November 20, 2025 • 40 mins
Voyager CEO and former head of R&D at Biogen Al Sandrock is more optimistic than ever about the prospect of bringing clinically meaningful solutions to patients with Alzheimer’s disease and other neurodegenerative disorders. The threads of progress are finally coming together, he said in a special episode of the BioCentury This Week podcast. From the first disease-modifying therapies for Alzheimer’s disease, to a growing biomarker toolkit, to an expanding set of genetically validated targets in other neurodegenerative conditions — and, crucially, to delivery vehicles capable of broadly and deeply penetrating the brain — neurology drug development may be poised to accelerate. This episode of the BioCentury This Week podcast is brought to you by Voyager Therapeutics.
View full story: https://www.biocentury.com/article/657678
#AlzheimersDisease #AAVGeneTherapy #BloodBrainBarrier #TauTargeting #Neurodegeneration
00:01 - Sponsor Message: Voyager Therapeutics
03:41 - Voyager's Approach to Gene Therapy
15:07 - Alzheimer's Disease
25:25 - Big Biotech to Small Biotech
29:21 - Neurodegenerative Diseases
31:19 - FDA Flexibility
To submit a question to BioCentury’s editors, email the BioCentury This Week team at podcasts@biocentury.com.
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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
by Voyager Therapeutics.
Voyager Therapeutics isdedicated to leveraging
the power of human geneticsto modify the course
of – and ultimately cure– neurological diseases.
Voyager addresses the challengeof delivering novel treatments
to the brain through thecompany's innovative TRACER™ AAV
capsid discovery platform, aswell as Voyager's NeuroShuttle™,
(00:25):
a non-viral delivery platformdesigned to transport multiple
modalities of neurotherapeuticsacross the blood-brain barrier.
The company's programs addressdiseases with substantial unmet
needs, including Alzheimer'sdisease, Friedrich's ataxia,
Parkinson's disease, ALS,and other diseases of the
central nervous system.
Jeff Cranmer (00:49):
Welcome to a Special Edition of the
BioCentury This Week podcast.
I'm your host, Jeff Cranmer, oneof the Executive Editors here
at BioCentury, and today I'mdelighted to have my colleagues
Lauren Martz and Selina Koch,join me for a conversation
with Al Sandrock, he's CEO ofneurogenetic medicines company
(01:11):
Voyager our sponsor this month.
Before joining Voyager inMarch of 2022, Al spent more
than 20 years at Biogen risingthrough the ranks, to become
CMO and eventually EVP of R&D.
Given his background, Al cancover any number of topics
(01:31):
in the field of neurology.
So I'd like to bring in mycolleagues now to find out
what they'd like to learnfrom Al. Well, Selina,
you, uh, lead our neurologycoverage, what are you,
hoping to talk about today?
Selina Koch (01:43):
Thanks Jeff.
So I recently wrote aboutthis, so the topic will show
my bias, but personally I thinkVoyager is working on one of
the most important challengesin neurology, which is the
difficulty of deliveringtreatments to the brain.
At the risk of soundingsimplistic, um, you know, drugs
don't work if you don't get themwhere they're needed, right?
(02:07):
Which makes CNS deliverykind of foundational, with
implications across, youknow, all of neurology,
well, even the psychiatry.
You know, it's an excitingtime because there's a lot
of activity aimed at solvingthis problem right now, and
I'm looking forward to hearinghow Voyager's approach kind
of fits into that landscape.
But maybe I'll bring up one moretopic before, uh, moving on to
(02:29):
Lauren, which is, of course,I want to pick Al's brain
on up and coming therapeuticapproaches to Alzheimer's
disease, where he's seeing themost promise in the short term.
What might be needed toadvance some newer hypotheses.
Jeff Cranmer (02:43):
Lauren, what are you, uh, curious about?
Lauren Martz (02:45):
Thanks, Jeff.
I'd love to hear a little bitabout the transition from a
large company to a leadershiprole in a small company.
And I'd also love to hearsome thoughts from Al on
transitioning the modalityfocus at a biotech.
So we know that Voyagerhas historically done a lot
of work in gene therapiesand has used some of the
(03:08):
expertise from that work tostart moving into delivery
of different modalities.
So I, I'd love to hear moreabout how that came about.
Jeff Cranmer (03:17):
Sounds good.
Well, Selina, why don'tyou, jump right in on the,
BBB question you wanna ask.
Well, just for our listenersout there, Selina has written
several pieces now on theblood brain barrier and, uh,
the companies, the players,the technology, the deals.
So do go to BioCentury.comto check those out.
And now I'm just gonnahand it over to Selina.
Selina Koch (03:39):
Yeah.
Well, I have a couple.
Um, I guess we could build onwhat Lauren was saying at the
start in the gene therapy space.
You know, we have seen a stringof safety incidents in the
clinic with gene therapies.
These are generally, youknow, inflammatory in nature.
So voyagers working inindications that span neurology
right from ultra rare likeFriedrich's ataxia all the
(04:02):
way to Alzheimer's disease.
So I guess al what's convincedyou, that you know, if you
have a highly penetrant, CNSpenetrant AV capsid, that
that's gonna be safe enough,even for the larger end,
that spectrum for a prevalentcondition like Alzheimer's.
Alfred Sandrock (04:18):
So there's two main reasons for that, Selina.
And, and maybe before I start,I'll say thank you for hosting
this and for talking to me,appreciate you, and I hope
you have a good conversation.
There's a couple of reasonswhy I came to Voyager.
And it was because I feltthat we can make gene therapy
work better, and more safely.
(04:40):
And there's two reasonswhy, I like the approach
that we're taking.
One is that we're engineeringcapsids that get across the
blood brain barrier afterIV delivery, and they're
so potent that we can lowerthe doses, from what's been
traditionally used for systemicor intravenously delivered
gene therapy, AAV gene therapy.
(05:02):
So typically, for example,people give, one E14 viral
genomes per kilogram, so onetimes 10 to the 14th viral
particles per kilogram.
And that's the dose, infact, of the approved gene
therapy for spinal muscularatrophy called Zolgensma.
(05:23):
So a basic tenet of drugdevelopment is if you
go lower in the dose,it's likely to be safer.
So we are dosing in theE13 VGs per kg. So an
order of magnitude lower.
In fact, we have data that saysthat at 1.3 E13 VGs per kg, we
(05:44):
can get delivery enough into thebrain to get the, therapeutic
effects we want to have.
The second thing is that youmay have noticed that some of
the issues that have plaguedthis field is liver toxicity.
In fact, we had a coupleof examples of patients
who unfortunately diedfrom liver failure.
(06:05):
So not only do we have a lowerdose, but we are det targeting
the liver with our capsid.
So they're great forgetting into the brain
better, but they don't getinto the liver any better.
In fact, they're 30fold less effective in
getting it to the liver.
So these are two reasonswhy I'm pretty excited.
And of course, what you want is.
(06:26):
Broad brain distribution.
You want better efficacytoo, and so our capsids,
promise to do that.
It's always benefit risk, right?
It's always the ratio ofbenefit to risk, if you will.
because it's hard to talkabout one without the other
really, or to consider howgood a drug is without talking
about both benefit and risk.
(06:49):
that's why I bring upthe benefit side as well.
Selina.
Selina Koch (06:52):
Yeah.
And so you've identifiedthe receptor for the capsid,
ALPL , and now, you've developedother kinds of ligands against
that receptor, so you canshuttle, not just AAV gene
therapies, but a kind ofa wider array of biologics
into the brain antibodies,enzymes, oligonucleotides.
Um, I think you've justkind of released the first
(07:13):
preclinical data on that.
If you want us totell us a little.
Well, one that's like gonnaincrease your optionality.
I can imagine.
You can be in situations whereyou could have a vectorized
gene therapy against to target.
Or you could just deliver,say, an siRNA with this ligand.
Maybe let's start,let's start there.
Like what's your guidingprinciples for like
picking a strategy?
Alfred Sandrock (07:33):
Yeah.
So this also gets into someof the questions I think
Lauren had about smallcompany, large company.
And, you know, look,I think it's important,
particularly in a smallcompany, to maintain focus.
If you're too unfocused, you'renot gonna be good at anything.
So we decided to stay focusedon neurotherapeutics and
not try to broaden intoother therapeutic areas.
(07:56):
So I'm hiring people andI've collected a group of
people who are specialistsin neurotherapeutics.
But I also said, hey,you know, patients.
In my experience, when Iused to see patients, they
don't care about the modality.
They want the treatment that'sgonna best meet their needs.
and in the case of neurologicaldiseases, we have so few
(08:18):
treatments that are effectivestill, and very few disease
modifying treatments.
We're in an era inneurotherapeutics where
I believe we have a lotof really well validated
targets to go after in thecentral nervous system.
The problem is, is that ifyou only have small molecules,
which which has up until now,up until very recently, then
(08:41):
the only way to get drugsacross the blood brainin
barrier when you only have smallmolecules at your disposal.
