 23 trials we're
talking about, a lot ofthose are still academic.
cause as I said, thebusiness proposition here
is still an area thatneeds, some fleshing out.
Jeff Cranmer (24:37):
Yeah, he's uh, published more than 275 papers.
Inventor on more than 110issued U.S. patents and
just a laundry list of,uh, prizes that he has won.
and those companies, quitea few, uh, were watching
quite closely nChroma Bio,Exo Therapeutics, Pairwise
(24:58):
Plants, a few of hisother companies as well.
okay, uh, well, I'd liketo bring it home by, uh,
heading to the clinic.
Parabilis, that's, uh, acompany led by Mathai Mammen.
had some pretty,promising data last week.
And, Lauren, you took alittle, uh, break out of your
(25:19):
busy week to write about it.
What did you learn?
Lauren Martz (25:22):
Yeah, so these were the first data
that we, clinical data thatwe've seen for FOG-001,
which was the β-catenin TCFinteraction inhibitor, that
Parabilis has been working on.
The data we're, we'rereally encouraging.
So at ESMO they presenteddata in desmoid tumors
(25:43):
showing that of all the10 patients that were,
treated with this at first.
They all had some tumorshrinkage, among the five in
that trial who had at leasttwo post baseline scans.
And, you know, it takessome time for tumor
shrinkage to occur here.
four had partial responses,so that's an ORR of 80%.
And you know, we've seenthis for other mechanisms
(26:05):
and other cancers, whatever.
But I think thisrepresents a potential
really big breakthrough.
Because of the target.
So β-catenin is just one ofthose historically intractable
cancer targets that everyonehas been trying to solve for
decades because it's mutated ina large percentage of cancer.
So, you know, in a normalstate, it's expression,
(26:28):
it is sort of tightlycontrolled, it's regularly
degraded and in cancers.
Its expression, it can becomemore stabilized and it's a
transcriptional regulatorthat when it's active, it
can activate, the Wnt pathwaygenes, which can, contribute
to cancer in multipledifferent downstream ways.
So you're sort of, whenthe mutations occur, you're
(26:50):
setting off this pathway.
And the problem is that theinteraction that activates these
cancerous gene expressions.
It doesn't have the typesof binding grooves that you
need for a small molecule tobe effective and selective.
And this isn't the only,function of this gene.
(27:11):
So it needs to be doneselectively, to not
disrupt normal functions.
So it's a very flat surface andwe just haven't been able to
target it with small molecules.
So what Parabilis hasdone is they've used their
α-helical stapled peptidetechnology to interact
selectively in that groove.
they also incorporatenon-natural amino acids to give
them more diversity in, thechemistry that they can use here
(27:35):
to make that binding selective.
And based on the data, it seemsthat, you know, we haven't
seen this level of response.
We haven't seen.
This level of safety oftenwhen you have a non-selective
inhibition of β-catenin, therecould be lots of downstream
safety issues as well.
(27:56):
So it, it's apotential breakthrough.
I think it's, it'svery exciting data.
Selina Koch (28:00):
I think we saw, um, some bone safety issues
with previous programs.
Like you said, it's acomplicated pathway with
lots of different, um,complexes of proteins.
And if you look at thediagram, it spins off in
various directions and there'scanonical and non-canonical.
We've had disheveled inhibitorinhibitors, porcupine
inhibitors, so on and so forth.
(28:20):
Drizzled Wnt, but actuallygetting in the nucleus just
at those, just at thosetranscription factors,
driving the, you know,the, addicted, cancer, um.
Does seem like progress andthis is, uh, originally came
out of Greg Verdine work right?
Lauren Martz (28:37):
It did.
Yes, the, the stapledpeptide technology.
Simone Fishburn (28:40):
Yeah, I was gonna say, so first of all,
this pathway, I think by somedistance, has the best names
in it drizzled you know,really cool proteins all
the way down to Porcupine.
And there's a very nice, uh,graphic actually depicting
this in the article there.
that we put together.
But yeah, this comes out of GregVerdine's lab stapled peptides.
(29:03):
I think it's a veryinteresting, twist.
You know, Selina, wetalk a lot about all of
these other modalities.
