HEALEY ALS Platform Trial with Dr. Merit Cudkowicz and Dr. Melanie Quintana

Judith: Welcome to Berry's In the
Interim podcast, where we explore the

cutting edge of innovative clinical
trial design for the pharmaceutical and

medical industries, and so much more.

Let's dive in.

Scott Berry: All right, wonderful.

Uh, I welcome everybody to in the interim.

We have a really cool, uh, session today.

We are joined by, uh, two
really interesting people.

Uh, the first Merit Sidkovich.

Who is, um, uh, at MGH and is going
to come talk to us today about the

Healy ALS trial and all things clinical
trial science related to, to that.

Uh, and we're joined by
Melanie Quintana, Dr.

Melanie Quintana of Berry
Consultants and she has been

working on the, uh, statistical
analysis and design of the same ALS.

Healy platform trial.

So welcome, both of you.

Uh, let's, let's start, Merritt, with
tell me about how this trial got started.

Merit Cudkowicz: Yeah, very nice to be
here with Melanie and with you, Scott.

You know, in about 2018, um, you know,
we were thinking about how we could be

more efficient in testing treatments for
people living with ALS, also known as

Lou Gehrig's disease, because finally
there was a big pipeline of therapies.

But, you know, the old
fashioned way of doing one at

a time was taking a long time.

So we read this New England Journal of
Medicine article by Janet Woodcock talking

about master platform trials, and it
was something we'd never heard about.

And so we started to call around, and
we, we really found that there was

a lot of experience in it, in cancer
and with the Berry Consultants Group.

So we got a group together to learn
from, from, um, From you guys as well

as people who had run them and other
diseases and the message was loud and

clear that ALS was ready for that.

So that's how we got started.

Scott Berry: Uh, and, and I
remember you came and you said,

we want to be enrolling in a year.

And Melanie and I looked at each
other and said, uh, yeah, wow.

And of course it happened.

Um, uh, uh, and of course you're,
you're a force behind that.

So, interestingly, Melanie, so, and when
it started, it started with five arms.

Is that right?

Merit Cudkowicz: Yes, we picked five.

We, we, um, and then because of the
timing of the drugs, we ended up with

three first and then we added the
fourth and fifth shortly afterwards.

Scott Berry: Okay.

So, just before this, Melanie and
I worked with an IMI Uh, EU IMI

funded project to do a very similar
thing in Alzheimer's disease.

Uh, 50 million plus euro was
spent to design this trial.

Beautiful trial with registries
that they would enroll from.

And it never brought
an arm from pharma in.

Uh, uh, both in this.

And so you had this amazing, opening
of this with five arms coming in.

May.

Maybe I'll ask Melanie, since you
were involved in both of these

efforts, what was the difference?

Melanie Quintana: Oh, I think
there were a lot of differences.

Like you said, Scott, from the beginning,
Merit, you came to us and you said,

we're going to do this in a year.

And I thought, Oh my
goodness, but okay, let's go.

And I think even from the first
meeting, you could tell that there

was such an energy about your
group and everybody had really.

And so I think that was a big, all
of the people that you have merit

and all of the team really supported
this to be able to go quickly.

and then I think a big part of it
was that there was funding from the

start and that it was almost like a
competition for the companies to come in.

But I think Merit could
speak to that more.

But for me, it was.

the solid team that was there, everybody
was just passionate about the work,

everybody wanted to see this move
forward, and it was just, wow, okay,

we're going, this is going to happen.

Merit Cudkowicz: Well, there's some, I
mean, all these illnesses need speed,

but, um, you know, in ALS, it's always
the thought is this is such a rapid

illness where people live three, three
years, you know, sometimes a little

longer, but you have to move fast.

And we have this network that
Neal's consortium with sites.

It was almost like we needed
to do the last 20 years of work

of, of building the ALS trial
network to be able to launch fast.

But as Melanie said, having the funding
was key, and that was a real, it was

a gift from a patient I took care of,
Sean Healy, for which we named the

platform trial after him, where he
gave us resources so that we could,

For the first four companies, um,
contribute some, uh, philanthropy,

um, to, to get it off the ground.

And as Melanie said,
we made a competition.

We had an RFP for the
first companies to join us.

So, so that helped get it off the ground.

And with pharma, who, who have
most of the really exciting drugs,

that's who we wanted to work with.

Scott Berry: So in thinking about the
role of the platform and having multiple

arms come in this, how many applications
did you get to join the master protocol?

