Welcome to the
Proteomics in Proximity podcast, where your co-hosts
Cindy Lawley and Sarantis Chlamydas from Olink Proteomics,
Talk about the intersection of proteomics with genomics for drug target
discovery, the application of proteomics to reveal disease biomarkers,
and current trends in using proteomics to unlock biological mechanisms.
Here we have your hosts, Cindy and Sarantis.
Hey everyone, welcome to Proteomics in Proximity.
Today I have, Evan Mills together with me to talk about a pretty exciting event
that we attended last week where keen to,
to share some of the learnings with you.
So. So, Evan, thanks so much for joining.
Would you mind just giving us a quick introduction?
Yeah. Thanks. Great to be on again.
Been with Olink for about eight years in the next gen proteomics field
for a dozen, former scientists converted into life science tools.
Business person, currently vice president of business development at Olink,
where Cindy and I and some other folks are trying to pave the way
for the future of protein based diagnostics biomarkers.
And, had a really interesting meeting that we're excited
to share the details with you.
Yeah, this is so this event was the Reagan-Udall
Foundation's FDA, event on geroscience.
So gero meaning elderly or aging
and, science and therapeutics, therapies to help us with aging,
of this brave new world that, that,
that seems like such a hot topic right now.
And this is actually putting it in front of the FDA.
So I want to definitely start our conversation.
Even with this image, I can't get out of my head from,
the discussions at Reagen-Udall Foundation's event.
Are you a chicken?
Yeah, exactly.
Exactly that chicken.
So, Sandra Kweder, former regulator at the FDA.
She was on the stage, and she was asked,
what would it feel like if a gerotherapeutic application,
if an application for something that is meant as an indication, for aging,
landed on an FDA desk today,
and she said it might feel like being on a packed 737
doors closed, taking off and someone lets a chicken loose.
It was really funny in the moment, but also like
a perfect metaphor, for the field today.
Yeah, exactly.
Because it's like it is exciting science in the room.
People get really excited about drugs, biologics devices,
mitochondrial peptides, rapamycin combinations
or even ultrasound, immune rejuvenation
proteomics, of course, aging clocks and then intrinsic capacity.
All these things that we'll talk about later. Yeah.
No, there's a lot going on and a really interesting mix of folks in the room.
And I think that's what made this meeting particularly valuable. Right.
Is there were people from the FDA, former regulators, current regulators,
the ARPA-H, XPRIZE,
academics, company representatives from pharma such as Novo Nordisk,
GSK, Regeneron, Bio Age, Cambrian, Stealth Biotherapeutics,
Altos Labs and of course Thermo Fisher, Olink.
All in the audience.
So good mix. Little ol' Olink.
Yeah, yeah.
What I thought, there weren't that many people in the room,
but it was an online event.
It was open and all of the assets are available
online will definitely provide a link in the show notes.
But it didn't feel like your niche longevity meeting.
And I've been to a few of those.
It was very much a field
that's beginning to organize itself around a serious question.
Yeah.
Like what evidence would make the FDA believe
that a therapy is improving how we age?
Yeah, to your point, Cindy, it wasn't, in Silicon Valley, it wasn't
full of ideas without merit or
Brian Johnson's vision for reversing aging.
Yeah, exactly.
I mean,it was very serious in some ways,
which I think the field needs and Susan Winckler was just a tremendous moderator.
So good because she kept pulling that back to
All right, well, let's talk about the exciting biology.
But then the practical regulatory questions.
Right. What is the claim.
Where's the evidence and what's the FDA actually going to be able to do with it.
Yeah, exactly.
So today we're going to talk about what we learned
from that Reagan-Udall Foundation meeting on gerotherapeutics.
What FDA seems ready to discuss
why this concept of intrinsic capacity became such a central idea,
I think of this is sort of the central character,
and where biomarkers and proteomics, because of course, we're at Olink,
Thermo Fisher Scientific, and what what should scientists expect from this?