Your limit there, thereare a lot of targets that
are considered undruggable.
And so that's a shame becausewe want to help the patients.
We have great targets to goafter, validated by a lot
of human genetics and humanbiology, but we don't have the
(09:02):
ability to target some of these,go after some of these targets.
But we do have these newermodalities, gene therapy,
genetic medicines more broadly,which would include, I, I
believe, oligonucleotidebased treatments as well
as protein therapeutics,antibodies, peptides.
And so the trick is then toget them into the brain better.
(09:25):
And so we started with the AAV.
We had a platform wherewe could make, essentially
random mutations, millions ofvariants of AAV and discover
only the few that get acrossthe blood brainin barrier.
Then we said, well, theseviral capsids have to
cross the BBB by binding tocertain receptors on the BBB.
(09:47):
We identified some of thosereceptors and you just mentioned
one of them, ALPL, and thenwe said, well, maybe then we
can then use them as shuttles.
Or receptors to make shuttlesthat cross the BBB and bring
in all the other modalities.
I was just talking aboutprotein therapeutics,
oligonucleotides, for example.
So maintaining focus on neuro,broadening the therapeutic
(10:11):
approach so that we can go afterthe highest unmet need diseases
and really help patients tothe best of our abilities.
Selina Koch (10:19):
Right.
Um, well, I know you have sayan, I think it's an siRNA that's
vectorized against tau, right.
But now that you have thisALPL, like non capsid shuttle,
you could also just linkthat up to that shuttle.
So I guess that's whereI was thinking like, are
there guiding principles towade through those options?
You just have a muchbigger option space.
Alfred Sandrock (10:41):
So we already have at least one
promising shuttle approach,uh, the transferrin receptor.
But each shuttle is gonnahave its own, advantages
and disadvantages.
The three maincharacteristics we focus
on are pharmacokinetics.
Standard things like Cmax,how high a concentration
(11:02):
you can achieve, and alsothe half life, if you will.
Uh, the distribution, in otherwords, where else in the body
does that shuttle take drugs to?
In some cases we want morebroad distribution because the
disease may involve more thanone organ, more than the brain.
In other cases, bringingthings into the other organs
(11:22):
effects first the pk, but alsomay cause safety liabilities.
Don't deliver the drug tothe organs where, where
you don't need to, you'rejust asking for trouble.
Uh, would be anotherway of saying it.
And the third thing is, eachreceptor and each shuttle
against the receptor is gonnahave its own safety issues.
You know, God didn't put thesereceptors on there just for
(11:43):
us to shuttle drugs there.
These receptors serve a purpose,and when you bind to them,
you might block them fromdoing their normal function.
So having an array of shuttlesagainst various receptors, they
give you the characteristics youneed for the particular disease
at hand, I think is going to bethe way to go, and that's why
(12:04):
we're doing what we're doing.
Selina Koch (12:06):
Yeah.
What?
What would you say right now,based on the data you have,
is the key differentiatorof your ALPL based shuttle
from a transferrin shuttle?
Alfred Sandrock (12:15):
So right now what we see is we
don't see quite as high aconcentration in the brain
after initially giving it.
But what we see is a nicesteady exposure in the brain.
So the half-life is much longer,and for many drugs, for example,
if you want to block a pathway.
You wanna maintainblockage 24/7.
(12:35):
Having a shorthalf-life is suboptimal.
Because if you do wannamaintain exposure, you have
to give it very frequently.
so that's one difference.
The second thing is that,a transferrin receptors,
because iron is so importantfor red blood cells.
That there are hematologicadverse events when
you use transferrinreceptor based shuttles.
(12:58):
We see none of thatwith ALPL so far we've
looked carefully at that.
Of course, we may have our ownseparate set of issues because
ALPL has a separate function,but we're, we're hoping
not, and we're investigating
Selina Koch (13:11):
How much is known about that function?
Alfred Sandrock (13:12):
Well, there are humans that have, uh, so that if
you've lost 50% of the functionof ALPL, you seem to be fine.
If you lose 70% or more,you can run into bone
mineralization problems.
So ALPL is not just expressedon the brain vasculature,
(13:33):
but it's expressed inother vascular beds.
And there is a disease ofsevere ALPL deficiency called
hypophosphatasia, which is abone mineralization problem.
So we're gonna haveto watch out for that.
But again, I thinkin humans anyway.
Humans seem relativelytolerant of at least
modest loss of function.
(13:55):
It has to be severe, sowe're hoping we can still
use it as a receptor.
Jeff Cranmer (14:00):
All right, we're gonna go to a quick break
and we're gonna come backand talk neurodegeneration,
what's happening in the space,and we're gonna talk a little
bit about moving from a big,big biotech to a smaller,
more nimble biotech, Al'smove from Biogen to Voyager.
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Jeff Cranmer (15:07):
We are back at the BioCentury podcast.
We have a special episodethat we're doing right now
with Al Sandrock, he's theCEO of Voyager Therapeutics.
Lauren, where doyou wanna go next?
Lauren Martz (15:22):
Al I'd love to hear about what you are
most excited about withinthe neurodegenerative disease
drug development space.
Alfred Sandrock (15:30):
Several things.
First of all, we, for example,in Alzheimer's disease, we have
the first disease modifyingtherapies that have been
approved in recent years.
They're drugs thataffect that, that bind to
amyloid, the anti-amyloidantibodies you know,
they're the very first ones.
And you know, on averagethere's a 30% effectiveness
(15:51):
slowing the progression.
When you look at largepopulations, it's
an average of 30%.
So what we need to understandis, well, does that mean that
everybody is 30% or does thatmean that some people get a
100% effect and some peopleget zero, and some people
get somewhere in between.
It looks like it'smore the latter.
That some people actuallycan, can actually, have
(16:14):
substantial slowing, infact, maybe even stabilize
and not get worse, whereasothers seem to deteriorate
at the same rate as before.
If that's the case, then itwould be great to know who
can be predicted to be inwhich category because you'd
be there, there'd be a highsense of urgency to put people.
Who are likely to be goodresponders onto the treatment.
(16:37):
The other thing that we'regonna learn shortly, because
the companies are doingthese large studies, is what
happens if you treat earlier?
there are studies nowwhere people are being
treated even before mildcognitive impairment.
So these are people whohave no outward symptoms
of, uh, memory loss or anyof the problems associated
(16:58):
with Alzheimer's disease.
But they're building upamyloid in the brain.
So if you treat even beforesymptoms, can you get a
bigger treatment effect?
I predict that that will be thecase, that we will get a bigger
treatment effect on average.
And I think that wouldbe hugely important.
Of course, what we need noware we need to then recognize
who's building the amyloidup, in a more convenient
(17:20):
way than we have now.
Selina Koch (17:22):
Those two different points, I wonder how intertwined
they might be, for example.
How much of identifyingresponders to that mechanism,
the anti amyloid mechanismis gonna come down to disease
stage, 'cause we saw that, tauPET Imaging data from Lilly.
That's really suggestedto me like you, you
gotta be early in tau.
You can't have Tau PET reallyescaping the medial temporal
(17:44):
area and still expect to seeefficacy or, or do we need
other things besides that?
Alfred Sandrock (17:49):
so there is some data to suggest
that if you take peoplewho have a low tau burden.
So tau is another proteinthat builds up in addition
to amyloid in the brainof Alzheimer's patients.
And there's some suggestionthat those with a low tau
burden, in other words, thosein which the tau hasn't spread
that much yet, have a biggereffect of the amyloid treatment.
(18:10):
But on the other hand, you know,many of these trials enrolled
people with mild cognitiveimpairment and early dementia.
So earlier and later stages.
And guess what?
The treatment effect sidewasn't all that different
between those two.
So there's someconflicting data there.
You would think that mild,mildly cognitively impaired
people would have a biggereffect than those who were
(18:31):
already demented and therewasn't a big difference.
so it's a little,uh, troubling to me.
So I think it's a mixed picture.
But I do think that, thereason why the heterogeneity
of, treatment responses I gonnabe is important is that when we
think about now tau treatments.
Where does that fit in, intothe treatment landscape?
(18:52):
If somebody is alreadycompletely stable
on antiamyloid.
Well, you don't have to worryabout adding any other treatment
or switching, but if you're inone of those people who have
either no effect or only apartial effect, for the former
category, those who have hadno effect from the anti-amyloid
antibodies, well then you shouldswitch to the tau treatments.
(19:12):
For those that have a partialeffect, maybe you add so
that you get a better effectby combining two treatments
So that's another value tounderstanding the heterogeneity
treatment response, 'causeit will tell you how you deal
with a new set of treatments.
And hopefully they'll come,the tau directed treatments,
in the clinical setting.
(19:33):
I want to just touch onthough the diagnostics piece
because, if we're gonna treatearly, we have to recognize
that somebody is building upamyloid before any symptoms.