Merit Cudkowicz: We got 33
applications in that first call.

Uh, now they weren't all ready
for, uh, you know, phase two trial,

but they were really good ones.

And we had a scientific review
and picked the first five.

Scott Berry: so this just points
out that this is not a disease where

there's one or two drugs of interest.

There's a huge number of ideas
in an incredibly hard book.

disease to treat.

But, uh, and so the part of the role was
bringing in these, the many drugs, taking

many shots on goal, uh, in this scenario.

Merit Cudkowicz: Yes, I think the
other thing that helped, um, I was just

thinking about this is that before we
issued the call for applications, we

had a, um, I think a one day industry
roundtable and then Melanie was there

and we, we spoke, we invited all the
companies we knew of that had drugs

that might be ready for phase two.

And we talked about the trial design
and we, we let, we gave time for

industry to voice their input in
the design and things that they.

might worry about or want to know
about before we finalize the design.

And, uh, you know, in retrospect,
that was a really good thing to do.

I don't know that we did it,
you know, so planned out, but

it was, um, a way to get buy in.

Melanie Quintana: Yeah,
I think you're right.

I think it was very helpful that there
was a convergence and a collaboration

with everybody, including patients.

You know, on what is
the best trial design.

So people knew, companies knew
that if they joined the platform,

they were joining the best
trial design that they could do.

And there wasn't a lot of argument around,
you know, which end point should we use?

What should we do here?

Everyone just was on board that
if we're joining a convergence of

collaboration across key opinion
leaders that was really the best design

that we could have run at the time.

Scott Berry: So a different groups
looking to start these master protocols,

it's almost like there are four
stakeholders that are a key here.

And if any one of these fail, the
trial may not go, which are sites.

You have to have the sites and you have
this incredible Neal's network of sites.

patients, if patients aren't
interested in the trial, there's

no trial, pharma and regulators.

So you've touched on a little bit about
patients and Sean Healy being very

excited, providing funding for this.

The Neal's Network, so you had
this incredible ability to put

this master protocol on the sites.

You, so you talked about the
patients you brought, you had this

one day consortium with pharma
and got them all excited about it.

What about the fourth pillar about that,
the FDA, how, what have your interactions

been with the FDA on the trial?

Yeah,

Merit Cudkowicz: Once
just with the design team.

So the team from Barry Consultants
and the team from MGH and Niels.

to just lay out our plans, get their
input, and they were so enthusiastic.

This was when, Dr.

Billy Dunn was in charge.

We actually left the meeting where
they said they hoped that one day

we'd be writing papers together
about this approach for neuro,

neurotherapeutics and you don't
usually leave a FDA meeting with that.

So that was step one.

And then step two, we came back
with the first, four companies.

And so we had a meeting all
together, and we had time each

company alone and time together,
and we took a nice picture of that.

And that was really uplifting as well.

Melanie Quintana: Yeah, I'll add,
you know, it can be a challenge

when you're, you know, statistically
speaking, you know, when you're putting

forth complex or innovative features,
you know, so it took work, right?

Like we had lots of, for, I would say
at least a year and a half, we had

many iterations back and forth with the
FDA, just getting them comfortable with

the complex and innovative approaches.

that we needed to take
within the platform trial.

But because we were able to do all
of that up front, really the back

and forth, the iteration, getting
them comfortable with what we were

proposing, each new industry sponsor
didn't have to go and then recreate

the wheel and do that all over again.

So it's almost like we did all of that
hard work up front to get the agency

comfortable with what we were doing,
and we didn't have to keep doing that

over and over and over again afterward.

Merit Cudkowicz: The other thing I'll
add, because Mellie, you can't say this,

but the respect they, um, The FDA has
for the Berry Consultants Group, um,

platform trial designs, probably on
more, but, uh, that helped a lot because

they, they want to learn about this.

This is new in, in, in a lot
of neurotherapeutic areas.

And, uh, so it really felt like
a partnership on trying to figure

out how to do this in the best way.

And then I'd also say that we just
recently went back to share our

learnings from the first five regiments
and again, just the design team.

And that was really positive as well.

Scott Berry: so I want to touch on
the five, but maybe for our listeners.

Uh, are dozens of listeners out there,
the, uh, Melanie, can you tell me a little

bit about the, the, the, the science
of the trial, the statistics, what's

the design for regimen a for regimen B.

Melanie Quintana: Right, so it's a shared
control design, um, and parallel what we

call regimens are enrolled in the design.