You know, we want to give a sort of a practical guide for what we heard
and where, where we might where scientists might put their attention.
Yeah, exactly.
And the short version and obviously, we won't get into a lot more detail,
but the future probably doesn't begin with the phrase.
Hey, we reversed aging, right?
It's again, it's going to begin with.
We've helped people function better, longer and more safely.
That's what my mom cares about.
That's what my 88 year old mom cares about, right.
So let's talk about the regulatory challenge.
So a lot of geroscience begins with the idea that aging biology
drives chronic diseases and
Nir Barzilai made that point
that aging is upstream actually, of these diseases, these cardiovascular
diseases, dementia, cancer, diabetes, kidney disease, frailty.
Yeah.
I mean, if you look at the data, right, the number one
risk factor for all these diseases is age.
So this is not a surprise.
And scientifically this is what makes the field so attractive.
If we as a community can figure out an upstream mechanism to target,
you can improve many, many conditions.
You can change the vulnerability
of diseases across multiple organ systems,
which of course just sounds like a panacea
of opportunity for, better health outcomes.
Well, for what I want for my future.
That's it's maybe it'll be just in time for me, but,
But the FDA's not approving enthusiasm.
Certainly there wasenthusiasm
as you said, Susan Winckler was good at keeping the enthusiasm high,
but keeping it, recognizing that that we have a job to do.
Yep. And Sandra Kweder made the, core point multiple times, right.
What's the indication? Because at the end of the day,
aging is
a bit broad and specific indications are how this world has to work.
Yeah. Who's the patient? Right.
Who are you treating and what claim can you put on the label and what's the dose?
What's the risk and how long does someone take it?
Are these things that people are popping every day of their lives?
Right. Right. What benefit are you taking?
What what benefit are you asking the FDA to recognize?
Yeah, yeah.
And Susan and others were kind of translating that language
of the scientific aspiration in the room back to.
All right, let's think about what's the regulatory
checklist one has to go through.
So very pragmatic.
Which is which is good.
It grounds some of the discussion that can be perceived
as pseudoscience if, you know, without that grounding.
So it was a very productive, counterbalance, I'd say.
Yeah, and aging is not a simple thing. Right.
Are we treating aging, age related disease, frailty, sarcopenia.
These are words we have,
batting around quality of life.
Right.
Immune decline, of course.
Resilience that comes up.
Early functional decline, etc..
And depending on what we look for it kind of has it.
Well, it's not kind of it absolutely has a very big impact
on the developmental path. Yeah. Yeah.
And Steven Kozlowski who I, I believe was actually
that Jamie Justice who we'll talk about later,
she actually came out of his, his group, but he spent years
thinking about how to bring geroscience into randomized clinical trials.
And so he opened up the meeting and reminded us that the current
biomedical paradigm is disease by disease, risk factor
by risk factor, and that geroscience is trying to do something broader.
And unfortunately for geroscience, broader is harder to prove.
And he was saying, it's not just
aging biology is promising,
it's what endpoint would convince us that a therapy really affected
the biology of aging in a way that improves human health and healthspan.
Yeah, and that's really where the practical tension starts, right?
I mean, the healthier
the population, the longer it's going to take to see events, right?
So inherently, if you think about a clinical trial,
if aging is your in endpoint, it's not very pragmatic.
If you want to prevent
disease, disability or death, you're going to need super long trials.
And they're very expensive and they're just not very practical.
And that's why people were talking about stepping stone indications.
Right, right, right.
So yeah in the field will decide.
Maybe we start with sarcopenia. We start with frailty.
Immune decline right.
Cardiovascular risk, obesity, diabetic macular edema, other age
related complications where there's some common biological drivers.
And the end point's a little more concrete.
So can we reduce risk of multiple age related diseases
or preserve the function across domains?
Right.
And I think the scientists in the room are very optimistic that we can.