This is a small moleculemodality that is, more
engineering in the smallmolecule space and really
trying to solve a problem.
That hasn't beensolved for a long time.
So if they can do that ata technical level, at the
same time as interrogatingor accessing a pathway
(29:26):
that's been resistant to,uh, to drug development,
that would be a big win.
Lauren Martz (29:33):
Yeah.
And so on Friday, they alsoshowed that in the same
trial, it wasn't limited tothe efficacy, wasn't limited
to the Desmoid tumors.
Um, they also showed efficacyat the triple meeting in
multiple other, Tumor typesthat don't have a particularly
high mutational burden.
So that's, that's whereParabilis is first taking
this technology becauseat that stage, you know,
(29:53):
there's a better chancethat if you have a β-catenin
mutation, that's the mutationthat's driving the cancer.
So, you know, you don'thave to worry about
additional mutations.
Uh.
Affecting the efficacy oftargeting this pathway.
but the company is lookingto expand into more complex
tumors, uh, specifically, uh,microsatellite stable colorectal
cancer, I think in combinations,um, just based on some of the
(30:16):
mechanisms of what happenswhen you do block this pathway.
Selina Koch (30:20):
Yeah.
And it'll beinteresting to see, um.
if they're hypothesis aboutit, being able to kind of
turn cold tumors warmer and,and synergize with PD-1, if
that, you know, works out.
Jeff Cranmer (30:32):
Sounds good.
Well, I'll drop a link.
To all of these storiesinto the show notes.
You can also find themat BioCenturypodcast.com.
And if you like what you'rehearing, uh, don't forget
to like and subscribe.
If you have a question forus drop us drop us a line,
coming up on Wednesday,we'll release the.
(30:54):
Podcast that we recordedin Shanghai on stage
with some special guests.
So look out for that.
we'd like to thank KendallSquare Orchestra for providing
the music to our podcasts.
Alanna Farro (31:08):
BioCentury would like to thank
Evotec for supporting theBioCentury This Week podcast.
To learn more about how Evoteccan support your goals through
pioneering drug discoveryand development solutions,
go to Evotec.com/innovation
[AI-generated transcript.]
Alanna Farro (00:02):
BioCentury This Week is brought
to you by Evotec.
Evotec is a life sciencecompany, pioneering drug
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Working across modalities,Evotec's, fully integrated
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Jeff Cranmer (00:51):
Novartis is getting three late stage
muscular dystrophy therapies viaa $12 billion takeout in what is
the Swiss pharma's biggest dealin a decade and more dealmaking,
a busy week for M&A last week,Alkermes hopes to establish
(01:13):
its commercial presence innarcolepsy via a $2.1 billion
buy of Avadel and takingn-of-1 base editing therapies.
Into broader populations.
Takeaways from BioCentury'sConversation with David Liu
of the Broad Institute of MITand Harvard . Plus promising
(01:35):
data sparks a clinicalopportunity for paralysis.
I'm Jeff Cranmer.
This is the BioCentury'sthis week podcast.
I'm one of the executive editorshere at BioCentury, and joining
me today are my colleagues.
Simone Fishburn (01:51):
Simone Fishburn, editor in chief.
Paul Bonanos (01:54):
Paul Bonanos, director of
Biopharma Intelligence.
Selina Koch (01:56):
Selina Koch, Executive editor.
Lauren Martz (02:00):
And Lauren Martz, executive Director
of Biopharma Intelligence.
Jeff Cranmer (02:04):
All right, Simone.
Uh, like me just offthe plane from Shanghai,
feeling a little, jet lag,but very, very energized.
how was your week in Shanghai?
Simone.
Simone (02:17):
really pretty exciting.
Okay.
so much energy atthis conference.
I think we probably say thatevery time because I feel like,
China Biotech only has sortof two levels, like highly
active and super highly active.
There's no kind of, youknow, slow day there.
but you know, I know there's,a podcast that we did,
(02:39):
especially at the meeting.
to wrap it up.
And I really encouragepeople to listen to that one.
And I'm gonna tell you someof the highlights for me
of that meeting, that mighttell you why you should
go and listen to that one.
obviously, you know, the weekkicked off with this big deal,
between Innovent and Takeda,with a 1.2 billion upfront.