That's gonna require forit to be feasible in the
primary care setting, you'regonna need a blood test.
And I'm happy to say that,you know, now that there are
treatments, people are now doingmore work on diagnostics and
(19:58):
so the blood-based diagnosticbiomarkers are coming.
I think that's gonna makethis early treatment feasible
if it does in fact show thatit's, it's of of high value.
I see it very similar tosort of what happened in
cardiovascular disease.
You know, we don't wait tillsomebody has a heart attack.
We treat the cholesterolor we treat the blood
(20:19):
pressure, so that we canprevent heart attacks.
Maybe that's where we'regonna be going with
Alzheimer's disease.
We can recognize early and startthe treatment and hopefully
maybe we can prevent peoplefrom getting demented ever.
That would be a, awonderful dream come true.
Selina Koch (20:36):
it sure would.
But to really go intothat preventative medicine
space where, okay, theymight, patient might have
amyloid in their brain, butthey're otherwise healthy.
Right?
Uh, you gotta be very safeand low burden with the
tone of treatment modality.
Where do you see that?
I mean, I know right now it'sthese leading MABs that are
(20:56):
being tested, but where do youthink ultimately is the right
kind of, product profile there?
Alfred Sandrock (21:02):
Yeah.
Maybe, if the earlier treatmentwith an antibody works, maybe
we can treat earlier with otherways of effect of lowering
amyloid that could be lessexpensive and maybe safer.
I'll also say that one thingwe don't know is how the safety
will be affected by going early.
So if you have lessamyloid in the brain,
(21:24):
it's still, it's buildingup, but if you have less.
Is it possible that thetreatment would be safer
because the antibody doesn'thave as much to interact
with, then we don't reallyknow what causes ARIA, which
is the main side effect thatyou're referring to, Selina.
But it could be that if youhave a lower amyloid burden,
the safety could improve.
That would be a,the hope anyway.
Selina Koch (21:46):
Totally, and these new shuttles could potentially
help with that as well?
Alfred Sandrock (21:50):
That's a great segue into the fact
that, you know, uh, there isan antiamyloid antibody that a
company actually discontinuedbecause it was modest in
efficacy, but still had allthe safety issues, very modest
in efficacy, so that in fact,they terminated the program.
They put a shuttle onit, and guess what?
The efficacy improvedand the safety improved.
(22:12):
Another example where fixingthe delivery really can
broaden the therapeuticwindow, increase efficacy,
and, uh, make it safer.
Selina Koch (22:21):
I wanna talk tau for a little bit, cause
I remember a time where I'mpretty sure, correct me if
I'm wrong, you were kind ofskeptical that tau would make a
really, good therapeutic target.
But clearly you've come around,Voyager has multiple programs.
You've got both the antibodyintercepting extracellular
tau, and then the RNAsilencing getting at
the intracellular form.
(22:41):
So I mean, what broughtyou around on that?
And also both of those are worthtesting, but like as the data
stand now, do you think one ofthose is a stronger hypothesis?
Alfred Sandrock (22:51):
Well, so, uh, skeptical might be a strong
word, but, well, we decided,uh, when I was, at Biogen
to go after amyloid first.
And of course we didhave multiple programs
in tau eventually.
But the reason why we wentafter amyloid first was
the strong human agenticevidence pointing to amyloid.
So, as you know, when youhave familial Alzheimer's
(23:13):
disease in the early days,we had these cases, we had
families that had single genemutations that increased the
risk of Alzheimer's disease.
They often developedAlzheimer's disease as
early as in their forties.
and they had often had ramore rapid progression.
After we figured out thegenes, it turned out they were
all in the amyloid cascade.
(23:33):
Either they were encoding forthe amyloid, amyloid precursor
protein gene itself, orenzymes that process that big
protein into the 42 amino acidpeptide, which is the toxic
species, if you will, afterit aggregates and misfolds.
So, the geneticsstrongly pointed to
amyloid as being causal.
(23:56):
Also APOE, the mostcommon among, not in
familial Alzheimer's, butin sporadic Alzheimer's.
The most, importantgenetic risk factor for
Alzheimer's disease is APOE.
And if you're homozygous forE4, you have a 90% likelihood
of getting Alzheimer's diseaseagain at an earlier age,
(24:16):
typically in your fiftiesand more rapidly progressive.
But APOE also affected thebuildup of amyloid in the brain.
So even APOEpointed to, amyloid.
So that's why wetargeted amyloid first.
But I do think thatthe evidence is growing
that tau is responsiblefor neurodegeneration.
(24:37):
In fact, there are mutationsin tau that cause a
different disease calledfrontal temporal dementia.
So clearly mutations in taucan cause neurodegeneration,
but the, uh, human biologyalso very strongly shows that
after the amyloid appears,then the tau starts to spread.
(24:58):
And a lot of people, includingmyself, believe that amyloid
actually triggers thespread of tau in the brain.
That a little bit of taumisfolding in the brain is
actually part of normal aging.
It's just that it'slocalized to a very small
part of the temporal lobeunless amyloid is present.
Once amyloid appears thattau now spreads, and that
(25:19):
misfolded tau spreadsthroughout the brain.
And so, we need to address that.
Jeff Cranmer (25:24):
I wanna get back to Lauren's initial question
now, uh, years at Biogen.
Really just movingup through the ranks.
And, and then you madethe jump to Voyager.
I'm sure a lot of ourlisteners, you know, may have
done something similar orcontemplating such a move.
How has that been for you andwhy, why did you make that move?
Alfred Sandrock (25:45):
Well, look, I kind of grew up at Biogen.
When I first joined Biogen, itwas about, I think it was five
or 600 people, so it was stilla relatively small company.
And, uh, we had justgotten started in multiple
sclerosis, actually, asa commercial company.
And we were able to developmultiple treatments for MS.
(26:05):
And, uh, boy, I, I grew up,like I said, I literally
grew up there and, loved it.
And I loved it right upuntil I left, actually.
still loved it when I left.
But I felt that, it had grownto the size where it was
kind of too large for me.
I'm not really big on kindof bureaucracy, if you will.
(26:25):
Not that Biogen's terriblybureaucratic, but there are a
lot of committees, you know.
when it gets to multiple, likeI think we were close to 8,000
people by the time I left.
So from 600 people to8,000, big difference.
And it's hard to make decisionskind of because there's a lot
more people involved and, Ilike smaller companies that
(26:46):
are, as you said it, you saidit yourself, Jeff Nimble.
Like I can walk down the hallhere and really talk to all the
people I need to, to get theinput I need to make a decision.
You know what I mean?
And I don't need toeven schedule a meeting,
which is wonderful.
I'll tell you the downsidethough is that we don't
have as much cash.
Um, you know, at Biogen, therewas a little bit more freedom
(27:10):
to explore areas that, uh.
May not immediatelylead to a product.
Which was great, becauseit allowed for exploration
into highly sort of riskyInnovent territories.
Of course, we do doa lot of innovative
stuff here at Voyager.
But I don't have as muchcash and I don't have as many
(27:30):
people, here, so I have to bea little bit more cautious.
In fact, I have to restrainmyself, because, some people
say I have too many ideas.
and so, so that's the,that's the difference.
Selina Koch (27:44):
Well, one important, oh, sorry.
Uh, one important sourceof cash for you all I
think has been like justpartnering out your capsid.
Now that you have thisother shuttle coming
online, is you going to tapinto that similarly, or?
Alfred Sandrock (27:58):
Oh yeah, I'm, I'm a big fan of partnerships.
Not only do they bring in,revenue, but you learn a
lot from your partners.
You know, when, when it's agreat scientific collaboration,
you know, the interactionscientist to scientist really
does increase, um, justaccelerates everything and
also increases the learning.
And then look, there's,there's so much to be done.
(28:20):
Once you've solved delivery forgene therapy, there's no way
we could prosecute every singletarget or go after every single
disease, and so why not partner?
Yeah, you give up someof the upside later.
But there's, so there's, youknow, if you're successful
and you can help a lot ofpatients, there's no problem in
giving up some of the upside.
(28:41):
And then, you're right, the,the shuttle program that
we just launched, there'sa lot of interest, a lot of
interest out there in shuttles.
And so yeah, I'mopen to partnerships.
Selina Koch (28:51):
Should your tau antibody, do well in the
clinic, and I think you've gota readout coming next year.
Um.
You know, as a smaller company,probably not gonna go the
Biogen route and think ofcommercializing yourself, right?
Like when, when would youthink about partnering?
Assuming you're partnering.
Alfred Sandrock (29:09):
Well, not only will we not commercialize, we
wouldn't want to be doing thebig Phase III trials either.
Those are usually massivetrials and global in nature.
And so we'd want topartner, before Phase III.
Jeff Cranmer (29:21):
So, Al uh, back in the day you were
at Mass General, you were aneuromuscular physician, ALS
any other neurodegenerativeneuromuscular diseases you'd
like to, uh, talk about?
