Alright,
welcome back everyone.
So for this session,
the real Focus first.
In the first half of the session,
it's a research update from wave,
life sciences,
and we have the wonderful Chelley.
Casey will go over with recent developments
in their hunting move lower approach.
Surely.
You want to share your slides on?
Take it away.
Sure,
and thank you,
Mustafa.
Okay,
great. 19 00:00:27,600 --> 00:00:27,599 Well,
thank you for the warm.
Welcome.
And hi everybody.
My name is Chelley,
Casey.
I'm the head of patient.
Advocacy at wave Life Sciences.
I joined wave just about six months.
So I'm still relatively new to the Huntington's
disease Community,
but it's been a great,
welcome and I'm excited to be here today.
To share an update on our select HD clinical trial,
which is a investigating our wave 003
molecule for Selective Huntington mutant huntingtin.
Lowering just a quick
mention about forward-looking statements.
I think as with any as is inherent
in research,
there's always uncertainty.
So just want to make mention that there will be some forward-looking
statements throughout the presentation.
Just a little bit about wave.
For those of you who are not familiar with the company.
We are a genetics medicine company focused on delivering
transformational therapies for people with serious genetically
defined diseases such as Huntington's disease.
We do have a unique approach to Huntington's disease research,
where we aim to selectively lower mutant huntingtin protein
while sparing healthy huntingtin.
Protein.
We initiated our select HD trial with huevos.
Three in September of 2021 and
this molecule incorporates.
Our new can chemistry and chemical back
rib bone.
And we also have additional programs additional
clinical programs in ALS frontal.
Temporal dementia and Duchene muscular dystrophy.
So to start just a little bit about our approach to Huntington's disease
again at Ames collectively lower mutant huntingtin protein.
The first principle I want to talk about is behind and Gene.
Huntington's disease is caused by a mutation in the Huntington Gene.
So in a healthy individual,
there are two copies of the Huntington Gene,
resulting in a 100% wild-type,
huntingtin protein,
in an individual with Huntington's disease.
They have both one copy or one healthy
copy of the Gene and one mutated copy of the gene
resulting in,
mutant huntingtin protein.
And some amount of wildlife,
Huntington protein,
but about half that present in a healthy individual.
And Huntington's disease is impacted by the accumulation
of toxic mutant huntingtin protein and the
reduction of wild-type mutant protein.
The second principle I wanted to talk about is just the preservation
of wild-type.
Huntington May support the health and function of the brain.
So evidence suggests that wild-type Huntington
promotes Health survival and communication between neurons
across important.
Brain regions.
It supports the CSF circulation,
too,
bright to provide neurons with nutrients and eliminate waste
and it alleviates effects of brain stressors.
Including in Huntington.
Mutant huntingtin cannot perform all the functions of wild-type
Huntington and may interfere with wild-type Huntington functions.
As the disease progresses,
the cellular stress has plus the effects of mutant huntingtin accumulate.
And we believe that will be beneficial to lower mutant huntingtin
and preserve the positive positive biological effects
of wild-type Huntington that is present in individuals
with Huntington's disease.
Waves approach is a little bit different from other huntingtin lowering
lowering approaches.
Most huntingtin lowering approaches are non-selective
and lower both mutant huntingtin and wild-type Huntington.
Waves approach aims to selectively lower
mutant huntingtin protein while preparing
wild-type,
Huntington,
protein and preserving,
its protective effects on the brain.
So,
how do we think about this?
Well,
it all starts with some of the the building blocks.
And what I want to do here is just walk you through.
Really,
the how DNA is is translated
into a protein.
So across the top of this slide,
you can see normal DNA that's transcribed
into wild-type,
Huntington RNA and then translated into healthy protein,
along the bottom.
There's the the mutated Gene in the mutated DNA,
which is then transcribed into mutant huntingtin.
Renee and translated into mutant protein.
So we believe that there's the potential for anti-sense all
ago nucleotides which are short stretches of DNA
that complement mutant RNA to
selectively Target,
mutant huntingtin.
Really preventing the translation into
of the RNA into mutant protein.
So how do we ensure that?
We only prevent the production or of
mutant huntingtin and not wild-type Huntington? 134 00:05:38,100 --> 00:05:38,099 Well,
it all starts with targeting Snips and a snip is
a single nucleotide polymorphism.