(03:01):
And Paul, you did a greatstory on that last week.
I think putting it as there.
Second biggest ever.
But I, I could even say,although there's a lot of buzz
about it, nobody in China issurprised about this anymore.
The China ecosystem has a lot ofconfidence in what they're doing
in their ability to competeglobally in their ability to
(03:23):
take anything that requiresan antibody and engineer the
heck out of it and do it reallyfast and well and generate
data and, Jeff, you mightallude to this in a minute.
The Hong Kong stockexchanges for biotech is
doing remarkably well.
So are sort of, I would sayquite a lot of buzz there,
(03:45):
and various threads that arecoming out that we are seeing
how that ecosystem is maturing.
seeing a next generation ofbiotech leaders coming up
who don't necessarily feelthat they need to gain their
chops outside of China,for example, in the U.S.
there's a lot of going ondomestically where they
(04:05):
can hone their skills.
That's just, you know, oneof several things now that
we'll tap into is, you know,RNA, the next frontier, what
they've done for antibodies,can they do for RNA?
So Jeff, what wereyour thoughts?
Jeff Cranmer (04:19):
Yeah, I mean, speed, like my trip started
with, uh, a ride into townon the maglev train at
301 kilometers per hour.
And I think that
Simone Fishburn (04:31):
Well, mine was terrible.
I took like an hour and a halfto go very little distance,
Jeff Cranmer (04:34):
you got the one New York cabbie,
uh, in, in Shanghai.
I, I actually hada, a terrifying.
cab ride or two, I, I actually,uh, screamed in my cab as,
uh, he, uh, launched hiselectric vehicle within one
inch of another car that wasattempting a, multi-point turn.
(04:56):
And, uh, when we got outof the cab, I, I, I said,
man, you're ready for F1?
And, and he understoodme and laughed.
but yeah, I think it'sjust the speed, The
ability to turn over thingsquickly, like back to cars.
Literally every car in Shanghaiis a brand new electric car.
(05:16):
suffice to say, therewas a McLaren parked
in front of the hotel.
but yeah, a lot of first timefolks, we went out to, uh, the
Zhangjiang life Sciences Park.
And for me it was surprisingto see so many Western
companies with theirincubators set up there.
I think we saw Bayer, wesaw a whole bunch, and
(05:40):
indeed, uh, Western companiesare all over the place.
as our CEO just said on oureditorial call or shared a
picture rather, Shanghai's,tallest building illuminated
in blue, with Pfizer'sname written down the side.
So, western companies,uh, are, are waking up.
Lot of folks at our conferencethere for the first time
wanted to see it with theirown eyes, but even they, they,
(06:02):
they're like, I'm gonna haveto like, convince people in
my home office that, thisShanghai thing is for real.
And one way they could dothat is pointing to what
you said earlier, Simone,the, the Innovent deal.
Uh, I just wanted to clarifywhen you said it was second
biggest, uh, that's the secondlargest upfront payment in a
(06:25):
licensing deal at 1.2 billion.
That's just on the heels of thePfizer 3SBio upfront payment
that we saw earlier this year.
Selina Koch (06:38):
Jeff, when you started talking about speed
and cars, I thought for sureyou were gonna pivot to CAR Ts.
Jeff Cranmer (06:43):
Yes.
Well, uh,
Selina Koch (06:45):
great precedent of Esobiotec showing
like China speed through,through InVivo CAR T, um,
early clinicaldevelopment there.
Simone Fishburn (06:54):
Selina, it's interesting that you
say that because, and I thinkwe should stop 'cause we'll
send people to the other pod.
But that inside China isconsidered probably one of the
seminal deals, like there arecertain nodes on the pathway.
I'm not sure that everybodyin the West understood the
significance of it, but theidea of a company in Europe
(07:15):
deciding it's got only so muchmoney and how's it gonna get
data and going to China to dothose early clinical trials.
The ecosystem there like lordsthat and thinks that that is,
that is the way things will go.
So really good callout by you on that one.
Yeah.
Jeff Cranmer (07:31):
Yeah, uh, I was, you know, uh, it's sort of like
a Stockton to Malone thing.
Uh, Selina, I was justsort of setting you up
for your slam dunk there.
