November 24, 2025 • 33 mins
A baffling decision by FDA to issue a complete response letter for a pediatric medicine the medical community stood behind is just the latest example raising concerns that the agency is shifting the regulatory goalposts amid a lack of transparency. On the latest BioCentury This Week podcast, Washington Editor Steve Usdin explains how the absence of advisory committee meetings at FDA is in part to blame for a lack of consistency in decision-making and divergence from decisions taken by other global regulatory agencies. VP and Editor-in-Chief Simone Fishburn then discusses the takeaways from Franck Le Deu’s guest commentary on how China’s biotech ecosystem is evolving, and whether government support for the sector is helping or hindering its overall health. BioCentury’s analysts also discuss whether conventional CRISPR therapies will ever be commercially successful, and what’s next for NLRP3 inhibitors to treat obesity following the first set of Phase II data for the class.
We'd also like to invite our listeners to participate in our important survey about their experiences interacting with FDA. To take the survey, please go to BioCentury's FDA Sentiment Survey. This episode of the BioCentury This Week podcast is brought to you by Voyager Therapeutics.
View full story: https://www.biocentury.com/article/657698
#FDARegulation #CRISPRTherapies #NLRP3Inhibitors #ChinaBiotech #DrugApproval
00:01 - Sponsor Message: Voyager Therapeutics
01:31 - FDA Sydnexis CRL
07:36 - CDC Vaccine Claims
09:55 - China’s Innovation Arc
16:49 - CRISPR Commercial Viability
26:39 - NLRP3 for Obesity
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.]
Eric Pierce (00:03):
BioCentury This Week is brought to you
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Stephen Hansen (00:50):
The curious case of Sydnexis CRL that is
questions about consistencyof decision making at FDA.
Plus a perspective onthe state of play for
China's biotech industry.
Can CRISPR therapies becommercially successful.
And NLRP3 inhibitors in obesity,we'll discuss all of this on
today's BioCentury This Week.
I'm Stephen Hansen, one ofthe Directors of Biopharma
(01:12):
Intelligence here atBioCentury, and joining
me are my colleagues.
Simone Fishburn (01:16):
Simone Fishburn, Editor in Chief.
Lauren Martz (01:19):
Lauren Martz, Executive Director of
Biopharma Intelligence.
Steve Usdin (01:22):
And Steve Usdin, Washington Editor.
Stephen Hansen (01:24):
Great.
So I'm, uh, fillingin for Jeff this week.
Who is off enjoying, I thinkthe best that the American
Midwest has to offer, sowe will be kicking off
here talking with, Steve.
I think you had a story thispast week on a surprising
FDA decision, regarding apediatric medicine, can
you just fill us in on thecontext and what it means
for how we should be thinkingabout FDA at this point?
Steve Usdin (01:47):
Yeah, so I highlighted the Sydnexis CRL,
which didn't get a lot ofattention in newspapers or
even in publications that coverbiopharma because I think it's,
one, it's really important topatients, and two, because I
think it illustrates the kindof problems that seem to be
coming more common at FDA.
So Sydnexis had out to solve avery specific problem to create
(02:08):
an FDA approved version oflow dose atropine and eyedrops
to treat myopia in kids.
This is in no waya rare condition.
In fact, it's a hugeproblem and it's growing.
Myopia that occurs whilechildren are developing
often creates lifelong visionproblems, even blindness.
It's growing as I said,probably at least in part
because kids are spending moretime with screens that are
(02:29):
six inches away from theirface and less time outdoors.
So you could say, well, kidsshould just spend less time with
screens and more time outdoors.
That isn't happening rightnow, and until it does
myopia needs to be treated.
Many physicians prescribelow dose atropine drops.
There isn't an FDA approvedproduct, so parents purchase
compounded drops, but thequality is really variable.
(02:51):
It turns out that preventingatropine from degrading in
these drops isn't simple, andmany compounded drops have
subtherapeutic concentrations.
They also have alot of contaminants.
So Sydnexis is set out tocreate an FDA approved product.
FDA recommended, or atleast signed off on an
endpoint for the Sydnexistrial of its drug SYD-101.
(03:13):
The company conducted what itsays is the largest trial ever
conducted pediatric myopia,and it hit the endpoint.
EMA approved the drug, so didMHRA in the U.K., but FDA issued
a CRL according to Sydnexis.
The CRL acknowledgedthat they hit the primary
endpoint, but FDA said itdoesn't believe that the
company demonstrated efficacy.
(03:34):
Physicians who treat pediatricmyopia are apoplectic.
One of the things they pointout is that FDA Center for
Devices has approved lensesto treat myopia based on less
robust evidence of efficacythan this Sydnexis trial.
So normally, FDA would've heldan advisory committee meeting
to discuss the application.
Its thinking would'vebeen made public, and it
would've been pressuretested by academic experts.
(03:57):
But FDA has sharply curtailedthe use of adcoms, and it didn't
hold one for Sydnexis' product.
Here we have, it looks likewe have shifting regulatory
goalposts, a divergencebetween FDA and regulators
and other jurisdictions, alack of transparency, and
parents and physicians usinga compounded product rather
than an FDA approved drug.
Stephen Hansen (04:18):
Steve, it seems hard to figure out exactly
why FDA reached this decisionbased on all, you know, the
reporting you had from other.
the physicians and, andthe company itself, and
what was in the CRL.
So I mean, is there anychance that this is just
the FDA being severely shortstaffed and so they're having
to issue CRLs as a way oftrying to manage the volume of
applications they're reviewing?
(04:38):
Uh, I'm just wondering whetherthe staffing issues that we've
already talked about, you know,previously, could in any way be
playing into this or is therea way to know that it's not
related to staffing issues?
Steve Usdin (04:47):
We really don't know.
We don't have anyinsight into why the CRL.
was issued.
There are issues, you know,I spoke with some physicians.
There are issues about theways that you can measure
progression in myopia.
There are ways that FDAcould look at the data and
say, well, you know, we'renot convinced about it.
The problem, of course, is thatregulators in other countries
(05:11):
looked exactly the same dataand found it persuasive.
So you know if FDA has somethingelse that it wants, I think
that it has responsibilityto the community, both
to the parents and to thephysicians to do two things.
One is to explain whatit is that, that this
company didn't provide thatthey think is necessary.
And two, to say, well, whatwould be a path forward?
(05:34):
So the parents and kidscould have access to an
FDA-approved therapy.
Simone Fishburn (05:39):
Steve, you talked about FDA, looking
at the data differently thanthe European regulators.
Now that's not obviously thefirst time it's happened.
In fact, I think we'vegenerated some data in the
past comparing, certainly Ithink it was in the context
of accelerated approvals.
How the two agencies look at it.
(05:59):
Can you talk a little bitabout how different this
is from anything else inthe past, whether you think
that this is prelude orwhy you think this might be
prelude to more discrepanciesfrom other agencies?
Steve Usdin (06:12):
Well, actually, I think if you go back and look
at it that most of the timeswhen there's been discrepancy
between FDA and Europe, it'sbeen because FDA has been more
permissive, it's approved thingsthat weren't approved in Europe.
Um, this is theopposite obviously.
I think also that this isn't alot of the, the controversies
(06:32):
have been around products wherethere was, uh, where they didn't
meet their endpoints or theywere very rare conditions where
there weren't large trialsand there weren't large effect
sizes and things like that.
That doesn't seemto be the case here.
And I would say, really,the core issue is the
lack of transparency.
You know, in the past we'vehad advisory committee meetings
(06:54):
where these issues come outand we, we know the public
knows, the physicians knowthe patients know where FDA's
coming from, why it's madethe decisions that it's made.
All of those things are alittle bit different from
what's happened in the past.
And then this gets backto what we talked about
last week, which is, youknow, 'cause this product,
by the way, it's at CDER.
So this gets back to whatwe talked about last week,
(07:15):
which is what are the kindof changes that we can expect
under Rick Pazdur at CDER?
One of the things that I thinkthat we can expect is more
advisory committee meetings.