Alfred S (29:34):
Yeah, so ALS for sure.
I mean, you know, I, I was atMass General right when Bob
Brown discovered the firstgene tic cause of ALS, which
was superoxide dismutase, SOD.
And so we were getting a lotof patients from all around the
world coming to Mass General.
And since Bob couldn'tsee them all, some of 'em
(29:54):
had the same me, you know.
And I'll tell you, it is oneof the worst diseases around.
I used to see people thatreminded me of loved ones you
know, some, sometimes thepatients, they were always
very, very nice people.
For some reason it seemed thatALS patients and I couldn't
help them, and that couldbe why I came to industry.
(30:15):
So at Biogen, they had adrug called tofersen, which is
an antisense oligonucleotidethat got approved recently.
Actually, uh, we hired TobyFerguson, to Voyager, and
by the way, tofersen isnamed after Toby Ferguson.
But anyway, I digress.
I wanted to bring up tofersenbecause for the first time
(30:36):
we see a drug that cannot only stabilize some
patients, but actually somepatients are improving.
So imagine that ALS patientswho are putting aside
their walker or gettingout of the wheelchair.
This is happening, is justlike a, you know, the fact
that I'm even saying it now isalmost hard for me to believe.
You know, it's a greatindication of how far
(30:58):
we've come in treatment ofneurodegenerative diseases.
So I'm very hopeful thatwe can do even more.
Unfortunately, only a fewpercentage of patients
have SOD1 mutations.
So the vast majority of ALSpatients need something as well.
And by the way, we areworking on ALS at Voyager too.
Selina Koch (31:17):
Okay, I have to ask an FDA question.
So tofersen, to getacross the finish line,
required some flexibilityover there at the agency.
You know, they tookneurofilament light chain
as the biomarker called ita surrogate, and they used
open-label efficacy data, right?
Because really if you justlook at the primary endpoint,
it, it on a population levelfailed rather spectacularly,
(31:40):
if you look at that P value.
Um, yet that has really,it seems like more to
do with the trial designthan the therapy, right?
And it's just hard in theserare indications where things
aren't well standardized,where you only kind of
understand the natural history.
And right now we're justgetting all these, I feel
like mixed signals out of FDA.
We all saw what happened withuniQure, who was gonna have
(32:01):
a natural history comparator,and then FDA agreed to it
and then changed his mind.
On the other hand Lexeogot some, good news that
its program might have someendpoints that could work
for accelerated approval.
I mean, how do you look atthese, I don't know what seemed
like mixed signals to me.
And what's your, what'syour view of them?
Alfred Sandrock (32:20):
Well I do think that, flexibility
is very important.
I do like the idea ofaccelerated approval, that
the use of biomarkers, perhapseven with uncontrolled trials
to basically acceleratedapproval is saying, you know
what, there's a chance wecould be wrong, that the drug
is safe and effective, butit's such a terrible disease.
(32:42):
There's so few optionsfor these patients.
Why don't we approve it?
And then let's see theconfirmatory trial.
And if the confirmatory trialis positive, then we know
we've made the right decision.
You know, I'm very proud ofthe fact that Amylyx, for
example, there was another ALSdrug that had been approved,
accelerated approval, theconfirmatory trial was negative
(33:04):
and the CEOs at Amylyx pulledthe drug off the market.
See, as long as I think industryleaders are responsible and
do the right thing, if theconfirmatory trial doesn't
confirm, then the drugshould come off the market.
But in the meantime, havingthese accelerated approvals
allows patients who arehave very few other options.
(33:24):
These are often deadly diseases.
And I think it makessense to grant approval
in an accelerated manner.
Look, FDA is in some flux.
I still believe, that if youhave a great drug for for
a bad disease, that we'restill gonna be approved.
And the companies and theshareholders will be rewarded.
(33:44):
If I stop believing in that,then I may as well quit.
But I, I firmly believe thatwe'll figure out a way to help
patients with bad diseases.
Selina Koch (33:52):
Yeah.
And is is, are you sayingit's not really changing
any decisions that you'remaking over there, that kind
of uncertainty right now?
You're just.
Alfred Sandrock (34:00):
No.
And, and, and look, we, weare, we are sticking to our
convictions that, as long as wemake transformative treatments
for patients with bad diseasesthat we will be successful.
Jeff Cranmer (34:13):
That is excellent to hear Al and, uh, I'm sure
you're joined by many of yourfellow CEOs and other folks,
working in the trenches andeven in FDA, uh, as we've talked
about on the podcast previously,a lot of great people there,
a lot of hardworking people.
Got Pazdur at thetop of CDER now.
Let's get those drugs approved.
(34:34):
Selina, we got timefor one more question.
I'm gonna give it to you.
Selina Koch (34:37):
Ooh, there are so many.
I'd love to ask.
Um, but I think I have toask about neuroinflammation,
just because we're thinkingabout like up and coming
therapeutic hypotheses thathave some genetic backing.
And might be usefulacross a wide swath of
neurological indications.
That's certainly one peopleare talking about a lot.
(34:59):
I noticed Voyager doesn'thave any neuro inflammation
targeting programsdisclosed in its pipeline.
So I guess I'm wondering,you know, where you think
the field is at when itcomes to understanding what
neuroinflammation is, howit contributes to disease
such as Alzheimer's, andI think importantly like,
how you can measure it?
Alfred Sandrock (35:18):
Yeah, so, um.
if you thought I wasskeptical about tau, I was
even more skeptical initiallyabout neuroinflammation.
Look, the thing is youdefinitely see evidence of
neuroinflammation in virtuallyall these neurodegenerative
diseases, certainly inAlzheimer's disease.
But the question is always iswhen you see it in the brain,
is it cause or is it effect?
(35:40):
And you know, a lot ofdying cells will cause
neuroinflammatory typecells to come and do the
cleanup, if you will.
and so, uh, I was a littlebit skeptical, but then
when we found that thereare certain genetic variants
that increase the risk ofAlzheimer's disease, such
as TREM2, I said, okay, it'sgotta be in the causal pathway.
(36:01):
Unfortunately, the earlythe first attempts at
making drugs against TREM2have not been successful.
But TREM2 is complicated, theirmembrane bound, soluble forms.
So maybe we haven't targeted thedrug in just the right way yet.
So I'm still hopeful.
I think the complicationof neuroinflammation
is that there's sort ofneuroinflammation that
(36:22):
occurs from the cells thatare innate in the brain,
such as microglial cells.
There's sometimes inflammationfrom cells that come from
the outside, from theimmune system that come in
and invade essentially thebrain, or come into the
brain and cause inflammation.
So it's complicated.
And then if you take themicroglial cells, the innate
cells in the brain thatshow inflammatory changes,
(36:45):
sometimes there's goodinflammation and sometimes
there's bad inflammation.
In fact, there's some formsof neuroinflammation, if you
will, or microglial activationthat we think are protective.
And so I think measuring itin the right way, we'd hate to
decrease the protective forms ofneuroinflammation, if you will.
We wanna dampen downthe harmful ones.
(37:07):
I think we're still at the veryearly stages of measuring it
properly and figuring out thecomplexity of neuroinflammation.
Selina Koch (37:15):
Do you think there's anything to learn
from multiple sclerosis here?
Because we did recently see aBTK couple of BTK inhibitors
slow the secondary or primaryprogressive form of that
disease was just kind of likeneurodegeneration, you know?
Alfred Sandrock (37:30):
Yeah.
So MS is a greatexample, Selina.
There's a heavy, contributionof cells that come in
from the outside, theadaptive immune system.
So we see T cells, B cells,and in fact, all the drugs that
work for MS now affect thatadaptive immunity, if you will.
The B-cell, drugs, BTKbeing one of them has been
(37:53):
among the most successful.
The issue there again,might be delivery.
There are these B cells thatsit in the brain, in the sub
meningeal space and they'renot affected by the current
B cell lowering treatments,certainly not by the
antibodies against a B cells.
You'd have to be sureyour BTK inhibitors, brain
(38:13):
penetrant, not all of them are.
There are these B cells that sitin the sub meningeal space that
I believe is responsible for theworsening that patients still
have, despite the best immunemodulating treatments that
we have on the market today.
And I think that's gonna requiregoing after those B cells in
the, in the sub meningeal space.
By the way, frequentlythey're infected with
(38:35):
Epstein-Barr virus.
So, people are startingto think about how to
target those as well.
Jeff Cranmer (38:41):
All right.
You've been listening toGeeking Out with Selina,
uh, with Al and Selina.
Al thank you for joining theBioCentury This Week podcast.
Appreciate you givingus so much of your time.
I now can see you, uh, justwandering down the halls,
uh, putting people looseon new projects, every day.
(39:03):
It's a great, greatvision and, uh, we're very
grateful to Voyager forsponsoring the podcast.
And, uh, thanks to Selina andLauren for joining me today.
Alfred Sandrock (39:14):
Thanks for having me, thanks
for geeking out with me..