And I mean, knowing the little I know about proteomics and pathway
level biology,
I'm confident that there are going to be some common nodes that we can nudge
in the right way,
but we have to prove something specific first.
Yeah.
And the FDA's answer. Their shift.
I think I sort of assumed that they were they were like, don't come to us.
But it wasn't that they didn't say, don't come.
They said, come prepared and know what we're saying in this meeting,
because this is how we need to think about it.
Yeah, I think that's a really important distinction, right?
I mean, the door is very much open, but there are some rules, right?
There's just some ground rules that despite the excitement
about the field and everyone's enthusiasm about some new ways
to approach aging, we still got to play by the rules
if we're going to move things forward meaningfully.
And that means we need to have preparation around.
There's a product, there's a population, there's an endpoint, there's a claim.
We're thinking about safety, we're thinking about dose.
And of course, there's should be a very credible biological rationale.
What's the mechanism? Why does it work.
Yeah. Yeah.
And if we're tracking toward that long arc of mortality.
Yeah.
Like you say, that's a long path.
This brings us now to this concept of intrinsic capacity.
That was such a big topic and as a sort of a main character,
what can we do with intrinsic capacity?
And it's probably worth spending some time unpacking that.
I think so.
So, there are several people that touched on, intrinsic capacity.
John Beard gave this conceptual foundation.
Health is a continuum.
Most of medicine's threshold based. Right.
You he crossed a line and suddenly you have diabetes or hypertension or dementia.
You start on a drug regimen or you have an ICD-10 code.
But aging doesn't work that way. Right?
As we all know, aging is gradual.
Functional decline is gradual.
And if we wait right until there is a very clear
manifestation or disability, it might be too late, right?
And we might miss an opportunity right?
So intrinsic capacity, this idea of capturing an individual's underlying
capacity across multiple domains and those domains or locomotor,
movement, cognitive, sensory, psychological.
And then this concept of vitality.
Yeah.
And I'll try to translate that to very simple language.
Can you move.
Can you think can you see in here.
Can you maintain your psychological well-being and can you withstand stress.
Yeah.
And what makes it powerful is that older adults like certainly my mother
she cares more about function
than wrinkles or diagnostic labels.
Exactly right.
I mean, that's at the end of the day, the only outcomes that matter to human
beings, labels might be convenient constructs for, the medical world.
But when we think of that aging, it's, you know, those moments that matter, right?
Can you hear your family?
Are you able to move to watch your grandkids
play soccer or whatever the case may be?
Can you maintain your independence?
That's obviously something I dealt with, with my grandparents
a decade or so ago it's challenging, right, to see the people,
just with far fewer capacities.
So. Yeah.
And this, I think, was important for us at Olink to be thinking about because certainly
people have been building these, these aging clocks and we're excited about that.
What what do you do with them?
So intrinsic capacity is giving us this vocabulary for health span
that's more clinically meaningful than your aging clock improved.
Yeah. Yeah.
And the meeting had a lot of caution right.
To be clear, I mean, I think as innovative proteomics
supporters as you know, Cindy and I are, I came out of meeting very positive.
But there was a lot of caution, right?
Kelly Anderson from ARPA-H, for example,
she had a consensus presentation that made it really clear
that intrinsic capacity is not yet a validated surrogate endpoint.
Right. We're not there.
Surrogate endpoint, just meaning it's not yet proven to stand in for later
outcomes like disability, disease survival, hospitalization.
Right.
And there was a general caution around surrogates
and a fairly high burden of proof for them to be implemented.
So the message was really intrinsic capacity is not quite ready
as a universal global primary endpoint for every aging trial.
Yeah, but it might still be useful. Yes.
And as a structured, yeah, multi-domain clinical
outcome framework I loved how that was positioned.
It really felt eye opening to me.
And that caution, that restraint as you say, mattered.
It gave credibility, I think, to the room.
And and that's where this a PROSPR data.
Andrew Brack talked quite a bit about PROSPR. Right.