And this controversy is kindof a poster child for why
advisory committee meetings canbe really, really important.
Stephen Hansen (07:31):
Great.
No, I I think you're absolutelyright Steve, and know, I also
wanted to get your thoughtson, I think everyone's probably
aware of the comments from CDCrelated to vaccines and autism.
But I wondered if you couldprovide some perspective on
kind of what you think theimplications are for industry,
maybe, just beyond you know,these initial comments.
Steve Usdin (07:49):
Yeah, so really quickly, CDC posted on
its website, a statementthat the claim vaccines
do not cause autism is notan evidence-based claim.
Look quick shout out to B io,they put out a statement this
morning saying that, extensivescientific research with dozens
of peer-reviewed studies andcontinuous safety monitoring
over decades have consistentlyshown that vaccines in their
(08:10):
ingredients do not cause autism.
So here's the forward lookingpart of it, which is even
worse or even more alarming,than what's happened to date,
which is that where SecretaryKennedy is going with this
is to investigate and tocast out on the safety of
vaccines that contain aluminum,which he claims contrary to
(08:32):
the evidence causes autism.
Polling vaccines with adjuvantscontaining aluminum would
re many essential vaccines,vaccines against polio, against
measles, against pertussis.
You know, it would have horrificpublic health consequences.
So that's why I think it's,it's important to kind of
stay on top of this one.
And honestly for peopleto speak out, speak out
(08:55):
publicly to prevent thisfrom going even farther.
Stephen Hansen (08:59):
Well, thank you for that, Steve.
We will continue thisconversation in a moment,
but we'll take a quickbreak and be right back.
Alanna Farro (09:05):
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Stephen Hansen (09:53):
Welcome back to BioCentury This Week I'd
like to now turn to Simoneto discuss a very interesting
guest commentary we had fromFranck Le Deu, Founder and
Managing Partner at KerZhengVentures, and Senior Partner
at Emeritus with McKinsey.
He highlighted some of thepromising aspects of China's
burgeoning biotech sector,but he also, you know, I
think, shared some concerns.
(10:14):
So what were your, whatwere some of your takeaways
from his piece, Simone?
Simone Fishburn (10:17):
Yeah, so I strongly encourage people to
read this, and I just wannatake a couple of minutes to
give some sort of context here.
So, Franck Le Deu recently leftMcKinsey where he'd been, oh,
I'm not gonna say how long,but like a very long time.
Like over 10 years.
I'm not sure if it's 20.
Anyway, he'd beenthere a very long time.
He is a very, very knowledgeableand informed observer of
(10:41):
the China biotech scene.
He's also been involvedwith BioCentury and our
conferences since we'vestarted them 12, 13 years ago.
And I think what's interestingis right now, as I've talked
about, this is the yearthe rest of the world woke
up to biotech in China.
Franck's several stepsahead of everybody, right.
So he has some verysophisticated thoughts
(11:02):
about how the Chinaecosystem is working out.
And he draws this analogy.
I gotta be honest, I'mnot a mixed martial arts.
expert or even person.
So I kind of had to look itup, to be quite honest, don't
tell Franck, but anyway, hecalls it, you know, is China
entering the Oktagon, that'sOktagon with a k, which is a
mixed martial arts concept.
(11:24):
What he talks about is Chinabeing the world's toughest
arena for innovation.
But he draws some reallyinteresting parallels with
electric vehicles, EVs, right.
And that was somethingwhere the China central
government made it a reallybig priority to create EVs.
I think early in the 2010s,you know, that has sort of had
(11:45):
this global impact, arguably,he argues leading to Tesla.
Many players now, rest of theworld, U.S., Europe, Japan,
South Korea, playing catch up.
What he says is that theindustry in inside China has
unsustainable economics becauseit's got a very deep price
war, over capacity is rampantand so on, I'm not gonna
go into that in too detail.
(12:06):
But what he says is, doesthe China biotech industry,
could that go the same way?
And he talks about some ofthe flaws that are reminiscent
of these other industries.
So I wanna wa just talkthrough a couple of the
ones that he mentions, hetalks about over capacity.
It's another parallel.
Too many companies goingoff the same target.
Too many investors, insufficientcapital allocation, insufficient
(12:31):
rewards by the local innovationmarket, which is like China
biotech's being driven to pricewar behaviors, 'cause they've
got volume-based procurementof generics, National
Reimbursement Drugs List,and it's not all sustainable.
Geopolitics as we know, limitsthe ability to go to the West.
So there are a few sort of,headwinds for that market.
And then he talks aboutthe ways that these flaws
(12:53):
could be addressed and thecertain levers, which I think
Americans call levers, right?
Whatever levers to pull.
Stephen Hansen (13:01):
That works.
Simone Fishburn (13:01):
And you know, market conditions access
conditions could improve andflight to quality and so on.
So I think that it'sreally worth reading.
He sort of talks throughthe prevailing headwinds
from inside China thatare making that ecosystem.
Might say vulnerable to someof the things that you know,
(13:23):
other sectors like electricvehicles have experienced.
Steve Usdin (13:27):
He mentions also in passing, the
possibility of Biosecurepassing in the United States.
And I would say from what theconversations that I'm having,
it seems very likely thatBiosecure 2.0 as we're calling
it will be part of the NationalDefense Authorization Act that's
likely to pass in December.
Simone Fishburn (13:44):
So let's just stay there for a minute,
Steve, especially given the1.0, the 2.0, and I know
you've written about this, butlet's just remind listeners.
What actually remained in this?
'cause it wasn't quite asdraconian if I understand
it as the first version.
But what are the actualimplications if or when
this does get passed?
Steve Usdin (14:05):
You know, the, the problem is that we won't
really know that for some time.
Because the second versiongives a lot of discretion to
the administration in terms ofwhat companies are swept up into
it, and what the implicationsof it are for the marketplace.
Basically, the biggestdifference between the second
version, the one that's likelyto pass now, and the first
(14:27):
version is, the first versionmentions specific companies
that would be subject to theBiosecure Act in particular
WuXi AppTec and WuXi Biologics.
The second version basicallysays, well, the, the
administration is going to setup a process for figuring out
what companies are so-calledbiotechnology companies
of concern, and it createsbroad parameters that the
(14:52):
administration could use, theycould, um, include the two
WuXi companies if they wantedto, but they could exclude
them if they want them also.
So it's not known whetherthey're gonna be included.
And then there's really alsoa certain amount of ambiguity
about what it actually means.
It's clear, or it seems tobe clear that, for example,
companies that use servicesfrom biotechnology companies
(15:13):
of concern, after a five-yeargrandfather period, won't be
able to sell their productsto NIH, to the Veterans
Administration, to otherdefense department programs.
What really isn't clear,is the extent to which it
would impact, for example,Medicaid, the Medicaid
markets, and that again,is going to have to depend
on implementation policiesfrom the administration.
Simone Fishburn (15:37):
That's very helpful, Steve.
So, you know, I just reallyencourage people to read
Franck's commentary, it is infact in front of the paywall.
And I, I think that justgaining really knowledgeable
insights from insidersabout the opportunities,
but also the headwinds forany particular ecosystem.
Reminding people we areglobal at BioCentury.
(16:00):
We care about all of it.
Who's where andwho can be where.
Um, and the China ecosystem isobviously a very important one.
So I really encouragereaders to go to that.
And I am sure that ourtrustee colleague Cole, will
put this in our show notes.
He's the guy who makeseverything happen, just
a shout out to Cole.
We get a lot of complimentsabout the podcast, but
(16:22):
really it's all Cole.
Stephen Hansen (16:24):
That's right.
I'm sure he will,that's wonderful.
Thanks Simone, and you know,I, I'm also just excited
'cause I got to cross off oneof the last few squares on
my 2025 Bingo card when youtalked about MMA, it was one
of the few remaining ones.
So nice to,
Simone Fishburn (16:37):
I am really excited to know what's on
the card for next year,so I'll be, uh, yeah,
Stephen Hansen (16:42):
Oh, well, we'll, we'll, we'll
keep that, we'll keep
Simone Fishburn (16:44):
we got the World Cup actually then don't
we, we got World Cup coming up.