Um, uh, industry sponsor would
come in, they would be a regimen.

We have sort of two part randomization.

One, you are randomized to any of the
available regimens, and then once you

are randomized to that regimen, you will
get more information about it, you would

get consent to be a part of the regimen.

There may be some slight minor inclusion,
extra minor inclusion exclusion criteria

that you need to pass for that regimen.

And then you're randomized
three to one active to placebo.

So we're able to eliminate a
lot of placebo subjects that

we need to do these tests.

And then we are able to share controls
across the different regimens.

So essentially when we had the
first three regimens, it was like a

one to one comparison, but we were
able to get away with, you know, 75

percent less placebo in doing that.

So that's the, that was the
main statistical efficiency

is sharing those placebos.

Across the different,
what we call regimens.

Um, and then because we have that
statistical complexity or because we,

we are trying to share that information,
we had to develop some more creative

primary analysis models that could account
for potential differences in the shared

controls across regimens, across time.

So that's where the more innovative
primary analysis methods came in,

where we need to, to do some Bayesian
borrowing across the, the regimen.

Scott Berry: So the first five
regimens have read out and that

that's become public, um, within that.

Um, have have you been able to address
the efficiency, uh, I know originally

when the trial came out, you talked about
speeding the time to effective therapies

by 50 percent reducing the resources.

Did that, was that
realized in the first five?

Merit Cudkowicz: Yes, absolutely.

we were able to read out these five drugs
in About two and a half years, if I can.

And usually you would read
out, maybe one if you're lucky,

maybe two in that time period.

we also found that enrollment was, two or
three times faster than typical trials.

And I, think that's because of
the, the patient group, engagement.

And they're really feeling that this type
of approach was very patient centered.

And our patient advisory group, is
really a community coming together.

So that helped with enrollment.

and then the costs are much less.

We actually have a paper coming out
too my, first and only economics

paper about the cost savings.

So there's more to come on that.

Yes,

Scott Berry: were there in the first five?

And what was the, statistical
significance of those controls?

Melanie Quintana: Yeah, so there was only
205, I believe about 205 placebo patients,

but they were used for all five regimens.

So almost like a thousand
patients worth of data.

So those 205 placebo participants, even
in those, testing of drugs almost counted.

five times as much as what they were.

So we're able to save, nearly
800 placebo participants in

testing those five regimens.

Which is a huge savings, and a huge
benefit to get participants to want

to be a part of the platform trial.

And then there's, we'll get to
this, but then there's the, those,

participants all are now going into
the data where we can learn more about

the science of ALS and design better
clinical trials, look at biomarkers.

So, now because we've collected
all this data within this

rigorous clinical trial setting.

And we, we say, you know, we're
quote unquote retiring this data,

but they're going to do more in
retirement that they maybe ever

did in the actual platform trial.

So that's the other huge
benefit of collecting all this

data within this platform.

Scott Berry: Yeah, that,
uh, that's incredible.

I, I know the PROACT database is
such a valuable resource, but had

these five arms been run in separate
trials, it would be very hard to

get the data together to analyze.

And now you've got this growing
resource of disease learning in it.

So, so Merrick, the,
the sixth and seventh.

Regimens, uh, have read out and it's
become public, uh, in that and, and

papers to come on those as well.

Uh, and so right now, currently, as
we sit in, uh, uh, spring of 2025,

there are no arms in the trial.

Merit Cudkowicz: That's right.

Scott Berry: No arms

Merit Cudkowicz: We're working
with a few companies to, uh, for

the, to start new arms, but we're
not enrolling in any right now.

Scott Berry: Yeah.

So, um, there has been, there have been
articles written about the first seven,

uh, from the perspective that none of them
hit the predefined success boundaries.

Now they're all phase two trials.

Each one of them are learning a great
deal and they're making decisions.

There may be promising aspects to
those, but they haven't hit success.

So there was, uh, an
article written in biospace.

Um, uh, by Heather
McKenzie, somewhat okay.

There have been seven arms and it's
been unsuccessful and I hate to say

it, but almost is there something
wrong with the healing trial?

Um, when in some sense this is
incredible progress and you're

taking multiple shots on goal and as.

Thomas Edison said, I, we haven't failed.

We've learned 10, 000
ways that don't work.

You're, you're learning
and you're moving through.

So what do you say to people who
say, well, you had, you weren't

seeing that none of the arms
met success in the first seven.

Merit Cudkowicz: Yeah,
no, and I've heard that.