They're normally occurring.
Variations in DNA where one letter on a
specific location is different.
They're located in different spots in our DNA,
kind of like a pin on a map and so certain steps
occur more frequently frequently on the mutant huntingtin.
A healthy Huntington and the association between
Snips and mutant huntingtin,
make it possible to design a SOS that
selectively Target mutant huntingtin and leave healthy
Huntington relatively intact.
Now I want to move just a little bit to our select HD
trial which again is the clinical trial to evaluate
wave 003 in Huntington's disease.
We vote 3 was designed to Target,
snip 3 to prevent the translation of mutant huntingtin
into protein.
It contains waves Next Generation.
PN chemistry,
which demonstrated improved form a logical profile and Print
in preclinical studies and increase
the strength.
And Ability compared to our previous molecule.
This this next slide really shows some of the data from
our early research studies in neurons.
So,
in cultured brain cells,
we're just to orient you to this Slide.
The y-axis is looking at normalized H
or mutant huntingtin and wild-type Huntington
mRNA and across the bottom.
You can see increasing doses or increasing
dose strength,
Oprah cross,
the x-axis.
So,
what this study was looking at.
Really to evaluate,
you know,
Huntington and wild-type Huntington,
and cultured cells.
Again in neurons.
These neurons have wild-type Huntington mutant huntingtin,
and sent three.
And so,
what you can see is that the non-selective reference compound
lowers,
both mutant and wild type Cummington,
and that the wave 03,
which is allele selective lowers mutant huntingtin
while leaving the healthy wild type Huntington,
relatively intact.
And as you can see,
again,
across the the x-axis,
as you increase the,
this the dose,
there was more a more profound effect.
Next slide looks at studies that we did
in a mosque in a mouse model for Huntington's disease.
So,
again,
just to orient you to the slide.
The y-axis looks at the percent of mRNA expressed.
And then along the x axis,
you can see the duration or weeks that
we studied during the
during this study.
So the mouse model expresses mutant huntingtin and
has snip 3.
And what you can see,
again?
We have the placebo control,
the non selective control and on the far right is
the allele selective molecule,
which is wave 003,
the mutant huntingtin was lowered in several brain regions.
The non selective control.
Mutant lowered,
both wild type and mutant huntingtin.
And then the allele selective molecule,
which is wave 003,
decrease both mutant huntingtin while sparing
Wild-type Huntington.
So,
the investigational study that we are conducting again.
As I mentioned is Select HD.
It's a phase one bead to a clinical trial,
which is really a combination of a first in human study and a proof
of concept.
So following the results of precision,
HD last March,
we were able to Pivot quickly and initiate.
Do seen in select HD.
And today,
we're continuing to recruit and and dose in the study.
There's a couple of things,
you know,
that we were able to leverage and From Precision HD1.
The starting dose was informed by experiments.
In the disease relevant animal models that we just
talked about.
We also improved the efficiency of patient identification
which increased the ability and time
to patients and then we were also able to Leverage
The substantial experience.
We had working with clinical trial,
sites and investigators.
Select HD.
As I mentioned is a phase 1,
b 2 a multicenter,
randomized,
double-blind,
placebo-controlled,
trial.
So what that means is that some individuals will receive
the active drug,
and then others will will receive a placebo.
We're targeting.
36 patients between 25 and 60 years
of age.
With confirmed early manifest,
HD diagnosis and the snip 3 variant.
The primary Objectives is safety and tolerability.
And the secondary objective is really to understand how wave
03 moves through the body,
help us understand whether the drug gets to the right place in the body
and does what it's supposed to do.
The exploratory objectives,
you know,
as we've been talking throughout this this session is
to really assess whether or not we've 03 lowers
mutant huntingtin protein and leaves wild-type Huntington
protein in tax.
And lastly,
the other thing I wanted to make sure was communicated
about our trial is that it is an Adaptive
study design.
And what that means is that there's multiple checkpoints throughout
the trial where we have a dose escalation committee
and an independent safety,
monitoring committee that really meet analyze
the data and assess and provide guidance
on increasing the dose and frequency.
As we move through subsequent cohorts.
Within the trial.
There's just a snapshot of our current clinical trial sites
for additional details.
Feel free to visit clinicaltrials.gov.
