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.