And I say, first of all, ALS
is a very complex disorder.

And as we learn more about the biology,
the therapies that come forward are

going to be more likely to be successful.

That, that, the number one thing
is we got to understand the biology

better and get even better drugs.

The second thing I would say is we
actually did learn a lot and of the seven,

three have had some success in secondary
or exploratory outcome measures, which

is what you want to look at in phase two.

and at least two of them are for sure
going forward to phase three testing.

The other one is still deciding
based on the rest of the analysis.

in that way, it, that is a success.

It's about learning more about
the drug and, pushing forward.

And the third thing I'd say is we, did
take, some time now, again, with Melanie

and other biostatisticians help to look
at what we learned about the first five

and do we want to adapt the, platform
trial, and we do, and maybe Melanie can

talk a little bit about those adaptions,
but we are going to make changes to

increase, success, the probability
of success, by the trial design.

So again the, and we're also re
looking at how we're picking drugs,

and we have to really look at
multiple things to get to success,

the drugs as well as the trial design.

Scott Berry: Yeah.

Yeah.

So now you took this pause, Melanie,
you've been able to analyze data.

What, what kind of changes
moving forward in the analysis

and the structure of the trial?

Melanie Quintana: Yeah.

So first of all, backing up when we
originally designed the trial, we were

so fortunate, you know, we designed
trials in so many disease areas.

Oftentimes, when you're designing
the trial, you're making wild

simulation assumptions about the
endpoints in the disease area.

You have no clue what's
going to happen in the trial.

But in ALS, we are so fortunate
to have historical clinical

trial databases like PROACT.

Like it's a statistician's dream,
honestly, to be able to jump

into ALS and just dig into real
data to design a clinical trial.

So we were able to use that PROACT
database to design the trial

for the first five regimens.

And then now that they've read
out, we're kind of retiring that

data, we're learning from it.

We summarized the, the first
five regimens and it was spot on

to our simulation assumptions.

So it, that just speaks to the benefit
of historical clinical trial databases

in that everybody should be putting
their data so that we can learn from

previous clinical trials into those.

But so the simulations were spot on.

I think in terms of power, we
still believe that our original

design was very appropriate.

Um, We are looking at some things, though.

We a lot in terms of
potential mechanism of action.

So while we still think we're very well
powered with the original six month

design, we do want to potentially move to.

We do want to move to a longer
design in case some of the

treatments take longer to start.

Um, we also looked at a wide range
of inclusion exclusion criteria.

There's this thought of like maybe
we want to get faster progressors

so we have more power and, and we
looked at lots of different things.

People are looking at, you know, NFL
as an inclusion exclusion criteria.

And really, you know, what we found
is there's no magic bullet to get

these sort of like Not too fast
progressors, not too slow progressors.

There's really, if you really whittle
it down to that real homogeneous

population, you're looking at such
a small subset of the disease.

So, we still felt pretty strongly
with our original inclusion exclusion

criteria, but again, because of potential
mechanism of action, and Merrick can

speak to this, you know, we wanted
to try to go in a little bit earlier.

We were originally randomizing up to,
Three years since onset and now we're

going to we're going to be looking
within two years of onset So in terms

of statistics and power, I think we
didn't need to make many modifications

But it was really about you know, the
drugs and are we missing anything?

Merit Cudkowicz: I'll add that, you
know, since we started, you know,

kind of a new biomarker came, uh, to
the world of a LS and neurofilament.

Um, and, um, there's been interest to, uh,
and that that can predict, um, you know,

speed of progression as well as possibly
being a biomarker of treatment effect.

So we, we, in the new, um, in what we call
the, the next, uh, master protocol, we

will also be stratifying by neurofilament
levels, uh, to try to balance the group.

So, but.

You know, that didn't exist when we, in
2018, when we were designing the study.

So we're adapting with learnings.

Scott Berry: So, so let me ask
a Merida a loaded question.

A lot of companies come to us and
they're interested in NFL and a

lot of neurodegenerative diseases.

So you mentioned it almost as a
demographic biomarker at the beginning.

Do you believe it's a surrogate
marker of clinical benefit,

um, as the patient progresses?

Now, now this is not, you're

not setting regulatory precedent, but as
an expert in ALS, do you believe in NFL

as a sort of surrogate clinical marker?

Merit Cudkowicz: believe in it, I guess,
uh, 50%, meaning that if it changes,

yes, I think we do have a good example
with a very targeted gene therapy that

if you, if you decrease neurofilament,
it, you have a clinical outcome.