Stephen Hansen (16:46):
Hmmm, yeah.
But anyways, let's turn now Iwould like to turn to Lauren,
who herself had a quite aninteresting commentary piece,
looking at whether conventionalCRISPR therapies will ever
demonstrate commercial success.
So, Lauren, give us abit of context here,
what were your takeaways?
Lauren Martz (17:03):
Thanks Stephen, and this is hard to write
because I'm gene therapygene editing's biggest fan.
But recently there have beena few events that I think
we've all Been followingthat have contributed to an
increasingly negative sentimentaround gene editing therapies.
You know, this isn't news, butit got me thinking about what
that opportunity is for whatwe would call conventional
(17:25):
or traditional CRISPR-Cas9therapy at this time.
And it's crazy that we'reeven calling it traditional
CRISPR-Cas9 because it'ssuch a new technology.
So one of the recent eventsthat we may have talked about
before on this podcast is thepatient death in Intellia's
Phase III trial of nex-z, totreat transthyretin amyloidosis.
(17:47):
So in that trial, a patientdied from liver toxicity,
which presented outside ofthe normal window for lipid
nanoparticle related toxicity.
You know, this patient wasolder, had comorbidities.
But it still raised thepotential for a toxicity that
we weren't anticipating, atoxicity that may be related to
the target or the to the geneticcargo, or something else.
(18:08):
And it, it's just an importantreminder I think for investors
and for everyone that there'sstill some uncertainty around
the long-term safety of invivo genetic editing therapies.
At the same time that thingslike this have been happening,
we've been watching thisincredible rise of the RNA
modalities, siRNA, antisense.
(18:30):
And there's a lot of overlap inthe indications that companies
are treating with in vivo geneediting therapies, and with
these RNA therapies, you know,transthyretin amyloidosis
is an example of one.
In both cases you canknock down gene expression.
With RNA therapies you can doit pretty durably, these are
dosed like every six monthsnow and quite efficiently,
(18:52):
during that durability window.
So I think what's happening isthat the difference in value
that you could get from aone-time CRISPR-Cas9 therapy and
RNA therapy is really shrinking.
The question kind of becomesfor patients and physicians, is
it worth taking the risks of aone-time gene editing therapy to
(19:13):
not have to take an injection,or an infusion every six months.
Steve Usdin (19:17):
Are there examples of things that can be done
or could be done with CRISPRtherapy that really aren't
possible with other modalities?
Lauren Martz (19:25):
So that's the question that I was thinking
about, and there may be.
With the knockdown knockoutapproaches, there's a
ton of overlap there.
With inducing expression ofa gene, this is something
that you can't do with thosetypes of RNA modalities.
It's something that you maypotentially be able to do with
a prime editor for example, orsome of the newer iterations
(19:45):
of the CRISPR technology.
But then the questionbecomes, if those are going
to advance through the clinic.
And we haven't been able todo that very efficiently with
a traditional CRISPR-Cas9.
You know, is there, is therean opportunity there either?
I think all of this may becomemore clear as the technology
is followed, as we learnmore about the safety and
(20:07):
efficacy in the long term.
And I think there's also animportant point to make here,
which is that the CRISPR-Cas9therapies that are in the clinic
have been working incrediblywell, and they just happen to
be overlapping with a lot ofother modalities, you know,
some other modalities that arein the clinic or in development
for the same indications.
(20:29):
There are all ofthese unaddressed
indications out there.
So, I think that everyoneshould be spreading out what
they're addressing with thesenewer technologies or with
these alternative technologies,and continuing to develop,
not abandoning what's effectivebecause in the future there
may be something that couldbe, you know, slightly safer,
slightly more effective.
Simone Fishburn (20:48):
Yeah.
So first of all, again,this won't surprise anybody.
I'm gonna encourageyou to read the piece.
It's really very well writtenand It's just a very interesting
field that we've been watchingliterally since its birth, we
don't often get to do that.
And, you know, acknowledgingthe huge impact.
I think there's one pointthat you've made, Lauren,
which is sort of in responseto Steve's thing, is like we
(21:08):
talked about herding, right,that Franck talked about, but
we all see that as going on.
And testing these newtechnologies at this point
it really needs to be goinginto areas where they're
not massively covered bysomething that could frankly
just do better than them.
But I do wanna ask you onequestion, you know, half of the
premise, your piece say's likehalf of it is what you just
(21:29):
said, which is like actuallyprime editing and base editing
might be better served, we'llfind that out, for some of
the more specific or advancedmutations that you might
want to address in disease.
But then the other half of it isthat RNAi so siRNA or antisense
have really you know taken thebusiness case, let's say, away
(21:52):
from some of the CRISPR-Cas9kind of gene editing.
So for prime editing,whatever they came afterwards.
But, siRNA and antisensehas been around a lot
longer than CRISPR.
And so we've been writing overthe years, like the market would
go crazy in CRISPR technologies,even just on a preclinical
preprint, it was insane.
(22:13):
So what is it that thisfrenzy is all about?
I mean, what I'm trying tosay is that, that information
was there also five yearsago and also 10 years
ago, about the potentialfor RNAi and antisense.
And so why is it onlynow that that argument
is coming to the front?
Lauren Martz (22:31):
In my opinion, I mean, we've watched
these parallel indicationsadvanced through the clinic.
And you're seeing knockdownlevels of the targets that are
not looking very different.
And I don't know if thatwas ever appreciated before.
Maybe it was, but it, I Icertainly didn't expect that,
you know, in the 90s, regardlessof what modality you're using.
The whole premise ofCRISPR-Cas9 was that you
(22:53):
could do this so efficientlyand you could do it one time.
And so I think, there justwasn't a full understanding
of how effective the RNA classof therapies could be, and
how long lasting, you know,the chemistry has changed
from where it started out, thelong lasting oligos are, it's
kind of a game changer, right?
If you can dose itonce a year or even.
Simone Fishburn (23:15):
Yeah, so what I'm hearing is that actually,
antisense technologieshave really moved a long
way in the last few years.
I mean, Stephen, you arenodding, I dunno if you
wanna weigh in on that.
And so, even though they'vebeen around a long while,
they've just got an incredibleamount of validation,
maybe extra commercialand technical validation
in the last few years.
Is that how yousee it, you guys?
Stephen Hansen (23:37):
Yeah, well, well, I was just gonna say,
I mean, one of the big gamechangers for the siRNA sort
of modality was the GalNAcstabilization technology, right.
When that came in, thatreally sort of changed
things and allowed companiesto move past that sort
of delivery formulationchallenge that they had faced.
And, I'm kind of putting youon the spot here line, but I'm,
I'm wondering if there's like a,a parallel sort of step change
(24:00):
that CRISPR modality wouldneed to see to sort of enable
it to be able to have the sameimpact that we're now seeing
from the RNA technologies?
technologies
Lauren Martz (24:10):
I actually don't have an answer to that.
I think as Simone mentioned,the markets have been
really tough on the CRISPRgene editing technologies.
I mean, the safety efficacyoverall is very strong for
the programs that we've seen.
One thing that I didn't touch onin the perspective is delivery.
So I think that back to Steve'soriginal question, this is an
(24:32):
opportunity, I think that'skind of still up for grabs, is
which modality will get outsideof the liver most effectively.
There could be some overlapin the types of technologies
that ultimately will be usedfor extra hepatic delivery.
But, you know, you coulduse something different
to deliver RNAi very wellto, to different tissues.
(24:53):
So, those are still justcompletely open, I think
for, for both of thesetypes of technologies.
Stephen Hansen (25:00):
I, I, I think just, just also real quickly
just to comment on when Simonewas mentioning about those, that
heyday for CRISPR companies,when they were flying up a
100% on preclinical data,there was probably a real
strong under appreciation forthe safety issues that they
could potentially face, right.