Jeff Cranmer (39:17):
Alright, well, hopefully you two can connect
at J.P. Morgan, uh, as youusually like to do, in sunny
San Francisco and you've beenlistening to the BioCentury This
Week Podcast, a Special Episode.
We will have anotherspecial episode this week
or early next, coming.
direct from Jefferies and thenwe will of course be back,
(39:41):
with our regular episode.
Uh, I'm escaping for a fewdays, so Stephen Hansen will
be your host, and we'd like tothank Kendall Square Orchestra
for making the music for allof BioCentury's podcasts.
Eric Pierce (39:57):
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
by Voyager Therapeutics.
Voyager Therapeutics isdedicated to leveraging
the power of human geneticsto modify the course
of – and ultimately cure– neurological diseases.
Voyager addresses the challengeof delivering novel treatments
to the brain through thecompany's innovative TRACER™ AAV
capsid discovery platform, aswell as Voyager's NeuroShuttle™,
(00:25):
a non-viral delivery platformdesigned to transport multiple
modalities of neurotherapeuticsacross the blood-brain barrier.
The company's programs addressdiseases with substantial unmet
needs, including Alzheimer'sdisease, Friedrich's ataxia,
Parkinson's disease, ALS,and other diseases of the
central nervous system.
Jeff Cranmer (00:49):
Welcome to a Special Edition of the
BioCentury This Week podcast.
I'm your host, Jeff Cranmer, oneof the Executive Editors here
at BioCentury, and today I'mdelighted to have my colleagues
Lauren Martz and Selina Koch,join me for a conversation
with Al Sandrock, he's CEO ofneurogenetic medicines company
(01:11):
Voyager our sponsor this month.
Before joining Voyager inMarch of 2022, Al spent more
than 20 years at Biogen risingthrough the ranks, to become
CMO and eventually EVP of R&D.
Given his background, Al cancover any number of topics
(01:31):
in the field of neurology.
So I'd like to bring in mycolleagues now to find out
what they'd like to learnfrom Al. Well, Selina,
you, uh, lead our neurologycoverage, what are you,
hoping to talk about today?
Selina Koch (01:43):
Thanks Jeff.
So I recently wrote aboutthis, so the topic will show
my bias, but personally I thinkVoyager is working on one of
the most important challengesin neurology, which is the
difficulty of deliveringtreatments to the brain.
At the risk of soundingsimplistic, um, you know, drugs
don't work if you don't get themwhere they're needed, right?
(02:07):
Which makes CNS deliverykind of foundational, with
implications across, youknow, all of neurology,
well, even the psychiatry.
You know, it's an excitingtime because there's a lot
of activity aimed at solvingthis problem right now, and
I'm looking forward to hearinghow Voyager's approach kind
of fits into that landscape.
But maybe I'll bring up one moretopic before, uh, moving on to
(02:29):
Lauren, which is, of course,I want to pick Al's brain
on up and coming therapeuticapproaches to Alzheimer's
disease, where he's seeing themost promise in the short term.
What might be needed toadvance some newer hypotheses.
Jeff Cranmer (02:43):
Lauren, what are you, uh, curious about?
Lauren Martz (02:45):
Thanks, Jeff.
I'd love to hear a little bitabout the transition from a
large company to a leadershiprole in a small company.
And I'd also love to hearsome thoughts from Al on
transitioning the modalityfocus at a biotech.
So we know that Voyagerhas historically done a lot
of work in gene therapiesand has used some of the
(03:08):
expertise from that work tostart moving into delivery
of different modalities.
So I, I'd love to hear moreabout how that came about.
Jeff Cranmer (03:17):
Sounds good.
Well, Selina, why don'tyou, jump right in on the,
BBB question you wanna ask.
Well, just for our listenersout there, Selina has written
several pieces now on theblood brain barrier and, uh,
the companies, the players,the technology, the deals.
So do go to BioCentury.comto check those out.
And now I'm just gonnahand it over to Selina.
Selina Koch (03:39):
Yeah.
Well, I have a couple.
Um, I guess we could build onwhat Lauren was saying at the
start in the gene therapy space.
You know, we have seen a stringof safety incidents in the
clinic with gene therapies.
These are generally, youknow, inflammatory in nature.
So voyagers working inindications that span neurology
right from ultra rare likeFriedrich's ataxia all the
(04:02):
way to Alzheimer's disease.
So I guess al what's convincedyou, that you know, if you
have a highly penetrant, CNSpenetrant AV capsid, that
that's gonna be safe enough,even for the larger end,
that spectrum for a prevalentcondition like Alzheimer's.
Alfred Sandrock (04:18):
So there's two main reasons for that, Selina.
And, and maybe before I start,I'll say thank you for hosting
this and for talking to me,appreciate you, and I hope
you have a good conversation.
There's a couple of reasonswhy I came to Voyager.
And it was because I feltthat we can make gene therapy
work better, and more safely.
(04:40):
And there's two reasonswhy, I like the approach
that we're taking.
One is that we're engineeringcapsids that get across the
blood brain barrier afterIV delivery, and they're
so potent that we can lowerthe doses, from what's been
traditionally used for systemicor intravenously delivered
gene therapy, AAV gene therapy.
(05:02):
So typically, for example,people give, one E14 viral
genomes per kilogram, so onetimes 10 to the 14th viral
particles per kilogram.
And that's the dose, infact, of the approved gene
therapy for spinal muscularatrophy called Zolgensma.
(05:23):
So a basic tenet of drugdevelopment is if you
go lower in the dose,it's likely to be safer.
So we are dosing in theE13 VGs per kg. So an
order of magnitude lower.
In fact, we have data that saysthat at 1.3 E13 VGs per kg, we
(05:44):
can get delivery enough into thebrain to get the, therapeutic
effects we want to have.
The second thing is that youmay have noticed that some of
the issues that have plaguedthis field is liver toxicity.
In fact, we had a coupleof examples of patients
who unfortunately diedfrom liver failure.
(06:05):
So not only do we have a lowerdose, but we are det targeting
the liver with our capsid.
So they're great forgetting into the brain
better, but they don't getinto the liver any better.
In fact, they're 30fold less effective in
getting it to the liver.
So these are two reasonswhy I'm pretty excited.
And of course, what you want is.
(06:26):
Broad brain distribution.
You want better efficacytoo, and so our capsids,
promise to do that.
It's always benefit risk, right?
It's always the ratio ofbenefit to risk, if you will.
because it's hard to talkabout one without the other
really, or to consider howgood a drug is without talking
about both benefit and risk.
(06:49):
that's why I bring upthe benefit side as well.
Selina.
Selina Koch (06:52):
Yeah.
And so you've identifiedthe receptor for the capsid,
ALPL , and now, you've developedother kinds of ligands against
that receptor, so you canshuttle, not just AAV gene
therapies, but a kind ofa wider array of biologics
into the brain antibodies,enzymes, oligonucleotides.
Um, I think you've justkind of released the first
(07:13):
preclinical data on that.
If you want us totell us a little.
Well, one that's like gonnaincrease your optionality.
I can imagine.
You can be in situations whereyou could have a vectorized
gene therapy against to target.
Or you could just deliver,say, an siRNA with this ligand.
Maybe let's start,let's start there.
Like what's your guidingprinciples for like
picking a strategy?
Alfred Sandrock (07:33):
Yeah.
So this also gets into someof the questions I think
Lauren had about smallcompany, large company.
And, you know, look,I think it's important,
particularly in a smallcompany, to maintain focus.
If you're too unfocused, you'renot gonna be good at anything.
So we decided to stay focusedon neurotherapeutics and
not try to broaden intoother therapeutic areas.
(07:56):
So I'm hiring people andI've collected a group of
people who are specialistsin neurotherapeutics.
But I also said, hey,you know, patients.
In my experience, when Iused to see patients, they
don't care about the modality.
They want the treatment that'sgonna best meet their needs.
and in the case of neurologicaldiseases, we have so few
(08:18):
treatments that are effectivestill, and very few disease
modifying treatments.
We're in an era inneurotherapeutics where
I believe we have a lotof really well validated
targets to go after in thecentral nervous system.
The problem is, is that ifyou only have small molecules,
which which has up until now,up until very recently, then
(08:41):
the only way to get drugsacross the blood brainin
barrier when you only have smallmolecules at your disposal.
Your limit there, thereare a lot of targets that
are considered undruggable.
And so that's a shame becausewe want to help the patients.
We have great targets to goafter, validated by a lot
of human genetics and humanbiology, but we don't have the
(09:02):
ability to target some of these,go after some of these targets.
But we do have these newermodalities, gene therapy,
genetic medicines more broadly,which would include, I, I
believe, oligonucleotidebased treatments as well
as protein therapeutics,antibodies, peptides.
And so the trick is then toget them into the brain better.
(09:25):
And so we started with the AAV.
