June 19, 2024 • 23 mins
In this episode, host Dr. Katherine Bowen, is joined by Harriet Edwards, Associate Director in Regulatory Affairs, to explore the fascinating world of genome editing technologies. Together, they delve into the ethical considerations of editing somatic versus germline cells and trace the historical progression of these technologies from agriculture to healthcare. Join us as we discuss the complexity of genome editing methods, the irreversible nature of genetic changes, and the associated risks.
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(00:00):
Music.
(00:06):
To the latest edition of Conversations in Drug Development, brought to you by the team at Boyds.
This podcast is for our fellow community of scientists and clinicians working
in the wonderful world of cell and gene therapy and drug development.
Thank you for tuning in, and we hope you enjoy the conversation.
Music.
(00:30):
Hello, and welcome to this latest episode of Conversations in Drug Development. My name is Dr.
Catherine Bowen. I'm a Senior Director in Regulatory Affairs at Boyds and I
am delighted to be joined on the other side of the studio to normal today by
Harriet Edwards, Associate Director in Regulatory Affairs, as our guest today.
(00:51):
And we have a fantastic topic, I think, today.
We are going to be talking all things genome editing technologies.
Now, I say all things. That would be a very, very long podcast. It would indeed.
So we're going to start off with a bit of an introduction today,
particularly with a focus on some of the regulatory elements and with a bit
(01:11):
of a focus, I guess, on the UK.
EU and US, because that's where a lot of the movement has been,
as we'll get to as we go through this. So a great topic.
But before we get into too much of the meat and bones of it,
Harriet, perhaps we could just start off by explaining exactly what we mean
when we say genome editing technologies. Yeah, absolutely.
(01:33):
And thank you for the great introduction, Catherine. It is indeed nice to be
a guest today rather than the host.
So I will attempt to give everybody a bit of an overview of what is now a really
interesting and novel topic in regulatory affairs.
And of course, we are the regulatory experts rather than the scientists working in this technology.
So there will indeed be a focus on the regulation of these types of products.
(01:55):
But in terms of genome editing, what do we mean?
Let's just break it down into healthcare in particular, because genome editing
means something entirely different when we think about agriculture and other applications.
So in the context of medicines and healthcare, genome edited technologies or
genome edited products are actually a subset of gene therapies.
(02:16):
They are quite niche, they are quite new when we think about healthcare,
and they are incredibly complex and diverse, as we'll see during the course
of the podcast. But generally, they're defined as a way of changing or altering DNA.
So whether that's through insertion, replacing, deleting, removing,
or modifying DNA in a particular point along the human genome,
(02:38):
that's what we're really referring to when we talk about genome editing.
And of course, in the context of deriving a therapeutic benefit.
So just to add a little bit more colour to that definition, we are limited in
drug development to somatic cells. So a really important distinction to make
is that we cannot or we should not be genome editing any germline cells.
(03:00):
And there is a very good reason for that. So there's a good example or an example,
I should say, not necessarily good in recent years of a Chinese researcher actually editing,
successfully claiming to edit
embryos, which were then implanted into a lady who gave birth to twins.
And they were successfully able to disable the pathway that HIV can utilize
(03:23):
if it's going to infect a cell.
So this was presented at the second annual conference of genome editing and
everybody went, oh my goodness, we need to think about restricting what is actually
we're allowed to genome edit and what we can't.
And of course, there are huge ethical implications. So it's very much limited
to editing the human genome at a specific point for therapeutic benefit that
(03:46):
cannot not be passed on to future generations essentially.
And we talk about these technologies as being really very new and I guess in
the field of development of medicines they are but actually the technology's
been around in some form or another for a long time in other areas.
Yeah absolutely and as I mentioned earlier agriculture is one
of those specific examples so we've been
(04:08):
modifying crops for well a really really
long time decades but in terms of health care
in terms of drug development the technology is very
new so there are some similarities in the technologies
that have been used at least initially when we
started to look at genome editing for drug development but now there are so
many different types of technologies that are specific to human genome editing
(04:32):
that actually is a distinct class within itself so and new as well so the first
types of genome edited products and technologies were trialed in the labs in the the mid-2000s,
so 2005 onwards in an academic setting.
And then when we think about actually clinical development and in vivo dosing
of a genome-edited technology, it was actually the mid-2010s and beyond.
(04:56):
So 2017, I think, was the first documented example of a proper clinical trial,
if you like, so a sponsored pharmaceutical.