And so now that they've gottenfurther into the clinic and some
of those issues, unlike genetherapy have come to the fore,
(25:21):
uh, I think there's a better,better maybe appreciation
of the, the benefit riskprofile that these therapies
maybe potentially carry.
Simone Fishburn (25:29):
Okay well, I'm gonna jump in here because then
shame on the investors, right.
Like the, the risk okay of thegene editing technologies was
there all the way along and wewere writing about it, right.
so shame on them if they didn'treally have a good understanding
of the risk at landscape.
doesn't mean you're wrong.
I'm just saying that,that investors need
(25:49):
to do their homework.
Lauren's not agreeing with me.
Lauren Martz (25:53):
I don't know.
I just think it'sbeen so up and down.
You know, you, there may bea slight indication that you
could have an off target editand the stock prices tank.
And then there dozens ofpatients are completely fine
after being treated with thisand everything seems fine.
And then, you know, oneliver toxicity, one severe
liver toxicity event.
It just goes up and down,I think there's been an
(26:14):
understanding all along that thestakes are high for a one time
therapy when it comes to safety.
Stephen Hansen (26:20):
Yeah, maybe one final thing is it's
just also a reflectionof how fast innovation
moves these days, right.
I mean, it's only been.
12, 13 years since we hadthe first CRISPR publication,
and it's already potentiallybecoming obsolete, you
know, too strong of a word.
But, uh, I think it's justa reflection of how fast
things move these days now.
Got to stay ahead.
Steve Usdin (26:39):
I want to, turn the tables a little bit on Stephen
Hansen and ask a question.
We've seen the firstclinical data on NLRP3
inhibitors in obesity.
What do we see?
Stephen Hans (26:49):
Yeah thanks Steve.
when I host, don't you?
You love turningthe tables on me.
Um, yeah, so we had thefirst data come in about a
month ago, Phase II data,and uh it wasn't good if
you were expecting an NLRP3inhibitor to show weight loss.
So a bit of context here, about18 months ago, there was some
very unexpected preclinical datapublished by private biotech
(27:09):
company NodThera, that showedthat an NLRP3 inhibitor can
lead to monotherapy, weightloss, and a mouse model.
And they also showed additiveweight loss when it was
combined with a GLP-1.
So that basically sent everycompany that had an NLRP3
inhibitor, scrambling totest their own programs in
preclinical models, and quitea few of them then quickly
(27:29):
moved into the clinic.
The first to do thiswas Ventyx Biosciences.
They had seen decent weightloss, in a DIO mouse model,
they showed 9% monotherapyweight loss after 28 days.
And then, when they added itto a GLP-1, they saw more than
what you got with a GLP-1 alone.
So that was enough for them.
They moved into a Phase IIstudy, late last year, I
(27:51):
think, uh, 175 patients,with their program VTX3232.
So that study was theone that just spread out
this past, a month ago.
And, first glance itseemed pretty clear cut.
There was no difference onweight loss from placebo at 12
weeks for the monotherapy arm.
And then patients in thecombination cohorts, where
(28:12):
they had this 3232 programcombined with semaglutide.
The weight loss wasactually numerically
worse than the weight lossfor semaglutide alone.
So it seemed, seemedpretty clear cut.
Right?
I mean, I, I spoke toVentyx’s Founder and CEO, Raju
Mohan, for him he thought itabsolutely was quite clear
cut, you know, he basicallysaid, there's no signal
(28:32):
here in this Phase II study.
there's no solid biologicalevidence to support the
role of NLRP3 in obesityother than this hypothesis
around neuroinflammation.
So, you know, he thought itwas pretty clear cut and dry,
we tried it, doesn't work.
We're moving on to other things.
But as you might suspect youknow, not everyone kind of
agree with that conclusion.
(28:53):
There are other biotechs, suchas aforementioned NodThera
and Neumora, that are pushingforward, and that is sort of
based on their suggestion,their hypothesis that their
compounds are either more potentor have a higher level of brain
penetration, necessary to hitthe target in the hypothalamus.
So they're moving forward,they also feel like they
showed greater efficacyin preclinical models.
(29:16):
Yeah, you know, I guess,we'll wait and see.
But, you know, I have to say,it was an interesting, finding
when we first wrote aboutit 18 months ago, I now kind
of consider myself, I guessmaybe a bit of, a bit of an
NLRP3 skeptic when it comesto weight loss and obesity.
I'm also of the opinion that.
I'm not really sure if itmatters a ton because you know
what Ventyx did demonstrateand what sent their stock up
(29:37):
quite a bit was that NLRP3s,you know, are pretty potent
anti-inflammatory moleculesand they showed some pretty
impressive, like 80 to 90%reduction in inflammatory
markers, for CV risk reductionin their obesity trial.
And so, I can envision ascenario in which even if you
don't show any weight losswhatsoever, you know, you
(29:57):
could see a scenario whereyou could combine an NLRP3 if,
obviously if this, you know,anti-inflammatory CV risk
reduction were to pan out.
You could see this being part ofthe regimen because, you know,
I think we all know obesitypatients, you know, have one
of the highest elevated levelsfor CV risk, of other patients
with these comorbidities.
And right now, you know,on GLP-1s, obesity patients
(30:21):
get about a 20% reductionin CV risk, based on the
semaglutide CVOT data.
So if you can add on NLRP3 andyou can dramatically boost or
substantially increase thatrisk reduction level, even
if you don't see more weightloss, I think there still
could be a role for NLRP3
Steve Usdin (30:39):
So,
Stephen Hansen (30:39):
in this space.
Steve Usdin (30:40):
what would it take to demonstrate that?
Because those kind oftrials are not short and
they're not cheap right?
Stephen Hansen (30:45):
That's true, that's true.
It would take a, it would take,a CV outcomes trial of its own.
So you're right, that isdefinitely not a space where
your typical small biotech wouldlikely be able to run a study.
So they'd probably have to dothis either with a partner or
they'd have to be able to raisea substantial amount of money.
That's, I guess, for theinvestors to try and figure
out whether they thinkit's, it's worth the risk.
(31:06):
But this isn't the only settingwhere they'd have to do that.
I think Ventyx is alsotesting this molecule in
a pericarditis, trial.
And so that also willpotentially require a
CV outcome trial too.
So these will be big studies.
But, for instance if I justthrow it a hypothetical.
If you can double therisk reduction, I think
that very well could beworth it, but we'll see.
(31:26):
Well, thank you to mycolleagues for joining me
today, and thanks to all ofyou for tuning in this week.
Before we go, I would alsolove for everyone, that is
listening, if they couldjoin us and participate in
our current survey that wehave ongoing about the FDA,
there will be a link inthe show notes, and I think
Simone wants to provide someemphasis as to how important
(31:47):
this is to us, so Simone.
Simone Fishburn (31:49):
It is important to us, Stephen,
because it's importantto them, to our audience,
Stephen Hansen (31:54):
That too.
That's too.
Simone Fishburn (31:55):
we live to serve them.
Yeah.
So the survey link everybodyis BioCenturysurvey.com.
That's BioCenturysurvey one word .com.
Cole aforementioned Cole.
We'll have the linkalso in the show notes.
This is a survey for investorsand biotechs, in particular
(32:17):
who've been working with FDA orother regulatory agencies, but
this is specifically about FDA.
We need to know what is working,what isn't working, good, bad.
It only takes five minutes.
It's an unbiased survey.
We are really justtaking the temperature.
We are trying to get intosome of the very specifics
of parts of the agency andinteractions where sponsors
(32:39):
are having productiveoutcomes or interactions
and areas where less so.
It's not a superficialsurvey, but it is a quick one.
Steve Usdin (32:50):
I wanna point out that it is anonymous also.
Because I've receivedconcerns from some people
who were thinking aboutfilling out the survey,
and they're concerned aboutanonymity, it is anonymous.
Simone Fishburn (33:00):
Our surveys are always anonymous.
Thank you, Steve.
That is really importantand we will be presenting
aggregate data from the surveybefore the end of the year.
If you all do your job andfill it out, then you'll
get the answers beforethe end of the year.