There's also in the last session.
I was just watching the HD trial finder,
that I believe would also be a great resource for all of you.
And as always,
definitely speak with your clinician and your clinical
team about whether or not this might be the right option for
you to participate in.
In summary,
we initiated select HD in 2021
in September to study the investigational candidate
wave 003 it,
but the dose was we'd selected the dose based
on preclinical modeling.
We incorporated advancements for our wave platform
including the PN chemistry into wave 003,
which we believe increase,
the potency durability and exposure and
cook in our Clinical studies.
We're on.
We're continuing to activate new clinical trial sites
and recruit patients to participate in the,
in the,
in select HD.
And lastly,
but certainly not least.
We do want to express sincere gratitude to all trial,
participants research,
collaborators trial investigators and staff and
really the entire HD community.
Here's just a snapshot of some of the
many organizations Who provided feedback
and support in designing our current clinical trial.
Again.
We couldn't do it without the collaboration of the community and
we are really grateful for all of your your input
and ongoing fat feedback.
As we continue to execute,
the select HD clinical trial.
So in summary,
thank you.
We encourage you to reach out to us with any questions to visit
our booth.
We also in the booth.
We do have a video if you want to check it out.
It's in the,
if you click the link the link approach to our clinical
trials,
that will bring you to the video,
which is just a short summary of the data that I presented today.
Exactly.
Yeah.
Yeah,
we have some we have some but I just want to mention that
so far,
this probably the clearest farmer representation
have seen in terms of community in the data.
So good job there.
Thank you.
Yeah,
there's a question in the chat and sort
of jump on this question as well.
They asked but their first off,
thank you for the comprehensive presentation.
And basically they also if you have any Our plans to expand
your trial sites in this case.
You ask,
if you have any plans,
specifically for Russia,
but I'll go beyond that.
Do you have any plans to expand your trial?
So it's beyond the current ones that you have going.
Yeah.
Thank you for the question,
you know,
the intention of the trial is to be Global and
so we're continuing to assess and activate clinical trials.
I don't know.
Russia specifically so happy to follow up on that one and
take it back to the team.
But again,
we are continuing Going to activate additional
geographies in our current program and
the intent,
the intent again is to be Global.
Yeah.
Absolutely.
There's a couple of more scientific questions in the
Q&A that I will get to.
So the first one is is there any evidence
that lowering wild-type Huntington has negative consequences
and the follow this up by saying wooden this mean that all nonsense?
Allele-specific luring strategies are physically,
harmful or noxious.
Yeah,
that's it.
That's a really good question.
And to be honest.
I am not I'm probably one of a handful of people
that wave who are not a clinician or a PhD.
So I would have to take that back to the team.
My my understanding though,
in the work in the,
you know,
what I've been educated on since joining.
The organization is is that,
you know,
we do,
we are.
Focused on preserving wild-type.
And so I don't know if there is a specific threshold.
If you will,
where there are negative consequences,
but certainly happy to take that back to the
clinical and medical team to follow up and
understand what the what research
has been done and what the scientific answer
to that question would be.
Yeah totally got it.
There is I think in a similar vein question
than us.
Why does allele-specific Luring Huntington also
decrease wild-type continent According to some of the slides you guys showed.
So there seems to be a little bit of wild.
Thyme Huntington.
That's also being lowered in addition to the mutant
huntingtin that targeting.
Yeah.
Again,
great question.
I'll have to take that back to our team as well.
I know again,
as I just mentioned,
Our Hope and our goal is to preserve Wildlife
because of the protective effect
and benefit that we see within the The with
the within the neurons and brain function,
so I think overall that is the goal is to maintain
and preserve as much as we can.
But I don't know again,
if they're,
you know,
what,
what detrimental effects there would be as
well as yeah,
what,
what harm,
maybe cause,
so happy to take that back and follow up with
the community as well.
All right,
I think.
If anyone has any follow-up questions,
you can reach out to the email address,
you so generously,
Hide it on your slide.
It was a couple of thank yous coming in for the chat.
So I would like to reiterate that.
We thank you Chelley for taking time out of your Sunday to be with
us here today.
I'm presenting us with the research update that wave has been working
on great.
Thanks to Mustafa.
Thanks for having us.
Yeah.
Thanks a lot.