Not that long ago. Not long ago at all. Particularly when you think about we
now have the first approved product on the market, which I know we'll come on to later.
It really is happening at warp speed. So very exciting, but lots still to learn.
(05:17):
And you keep saying these technologies, and we tend to think of genome editing as one thing.
But of course, the reality is there's an awful lot of complexity and different
elements that actually go into developing one of these medicines.
So should we talk a little bit
about some of those elements and how we actually go about defining them?
Yeah, and it's a really difficult one. I think the way that we will define genome
(05:40):
edited technologies will evolve.
So just to caveat that, but today, largely the biggest distinction is the way
that the genome edited technology works.
So how does it actually introduce the change to the DNA?
And that's either what we call nuclease dependent.
So it introduces cleavage at specific sites within the DNA.
So there is a break there to either replace, delete, insert a change or nuclease
(06:05):
independent where that cleavage doesn't happen.
So some examples of that nuclease dependent
are perhaps the the more established
gene edited technologies if we can even call them
established at this point but things like zinc finger nucleases talons CRISPR-Cas9
which obviously I know lots of people will be familiar with at least the terminology
(06:27):
of that they're all nuclease dependent methodologies so they they introduce
a site-specific break at the site of interest in the DNA.
Whereas the newer, more specific types of technologies, the nucleus independent
are things like base editing and prime editing, which are just starting to come
(06:48):
into development now and could be very exciting.
They are more sensitive and potentially better.
And then there's obviously other complexities as well. So we're just talking
about mechanism of action here.
The type and degree of genomic modification is also an added complexity,
as is how we deliver the technology.
So gene editing has the same complications as gene therapy in terms of whether it's in or ex vivo.
(07:13):
And then there are obviously other things that are associated with gene therapy
generally that also come into play for genome edited technologies.
So they're kind of like Tetris that's fighting back, I think,
because gene therapies as a whole are very complicated.
And then you have this extra complication of how the genome edited technologies
(07:35):
work on top of that, that make it even more challenging for developers.
And you look at all the developments just with gene therapies,
and you mentioned their delivery systems, all the work that's going on at the
moment with non-viral vectors, for example, all these new delivery mechanisms.
So can we talk a little bit about what the potential issues are with these products?
(07:56):
Yeah and I think this is where they really do become a
class of their own actually and it makes it very difficult for regulators to
throw them under the umbrella of gene therapy because they are some distinct
differences and risks and it's particularly we say this all the time balancing
innovation with safety is critical and that's true for all advanced therapies.
(08:18):
But I think it becomes even more of a consideration for genome-edited technologies
because there are such huge, huge risks.
And the risks depend on the mechanism of action, of course, but they are essentially
irreversible and permanent in nature.
And that's something that we haven't necessarily seen before.
(08:38):
We have no idea what the magnitude of the changes that could be made to these
DNA breakages or insertions, which, you know, is quite worrying.
So we could potentially have a therapeutic benefit, which is wonderful and,
you know, what we're aiming to get, but actually...
The off-target effects or even on-target effects that are exacerbated are considerable
(09:00):
and they could be catastrophic to the patient that we're actually trying to
make better, we might actually make considerably worse.
So just some examples in terms of the molecular level, we could have what we
call indels, so random insertions or deletions at the wrong point in the DNA,
translocations, template copy errors, mutations, all
sorts of things which then lead to cellular changes which could
(09:22):
alter cellular function they could actually initiate apoptosis
so cell death uncontrolled proliferation if it's
all going well and you're actually getting the therapeutic benefit it could
be exacerbated and that then introduce what we
see on a clinical manifestation as potentially malignancies genotoxicity dysfunction
of the cell which then obviously translates to something else it's it could
(09:47):
be catastrophic and that's why we need to really proceed with caution when we
think about developing these products.
And in reality and we talk an awful
lot on these podcasts actually about benefit risk because it's a
fundamental regulatory principle right
so we need to be trying to identify those patients who
could potentially have so much benefit here
(10:08):
that those risks and those uncertainties those
things that we simply don't know at this stage in
the development of these technologies can can be be balanced out but
I'm assuming therefore that we're really looking at
quite rare diseases in general here higher met
need no treatment options absolutely I mean
the the goal will ultimately be and I think this
(10:29):
is definitely an ideal world genome editing does
have the potential to well not just
change the way that we treat diseases but you know
it could in an extreme way change humanity as
a whole and when we start thinking about introducing changes not
just for the benefit of treating disease you know
it gets into realms and realms of possibilities but
(10:50):
actually in terms of healthcare the scalability of genome
edited technologies i don't think is there at the moment because the the
benefit risks simply wouldn't let us approve these types of products they're
pretty expensive to make sometimes as well so there's there's the challenges
you can if you can treat with a a pill yeah that's cheap and easy to make and
you can take it away if someone one gets the side effect significantly fewer
(11:14):
unknowns generally speaking yeah.