So there's there's ARPA-H, PROSPR and there's
XPRIZE and these things are coming and what we'll get to those.
But, he basically was saying we need to build the data
before we can expect regulation to move.
Exactly.
Innovation often precedes regulation. Right.
And that's very clear here.
And the onus is on the innovators to to build the proof.
So PROSPR is actually really interesting.
It's not just another aging study.
It's an effort, very focused effort to build the infrastructure,
intrinsic capacity scoring at home measurements, blood
based biomarkers, intervention studies and validation pathways.
And Andrew made the case that that intrinsic capacity can be a North star.
But not necessarily a single label tomorrow.
Exactly. Like we said before. Right.
It can be a one in a series
of important steps to build the evidence required in the field.
Yeah.
So so how can intrinsic capacity be used now what did you hear.
Not not someday, but in the next wave of trials.
I mean, I think there were a few examples, right, that come to mind.
First enrichment. Right.
Let's identify people who are having early decline.
And might be more likely to benefit from an intervention.
So so pharma tries to do this across lots of disease areas.
You want to enrich your population for the patients most best suited to benefit.
So that could be a pretty low bar I would say to use the score.
So pick your pick the right folks for your team.
Second.
Stratification. Right.
So that would be making sure that the groups are, balanced at baseline.
Obviously you're going to have some sort of control arm in any trial,
for an RCT.
You want starting from the same
basic area, right?
The same starting block, if you will, in the race.
That that could be another use.
And third intrinsic capacity could also be used
as a secondary endpoint. Right.
There's a lower bar if it's a secondary endpoint.
So if the trial's constructed around mortality and disease
you could still have, this IC measure
to track comparable data on function across different domains.
And in some cases,
the intrinsic capacity could act as a domain specific primary endpoint,
especially if the mechanism clearly maps to that domain.
Got it.
So if you're doing locomotor or muscle function
endpoints, a therapy targeting immune
aging might focus on immune response or an infection related outcome.
So you can stick to the domain that seems relevant to that indication.
Yeah. Exactly. Right.
And domain level reporting can avoid the hiding of trade offs.
Right.
If we can narrow in on one of those five domains,
we can have a more real picture of what's happening.
If a composite score improves,
let's say locomotor function is better,
but cognitive function is declining or there's some sort of adverse effect,
you would uncover that in a, in a more focused.
Yeah. Scoring. Got it.
So so we've got intrinsic capacity just to kind of close us on this.
Intrinsic capacity is not a destination yet, but it is.
It does appear like it can be a very useful bridge.
Yeah.
And I think there is a lot of enthusiasm in the audience, for
something to bridge the aging biology
that we're all aware of and better able to measure to some clinical benefit.
So I do believe that there will be a lot more work done on this
intrinsic capacity concept, and it holds a lot of promise.
Yeah. That's awesome.
Okay, so now let's switch over to our, you know,
love biomarkers proteomics and and and evidence.
Right. So
You got on the stage and you were able to, to speak to how we see things.
Yeah, we certainly have, I think a pretty humble
approach to, to where it fits into all of this.
Yeah.
No, I think we're trying to be,
realistic. Right?
And knowing that there's a big burden of proof for biomarkers.
And the meeting was helpful in that regard. Right.
It was a bit of a reality check so we've done some incredible studies.
We've supported studies, I should say from large populations
where there's some really powerful signals for aging biology.
Right. There's Austin Argentieri.
I always think of his publication where a 200 protein
signature is incredibly powerful at predicting biological age
and possible, disease risks.
And you could even get down to 20 proteins and get some really powerful data.
But the practical question is, okay, now what what are we going to do with that?
So there's recognition that biomarkers have tremendous promise.
But they're not magic.
And there's a lot of work that needs to be done.
So a biomarker can do many jobs right.
It can show targeted engagement.
It's certainly we're seeing that in pharma.
It can help select patients.
It can help identify responders.
Where we see a lot of this evidence and publications that come out on Olink,
it can track biology over time.