Stephen Hansen (33:13):
Great.
Thank you Simone.
and thank you allfor joining us.
As I've mentioned before, allof the stories that, uh, we've
discussed today, you can findat BioCentury podcast.com.
You can also check out oursister podcast The BioCentury
Show, where believe themost recent episode featured
Steve, in conversation withElias Zerhouni former NIH
(33:33):
Director, and after thatGlobal Head of R&D at Sanofi.
Thank you again and wewill catch you next week.
Eric Pierce (33:41):
BioCentury would like to thank Voyager
Therapeutics for supporting theBioCentury This Week podcast.
To learn more aboutVoyager's programs advancing
transformative medicines forneurological diseases, visit
voyagertherapeutics.com.
[AI-generated transcript.]
Eric Pierce (00:03):
BioCentury This Week is brought to you
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Voyager addresses the challengeof delivering novel treatments
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Stephen Hansen (00:50):
The curious case of Sydnexis CRL that is
questions about consistencyof decision making at FDA.
Plus a perspective onthe state of play for
China's biotech industry.
Can CRISPR therapies becommercially successful.
And NLRP3 inhibitors in obesity,we'll discuss all of this on
today's BioCentury This Week.
I'm Stephen Hansen, one ofthe Directors of Biopharma
(01:12):
Intelligence here atBioCentury, and joining
me are my colleagues.
Simone Fishburn (01:16):
Simone Fishburn, Editor in Chief.
Lauren Martz (01:19):
Lauren Martz, Executive Director of
Biopharma Intelligence.
Steve Usdin (01:22):
And Steve Usdin, Washington Editor.
Stephen Hansen (01:24):
Great.
So I'm, uh, fillingin for Jeff this week.
Who is off enjoying, I thinkthe best that the American
Midwest has to offer, sowe will be kicking off
here talking with, Steve.
I think you had a story thispast week on a surprising
FDA decision, regarding apediatric medicine, can
you just fill us in on thecontext and what it means
for how we should be thinkingabout FDA at this point?
Steve Usdin (01:47):
Yeah, so I highlighted the Sydnexis CRL,
which didn't get a lot ofattention in newspapers or
even in publications that coverbiopharma because I think it's,
one, it's really important topatients, and two, because I
think it illustrates the kindof problems that seem to be
coming more common at FDA.
So Sydnexis had out to solve avery specific problem to create
(02:08):
an FDA approved version oflow dose atropine and eyedrops
to treat myopia in kids.
This is in no waya rare condition.
In fact, it's a hugeproblem and it's growing.
Myopia that occurs whilechildren are developing
often creates lifelong visionproblems, even blindness.
It's growing as I said,probably at least in part
because kids are spending moretime with screens that are
(02:29):
six inches away from theirface and less time outdoors.
So you could say, well, kidsshould just spend less time with
screens and more time outdoors.
That isn't happening rightnow, and until it does
myopia needs to be treated.
Many physicians prescribelow dose atropine drops.
There isn't an FDA approvedproduct, so parents purchase
compounded drops, but thequality is really variable.
(02:51):
It turns out that preventingatropine from degrading in
these drops isn't simple, andmany compounded drops have
subtherapeutic concentrations.
They also have alot of contaminants.
So Sydnexis is set out tocreate an FDA approved product.
FDA recommended, or atleast signed off on an
endpoint for the Sydnexistrial of its drug SYD-101.
(03:13):
The company conducted what itsays is the largest trial ever
conducted pediatric myopia,and it hit the endpoint.
EMA approved the drug, so didMHRA in the U.K., but FDA issued
a CRL according to Sydnexis.
The CRL acknowledgedthat they hit the primary
endpoint, but FDA said itdoesn't believe that the
company demonstrated efficacy.
(03:34):
Physicians who treat pediatricmyopia are apoplectic.
One of the things they pointout is that FDA Center for
Devices has approved lensesto treat myopia based on less
robust evidence of efficacythan this Sydnexis trial.
So normally, FDA would've heldan advisory committee meeting
to discuss the application.
Its thinking would'vebeen made public, and it
would've been pressuretested by academic experts.
(03:57):
But FDA has sharply curtailedthe use of adcoms, and it didn't
hold one for Sydnexis' product.
Here we have, it looks likewe have shifting regulatory
goalposts, a divergencebetween FDA and regulators
and other jurisdictions, alack of transparency, and
parents and physicians usinga compounded product rather
than an FDA approved drug.
Stephen Hansen (04:18):
Steve, it seems hard to figure out exactly
why FDA reached this decisionbased on all, you know, the
reporting you had from other.
the physicians and, andthe company itself, and
what was in the CRL.
So I mean, is there anychance that this is just
the FDA being severely shortstaffed and so they're having
to issue CRLs as a way oftrying to manage the volume of
applications they're reviewing?
(04:38):
Uh, I'm just wondering whetherthe staffing issues that we've
already talked about, you know,previously, could in any way be
playing into this or is therea way to know that it's not
related to staffing issues?
Steve Usdin (04:47):
We really don't know.
We don't have anyinsight into why the CRL.
was issued.
There are issues, you know,I spoke with some physicians.
There are issues about theways that you can measure
progression in myopia.
There are ways that FDAcould look at the data and
say, well, you know, we'renot convinced about it.
The problem, of course, is thatregulators in other countries
(05:11):
looked exactly the same dataand found it persuasive.
So you know if FDA has somethingelse that it wants, I think
that it has responsibilityto the community, both
to the parents and to thephysicians to do two things.
One is to explain whatit is that, that this
company didn't provide thatthey think is necessary.
And two, to say, well, whatwould be a path forward?
(05:34):
So the parents and kidscould have access to an
FDA-approved therapy.
Simone Fishburn (05:39):
Steve, you talked about FDA, looking
at the data differently thanthe European regulators.
Now that's not obviously thefirst time it's happened.
In fact, I think we'vegenerated some data in the
past comparing, certainly Ithink it was in the context
of accelerated approvals.
How the two agencies look at it.
(05:59):
Can you talk a little bitabout how different this
is from anything else inthe past, whether you think
that this is prelude orwhy you think this might be
prelude to more discrepanciesfrom other agencies?
Steve Usdin (06:12):
Well, actually, I think if you go back and look
at it that most of the timeswhen there's been discrepancy
between FDA and Europe, it'sbeen because FDA has been more
permissive, it's approved thingsthat weren't approved in Europe.
Um, this is theopposite obviously.
I think also that this isn't alot of the, the controversies
(06:32):
have been around products wherethere was, uh, where they didn't
meet their endpoints or theywere very rare conditions where
there weren't large trialsand there weren't large effect
sizes and things like that.
That doesn't seemto be the case here.
And I would say, really,the core issue is the
lack of transparency.
You know, in the past we'vehad advisory committee meetings
(06:54):
where these issues come outand we, we know the public
knows, the physicians knowthe patients know where FDA's
coming from, why it's madethe decisions that it's made.
All of those things are alittle bit different from
what's happened in the past.
And then this gets backto what we talked about
last week, which is, youknow, 'cause this product,
by the way, it's at CDER.
So this gets back to whatwe talked about last week,
(07:15):
which is what are the kindof changes that we can expect
under Rick Pazdur at CDER?
One of the things that I thinkthat we can expect is more
advisory committee meetings.
And this controversy is kindof a poster child for why
advisory committee meetings canbe really, really important.
Stephen Hansen (07:31):
Great.
No, I I think you're absolutelyright Steve, and know, I also
wanted to get your thoughtson, I think everyone's probably
aware of the comments from CDCrelated to vaccines and autism.
But I wondered if you couldprovide some perspective on
kind of what you think theimplications are for industry,
maybe, just beyond you know,these initial comments.
Steve Usdin (07:49):
Yeah, so really quickly, CDC posted on
its website, a statementthat the claim vaccines
do not cause autism is notan evidence-based claim.
Look quick shout out to B io,they put out a statement this
morning saying that, extensivescientific research with dozens
of peer-reviewed studies andcontinuous safety monitoring
over decades have consistentlyshown that vaccines in their
(08:10):
ingredients do not cause autism.