I'm not convinced yet of the opposite.

that if a drug doesn't change
it, that it's not going to

have a clinical efficacy.

I just think we don't have enough
data to be confident of that.

Um, uh, but I hope we'll learn,
you know, we'll learn more because

every clinical trial in ALS is
now including neurofilament,

including the platform trial.

Scott Berry: Yeah.

Yeah.

So, amazing learnings on things
like that within the trial.

So, a lot of groups that are interested,
uh, by the way, you're, the success

you've had in the seven regimens
coming in, in the time frame and all

that has been absolutely incredible.

But other groups that may be in cancer
and in this phase two space, invariably

they start thinking about phase three.

Have you thought about an arm that
kind of hits success that they can

immediately seamlessly enroll phase three?

Is that something you've thought about?

Is that a possibility in the Healy trial?

Merit Cudkowicz: We've been thinking
about it, yeah, and we haven't designed

it yet, but yes, yes, I'd like to.

I'd like to keep thinking about that.

We haven't designed that yet.

I'd love to hear Melanie's thoughts.

But I'll say we, we have
also been thinking about the

other end, the phase 2a end.

Because we find a lot of
companies with really great

ideas are kind of stuck there.

They can't develop that initial data on
dose and biomarker effect to even get to

going to the Healy ALS platform trial.

So we're thinking about designing,
um, an approach there and maybe

linking that to the platform trial.

Scott Berry: Oh, very neat.

Yeah.

Nice.

Uh, and, and you, you have this pause
right now and Are, are pharma, uh, is

there still a lot of excitement about it?

Uh, interest from pharma, new
drugs, exciting new drugs coming?

Merit Cudkowicz: Yes, there are.

We're, we're, we're actually working
with four companies on design.

A lot of the companies don't want
to share publicly that they're

working with us until, you know,
they have the FDA, the IND.

Um, so there is lots of interest.

I think in general in the ALS field,
you know, the interest from, I guess,

VCs and pharma kind of waxes and wanes,
uh, depending on kind of recent results.

So I think that, you know, some of
the recent results, for example, with

the Amalex trial, You know, kind of
had a couple companies pulling back,

but I, I think they're coming, coming
back into ALS because the science

again and the need is so great.

Scott Berry: yeah, yeah.

Uh, interesting, yeah.

I, the, Melanie, when you work with
a sponsor, I, a lot of, a lot of

people Uh, in terms of a master
protocol, um, when you work with the

pharma, how do you convince them?

What are they concerned about?

When pharma comes in, is it hard to,
to, to create an analysis plan for them?

To, to, to address their arm
and the statistical parts to

that when pharma comes in?

Melanie Quintana: You know for this
platform there's not there's small

customizations that we need to do
when the industry part Um, you know,

there's small sort of fine tuning that
we have to do, but largely this this

platform is master protocol driven.

We try to keep everyone kind of
enrolling the same population.

That's important for sharing the controls.

We try to the visits.

The schedule of assessments
are all very similar.

So for the most part, I think
we've done a good job up front.

And explaining to the partners, you
know, why this is the best way to go.

Um, not forcing them, not having them
come in and say, like, you will do this

if you want to be a part of our platform.

We try to, like, bring them along,
we show them the simulations, we show

them why this is the best way to go.

And for the most part, I would
say that's pretty smooth sailing.

The hardest part, I, I don't know what
you think Merit, but my opinion is the

hardest part is the inclusion exclusion,
is, is really like negotiating and making

sure that we can get that to be quite
synergistic across all of the regiments.

Every industry partner comes in with their
like small inclusion exclusion that they

want to add and we need to really make
sure it's necessary, um, for safety or

for mechanism of action regions, reasons.

Scott Berry: Hmm.

Merit Cudkowicz: Yeah, I agree.

Those are really the two only
ones that would make sense to

change it for in a platform trial.

Scott Berry: Hmm.

Interesting.

Well, I, it's, it's uh, really neat
that you've come in the interim.

Uh, of the trial with this pause.

I know you have a lot of
exciting things coming forward.

I want to congratulate both of you.

It's amazing clinical trial
science, amazing thing for ALS.

It's also moved other
disease areas forward.

It's set this incredible example.

So Merit, congratulations to you.

Melanie, congratulations on this work.

And thank you both very much
for joining in the interim.

Merit Cudkowicz: Thank you, Scott.

Thank you, Melanie.

Melanie Quintana: Yeah, thank you.