It can certainly support mechanisms.
So I see these as layers. Right.
But it's not automatically a surrogate endpoint.
I think that was really, really crystal clear.
Yeah. And it is it's crucial right.
It's a crucial distinction a surrogate endpoint
has to predict clinical benefit right.
Not just correlate that big difference.
Not just look different in older people or as we age,
not just change after a therapy.
It has to be tied to something
meaningful function, disease risk, disability survival.
Yeah. So the aging clock is interesting.
And there are several organ aging clocks now that have come out.
We'll put the links in the show notes for those publications.
But the regulatory question is what does that change mean for the person exactly.
Does it mean that they walk better?
Do they think better?
Do they get fewer infections?
Do they avoid hospitalization?
Do they live longer? Right.
These are the questions. Yeah.
And that's where proteomics I think can be very powerful.
But only only if it's connected to outcomes.
Yeah.
And being there
and having some sidebar conversations I mean this is how I see it, right?
Proteomics is a biological information layer, right?
Aging is very dynamic and multisystem.
It's literally the perfect application for proteomics versus other omics.
Because of the dynamic nature of the human proteome, proteins are reflective
of immune function, inflammation, tissue remodeling,
metabolism, organ stress and responses to interventions.
Right.
So it's just so intuitive that proteomics are going
to be a very powerful tool.
We just need to build the evidence.
Like Kári Stefánsson says they are the
business molecules of the body.
But but I loved your phrase.
They're not biological entertainment.
Yeah.
I mean I, I wasn't sure that was the right way to go,
but I think that there's some fear of pseudoscience, in this field.
Right.
There's a lot of people
that have made some claims about aging reversal and chasing numbers.
Yeah, yeah, things that just feel a little icky.
If you're a scientist and you really are,
focused on hard data and hard outcomes,
so even these protein signatures that,
I've gotten excited about for the last decade of my career,
it doesn't prove that we have enough information, right?
It's not.
The goal is in producing cool dashboards and cool signatures.
How do we help drug development and patient care?
Yeah, yeah.
And that's where the company representation was interesting.
So there are these these therapeutic developers, right.
You mentioned some of them BioAge,Cambrian,
Stealth Biotherapeutics, Regeneron.
They were all thinking about targets and trials.
Right.
We also had Novo Nordisk and GSK in the in the panel session
that you participated in.
They're talking and thinking about of course,
chronic disease prevention and trial strategy.
And then of course, you were representing Olink and
that is that technology layer, right for the data layer.
Yeah, exactly.
And for an enabling platform, which is what we would consider ourselves.
The question is not what claim do we want from our drug?
It's how can this measurement help the whole field make better claims?
Is there some sort of common biology that can be uncovered
in this information layer that can help the whole field?
And what do you think is going to make proteomics actionable in this space?
I think honestly, Cindy I think about this a lot because,
and you and I,
have been very fortunate to be a part of the generation of a lot of data,
and other companies have generated a lot of data.
And I think everyone's appetite is really,
is rising for what's going to happen next.
And I think it's going to come from two key things, right?
We need longitudinal data.
We need to see how proteins are changing over time in relation to the endpoints
that we're trying to measure.
And we need interventional data.
We have to show sensitivity to change.
Otherwise a signature of the biomarkers are going to have very limited utility.
We could even talk about functional data, clinical outcomes.
Obviously.
I mean, if a protein signature that's an easy blood draw,
can predict a decline in intrinsic capacity
or changes when a therapy works or it tracks with improvement.
In one of those five conditions that we mentioned,
I think it becomes super valued.
So it's I think it's a combination of the industry partners and perhaps
governments coming together to realize we need to make some investments.
We and we need to generate this data now.
And so the future evidence, I think,
that package is going to have layers.
It's a it's a stack with mechanistic foundation.
Right.
That mechanistic foundation I think Olink is showing to be incredibly valuable.
I think that's a good analogy.
I mean, I think a stack works, right.