I will say that, uh, JP,the CEO of Esobiotec, was
a very, very popular person.
At the meeting.
And with that, look outfor, BioCentury this week.
(07:53):
live on tape from Shanghai.
it's a good one.
Uh, we had, the CEO of Duality.
Uh, we had the CFO of a Akeso,and we had, one of the top
guys, from, Charles River.
on the podcast.
all right, I'd liketo bring in Paul now.
(08:14):
Paul has been busy.
He, he, wrote about Innovent,last week, uh, yesterday.
He, uh, took a littlebreak from, uh, playing
baseball in the yard orwatching football, whatever
he gets up to down in, uh.
Florida to, uh, write aboutNovartis, uh, Novartis
getting three late stage RNAtherapeutics for muscular
dystrophies via a $12 billionacquisition of Avidity.
(08:40):
Paul.
Paul Bonanos (08:41):
Yeah, so it's a big deal even for a
company of Novartis's size.
Uh, we've written about how,Vas Narasimhan, the CEO.
He said he prefers smallerdeals with, big potential.
so presumably Novartis believesthe assets it's getting from
Avidity are, um, potentialmulti-billion dollar sellers.
That's what Vas says.
He's always looking forhigh value programs.
(09:01):
and just to clarify, when wetalk about getting assets,
yes, Novartis is buying thewhole company Avidity, but
it's also planning a spin out.
So we'll get tothat in a second.
Um, they're doing the dealto get three late stage
programs all for differenttypes of muscular dystrophy.
They could all be on themarket in the next few years.
Uh, avidity had been liningup submissions for 2026.
(09:22):
all three areantibody-oligonucleotide
conjugates.
We talk about ADCs antibodydrug conjugates all the time.
These have an oligo linked to anantibody for specific delivery
into, Cell types or tissues.
and in this case, all threehave del in their names short
for delpacibart, that's onecomponent of the therapies.
So Del-zota is for Duchennemuscular dystrophy,
(09:44):
specifically for Exon 44skipping, that has shown
both biomarker and functionalimprovements in the clinic.
And Avidity thinks it cansubmit for accelerated
approval next quarter.
There's Del-desiran, that'sfor myotonic dystrophy.
Type one, DM1, and then there'sDel-brax for, and this is a
mouthful, fascioscapulohumeralmuscular dystrophy.
(10:06):
I hope I said that right.
Uh, those latter two programshave both generated clinical
data already more due by thesecond quarter of 2026, and
um, they could go to regulatorsby year end next year.
Simone Fishburn (10:18):
Paul.
So, you know, we'reseeing a fair number
of deals at Novartis.
Some of them sinceRonny Gal joined as.
Chief Strategy Officer.
and then this one in theantisense space sort of
comes on the heels ofthey've got Leqvio right
Paul Bonanos (10:38):
That's via a very large deal with
the medicines Co. Uh, toobtain the medicines co to
acquire it in, I think 2019.
And that's before Ronniegal's time, but um,
that was 9.7 billion.
This is even bigger.
Yes.
Simone Fishburn (10:50):
And they have one against Lp(a)
Both of those are sortof in the cardiovascular
space, it feels like this.
modality is one thatthey're moving into, they're
putting more money into.
They obviously, feel thatthey've got good traction there.
It's probably been commerciallyde-risked and maybe even
scientifically de-risked or.
If that's the right word.
(11:12):
Um, so I don't know Selina,Lauren, how do you look at this
technology in what Novartisis doing and maybe even other
companies, do you think?
Selina Koch (11:21):
I was gonna
Simone Fishburn (11:22):
things to come.
Selina Koch (11:23):
yeah, I was gonna say we should bring
it in Lauren, because sherecently spoke to Tony Wood
at GSK, they've really, theystopped their sort of AAV
development, but they're kindof really doubling down on
RNA modalities, so maybe shewants to talk about that.
Lauren Martz (11:37):
I think just the fact that we're seeing
multiple large pharma companiesexiting gene therapies or
gene editing therapies, orat least deprioritizing some
of these and, looking moreinto the oligos, the siRNAs,
the, you know, uh, all ofthe RNA based modalities.
I think that's just a testamentto where this modality stands.