We had a platform wherewe could make, essentially
random mutations, millions ofvariants of AAV and discover
only the few that get acrossthe blood brainin barrier.
Then we said, well, theseviral capsids have to
cross the BBB by binding tocertain receptors on the BBB.
(09:47):
We identified some of thosereceptors and you just mentioned
one of them, ALPL, and thenwe said, well, maybe then we
can then use them as shuttles.
Or receptors to make shuttlesthat cross the BBB and bring
in all the other modalities.
I was just talking aboutprotein therapeutics,
oligonucleotides, for example.
So maintaining focus on neuro,broadening the therapeutic
(10:11):
approach so that we can go afterthe highest unmet need diseases
and really help patients tothe best of our abilities.
Selina Koch (10:19):
Right.
Um, well, I know you have sayan, I think it's an siRNA that's
vectorized against tau, right.
But now that you have thisALPL, like non capsid shuttle,
you could also just linkthat up to that shuttle.
So I guess that's whereI was thinking like, are
there guiding principles towade through those options?
You just have a muchbigger option space.
Alfred Sandrock (10:41):
So we already have at least one
promising shuttle approach,uh, the transferrin receptor.
But each shuttle is gonnahave its own, advantages
and disadvantages.
The three maincharacteristics we focus
on are pharmacokinetics.
Standard things like Cmax,how high a concentration
(11:02):
you can achieve, and alsothe half life, if you will.
Uh, the distribution, in otherwords, where else in the body
does that shuttle take drugs to?
In some cases we want morebroad distribution because the
disease may involve more thanone organ, more than the brain.
In other cases, bringingthings into the other organs
(11:22):
effects first the pk, but alsomay cause safety liabilities.
Don't deliver the drug tothe organs where, where
you don't need to, you'rejust asking for trouble.
Uh, would be anotherway of saying it.
And the third thing is, eachreceptor and each shuttle
against the receptor is gonnahave its own safety issues.
You know, God didn't put thesereceptors on there just for
(11:43):
us to shuttle drugs there.
These receptors serve a purpose,and when you bind to them,
you might block them fromdoing their normal function.
So having an array of shuttlesagainst various receptors, they
give you the characteristics youneed for the particular disease
at hand, I think is going to bethe way to go, and that's why
(12:04):
we're doing what we're doing.
Selina Koch (12:06):
Yeah.
What?
What would you say right now,based on the data you have,
is the key differentiatorof your ALPL based shuttle
from a transferrin shuttle?
Alfred Sandrock (12:15):
So right now what we see is we
don't see quite as high aconcentration in the brain
after initially giving it.
But what we see is a nicesteady exposure in the brain.
So the half-life is much longer,and for many drugs, for example,
if you want to block a pathway.
You wanna maintainblockage 24/7.
(12:35):
Having a shorthalf-life is suboptimal.
Because if you do wannamaintain exposure, you have
to give it very frequently.
so that's one difference.
The second thing is that,a transferrin receptors,
because iron is so importantfor red blood cells.
That there are hematologicadverse events when
you use transferrinreceptor based shuttles.
(12:58):
We see none of thatwith ALPL so far we've
looked carefully at that.
Of course, we may have our ownseparate set of issues because
ALPL has a separate function,but we're, we're hoping
not, and we're investigating
Selina Koch (13:11):
How much is known about that function?
Alfred Sandrock (13:12):
Well, there are humans that have, uh, so that if
you've lost 50% of the functionof ALPL, you seem to be fine.
If you lose 70% or more,you can run into bone
mineralization problems.
So ALPL is not just expressedon the brain vasculature,
(13:33):
but it's expressed inother vascular beds.
And there is a disease ofsevere ALPL deficiency called
hypophosphatasia, which is abone mineralization problem.
So we're gonna haveto watch out for that.
But again, I thinkin humans anyway.
Humans seem relativelytolerant of at least
modest loss of function.
(13:55):
It has to be severe, sowe're hoping we can still
use it as a receptor.
Jeff Cranmer (14:00):
All right, we're gonna go to a quick break
and we're gonna come backand talk neurodegeneration,
what's happening in the space,and we're gonna talk a little
bit about moving from a big,big biotech to a smaller,
more nimble biotech, Al'smove from Biogen to Voyager.
Alanna Farro (14:20):
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Jeff Cranmer (15:07):
We are back at the BioCentury podcast.
We have a special episodethat we're doing right now
with Al Sandrock, he's theCEO of Voyager Therapeutics.
Lauren, where doyou wanna go next?
Lauren Martz (15:22):
Al I'd love to hear about what you are
most excited about withinthe neurodegenerative disease
drug development space.
Alfred Sandrock (15:30):
Several things.
First of all, we, for example,in Alzheimer's disease, we have
the first disease modifyingtherapies that have been
approved in recent years.
They're drugs thataffect that, that bind to
amyloid, the anti-amyloidantibodies you know,
they're the very first ones.
And you know, on averagethere's a 30% effectiveness
(15:51):
slowing the progression.
When you look at largepopulations, it's
an average of 30%.
So what we need to understandis, well, does that mean that
everybody is 30% or does thatmean that some people get a
100% effect and some peopleget zero, and some people
get somewhere in between.
It looks like it'smore the latter.
That some people actuallycan, can actually, have
(16:14):
substantial slowing, infact, maybe even stabilize
and not get worse, whereasothers seem to deteriorate
at the same rate as before.
If that's the case, then itwould be great to know who
can be predicted to be inwhich category because you'd
be there, there'd be a highsense of urgency to put people.
Who are likely to be goodresponders onto the treatment.
(16:37):
The other thing that we'regonna learn shortly, because
the companies are doingthese large studies, is what
happens if you treat earlier?
there are studies nowwhere people are being
treated even before mildcognitive impairment.
So these are people whohave no outward symptoms
of, uh, memory loss or anyof the problems associated
(16:58):
with Alzheimer's disease.
But they're building upamyloid in the brain.
So if you treat even beforesymptoms, can you get a
bigger treatment effect?
I predict that that will be thecase, that we will get a bigger
treatment effect on average.
And I think that wouldbe hugely important.
Of course, what we need noware we need to then recognize
who's building the amyloidup, in a more convenient
(17:20):
way than we have now.
Selina Koch (17:22):
Those two different points, I wonder how intertwined
they might be, for example.
How much of identifyingresponders to that mechanism,
the anti amyloid mechanismis gonna come down to disease
stage, 'cause we saw that, tauPET Imaging data from Lilly.
That's really suggestedto me like you, you
gotta be early in tau.
You can't have Tau PET reallyescaping the medial temporal
(17:44):
area and still expect to seeefficacy or, or do we need
other things besides that?
Alfred Sandrock (17:49):
so there is some data to suggest
that if you take peoplewho have a low tau burden.
So tau is another proteinthat builds up in addition
to amyloid in the brainof Alzheimer's patients.
And there's some suggestionthat those with a low tau
burden, in other words, thosein which the tau hasn't spread
that much yet, have a biggereffect of the amyloid treatment.
(18:10):
But on the other hand, you know,many of these trials enrolled
people with mild cognitiveimpairment and early dementia.
So earlier and later stages.
And guess what?
The treatment effect sidewasn't all that different
between those two.
So there's someconflicting data there.
You would think that mild,mildly cognitively impaired
people would have a biggereffect than those who were
(18:31):
already demented and therewasn't a big difference.
so it's a little,uh, troubling to me.
So I think it's a mixed picture.
But I do think that, thereason why the heterogeneity
of, treatment responses I gonnabe is important is that when we
think about now tau treatments.
Where does that fit in, intothe treatment landscape?
(18:52):
If somebody is alreadycompletely stable
on antiamyloid.
Well, you don't have to worryabout adding any other treatment
or switching, but if you're inone of those people who have
either no effect or only apartial effect, for the former
category, those who have hadno effect from the anti-amyloid
antibodies, well then you shouldswitch to the tau treatments.
(19:12):
For those that have a partialeffect, maybe you add so
that you get a better effectby combining two treatments
So that's another value tounderstanding the heterogeneity
treatment response, 'causeit will tell you how you deal
with a new set of treatments.
And hopefully they'll come,the tau directed treatments,
in the clinical setting.
(19:33):
I want to just touch onthough the diagnostics piece
because, if we're gonna treatearly, we have to recognize
that somebody is building upamyloid before any symptoms.
That's gonna require forit to be feasible in the
primary care setting, you'regonna need a blood test.
And I'm happy to say that,you know, now that there are
treatments, people are now doingmore work on diagnostics and
(19:58):
so the blood-based diagnosticbiomarkers are coming.
I think that's gonna makethis early treatment feasible
if it does in fact show thatit's, it's of of high value.
I see it very similar tosort of what happened in
cardiovascular disease.
You know, we don't wait tillsomebody has a heart attack.
We treat the cholesterolor we treat the blood
(20:19):
pressure, so that we canprevent heart attacks.
Maybe that's where we'regonna be going with
Alzheimer's disease.