Like at the bottom you're going to have mechanisms.
So I go so what's the mechanisms that we're trying to treat and measure
and understand whether it's mTOR, mitochondrial activation,
inflammation, senescence of cells, metabolism etc. .
Then there's the biomarkers and the omics.
I kind of layer on top of that
to tell us what's going on when we're modifying these things.
Right.
And then ultimately it's functional measures.
So impact the mechanism measure that impact
and then see the actual impact in human function.
That's where I think it's all going.
Yeah, and the stronger the connection among those layers, the stronger the evidence.
I think that's where we need to track to 100% .
And if your mechanism and biomarker response and the functional improvement
all kind of align and it makes biological sense,
then we have a very convincing story.
And that's how I think the field really moves forward.
That's exciting okay.
So so the field is not waiting for this right there.
There are trials going now.
There are already underway.
So let's talk about XPRIZE and PROSPR.
PROSPR being the ARPA-H.
That made it feel urgent that human human studies are already happening.
Yeah, it's. Which is amazing, right?
I mean, I remember reading about some crazy parabiosis
experiments with mice and all these things.
But, yes, this is not theoretical.
There's there's real things happening in humans.
And we just had a podcast, recording that'll be up soon, with Tony Wyss-Coray,
talking a little bit about parabiosis.
So that'll that'll be coming soon, but, but yeah.
So Jamie Justice.
So we promised we'd talk a bit about Jamie.
So her XPRIZE, this Healthspan XPRIZE,
competition, made it really clear.
And she has this role. It's so phenomenal.
She's the perfect person for this, where she's willing to
to step out onto this ledge and say, hey, look, we need to start
defining what this looks like, and we won't get it perfect.
But let's not let perfect be the enemy of the good.
Let's move this forward.
And we need to have a framework within which we are moving.
And her.
She's just so easy to iterate with, right?
She's so great at bringing community together and helping them,
feel not left out.
Help them feel part of the discussion.
She kept bringing discussion back to action.
Teams are already testing interventions.
They're already collecting human data.
They need a framework.
Now, what can we do to help them?
Yeah, I mean, she was, very powerful speaker.
Her point was really powerful because Prize isn't asking the field
to debate on and on, because you could imagine
getting into a loop of academic debate about what's the best.
You know, they're moving, right?
They're they're funding these studies, which is amazing.
But they're asking these teams to demonstrate restoration
of muscle cognitive function and immune function.
Yeah.
And that is aligning with that broader conversation or around intrinsic capacity.
Multi-domain function based not just a biomarker contest.
Right? Right. Yeah.
And so so this competition is really trying to motivate and,
help fund some of the most innovative, gerotherapeutic companies.
And the diversity in the approaches
that were presented at the meeting were really, really interesting.
Stealth Biotherapeutics is doing
a mitochondrial activation peptide.
Mount Sinai, has a team with exercise rapamycin,
spermidine, macrophages and inflammatory biology as a focus.
and then UT Health SanAntonio
Yeah. And so it's a mouthful.
UT Health San Antonio using low frequency ultrasound right.
Now the device. Yeah. Cool.
As I was at ASCO this past weekend, American Society of Clinical Oncology
there were numerous devices that are...
I forget what it is, but it's different wavelengths of
sound and light to help with the cancer cell division.
So anyway, amazing.
I think the diversity was just fascinating to me.
So the gerotherapeutics may not be one modality, right?
It may be drugs, it may be biologics, peptides
may be devices, it may be lifestyle combinations.
Right.
That exercise is a very powerful intervention.
If we can structure and understand
the nature of what's most effective, I think that's really important.
And then of course,
cell therapies and other approaches that might be a little more complex.
Yeah.
And then PROSPR.
This ARPA-H initiative, PROSPR, is focus on the other side
of the equation, which is the measurement in the regulatory infrastructure.
And both these innovative companies are working together
hand in hand so that as we've been kind of circling around, we make real progress.
Right.