And the great news now, particularly in terms of our understanding of where
this is going from a regulatory perspective, is we do now have some precedent.
We do. And it's so, so exciting.
I mean, to be involved in genome-edited technologies in any shape,
way or form is, you know, really wonderfully exciting.
(11:35):
As I said, I do think they have the potential to change the way that we treat disease in the future.
And to be part of a time in regulatory affairs where we actually have an approval is so exciting.
And even more exciting to be able to say that the MHRA here in the UK were the
first ever agency to approve a genome-edited technology is even more exciting, I think.
(11:56):
So, yes, there's a reason why we're talking about the UK, the EU and the US,
and that's because they're the agencies that probably unsurprisingly have approved
the world's first genome-edited technology.
So it will happen across the rest of the world. It is happening across the rest
of the world now as CasGevi starts to be rolled out.
But they were the world's first agencies in quick succession to approve,
(12:21):
and hence why we're concentrating on that here.
But just for a bit of background to those people that maybe haven't heard about
CasGevi yet, it's a CRISPR-Cas9 technology.
So basically, it's a stem cell-based product, so CD34 plus cells that are ex
vivo edited. So they're taken away from the patient, they're edited in the lab
and then implanted back into the patient.
(12:43):
And essentially, they reduce expression of a gene, a particular gene of interest,
the BCL11A gene, which increases fetal hemoglobin.
So the idea of CasGemmy is to treat rare blood disorders, essentially,
so beta thalassemia and sickle cell disease, severe sickle cell disease to be precise.
(13:04):
And then obviously the potential will be there to be rolled out for further
indications in the future. But that's what's approved right now.
And excitingly, it was approved, as I said, in those three territories.
So really, really great news.
In terms of approval and route to approval, I know we'll talk about regulation.
Really, the existing regulatory pathways were sufficient to support approval
(13:28):
of CASGEV in these regions.
And were really leveraged, you could say. Yeah, absolutely.
And I think they needed to be. You know, when we think about the EU,
CASGEV was eligible for the prime scheme.
And I know you're really familiar with that, Catherine. But I think the opportunity
to leverage early interactions was probably really beneficial in this instance
(13:48):
to be able to have those interactions with the regulators.
Now, interestingly, Casgevi was actually supposed to be a full application, so not conditional.
It was supposed to be approved and good to go once the application had gone in.
But actually, due to those interactions with the regulators.
Or I guess we should speculate that it was due to those interactions,
(14:08):
there was a change in strategy.
So actually, Casgevi has now been approved by a conditional.
I think it went in with the hope of getting full and came out with conditional
on the basis of the uncertainty. Which makes sense. It says,
and that's what the pathway is there for.
Yeah, yeah. It'd be interesting to know whether they were recommended to follow
that pathway in the first instance, but we do not know.
I mean, with the amount of risks that are associated with this and the incredible
(14:32):
amount of unknowns, this being the world's first product, now there's precedent.
Things may change in the future for future CRISPR-Cas9 technologies.
But, you know, I think that was probably quite a smart move by the regulator
to have a conditional approval.
There was one combined phase 1, 2, 3 study in limited patients and the approval
was based on interim safety data and analysis that, you know,
(14:56):
the study hadn't finished at that point.
So the concerns over data comprehensiveness, actually, I think are really valid.
And the same happened in the UK as well.
Now, the FDA took a slightly different approach and they approved the indication
separately. So one indication was approved in December, and then I think it
was the beta thalassemia that was approved afterwards in January in 2024.
(15:20):
But they did have a particular route to approval as well, not conditional, but priority review.
Orphan drug designation was granted, obviously, FastTrack and RMAT designations as well.
So the developers did really leverage
the opportunities that were there in existing regulatory pathways.
Yeah, and importantly, there were advisory committee meetings.
As well yeah which you know it's always worth going and having a read of the
(15:44):
transcripts and the slides and things from those they're usually an absolute wealth of information.