So here's the forward lookingpart of it, which is even
worse or even more alarming,than what's happened to date,
which is that where SecretaryKennedy is going with this
is to investigate and tocast out on the safety of
vaccines that contain aluminum,which he claims contrary to
(08:32):
the evidence causes autism.
Polling vaccines with adjuvantscontaining aluminum would
re many essential vaccines,vaccines against polio, against
measles, against pertussis.
You know, it would have horrificpublic health consequences.
So that's why I think it's,it's important to kind of
stay on top of this one.
And honestly for peopleto speak out, speak out
(08:55):
publicly to prevent thisfrom going even farther.
Stephen Hansen (08:59):
Well, thank you for that, Steve.
We will continue thisconversation in a moment,
but we'll take a quickbreak and be right back.
Alanna Farro (09:05):
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Stephen Hansen (09:53):
Welcome back to BioCentury This Week I'd
like to now turn to Simoneto discuss a very interesting
guest commentary we had fromFranck Le Deu, Founder and
Managing Partner at KerZhengVentures, and Senior Partner
at Emeritus with McKinsey.
He highlighted some of thepromising aspects of China's
burgeoning biotech sector,but he also, you know, I
think, shared some concerns.
(10:14):
So what were your, whatwere some of your takeaways
from his piece, Simone?
Simone Fishburn (10:17):
Yeah, so I strongly encourage people to
read this, and I just wannatake a couple of minutes to
give some sort of context here.
So, Franck Le Deu recently leftMcKinsey where he'd been, oh,
I'm not gonna say how long,but like a very long time.
Like over 10 years.
I'm not sure if it's 20.
Anyway, he'd beenthere a very long time.
He is a very, very knowledgeableand informed observer of
(10:41):
the China biotech scene.
He's also been involvedwith BioCentury and our
conferences since we'vestarted them 12, 13 years ago.
And I think what's interestingis right now, as I've talked
about, this is the yearthe rest of the world woke
up to biotech in China.
Franck's several stepsahead of everybody, right.
So he has some verysophisticated thoughts
(11:02):
about how the Chinaecosystem is working out.
And he draws this analogy.
I gotta be honest, I'mnot a mixed martial arts.
expert or even person.
So I kind of had to look itup, to be quite honest, don't
tell Franck, but anyway, hecalls it, you know, is China
entering the Oktagon, that'sOktagon with a k, which is a
mixed martial arts concept.
(11:24):
What he talks about is Chinabeing the world's toughest
arena for innovation.
But he draws some reallyinteresting parallels with
electric vehicles, EVs, right.
And that was somethingwhere the China central
government made it a reallybig priority to create EVs.
I think early in the 2010s,you know, that has sort of had
(11:45):
this global impact, arguably,he argues leading to Tesla.
Many players now, rest of theworld, U.S., Europe, Japan,
South Korea, playing catch up.
What he says is that theindustry in inside China has
unsustainable economics becauseit's got a very deep price
war, over capacity is rampantand so on, I'm not gonna
go into that in too detail.
(12:06):
But what he says is, doesthe China biotech industry,
could that go the same way?
And he talks about some ofthe flaws that are reminiscent
of these other industries.
So I wanna wa just talkthrough a couple of the
ones that he mentions, hetalks about over capacity.
It's another parallel.
Too many companies goingoff the same target.
Too many investors, insufficientcapital allocation, insufficient
(12:31):
rewards by the local innovationmarket, which is like China
biotech's being driven to pricewar behaviors, 'cause they've
got volume-based procurementof generics, National
Reimbursement Drugs List,and it's not all sustainable.
Geopolitics as we know, limitsthe ability to go to the West.
So there are a few sort of,headwinds for that market.
And then he talks aboutthe ways that these flaws
(12:53):
could be addressed and thecertain levers, which I think
Americans call levers, right?
Whatever levers to pull.
Stephen Hansen (13:01):
That works.
Simone Fishburn (13:01):
And you know, market conditions access
conditions could improve andflight to quality and so on.
So I think that it'sreally worth reading.
He sort of talks throughthe prevailing headwinds
from inside China thatare making that ecosystem.
Might say vulnerable to someof the things that you know,
(13:23):
other sectors like electricvehicles have experienced.
Steve Usdin (13:27):
He mentions also in passing, the
possibility of Biosecurepassing in the United States.
And I would say from what theconversations that I'm having,
it seems very likely thatBiosecure 2.0 as we're calling
it will be part of the NationalDefense Authorization Act that's
likely to pass in December.
Simone Fishburn (13:44):
So let's just stay there for a minute,
Steve, especially given the1.0, the 2.0, and I know
you've written about this, butlet's just remind listeners.
What actually remained in this?
'cause it wasn't quite asdraconian if I understand
it as the first version.
But what are the actualimplications if or when
this does get passed?
Steve Usdin (14:05):
You know, the, the problem is that we won't
really know that for some time.
Because the second versiongives a lot of discretion to
the administration in terms ofwhat companies are swept up into
it, and what the implicationsof it are for the marketplace.
Basically, the biggestdifference between the second
version, the one that's likelyto pass now, and the first
(14:27):
version is, the first versionmentions specific companies
that would be subject to theBiosecure Act in particular
WuXi AppTec and WuXi Biologics.
The second version basicallysays, well, the, the
administration is going to setup a process for figuring out
what companies are so-calledbiotechnology companies
of concern, and it createsbroad parameters that the
(14:52):
administration could use, theycould, um, include the two
WuXi companies if they wantedto, but they could exclude
them if they want them also.
So it's not known whetherthey're gonna be included.
And then there's really alsoa certain amount of ambiguity
about what it actually means.
It's clear, or it seems tobe clear that, for example,
companies that use servicesfrom biotechnology companies
(15:13):
of concern, after a five-yeargrandfather period, won't be
able to sell their productsto NIH, to the Veterans
Administration, to otherdefense department programs.
What really isn't clear,is the extent to which it
would impact, for example,Medicaid, the Medicaid
markets, and that again,is going to have to depend
on implementation policiesfrom the administration.
Simone Fishburn (15:37):
That's very helpful, Steve.
So, you know, I just reallyencourage people to read
Franck's commentary, it is infact in front of the paywall.
And I, I think that justgaining really knowledgeable
insights from insidersabout the opportunities,
but also the headwinds forany particular ecosystem.
Reminding people we areglobal at BioCentury.
(16:00):
We care about all of it.
Who's where andwho can be where.
Um, and the China ecosystem isobviously a very important one.
So I really encouragereaders to go to that.
And I am sure that ourtrustee colleague Cole, will
put this in our show notes.
He's the guy who makeseverything happen, just
a shout out to Cole.
We get a lot of complimentsabout the podcast, but
(16:22):
really it's all Cole.
Stephen Hansen (16:24):
That's right.
I'm sure he will,that's wonderful.
Thanks Simone, and you know,I, I'm also just excited
'cause I got to cross off oneof the last few squares on
my 2025 Bingo card when youtalked about MMA, it was one
of the few remaining ones.
So nice to,
Simone Fishburn (16:37):
I am really excited to know what's on
the card for next year,so I'll be, uh, yeah,
Stephen Hansen (16:42):
Oh, well, we'll, we'll, we'll
keep that, we'll keep
Simone Fishburn (16:44):
we got the World Cup actually then don't
we, we got World Cup coming up.
Stephen Hansen (16:46):
Hmmm, yeah.
But anyways, let's turn now Iwould like to turn to Lauren,
who herself had a quite aninteresting commentary piece,
looking at whether conventionalCRISPR therapies will ever
demonstrate commercial success.
So, Lauren, give us abit of context here,
what were your takeaways?
Lauren Martz (17:03):
Thanks Stephen, and this is hard to write
because I'm gene therapygene editing's biggest fan.
But recently there have beena few events that I think
we've all Been followingthat have contributed to an
increasingly negative sentimentaround gene editing therapies.