(11:58):
You know, it'srelatively de-risk.
There are multiple programson the market that, you
know, commercially arerelatively de-risked too.
And you've also got thefact that, with a CRISPR
based therapy for multipleindications, you're not
actually seeing necessarilymore knockdown of whatever the
target is than you might seewith an RNA therapy like this.
(12:20):
it's opening the world oftargets to something that
you can't address rightnow with, with more of the
traditional modalities.
And it seems to have a morede-risked path than some of
the even newer modalities,than, than what we have for
potentially comparable efficacyand long term efficacy,
just not one and done.
yeah, I, I think moreto, more to come from
(12:41):
the pharmacist probably.
Selina Koch (12:42):
I think that comparison to gene editing
is really interesting becausethere was a time, a moment in
time where we're like, is geneediting just gonna supplant
all of these RA modalities?
And that just hasn'tbeen the case at all.
Simone Fishburn (12:53):
I mean, I think we also have to give some credit
to Alnylam who really did theheavy lifting on a lot of this.
It was not a short journey,you know, one of the 20
year overnight successstories that we talk about.
And they as a company havereally dominated this space.
And now there areother companies,
obviously with products.
Many of those, you know,came from that technology.
(13:15):
And I think it's, we don't knowyet whether gene editing is
sort of just partway throughits journey and gonna make it,
there seems to be a, I dunnoif I would call it cyclical,
but certainly something likea sine wave going up and down
there on, on gene therapies.
But there are lots of reasonsand there are people who,
even in the heyday, whichis just a few years ago, if
Gene therapies were sayinglogically these antisense,
(13:40):
even mRNA or you know, sRNAmodalities carry lower risk
and can do the same thing,there's still genetic medicines.
They're still givingyou the same kind of.
Biological risk profile orlower biological risk profile,
say small molecules ever will.
So there's still a lot of thethings that gene therapies do,
(14:04):
these modalities do withoutperhaps some of the drawbacks.
Lauren Martz (14:08):
Tony Wood made a really interesting comment,
which is that, you know, it'sall about the durability.
I don't think anyoneexpected these oligo
therapies to be as durable.
As they are when we set out,you know, RNA inherently is
unstable, and so there's beena lot of work going into making
these more stable and the factthat you could treat someone
(14:29):
and have it last for six monthsmakes a huge difference when
you're comparing it with withother modalities as well.
Selina Koch (14:35):
We are at our Bio€quity conference.
I talked to somebody at Alnylamabout that who said it's
really like they get trappedin the endozome but then they
can like leak out slowly.
So actually you turn that intoto your advantage 'cause you
get a bit of a time releaseand an extended activity, which
is kind of neat and yeah, Idon't think that was expected.
Paul Bonanos (14:55):
Simone, you mentioned the Novartis's
experience with inclisiranUm, Leqvio, you know, in this
modality, uh, you know, alot of their deals are, into
adjacent areas or other areasthat they have experience with,
and I thought I'd just mentionalso, This takeout, builds in
musculoskeletal disease and, andyou know, Novartis has had a lot
of success in spinal muscularatrophy with that gene therapy.
(15:17):
So this is adjacent to that.
And Novartis also saidit's complimentary to
its neuro offerings.
So, it's also adjacent totheir MS drugs, and that's
another area that they'rebuilding in with their deals.
they've done deals,successive deals in, um,
in kidney disease as well.
they've done a really a, awhole lot of deals this year.
This is the fourth prettybig one with Tourmaline,
(15:38):
Regulus, and Anthos comingin last year was MorphoSys
and a couple others as well.
they've done a lot of dealssince bringing in Ronny Gal
as the gatekeeper, lookingfor high value products.
So I just thought I'dmention all of that.
Jeff Cranmer (15:50):
And the, the Regulus deal brought
in, earlier this year, amicro RNA, technology.
Paul, um, there was aspin out in this deal.
Paul Bonanos (16:01):
Yes, I did mention that.
so Avidity has some morepreclinical programs
that a couple of r sorry,mRNA, DEGRADERS for
Cardiology indications.
And those are going into thespin out, two rare cardio
diseases, uh, associatedwith specific genetic causes.