And they did have a fair old list of post-marketing requests yes and not unsurprisingly
given all the uncertainties that we've talked around about you know particularly
around some of these these long-term risks the risk of secondary malignancies
in particular which we know is
(16:04):
a particular concern it's a hot topic right now isn't it but I mean just
so exciting absolutely we've got these therapies approved.
And if I were a new person in regulatory coming in looking to one of these projects landed on my desk.
Oh gosh, that would be tough. And I could go and read the SBA and the EPAS,
et cetera, for the Kazjevi review.
(16:25):
But in terms of what other guidance and regulation is out there,
what do we really have, Harriet?
Well, I guess in short, the answer is not much. However, I don't think that
actually does justice to the effort that's going in by the regulators and also industry alike.
Everybody wants to get these technologies as safely to market as possible.
(16:47):
And so there is a lot of collaboration that's happening. In terms of specific
guidance and legislation, there isn't any specific legislation yet.
That will come in the future when we have a bit more precedent and a bit more
knowledge and understanding.
But there is a specific FDA guidance document. They are the first agency actually
to put something out that is solely focused on genome edited technologies.
(17:08):
It's currently draft as is most FDA guidance,
but there is a huge effort by FDA to actually add some colour to what is a relatively
broad and vague guidance,
of course, because these technologies are also different and they are evolving
and there are new technologies coming to the fore as well under that genome
edited technology umbrella.
(17:30):
So very good. I would advise people to look at the guidance and then maybe listen
to the webinar that FDA have put out as well, just again, to add some colour,
answer specific questions by developers. There is this real engagement.
And then of course, you and I had the absolute pleasure of being able to speak to Dr.
Marks from CBER, so director of CBER recently, and he shed some light on where
(17:53):
the agency is going in terms of developing future guidance, not just for genome
edited to technologies but innovative therapies in general and I think you'll
agree it was a real career highlight.
It really was a career highlight absolutely.
And really really enjoyed that so I urge anybody to go and read that interview
because it was incredibly insightful.
So there is this real desire I think by the agencies to actually want to work together.
(18:16):
EMA are doing something similar they have a dedicated working party they've
released a horizon scanning report and that's That's not retrospective of this
approval that was back in 2019.
So, you know, there is real effort by all the major agencies,
at least, that are trying to learn as the developers are.
So we're all learning as we go along. It is important to say,
(18:38):
though, there's lots of guidance that exists that isn't specific to genome-edited
technologies, but is still applicable.
So ultimately, there are elements of genome-editing products.
Are essentially advanced therapies or regenerative medicines
or gene therapies depending on where you are in the world and the
use of viral vectors for example there's plenty of
(18:59):
guidance and legislation out that relate
to that and that's the same is true for genome edited products that
utilize viral vectors as an example or modified cells
so it's not a complete desert it's
not a of vacuum yeah and it's
interesting and i i i do feel as if we've heard more
from the fda on this topic but i don't think
(19:21):
we should read that as as you said that the european regulators aren't engaged
in this and you've had some really good interactions through the innovation
task force for example where you had a lot of engagements oh absolutely and
i think that's a really great point to make actually katherine because there
is this real desire by ema and and MHRA as well, to learn.
And leveraging existing pathways like the Innovation Task Force actually is
(19:45):
a wonderful way to be able to educate the agency as well as learn from them.
And they're really engaged in that. So yeah, for anybody that is thinking about
developing these technologies, I would definitely advise,
certainly from our experience, it's been a great way to interact,
build that relationship,
start to educate, and then hopefully further down the line, when you do get
(20:08):
to your clinical trial applications and then beyond, it will pay dividends because
it's not a foreign concept anymore.
So, yeah. And that's often the case with new technologies coming through.
The developers are often really the experts and agencies do want to learn.
They do want to learn and they do want to understand.
So what's next? Oh, gosh.
(20:29):
Where is all of this going? I wish I had my crystal ball. Well,
you're in regulatory, so you are supposed to have one. Does no one tell you?
Hence the PhD research, I think, so I can try and help to advise people in the future.
But ultimately, it's the same as anything innovative, isn't it?