And then Andrew Brack, his ARPA-H framing
was that the field needs data to support regulatory decisions.
You have to regulate evidence.
You can't regulate hope.
Yes. And PROSPR is trying to generate that evidence.
Right.
Clinical trial ready
intrinsic capacity at home measurements blood biomarkers and intervention studies.
Yeah.
And then Brianna Stubbs her THRIVE presentation, she's she's out of Buck.
I believe I think of their collaborators and also a Stanford right.
Yeah that's a great example right.
The teams are developing clinical at home intrinsic capacity scores
with wearables app based assessments, patient reported outcomes voice and video.
And then there's these blood micro sampling for the omics.
So excited about that.
Yeah.
And I think I mean we might need
those kinds of creative infrastructures to actually measure healthspan at scale.
Right.
It's not going to be as simple as some of the existing,
method methodologies, I think. Yeah.
And they're not just saying, hey, does intrinsic capacity correlate with age.
They're asking whether it predicts meaningful outcomes and whether it changes
with interventions just to be super crystal clear about the the structure.
Yep, yep.
As we were saying earlier, right.
The response to intervention is critical.
If it predicts risk, if a measurement.
It predicts risk, but it does not respond when that risk profile is changed.
It could be useful for prognosis. Right.
But it's not going to have nearly the utility for a trial endpoint.
In fact it will it won't work.
Yeah. Yeah. And we need to know that right.
So XPRIZE is pushing intervention teams to show functional efforts.
And PROSPR is building the tools to measure those efforts more consistently.
That's that's kind of how I saw it.
Yeah. And it's a really nice partnership. Right.
Because both are creating data that the field just needs so badly.
Awesome. So okay.
So let's transition to what scientists and maybe sponsors, people who are in this
area of a scientist or a biotech leader or a translational team is listening.
What should they take away from this meeting?
Yeah.
So I think a piece of very practical advice
and strong advice would be let's not lead with we reverse aging.
I think that immediately and immediately discredits anything that comes after.
So let's start there.
What function improves?
Right. What risk is reduced?
What population level benefits are we experiencing with this.
Right. What's the mechanism. What's the endpoint?
I mean, it's almost like we have to think of an exotic, super cool
concept and dumb it down a bit to be more believable.
If that makes sense.
I think I think manage it, manage expectations on it.
Right?
Dumb it down is a tricky but yeah, I yeah, I know what you mean.
Yeah, it's bad and it's.
Yeah. But being it we need to be specific.
Right, right, right. Exactly.
I mean I think that's what I'm trying to get at is
the FDA can respond to specific questions.
It's much, much harder to support broad
philosophical claims about aging and reversal.
Yeah. Yeah.
And then I think the third thing is to think domain by domain, right.
We talked about these domains like that make up intrinsic capacity.
Right.
The mitochondrial presentation was super interesting.
So if there is a functional outcome that is linked to
what one would expect if you improve mitochondrial function, focus there.
Right.
If you're focused on muscle biology, let's talk
about a locomotor story.
I think that that helps build the credibility.
Awesome.
And then collect intrinsic capacity measures.
Now even as exploratory endpoints right
track to, to get to where we want to be.
Yeah.
And we'll know from the evidence if we can get there.
Yeah.
And I think I mean, it doesn't it feels like a low risk move to start doing that.
It feels like there's a real inertia behind the concept.
You know, Andrew Brack had had that ask.
Right.
The field needs data across these trials.
And if everyone's using these
different measurements, it's going to be super hard to build consensus.
So I think it would be a great proactive move for scientists in the field
to kind of come together around this intrinsic capacity concept.
Loveit.
And then biomarkers need a job right.
Don't measure everything just because you can, decide
what each biomarker or signature contributes, right.
Does it contribute to your claim for targeted engagement for patients,
selection for safety response mechanism or surrogate development.
Yeah. Yeah. And do not.
This is so crystal clear.
So it's sort of really put a damper on things.