Avidity also has partnerships,two partnerships of note BMS,
in cardiovascular indicationsand with Lilly in immunology.
(16:25):
The deals also go intothe spin out, and although
Novartis gets the existing,AOC platform that's, um,
antibody-oligonucleotideconjugate platform.
That it makes the conjugatesfrom, Avidity says the spin
out will be able to iterate onit in, cardio disease to make
technological modifications andmaybe next generation products.
(16:46):
So there's still someroom to innovate there.
And the, the chief programsofficer at Avidity will become
the CEO and the CEO will becomethe chair of the spin out.
So retainingleadership continuity.
Jeff Cranmer (16:58):
All right, so the other big deal last
week, Alkermes , Lauren,you just, wrote a story a
couple of weeks ago about.
Some really interestingnarcolepsy data, from
Alkermes as well as Takeda.
both leaders in the space andnow we see Alkermes, making
a play for, Dublin Irelandbased Avadel Pharmaceuticals.
(17:24):
Tell us.
a little bit about that.
Lauren Martz (17:26):
Thanks, Jeff.
through this deal, they gain anapproved drug for, some of the
symptoms of narcolepsy, whichis LUMRYZ (sodium oxybate).
I think this deal reallydoes two things for
Alkermes, uh, maybe more.
It gives them this commercialstage product, which may be
complimentary to the internalprograms that they have.
(17:47):
It also gives them a commercialinfrastructure in the sleep
space, which is somethingthat they didn't have.
So the story that we wroterecently was about Phase II data
for, um, the orexin 2 receptoragonists that Alkermes has.
this is a new classin narcolepsy.
they're slightly behind Takeda,which just released Phase
III data for their program.
(18:08):
as a new class, this worksto replace the functionality
that's lost specifically, intype 1 narcolepsy when these
patients don't have the ligandfor high enough expression
ligand for this receptor.
So these drugs aretaken during the day to
help people stay awake.
Alkermes think they may have anadvantage there as a once daily,
(18:28):
once in the morning therapy.
the sodium oxybate class oftherapies is used at nighttime
to help patients stay asleep.
this particular one is alsodosed once when patients go to
bed, um, which, you know, may bea differentiation in that space.
So there are these two programsin the narcolepsy space.
Both could potentiallyhave a dosing advantage.
(18:50):
And, you know, as thiscompany's preparing to advance
this in this new class in theorexin 2 receptor agonist.
they now are inheritingthis, commercial team,
commercial structure that,that's capable of, of working
within the narcolepsy space.
Jeff Cranmer (19:06):
All right.
We are gonna take a quickbreak and we'll come back
to talk base editing.
Alanna Farro (19:14):
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Jeff Cranmer (20:01):
And we're back.
And I just wanted to giveyou a little shout out.
Simone will be takingBioCentury's this
week on the road toCambridge, Massachusetts.
So just wanted to give a shoutout to our Boston listeners.
we will be on the road, November6th in the Boston, Cambridge
area for K Blockbuster Night.
(20:25):
I'm sure it will be golden.
join us at Venture CafeCambridge and watch a live
recording of the podcast withspecial guests joining Simone
to discuss Korea biotech.
Register for free atventurecafecambridge.org.
or you can hit up our buddyJosh Berlin, our head of bd.
(20:48):
On LinkedIn, you can hit meup as well to learn more and
we hope to see you there.
well, David Liu joined ourcolleague Danielle Golovin in
conversation, recently and weran a q and A in BioCentury
and here with some takeaways.
Uh, Selina.
Selina Koch (21:09):
thanks Jeff.
I guess there were two thingsthat really struck me about
what he, um, said to Danielle.
first is that his lab is workingon a technology that could.
Kind of overcome one ofthe big issues with base
editing that makes it hardto, build a business on it.
one of the great thingsabout base editing is it
goes after causal biology,pretty much by definition,
(21:32):
It corrects a specific pointmutation in a specific gene.
And, often that's used forn-of-1 type bespoke therapies
or n of a few, right?
So super ultra rare indications,where the economics are
hard to work out from abusiness kind of perspective.
Um, so now they're workingon something over there
(21:53):
where you're still changinga specific, base, but instead
of doing it in, in a gene thatcauses, you know, a specific
disease or trying to do it in agene that causes many diseases.