You know, this isn't news, butit got me thinking about what
that opportunity is for whatwe would call conventional
(17:25):
or traditional CRISPR-Cas9therapy at this time.
And it's crazy that we'reeven calling it traditional
CRISPR-Cas9 because it'ssuch a new technology.
So one of the recent eventsthat we may have talked about
before on this podcast is thepatient death in Intellia's
Phase III trial of nex-z, totreat transthyretin amyloidosis.
(17:47):
So in that trial, a patientdied from liver toxicity,
which presented outside ofthe normal window for lipid
nanoparticle related toxicity.
You know, this patient wasolder, had comorbidities.
But it still raised thepotential for a toxicity that
we weren't anticipating, atoxicity that may be related to
the target or the to the geneticcargo, or something else.
(18:08):
And it, it's just an importantreminder I think for investors
and for everyone that there'sstill some uncertainty around
the long-term safety of invivo genetic editing therapies.
At the same time that thingslike this have been happening,
we've been watching thisincredible rise of the RNA
modalities, siRNA, antisense.
(18:30):
And there's a lot of overlap inthe indications that companies
are treating with in vivo geneediting therapies, and with
these RNA therapies, you know,transthyretin amyloidosis
is an example of one.
In both cases you canknock down gene expression.
With RNA therapies you can doit pretty durably, these are
dosed like every six monthsnow and quite efficiently,
(18:52):
during that durability window.
So I think what's happening isthat the difference in value
that you could get from aone-time CRISPR-Cas9 therapy and
RNA therapy is really shrinking.
The question kind of becomesfor patients and physicians, is
it worth taking the risks of aone-time gene editing therapy to
(19:13):
not have to take an injection,or an infusion every six months.
Steve Usdin (19:17):
Are there examples of things that can be done
or could be done with CRISPRtherapy that really aren't
possible with other modalities?
Lauren Martz (19:25):
So that's the question that I was thinking
about, and there may be.
With the knockdown knockoutapproaches, there's a
ton of overlap there.
With inducing expression ofa gene, this is something
that you can't do with thosetypes of RNA modalities.
It's something that you maypotentially be able to do with
a prime editor for example, orsome of the newer iterations
(19:45):
of the CRISPR technology.
But then the questionbecomes, if those are going
to advance through the clinic.
And we haven't been able todo that very efficiently with
a traditional CRISPR-Cas9.
You know, is there, is therean opportunity there either?
I think all of this may becomemore clear as the technology
is followed, as we learnmore about the safety and
(20:07):
efficacy in the long term.
And I think there's also animportant point to make here,
which is that the CRISPR-Cas9therapies that are in the clinic
have been working incrediblywell, and they just happen to
be overlapping with a lot ofother modalities, you know,
some other modalities that arein the clinic or in development
for the same indications.
(20:29):
There are all ofthese unaddressed
indications out there.
So, I think that everyoneshould be spreading out what
they're addressing with thesenewer technologies or with
these alternative technologies,and continuing to develop,
not abandoning what's effectivebecause in the future there
may be something that couldbe, you know, slightly safer,
slightly more effective.
Simone Fishburn (20:48):
Yeah.
So first of all, again,this won't surprise anybody.
I'm gonna encourageyou to read the piece.
It's really very well writtenand It's just a very interesting
field that we've been watchingliterally since its birth, we
don't often get to do that.
And, you know, acknowledgingthe huge impact.
I think there's one pointthat you've made, Lauren,
which is sort of in responseto Steve's thing, is like we
(21:08):
talked about herding, right,that Franck talked about, but
we all see that as going on.
And testing these newtechnologies at this point
it really needs to be goinginto areas where they're
not massively covered bysomething that could frankly
just do better than them.
But I do wanna ask you onequestion, you know, half of the
premise, your piece say's likehalf of it is what you just
(21:29):
said, which is like actuallyprime editing and base editing
might be better served, we'llfind that out, for some of
the more specific or advancedmutations that you might
want to address in disease.
But then the other half of it isthat RNAi so siRNA or antisense
have really you know taken thebusiness case, let's say, away
(21:52):
from some of the CRISPR-Cas9kind of gene editing.
So for prime editing,whatever they came afterwards.
But, siRNA and antisensehas been around a lot
longer than CRISPR.
And so we've been writing overthe years, like the market would
go crazy in CRISPR technologies,even just on a preclinical
preprint, it was insane.
(22:13):
So what is it that thisfrenzy is all about?
I mean, what I'm trying tosay is that, that information
was there also five yearsago and also 10 years
ago, about the potentialfor RNAi and antisense.
And so why is it onlynow that that argument
is coming to the front?
Lauren Martz (22:31):
In my opinion, I mean, we've watched
these parallel indicationsadvanced through the clinic.
And you're seeing knockdownlevels of the targets that are
not looking very different.
And I don't know if thatwas ever appreciated before.
Maybe it was, but it, I Icertainly didn't expect that,
you know, in the 90s, regardlessof what modality you're using.
The whole premise ofCRISPR-Cas9 was that you
(22:53):
could do this so efficientlyand you could do it one time.
And so I think, there justwasn't a full understanding
of how effective the RNA classof therapies could be, and
how long lasting, you know,the chemistry has changed
from where it started out, thelong lasting oligos are, it's
kind of a game changer, right?
If you can dose itonce a year or even.
Simone Fishburn (23:15):
Yeah, so what I'm hearing is that actually,
antisense technologieshave really moved a long
way in the last few years.
I mean, Stephen, you arenodding, I dunno if you
wanna weigh in on that.
And so, even though they'vebeen around a long while,
they've just got an incredibleamount of validation,
maybe extra commercialand technical validation
in the last few years.
Is that how yousee it, you guys?
Stephen Hansen (23:37):
Yeah, well, well, I was just gonna say,
I mean, one of the big gamechangers for the siRNA sort
of modality was the GalNAcstabilization technology, right.
When that came in, thatreally sort of changed
things and allowed companiesto move past that sort
of delivery formulationchallenge that they had faced.
And, I'm kind of putting youon the spot here line, but I'm,
I'm wondering if there's like a,a parallel sort of step change
(24:00):
that CRISPR modality wouldneed to see to sort of enable
it to be able to have the sameimpact that we're now seeing
from the RNA technologies?
technologies
Lauren Martz (24:10):
I actually don't have an answer to that.
I think as Simone mentioned,the markets have been
really tough on the CRISPRgene editing technologies.
I mean, the safety efficacyoverall is very strong for
the programs that we've seen.
One thing that I didn't touch onin the perspective is delivery.
So I think that back to Steve'soriginal question, this is an
(24:32):
opportunity, I think that'skind of still up for grabs, is
which modality will get outsideof the liver most effectively.
There could be some overlapin the types of technologies
that ultimately will be usedfor extra hepatic delivery.
But, you know, you coulduse something different
to deliver RNAi very wellto, to different tissues.
(24:53):
So, those are still justcompletely open, I think
for, for both of thesetypes of technologies.
Stephen Hansen (25:00):
I, I, I think just, just also real quickly
just to comment on when Simonewas mentioning about those, that
heyday for CRISPR companies,when they were flying up a
100% on preclinical data,there was probably a real
strong under appreciation forthe safety issues that they
could potentially face, right.
And so now that they've gottenfurther into the clinic and some
of those issues, unlike genetherapy have come to the fore,
(25:21):
uh, I think there's a better,better maybe appreciation
of the, the benefit riskprofile that these therapies
maybe potentially carry.
Simone Fishburn (25:29):
Okay well, I'm gonna jump in here because then
shame on the investors, right.
Like the, the risk okay of thegene editing technologies was
there all the way along and wewere writing about it, right.
so shame on them if they didn'treally have a good understanding
of the risk at landscape.
doesn't mean you're wrong.
I'm just saying that,that investors need
(25:49):
to do their homework.
Lauren's not agreeing with me.
Lauren Martz (25:53):
I don't know.
I just think it'sbeen so up and down.
You know, you, there may bea slight indication that you
could have an off target editand the stock prices tank.