As experience with these types of technologies and products grow,
then agencies will develop regulatory guidance to support developers based on
(20:54):
their knowledge and understanding,
which will continue to evolve potentially new regulatory
pathways and specific pathways or processes might
come to the fore and may be leveraged but
things to watch out for I think you know ultimately as we've said benefit risk
is key here there's no getting away from that and the benefit risk in genome
edited technologies is so skewed that we really need to know a little bit more
(21:17):
about off-target effects and you know that's not going to be quick it's not
it's not And what we know right now,
sort of delivering the product and then having a few months of data is not necessarily enough.
You know, these side effects could be long term. If we're changing someone's
DNA, there is the possibility that it could be decades down the line before
(21:38):
we actually see something.
So long term follow up is key. And there are some sort of specifics now from
FDA, particularly asking for 15 years follow up.
EMA are likely to follow suit. Their guidance is a little bit older,
so hasn't specifically called out genome-edited technologies yet,
but certainly watch this space.
And I think there needs to be a continued collaboration, really,
(22:00):
more so for these types of products and technologies than anything else before,
because the benefits are potentially so great.
But the risks are too. And we don't know what we don't know.
Precisely. It's the uncertainty, isn't it? Yeah, absolutely.
But an incredibly exciting space, Harriet.
(22:21):
It feels like a good thing to do a PhD on. Yes. So we should do that.
Absolutely. So that's happening at the moment. So as I said,
I hope very much to be able to share some of that research, maybe in a future
podcast as we learn a little bit more.
Absolutely. I think given the rate that things are happening in this area,
we should absolutely get you back in to discuss this at
least once more in the future and see where we're
(22:43):
at watch this space watch this space well thank you so
much Harriet that's been an absolutely fascinating introduction was it okay
on the other side of the on the other side of the room well we'll let the listeners
decide I guess but absolutely it was it was great really wonderful and as you
said a good introduction I hope there's so much more that we could cover but
not in the the timeframe that we have.
(23:04):
And I think there's lots of exciting developments. So do watch this space.
We'll be talking about it more in the future. Definitely.
Fantastic. Thank you very much, Harriet. Thank you, Catherine.
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the podcast series brought to you by the team of boys.
(23:25):
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Music.
Music.
(00:06):
To the latest edition of Conversations in Drug Development, brought to you by the team at Boyds.
This podcast is for our fellow community of scientists and clinicians working
in the wonderful world of cell and gene therapy and drug development.
Thank you for tuning in, and we hope you enjoy the conversation.
Music.
(00:30):
Hello, and welcome to this latest episode of Conversations in Drug Development. My name is Dr.
Catherine Bowen. I'm a Senior Director in Regulatory Affairs at Boyds and I
am delighted to be joined on the other side of the studio to normal today by
Harriet Edwards, Associate Director in Regulatory Affairs, as our guest today.
(00:51):
And we have a fantastic topic, I think, today.
We are going to be talking all things genome editing technologies.
Now, I say all things. That would be a very, very long podcast. It would indeed.
So we're going to start off with a bit of an introduction today,
particularly with a focus on some of the regulatory elements and with a bit
(01:11):
of a focus, I guess, on the UK.
EU and US, because that's where a lot of the movement has been,
as we'll get to as we go through this. So a great topic.
But before we get into too much of the meat and bones of it,
Harriet, perhaps we could just start off by explaining exactly what we mean
when we say genome editing technologies. Yeah, absolutely.
(01:33):
And thank you for the great introduction, Catherine. It is indeed nice to be
a guest today rather than the host.
So I will attempt to give everybody a bit of an overview of what is now a really
interesting and novel topic in regulatory affairs.
And of course, we are the regulatory experts rather than the scientists working in this technology.
So there will indeed be a focus on the regulation of these types of products.
(01:55):
But in terms of genome editing, what do we mean?
Let's just break it down into healthcare in particular, because genome editing
means something entirely different when we think about agriculture and other applications.
So in the context of medicines and healthcare, genome edited technologies or
genome edited products are actually a subset of gene therapies.
(02:16):
They are quite niche, they are quite new when we think about healthcare,
and they are incredibly complex and diverse, as we'll see during the course
of the podcast. But generally, they're defined as a way of changing or altering DNA.
So whether that's through insertion, replacing, deleting, removing,
or modifying DNA in a particular point along the human genome,
(02:38):
that's what we're really referring to when we talk about genome editing.
And of course, in the context of deriving a therapeutic benefit.
So just to add a little bit more colour to that definition, we are limited in
drug development to somatic cells. So a really important distinction to make
is that we cannot or we should not be genome editing any germline cells.