So for example, there'sa kind of wide range of
diseases that are causedby premature stop codons.
And so they now have atechnology that can recognize
(22:14):
this premature stop codonacross many different genes,
and therefore across manydifferent rare diseases.
And so once you startaggregating up these ultra
rare diseases, maybe theeconomics can change.
So I thought that waskind of interesting future
direction of a technology.
Jeff Cranmer (22:30):
good stuff.
Selina, what wasyour second takeaway?
I.
Selina Koch (22:33):
So he mentioned in this interview that there
are now 23 base editors in theclinic, um, which I had not
realized there quite that manyhad advanced to the clinic.
Um, so Danielle thenwent in a second story.
She rounded all of those up.
kind of assess theirearly track record.
So, 13 of them have producedinitial data and all 13 of them
(22:55):
have made the intended changeto the, the base, the base edit.
And all of them have movedbiomarkers in a direction that
indicates clinical activitywith, except for one case.
mild manageable, safety.
So when I think of like justearly clinical track records
for say, gene therapy, othernew modalities, um, you'd
(23:18):
be hard pressed to find oneas looking as promising.
I think.
Simone Fishburn (23:22):
So Selina, I think for many people he's a
very known name, but some peopleprobably know less about him.
So just for context, He'sfounded some pretty big
companies in this space, Iimagine we expect to see more.
You wanna just fill in anythingon, uh, on the background of
David Liu for our listeners?
Selina Koch (23:40):
Well, base editing that technology, led
him to found a company calledBeam Therapeutics, which is
still a leader in that space.
after, Base editing, which heinvented around 2016 and 2019.
there's a next generationtechnology called prime editing
that can do some things.
Base editing can't, that healso invented base editing can
(24:02):
change something like 4 of the12 possible base pair changes.
Prime editing can hit themall and it can do some small
in insertions and deletions.
So that's an excitingdevelopment off of base editing.
And that led to a companycalled Prime Medicine.
which is so far the first andstill only biotech to bring a
prime editor into the clinic.
(24:23):
that's an area towatch in the future.
but then a lot of the, thework, those 23 trials we're
talking about, a lot ofthose are still academic.
cause as I said, thebusiness proposition here
is still an area thatneeds, some fleshing out.
Jeff Cranmer (24:37):
Yeah, he's uh, published more than 275 papers.
Inventor on more than 110issued U.S. patents and
just a laundry list of,uh, prizes that he has won.
and those companies, quitea few, uh, were watching
quite closely nChroma Bio,Exo Therapeutics, Pairwise
(24:58):
Plants, a few of hisother companies as well.
okay, uh, well, I'd liketo bring it home by, uh,
heading to the clinic.
Parabilis, that's, uh, acompany led by Mathai Mammen.
had some pretty,promising data last week.
And, Lauren, you took alittle, uh, break out of your
(25:19):
busy week to write about it.
What did you learn?
Lauren Martz (25:22):
Yeah, so these were the first data
that we, clinical data thatwe've seen for FOG-001,
which was the β-catenin TCFinteraction inhibitor, that
Parabilis has been working on.
The data we're, we'rereally encouraging.
So at ESMO they presenteddata in desmoid tumors
(25:43):
showing that of all the10 patients that were,
treated with this at first.
They all had some tumorshrinkage, among the five in
that trial who had at leasttwo post baseline scans.
And, you know, it takessome time for tumor
shrinkage to occur here.
four had partial responses,so that's an ORR of 80%.
And you know, we've seenthis for other mechanisms
(26:05):
and other cancers, whatever.
But I think thisrepresents a potential
really big breakthrough.
Because of the target.
So β-catenin is just one ofthose historically intractable
cancer targets that everyonehas been trying to solve for
decades because it's mutated ina large percentage of cancer.
So, you know, in a normalstate, it's expression,
(26:28):
it is sort of tightlycontrolled, it's regularly
degraded and in cancers.
Its expression, it can becomemore stabilized and it's a
transcriptional regulatorthat when it's active, it
can activate, the Wnt pathwaygenes, which can, contribute
to cancer in multipledifferent downstream ways.
So you're sort of, whenthe mutations occur, you're
(26:50):
setting off this pathway.