And then there dozens ofpatients are completely fine
after being treated with thisand everything seems fine.
And then, you know, oneliver toxicity, one severe
liver toxicity event.
It just goes up and down,I think there's been an
(26:14):
understanding all along that thestakes are high for a one time
therapy when it comes to safety.
Stephen Hansen (26:20):
Yeah, maybe one final thing is it's
just also a reflectionof how fast innovation
moves these days, right.
I mean, it's only been.
12, 13 years since we hadthe first CRISPR publication,
and it's already potentiallybecoming obsolete, you
know, too strong of a word.
But, uh, I think it's justa reflection of how fast
things move these days now.
Got to stay ahead.
Steve Usdin (26:39):
I want to, turn the tables a little bit on Stephen
Hansen and ask a question.
We've seen the firstclinical data on NLRP3
inhibitors in obesity.
What do we see?
Stephen Hans (26:49):
Yeah thanks Steve.
when I host, don't you?
You love turningthe tables on me.
Um, yeah, so we had thefirst data come in about a
month ago, Phase II data,and uh it wasn't good if
you were expecting an NLRP3inhibitor to show weight loss.
So a bit of context here, about18 months ago, there was some
very unexpected preclinical datapublished by private biotech
(27:09):
company NodThera, that showedthat an NLRP3 inhibitor can
lead to monotherapy, weightloss, and a mouse model.
And they also showed additiveweight loss when it was
combined with a GLP-1.
So that basically sent everycompany that had an NLRP3
inhibitor, scrambling totest their own programs in
preclinical models, and quitea few of them then quickly
(27:29):
moved into the clinic.
The first to do thiswas Ventyx Biosciences.
They had seen decent weightloss, in a DIO mouse model,
they showed 9% monotherapyweight loss after 28 days.
And then, when they added itto a GLP-1, they saw more than
what you got with a GLP-1 alone.
So that was enough for them.
They moved into a Phase IIstudy, late last year, I
(27:51):
think, uh, 175 patients,with their program VTX3232.
So that study was theone that just spread out
this past, a month ago.
And, first glance itseemed pretty clear cut.
There was no difference onweight loss from placebo at 12
weeks for the monotherapy arm.
And then patients in thecombination cohorts, where
(28:12):
they had this 3232 programcombined with semaglutide.
The weight loss wasactually numerically
worse than the weight lossfor semaglutide alone.
So it seemed, seemedpretty clear cut.
Right?
I mean, I, I spoke toVentyx’s Founder and CEO, Raju
Mohan, for him he thought itabsolutely was quite clear
cut, you know, he basicallysaid, there's no signal
(28:32):
here in this Phase II study.
there's no solid biologicalevidence to support the
role of NLRP3 in obesityother than this hypothesis
around neuroinflammation.
So, you know, he thought itwas pretty clear cut and dry,
we tried it, doesn't work.
We're moving on to other things.
But as you might suspect youknow, not everyone kind of
agree with that conclusion.
(28:53):
There are other biotechs, suchas aforementioned NodThera
and Neumora, that are pushingforward, and that is sort of
based on their suggestion,their hypothesis that their
compounds are either more potentor have a higher level of brain
penetration, necessary to hitthe target in the hypothalamus.
So they're moving forward,they also feel like they
showed greater efficacyin preclinical models.
(29:16):
Yeah, you know, I guess,we'll wait and see.
But, you know, I have to say,it was an interesting, finding
when we first wrote aboutit 18 months ago, I now kind
of consider myself, I guessmaybe a bit of, a bit of an
NLRP3 skeptic when it comesto weight loss and obesity.
I'm also of the opinion that.
I'm not really sure if itmatters a ton because you know
what Ventyx did demonstrateand what sent their stock up
(29:37):
quite a bit was that NLRP3s,you know, are pretty potent
anti-inflammatory moleculesand they showed some pretty
impressive, like 80 to 90%reduction in inflammatory
markers, for CV risk reductionin their obesity trial.
And so, I can envision ascenario in which even if you
don't show any weight losswhatsoever, you know, you
(29:57):
could see a scenario whereyou could combine an NLRP3 if,
obviously if this, you know,anti-inflammatory CV risk
reduction were to pan out.
You could see this being part ofthe regimen because, you know,
I think we all know obesitypatients, you know, have one
of the highest elevated levelsfor CV risk, of other patients
with these comorbidities.
And right now, you know,on GLP-1s, obesity patients
(30:21):
get about a 20% reductionin CV risk, based on the
semaglutide CVOT data.
So if you can add on NLRP3 andyou can dramatically boost or
substantially increase thatrisk reduction level, even
if you don't see more weightloss, I think there still
could be a role for NLRP3
Steve Usdin (30:39):
So,
Stephen Hansen (30:39):
in this space.
Steve Usdin (30:40):
what would it take to demonstrate that?
Because those kind oftrials are not short and
they're not cheap right?
Stephen Hansen (30:45):
That's true, that's true.
It would take a, it would take,a CV outcomes trial of its own.
So you're right, that isdefinitely not a space where
your typical small biotech wouldlikely be able to run a study.
So they'd probably have to dothis either with a partner or
they'd have to be able to raisea substantial amount of money.
That's, I guess, for theinvestors to try and figure
out whether they thinkit's, it's worth the risk.
(31:06):
But this isn't the only settingwhere they'd have to do that.
I think Ventyx is alsotesting this molecule in
a pericarditis, trial.
And so that also willpotentially require a
CV outcome trial too.
So these will be big studies.
But, for instance if I justthrow it a hypothetical.
If you can double therisk reduction, I think
that very well could beworth it, but we'll see.
(31:26):
Well, thank you to mycolleagues for joining me
today, and thanks to all ofyou for tuning in this week.
Before we go, I would alsolove for everyone, that is
listening, if they couldjoin us and participate in
our current survey that wehave ongoing about the FDA,
there will be a link inthe show notes, and I think
Simone wants to provide someemphasis as to how important
(31:47):
this is to us, so Simone.
Simone Fishburn (31:49):
It is important to us, Stephen,
because it's importantto them, to our audience,
Stephen Hansen (31:54):
That too.
That's too.
Simone Fishburn (31:55):
we live to serve them.
Yeah.
So the survey link everybodyis BioCenturysurvey.com.
That's BioCenturysurvey one word .com.
Cole aforementioned Cole.
We'll have the linkalso in the show notes.
This is a survey for investorsand biotechs, in particular
(32:17):
who've been working with FDA orother regulatory agencies, but
this is specifically about FDA.
We need to know what is working,what isn't working, good, bad.
It only takes five minutes.
It's an unbiased survey.
We are really justtaking the temperature.
We are trying to get intosome of the very specifics
of parts of the agency andinteractions where sponsors
(32:39):
are having productiveoutcomes or interactions
and areas where less so.
It's not a superficialsurvey, but it is a quick one.
Steve Usdin (32:50):
I wanna point out that it is anonymous also.
Because I've receivedconcerns from some people
who were thinking aboutfilling out the survey,
and they're concerned aboutanonymity, it is anonymous.
Simone Fishburn (33:00):
Our surveys are always anonymous.
Thank you, Steve.
That is really importantand we will be presenting
aggregate data from the surveybefore the end of the year.
If you all do your job andfill it out, then you'll
get the answers beforethe end of the year.
Stephen Hansen (33:13):
Great.
Thank you Simone.
and thank you allfor joining us.
As I've mentioned before, allof the stories that, uh, we've
discussed today, you can findat BioCentury podcast.com.
You can also check out oursister podcast The BioCentury
Show, where believe themost recent episode featured
Steve, in conversation withElias Zerhouni former NIH
(33:33):
Director, and after thatGlobal Head of R&D at Sanofi.
Thank you again and wewill catch you next week.
Eric Pierce (33:41):
BioCentury would like to thank Voyager
Therapeutics for supporting theBioCentury This Week podcast.
To learn more aboutVoyager's programs advancing
transformative medicines forneurological diseases, visit
voyagertherapeutics.com.
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