(03:00):
And there is a very good reason for that. So there's a good example or an example,
I should say, not necessarily good in recent years of a Chinese researcher actually editing,
successfully claiming to edit
embryos, which were then implanted into a lady who gave birth to twins.
And they were successfully able to disable the pathway that HIV can utilize
(03:23):
if it's going to infect a cell.
So this was presented at the second annual conference of genome editing and
everybody went, oh my goodness, we need to think about restricting what is actually
we're allowed to genome edit and what we can't.
And of course, there are huge ethical implications. So it's very much limited
to editing the human genome at a specific point for therapeutic benefit that
(03:46):
cannot not be passed on to future generations essentially.
And we talk about these technologies as being really very new and I guess in
the field of development of medicines they are but actually the technology's
been around in some form or another for a long time in other areas.
Yeah absolutely and as I mentioned earlier agriculture is one
of those specific examples so we've been
(04:08):
modifying crops for well a really really
long time decades but in terms of health care
in terms of drug development the technology is very
new so there are some similarities in the technologies
that have been used at least initially when we
started to look at genome editing for drug development but now there are so
many different types of technologies that are specific to human genome editing
(04:32):
that actually is a distinct class within itself so and new as well so the first
types of genome edited products and technologies were trialed in the labs in the the mid-2000s,
so 2005 onwards in an academic setting.
And then when we think about actually clinical development and in vivo dosing
of a genome-edited technology, it was actually the mid-2010s and beyond.
(04:56):
So 2017, I think, was the first documented example of a proper clinical trial,
if you like, so a sponsored pharmaceutical.
Not that long ago. Not long ago at all. Particularly when you think about we
now have the first approved product on the market, which I know we'll come on to later.
It really is happening at warp speed. So very exciting, but lots still to learn.
(05:17):
And you keep saying these technologies, and we tend to think of genome editing as one thing.
But of course, the reality is there's an awful lot of complexity and different
elements that actually go into developing one of these medicines.
So should we talk a little bit
about some of those elements and how we actually go about defining them?
Yeah, and it's a really difficult one. I think the way that we will define genome
(05:40):
edited technologies will evolve.
So just to caveat that, but today, largely the biggest distinction is the way
that the genome edited technology works.
So how does it actually introduce the change to the DNA?
And that's either what we call nuclease dependent.
So it introduces cleavage at specific sites within the DNA.
So there is a break there to either replace, delete, insert a change or nuclease
(06:05):
independent where that cleavage doesn't happen.
So some examples of that nuclease dependent
are perhaps the the more established
gene edited technologies if we can even call them
established at this point but things like zinc finger nucleases talons CRISPR-Cas9
which obviously I know lots of people will be familiar with at least the terminology
(06:27):
of that they're all nuclease dependent methodologies so they they introduce
a site-specific break at the site of interest in the DNA.
Whereas the newer, more specific types of technologies, the nucleus independent
are things like base editing and prime editing, which are just starting to come
(06:48):
into development now and could be very exciting.
They are more sensitive and potentially better.
And then there's obviously other complexities as well. So we're just talking
about mechanism of action here.
The type and degree of genomic modification is also an added complexity,
as is how we deliver the technology.
So gene editing has the same complications as gene therapy in terms of whether it's in or ex vivo.
(07:13):
And then there are obviously other things that are associated with gene therapy
generally that also come into play for genome edited technologies.
So they're kind of like Tetris that's fighting back, I think,
because gene therapies as a whole are very complicated.
And then you have this extra complication of how the genome edited technologies
(07:35):
work on top of that, that make it even more challenging for developers.
And you look at all the developments just with gene therapies,
and you mentioned their delivery systems, all the work that's going on at the
moment with non-viral vectors, for example, all these new delivery mechanisms.
So can we talk a little bit about what the potential issues are with these products?
(07:56):
Yeah and I think this is where they really do become a
class of their own actually and it makes it very difficult for regulators to
throw them under the umbrella of gene therapy because they are some distinct
differences and risks and it's particularly we say this all the time balancing
innovation with safety is critical and that's true for all advanced therapies.
(08:18):
But I think it becomes even more of a consideration for genome-edited technologies
because there are such huge, huge risks.
And the risks depend on the mechanism of action, of course, but they are essentially
irreversible and permanent in nature.
And that's something that we haven't necessarily seen before.
(08:38):
We have no idea what the magnitude of the changes that could be made to these
DNA breakages or insertions, which, you know, is quite worrying.