And the problem is that theinteraction that activates these
cancerous gene expressions.
It doesn't have the typesof binding grooves that you
need for a small molecule tobe effective and selective.
And this isn't the only,function of this gene.
(27:11):
So it needs to be doneselectively, to not
disrupt normal functions.
So it's a very flat surface andwe just haven't been able to
target it with small molecules.
So what Parabilis hasdone is they've used their
α-helical stapled peptidetechnology to interact
selectively in that groove.
they also incorporatenon-natural amino acids to give
them more diversity in, thechemistry that they can use here
(27:35):
to make that binding selective.
And based on the data, it seemsthat, you know, we haven't
seen this level of response.
We haven't seen.
This level of safety oftenwhen you have a non-selective
inhibition of β-catenin, therecould be lots of downstream
safety issues as well.
(27:56):
So it, it's apotential breakthrough.
I think it's, it'svery exciting data.
Selina Koch (28:00):
I think we saw, um, some bone safety issues
with previous programs.
Like you said, it's acomplicated pathway with
lots of different, um,complexes of proteins.
And if you look at thediagram, it spins off in
various directions and there'scanonical and non-canonical.
We've had disheveled inhibitorinhibitors, porcupine
inhibitors, so on and so forth.
(28:20):
Drizzled Wnt, but actuallygetting in the nucleus just
at those, just at thosetranscription factors,
driving the, you know,the, addicted, cancer, um.
Does seem like progress andthis is, uh, originally came
out of Greg Verdine work right?
Lauren Martz (28:37):
It did.
Yes, the, the stapledpeptide technology.
Simone Fishburn (28:40):
Yeah, I was gonna say, so first of all,
this pathway, I think by somedistance, has the best names
in it drizzled you know,really cool proteins all
the way down to Porcupine.
And there's a very nice, uh,graphic actually depicting
this in the article there.
that we put together.
But yeah, this comes out of GregVerdine's lab stapled peptides.
(29:03):
I think it's a veryinteresting, twist.
You know, Selina, wetalk a lot about all of
these other modalities.
This is a small moleculemodality that is, more
engineering in the smallmolecule space and really
trying to solve a problem.
That hasn't beensolved for a long time.
So if they can do that ata technical level, at the
same time as interrogatingor accessing a pathway
(29:26):
that's been resistant to,uh, to drug development,
that would be a big win.
Lauren Martz (29:33):
Yeah.
And so on Friday, they alsoshowed that in the same
trial, it wasn't limited tothe efficacy, wasn't limited
to the Desmoid tumors.
Um, they also showed efficacyat the triple meeting in
multiple other, Tumor typesthat don't have a particularly
high mutational burden.
So that's, that's whereParabilis is first taking
this technology becauseat that stage, you know,
(29:53):
there's a better chancethat if you have a β-catenin
mutation, that's the mutationthat's driving the cancer.
So, you know, you don'thave to worry about
additional mutations.
Uh.
Affecting the efficacy oftargeting this pathway.
but the company is lookingto expand into more complex
tumors, uh, specifically, uh,microsatellite stable colorectal
cancer, I think in combinations,um, just based on some of the
(30:16):
mechanisms of what happenswhen you do block this pathway.
Selina Koch (30:20):
Yeah.
And it'll beinteresting to see, um.
if they're hypothesis aboutit, being able to kind of
turn cold tumors warmer and,and synergize with PD-1, if
that, you know, works out.
Jeff Cranmer (30:32):
Sounds good.
Well, I'll drop a link.
To all of these storiesinto the show notes.
You can also find themat BioCenturypodcast.com.
And if you like what you'rehearing, uh, don't forget
to like and subscribe.
If you have a question forus drop us drop us a line,
coming up on Wednesday,we'll release the.
(30:54):
Podcast that we recordedin Shanghai on stage
with some special guests.
So look out for that.
we'd like to thank KendallSquare Orchestra for providing
the music to our podcasts.
Alanna Farro (31:08):
BioCentury would like to thank
Evotec for supporting theBioCentury This Week podcast.
To learn more about how Evoteccan support your goals through
pioneering drug discoveryand development solutions,
go to Evotec.com/innovation
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