We can recognize early and startthe treatment and hopefully
maybe we can prevent peoplefrom getting demented ever.
That would be a, awonderful dream come true.
Selina Koch (20:36):
it sure would.
But to really go intothat preventative medicine
space where, okay, theymight, patient might have
amyloid in their brain, butthey're otherwise healthy.
Right?
Uh, you gotta be very safeand low burden with the
tone of treatment modality.
Where do you see that?
I mean, I know right now it'sthese leading MABs that are
(20:56):
being tested, but where do youthink ultimately is the right
kind of, product profile there?
Alfred Sandrock (21:02):
Yeah.
Maybe, if the earlier treatmentwith an antibody works, maybe
we can treat earlier with otherways of effect of lowering
amyloid that could be lessexpensive and maybe safer.
I'll also say that one thingwe don't know is how the safety
will be affected by going early.
So if you have lessamyloid in the brain,
(21:24):
it's still, it's buildingup, but if you have less.
Is it possible that thetreatment would be safer
because the antibody doesn'thave as much to interact
with, then we don't reallyknow what causes ARIA, which
is the main side effect thatyou're referring to, Selina.
But it could be that if youhave a lower amyloid burden,
the safety could improve.
That would be a,the hope anyway.
Selina Koch (21:46):
Totally, and these new shuttles could potentially
help with that as well?
Alfred Sandrock (21:50):
That's a great segue into the fact
that, you know, uh, there isan antiamyloid antibody that a
company actually discontinuedbecause it was modest in
efficacy, but still had allthe safety issues, very modest
in efficacy, so that in fact,they terminated the program.
They put a shuttle onit, and guess what?
The efficacy improvedand the safety improved.
(22:12):
Another example where fixingthe delivery really can
broaden the therapeuticwindow, increase efficacy,
and, uh, make it safer.
Selina Koch (22:21):
I wanna talk tau for a little bit, cause
I remember a time where I'mpretty sure, correct me if
I'm wrong, you were kind ofskeptical that tau would make a
really, good therapeutic target.
But clearly you've come around,Voyager has multiple programs.
You've got both the antibodyintercepting extracellular
tau, and then the RNAsilencing getting at
the intracellular form.
(22:41):
So I mean, what broughtyou around on that?
And also both of those are worthtesting, but like as the data
stand now, do you think one ofthose is a stronger hypothesis?
Alfred Sandrock (22:51):
Well, so, uh, skeptical might be a strong
word, but, well, we decided,uh, when I was, at Biogen
to go after amyloid first.
And of course we didhave multiple programs
in tau eventually.
But the reason why we wentafter amyloid first was
the strong human agenticevidence pointing to amyloid.
So, as you know, when youhave familial Alzheimer's
(23:13):
disease in the early days,we had these cases, we had
families that had single genemutations that increased the
risk of Alzheimer's disease.
They often developedAlzheimer's disease as
early as in their forties.
and they had often had ramore rapid progression.
After we figured out thegenes, it turned out they were
all in the amyloid cascade.
(23:33):
Either they were encoding forthe amyloid, amyloid precursor
protein gene itself, orenzymes that process that big
protein into the 42 amino acidpeptide, which is the toxic
species, if you will, afterit aggregates and misfolds.
So, the geneticsstrongly pointed to
amyloid as being causal.
(23:56):
Also APOE, the mostcommon among, not in
familial Alzheimer's, butin sporadic Alzheimer's.
The most, importantgenetic risk factor for
Alzheimer's disease is APOE.
And if you're homozygous forE4, you have a 90% likelihood
of getting Alzheimer's diseaseagain at an earlier age,
(24:16):
typically in your fiftiesand more rapidly progressive.
But APOE also affected thebuildup of amyloid in the brain.
So even APOEpointed to, amyloid.
So that's why wetargeted amyloid first.
But I do think thatthe evidence is growing
that tau is responsiblefor neurodegeneration.
(24:37):
In fact, there are mutationsin tau that cause a
different disease calledfrontal temporal dementia.
So clearly mutations in taucan cause neurodegeneration,
but the, uh, human biologyalso very strongly shows that
after the amyloid appears,then the tau starts to spread.
(24:58):
And a lot of people, includingmyself, believe that amyloid
actually triggers thespread of tau in the brain.
That a little bit of taumisfolding in the brain is
actually part of normal aging.
It's just that it'slocalized to a very small
part of the temporal lobeunless amyloid is present.
Once amyloid appears thattau now spreads, and that
(25:19):
misfolded tau spreadsthroughout the brain.
And so, we need to address that.
Jeff Cranmer (25:24):
I wanna get back to Lauren's initial question
now, uh, years at Biogen.
Really just movingup through the ranks.
And, and then you madethe jump to Voyager.
I'm sure a lot of ourlisteners, you know, may have
done something similar orcontemplating such a move.
How has that been for you andwhy, why did you make that move?
Alfred Sandrock (25:45):
Well, look, I kind of grew up at Biogen.
When I first joined Biogen, itwas about, I think it was five
or 600 people, so it was stilla relatively small company.
And, uh, we had justgotten started in multiple
sclerosis, actually, asa commercial company.
And we were able to developmultiple treatments for MS.
(26:05):
And, uh, boy, I, I grew up,like I said, I literally
grew up there and, loved it.
And I loved it right upuntil I left, actually.
still loved it when I left.
But I felt that, it had grownto the size where it was
kind of too large for me.
I'm not really big on kindof bureaucracy, if you will.
(26:25):
Not that Biogen's terriblybureaucratic, but there are a
lot of committees, you know.
when it gets to multiple, likeI think we were close to 8,000
people by the time I left.
So from 600 people to8,000, big difference.
And it's hard to make decisionskind of because there's a lot
more people involved and, Ilike smaller companies that
(26:46):
are, as you said it, you saidit yourself, Jeff Nimble.
Like I can walk down the hallhere and really talk to all the
people I need to, to get theinput I need to make a decision.
You know what I mean?
And I don't need toeven schedule a meeting,
which is wonderful.
I'll tell you the downsidethough is that we don't
have as much cash.
Um, you know, at Biogen, therewas a little bit more freedom
(27:10):
to explore areas that, uh.
May not immediatelylead to a product.
Which was great, becauseit allowed for exploration
into highly sort of riskyInnovent territories.
Of course, we do doa lot of innovative
stuff here at Voyager.
But I don't have as muchcash and I don't have as many
(27:30):
people, here, so I have to bea little bit more cautious.
In fact, I have to restrainmyself, because, some people
say I have too many ideas.
and so, so that's the,that's the difference.
Selina Koch (27:44):
Well, one important, oh, sorry.
Uh, one important sourceof cash for you all I
think has been like justpartnering out your capsid.
Now that you have thisother shuttle coming
online, is you going to tapinto that similarly, or?
Alfred Sandrock (27:58):
Oh yeah, I'm, I'm a big fan of partnerships.
Not only do they bring in,revenue, but you learn a
lot from your partners.
You know, when, when it's agreat scientific collaboration,
you know, the interactionscientist to scientist really
does increase, um, justaccelerates everything and
also increases the learning.
And then look, there's,there's so much to be done.
(28:20):
Once you've solved delivery forgene therapy, there's no way
we could prosecute every singletarget or go after every single
disease, and so why not partner?
Yeah, you give up someof the upside later.
But there's, so there's, youknow, if you're successful
and you can help a lot ofpatients, there's no problem in
giving up some of the upside.
(28:41):
And then, you're right, the,the shuttle program that
we just launched, there'sa lot of interest, a lot of
interest out there in shuttles.
And so yeah, I'mopen to partnerships.
Selina Koch (28:51):
Should your tau antibody, do well in the
clinic, and I think you've gota readout coming next year.
Um.
You know, as a smaller company,probably not gonna go the
Biogen route and think ofcommercializing yourself, right?
Like when, when would youthink about partnering?
Assuming you're partnering.
Alfred Sandrock (29:09):
Well, not only will we not commercialize, we
wouldn't want to be doing thebig Phase III trials either.
Those are usually massivetrials and global in nature.
And so we'd want topartner, before Phase III.
Jeff Cranmer (29:21):
So, Al uh, back in the day you were
at Mass General, you were aneuromuscular physician, ALS
any other neurodegenerativeneuromuscular diseases you'd
like to, uh, talk about?
Alfred S (29:34):
Yeah, so ALS for sure.
I mean, you know, I, I was atMass General right when Bob
Brown discovered the firstgene tic cause of ALS, which
was superoxide dismutase, SOD.
And so we were getting a lotof patients from all around the
world coming to Mass General.
And since Bob couldn'tsee them all, some of 'em
(29:54):
had the same me, you know.
And I'll tell you, it is oneof the worst diseases around.
I used to see people thatreminded me of loved ones you
know, some, sometimes thepatients, they were always
very, very nice people.
For some reason it seemed thatALS patients and I couldn't
help them, and that couldbe why I came to industry.