But it's like do not neglect dose duration safety and manufacturing.
These are critical pieces the FDA cares a lot about.
Yeah, I mean, in the defense of the folks who presented their visions
for their therapeutic concepts, they had ten minutes.
But there was a comment at the end from the regulators,
not one presentation addressed those things.
And you just mentioned. Yeah.
And they're super important.
So yeah, again brings.
Us down to earth. Right.
Well said I'll say.
And collaborate where collaboration makes sense.
Yeah. Aligning on endpoints.
The IC concept I think is really powerful.
One of the things, Cindy, that you and I have lived
is the collaboration of the pharma
partners to run 600,000 human samples in the UK Biobank, right.
Those kinds of collaborative industry, government efforts.
I mean, UK government has co-funded that work.
I think in the US, we should really take a look in the mirror
and think about how can we co-fund some work
to build data at scale, because that data is part
of that biological foundation layer that we talked about.
From that, one can then build these signatures, build things that,
once tested properly, could become extremely valuable in the field.
And it's by leveraging that, measuring millions to understand one
that we're laying the foundation and building harmonization structure
to know what these biomarkers, what we can expect from them.
Give them that job and then individual sponsors.
The message was individual
sponsors still need to go to the FDA with their own products
and their own development plans.
True, right?
I mean, even if we have this shared infrastructure
and shared data generation and shared endpoint harmonization,
you still have to get your product specific evidence right.
You still have to get through the typical process.
Yeah.
And I think Susan Winckler, she was so great.
I just loved her moderation the whole day.
She so much, so much energy.
And she kept bringing the room back to practical next steps.
Right? Yeah. She didn't dampen the enthusiasm.
But what can be done collectively?
What must be done, you know, sponsored by sponsor?
What needs FDA input?
What needs more evidence? Exactly.
And I think that is the right balance.
I think this theme has come up in this podcast multiple times, but
I think it was one of the best parts of the meeting is that there was
a pragmatic realization on both sides that we have to meet in the middle,
to make things actually happen and move things forward.
Yeah, yeah.
And that is how healthspan therapeutics will advance.
Not one giant leap, but a series of credible
stepping stone steps in the right direction. So.
Okay, so so after this meeting, then
are you more optimistic or are you more cautious? Boy.
I'm going to take the easy way out.
You're going to say both. Yeah.
So you cop out, right?
I'll make a stand and say optimistic.
Because the fact that the meeting happened means that regulators
want there to be progress.
The fact that they said come to us means that they want,
gerotherapeutics to be brought to market.
So on balance, I'm very optimistic now
that the doses of realism are hard to ignore.
So I'm optimistic, but I think the timeline might be longer
than people want it to be because there's a process that needs to be gone through.
So I hold optimism.
And I do hope that with increasing evidence of perhaps some novel approaches,
there will be a true
meeting in the middle of the regulators and the innovative science.
I think that's fair. I think that's fair.
Opt optimism with discipline.
So so my takeaway
is that gerotherapeutics may not arrive first as a broad aging indication.
They may arrive through frailty, sarcopenia, immune function,
metabolic disease, locomotor decline, cognitive domains,
other age related conditions, more and more domain specific.
Yes. And I think that's exactly where the conclusion fell.
And as a stepping stones accumulate as more and more of them are developed,
the field will eventually build sufficient evidence for broader healthspan claims.
Yeah.
And the and the story is not that the FDA is blocking longevity.
That is not the story.
No, I don't think so. Not at all.
I think the story is longevity.
Science is maturing.
And it's growing up.
And that means moving from this
fascinating biology to evidence that people can trust.
Evidence that shows people can feel, function and survive better and longer.
Perfect.
That's the real promise of better aging.
And maybe the best way to get that chicken
safely back in its cage on the 737.
Well done way to bring it back home Evan.
Thanks so much and everybody out there,
thanks for listening. I hope this was useful.
Well, that wraps up this episode of Proteomics in Proximity.
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