(30:15):
So at Biogen, they had adrug called tofersen, which is
an antisense oligonucleotidethat got approved recently.
Actually, uh, we hired TobyFerguson, to Voyager, and
by the way, tofersen isnamed after Toby Ferguson.
But anyway, I digress.
I wanted to bring up tofersenbecause for the first time
(30:36):
we see a drug that cannot only stabilize some
patients, but actually somepatients are improving.
So imagine that ALS patientswho are putting aside
their walker or gettingout of the wheelchair.
This is happening, is justlike a, you know, the fact
that I'm even saying it now isalmost hard for me to believe.
You know, it's a greatindication of how far
(30:58):
we've come in treatment ofneurodegenerative diseases.
So I'm very hopeful thatwe can do even more.
Unfortunately, only a fewpercentage of patients
have SOD1 mutations.
So the vast majority of ALSpatients need something as well.
And by the way, we areworking on ALS at Voyager too.
Selina Koch (31:17):
Okay, I have to ask an FDA question.
So tofersen, to getacross the finish line,
required some flexibilityover there at the agency.
You know, they tookneurofilament light chain
as the biomarker called ita surrogate, and they used
open-label efficacy data, right?
Because really if you justlook at the primary endpoint,
it, it on a population levelfailed rather spectacularly,
(31:40):
if you look at that P value.
Um, yet that has really,it seems like more to
do with the trial designthan the therapy, right?
And it's just hard in theserare indications where things
aren't well standardized,where you only kind of
understand the natural history.
And right now we're justgetting all these, I feel
like mixed signals out of FDA.
We all saw what happened withuniQure, who was gonna have
(32:01):
a natural history comparator,and then FDA agreed to it
and then changed his mind.
On the other hand Lexeogot some, good news that
its program might have someendpoints that could work
for accelerated approval.
I mean, how do you look atthese, I don't know what seemed
like mixed signals to me.
And what's your, what'syour view of them?
Alfred Sandrock (32:20):
Well I do think that, flexibility
is very important.
I do like the idea ofaccelerated approval, that
the use of biomarkers, perhapseven with uncontrolled trials
to basically acceleratedapproval is saying, you know
what, there's a chance wecould be wrong, that the drug
is safe and effective, butit's such a terrible disease.
(32:42):
There's so few optionsfor these patients.
Why don't we approve it?
And then let's see theconfirmatory trial.
And if the confirmatory trialis positive, then we know
we've made the right decision.
You know, I'm very proud ofthe fact that Amylyx, for
example, there was another ALSdrug that had been approved,
accelerated approval, theconfirmatory trial was negative
(33:04):
and the CEOs at Amylyx pulledthe drug off the market.
See, as long as I think industryleaders are responsible and
do the right thing, if theconfirmatory trial doesn't
confirm, then the drugshould come off the market.
But in the meantime, havingthese accelerated approvals
allows patients who arehave very few other options.
(33:24):
These are often deadly diseases.
And I think it makessense to grant approval
in an accelerated manner.
Look, FDA is in some flux.
I still believe, that if youhave a great drug for for
a bad disease, that we'restill gonna be approved.
And the companies and theshareholders will be rewarded.
(33:44):
If I stop believing in that,then I may as well quit.
But I, I firmly believe thatwe'll figure out a way to help
patients with bad diseases.
Selina Koch (33:52):
Yeah.
And is is, are you sayingit's not really changing
any decisions that you'remaking over there, that kind
of uncertainty right now?
You're just.
Alfred Sandrock (34:00):
No.
And, and, and look, we, weare, we are sticking to our
convictions that, as long as wemake transformative treatments
for patients with bad diseasesthat we will be successful.
Jeff Cranmer (34:13):
That is excellent to hear Al and, uh, I'm sure
you're joined by many of yourfellow CEOs and other folks,
working in the trenches andeven in FDA, uh, as we've talked
about on the podcast previously,a lot of great people there,
a lot of hardworking people.
Got Pazdur at thetop of CDER now.
Let's get those drugs approved.
(34:34):
Selina, we got timefor one more question.
I'm gonna give it to you.
Selina Koch (34:37):
Ooh, there are so many.
I'd love to ask.
Um, but I think I have toask about neuroinflammation,
just because we're thinkingabout like up and coming
therapeutic hypotheses thathave some genetic backing.
And might be usefulacross a wide swath of
neurological indications.
That's certainly one peopleare talking about a lot.
(34:59):
I noticed Voyager doesn'thave any neuro inflammation
targeting programsdisclosed in its pipeline.
So I guess I'm wondering,you know, where you think
the field is at when itcomes to understanding what
neuroinflammation is, howit contributes to disease
such as Alzheimer's, andI think importantly like,
how you can measure it?
Alfred Sandrock (35:18):
Yeah, so, um.
if you thought I wasskeptical about tau, I was
even more skeptical initiallyabout neuroinflammation.
Look, the thing is youdefinitely see evidence of
neuroinflammation in virtuallyall these neurodegenerative
diseases, certainly inAlzheimer's disease.
But the question is always iswhen you see it in the brain,
is it cause or is it effect?
(35:40):
And you know, a lot ofdying cells will cause
neuroinflammatory typecells to come and do the
cleanup, if you will.
and so, uh, I was a littlebit skeptical, but then
when we found that thereare certain genetic variants
that increase the risk ofAlzheimer's disease, such
as TREM2, I said, okay, it'sgotta be in the causal pathway.
(36:01):
Unfortunately, the earlythe first attempts at
making drugs against TREM2have not been successful.
But TREM2 is complicated, theirmembrane bound, soluble forms.
So maybe we haven't targeted thedrug in just the right way yet.
So I'm still hopeful.
I think the complicationof neuroinflammation
is that there's sort ofneuroinflammation that
(36:22):
occurs from the cells thatare innate in the brain,
such as microglial cells.
There's sometimes inflammationfrom cells that come from
the outside, from theimmune system that come in
and invade essentially thebrain, or come into the
brain and cause inflammation.
So it's complicated.
And then if you take themicroglial cells, the innate
cells in the brain thatshow inflammatory changes,
(36:45):
sometimes there's goodinflammation and sometimes
there's bad inflammation.
In fact, there's some formsof neuroinflammation, if you
will, or microglial activationthat we think are protective.
And so I think measuring itin the right way, we'd hate to
decrease the protective forms ofneuroinflammation, if you will.
We wanna dampen downthe harmful ones.
(37:07):
I think we're still at the veryearly stages of measuring it
properly and figuring out thecomplexity of neuroinflammation.
Selina Koch (37:15):
Do you think there's anything to learn
from multiple sclerosis here?
Because we did recently see aBTK couple of BTK inhibitors
slow the secondary or primaryprogressive form of that
disease was just kind of likeneurodegeneration, you know?
Alfred Sandrock (37:30):
Yeah.
So MS is a greatexample, Selina.
There's a heavy, contributionof cells that come in
from the outside, theadaptive immune system.
So we see T cells, B cells,and in fact, all the drugs that
work for MS now affect thatadaptive immunity, if you will.
The B-cell, drugs, BTKbeing one of them has been
(37:53):
among the most successful.
The issue there again,might be delivery.
There are these B cells thatsit in the brain, in the sub
meningeal space and they'renot affected by the current
B cell lowering treatments,certainly not by the
antibodies against a B cells.
You'd have to be sureyour BTK inhibitors, brain
(38:13):
penetrant, not all of them are.
There are these B cells that sitin the sub meningeal space that
I believe is responsible for theworsening that patients still
have, despite the best immunemodulating treatments that
we have on the market today.
And I think that's gonna requiregoing after those B cells in
the, in the sub meningeal space.
By the way, frequentlythey're infected with
(38:35):
Epstein-Barr virus.
So, people are startingto think about how to
target those as well.
Jeff Cranmer (38:41):
All right.
You've been listening toGeeking Out with Selina,
uh, with Al and Selina.
Al thank you for joining theBioCentury This Week podcast.
Appreciate you givingus so much of your time.
I now can see you, uh, justwandering down the halls,
uh, putting people looseon new projects, every day.
(39:03):
It's a great, greatvision and, uh, we're very
grateful to Voyager forsponsoring the podcast.
And, uh, thanks to Selina andLauren for joining me today.
Alfred Sandrock (39:14):
Thanks for having me, thanks
for geeking out with me..
Jeff Cranmer (39:17):
Alright, well, hopefully you two can connect
at J.P. Morgan, uh, as youusually like to do, in sunny
San Francisco and you've beenlistening to the BioCentury This
Week Podcast, a Special Episode.
We will have anotherspecial episode this week
or early next, coming.
direct from Jefferies and thenwe will of course be back,
(39:41):
with our regular episode.
Uh, I'm escaping for a fewdays, so Stephen Hansen will
be your host, and we'd like tothank Kendall Square Orchestra
for making the music for allof BioCentury's podcasts.
Eric Pierce (39:57):
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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