So we could potentially have a therapeutic benefit, which is wonderful and,
you know, what we're aiming to get, but actually...
The off-target effects or even on-target effects that are exacerbated are considerable
(09:00):
and they could be catastrophic to the patient that we're actually trying to
make better, we might actually make considerably worse.
So just some examples in terms of the molecular level, we could have what we
call indels, so random insertions or deletions at the wrong point in the DNA,
translocations, template copy errors, mutations, all
sorts of things which then lead to cellular changes which could
(09:22):
alter cellular function they could actually initiate apoptosis
so cell death uncontrolled proliferation if it's
all going well and you're actually getting the therapeutic benefit it could
be exacerbated and that then introduce what we
see on a clinical manifestation as potentially malignancies genotoxicity dysfunction
of the cell which then obviously translates to something else it's it could
(09:47):
be catastrophic and that's why we need to really proceed with caution when we
think about developing these products.
And in reality and we talk an awful
lot on these podcasts actually about benefit risk because it's a
fundamental regulatory principle right
so we need to be trying to identify those patients who
could potentially have so much benefit here
(10:08):
that those risks and those uncertainties those
things that we simply don't know at this stage in
the development of these technologies can can be be balanced out but
I'm assuming therefore that we're really looking at
quite rare diseases in general here higher met
need no treatment options absolutely I mean
the the goal will ultimately be and I think this
(10:29):
is definitely an ideal world genome editing does
have the potential to well not just
change the way that we treat diseases but you know
it could in an extreme way change humanity as
a whole and when we start thinking about introducing changes not
just for the benefit of treating disease you know
it gets into realms and realms of possibilities but
(10:50):
actually in terms of healthcare the scalability of genome
edited technologies i don't think is there at the moment because the the
benefit risks simply wouldn't let us approve these types of products they're
pretty expensive to make sometimes as well so there's there's the challenges
you can if you can treat with a a pill yeah that's cheap and easy to make and
you can take it away if someone one gets the side effect significantly fewer
(11:14):
unknowns generally speaking yeah.
And the great news now, particularly in terms of our understanding of where
this is going from a regulatory perspective, is we do now have some precedent.
We do. And it's so, so exciting.
I mean, to be involved in genome-edited technologies in any shape,
way or form is, you know, really wonderfully exciting.
(11:35):
As I said, I do think they have the potential to change the way that we treat disease in the future.
And to be part of a time in regulatory affairs where we actually have an approval is so exciting.
And even more exciting to be able to say that the MHRA here in the UK were the
first ever agency to approve a genome-edited technology is even more exciting, I think.
(11:56):
So, yes, there's a reason why we're talking about the UK, the EU and the US,
and that's because they're the agencies that probably unsurprisingly have approved
the world's first genome-edited technology.
So it will happen across the rest of the world. It is happening across the rest
of the world now as CasGevi starts to be rolled out.
But they were the world's first agencies in quick succession to approve,
(12:21):
and hence why we're concentrating on that here.
But just for a bit of background to those people that maybe haven't heard about
CasGevi yet, it's a CRISPR-Cas9 technology.
So basically, it's a stem cell-based product, so CD34 plus cells that are ex
vivo edited. So they're taken away from the patient, they're edited in the lab
and then implanted back into the patient.
(12:43):
And essentially, they reduce expression of a gene, a particular gene of interest,
the BCL11A gene, which increases fetal hemoglobin.
So the idea of CasGemmy is to treat rare blood disorders, essentially,
so beta thalassemia and sickle cell disease, severe sickle cell disease to be precise.
(13:04):
And then obviously the potential will be there to be rolled out for further
indications in the future. But that's what's approved right now.
And excitingly, it was approved, as I said, in those three territories.
So really, really great news.
In terms of approval and route to approval, I know we'll talk about regulation.
Really, the existing regulatory pathways were sufficient to support approval
(13:28):
of CASGEV in these regions.
And were really leveraged, you could say. Yeah, absolutely.
And I think they needed to be. You know, when we think about the EU,
CASGEV was eligible for the prime scheme.
And I know you're really familiar with that, Catherine. But I think the opportunity
to leverage early interactions was probably really beneficial in this instance
(13:48):
to be able to have those interactions with the regulators.
Now, interestingly, Casgevi was actually supposed to be a full application, so not conditional.
It was supposed to be approved and good to go once the application had gone in.
But actually, due to those interactions with the regulators.
Or I guess we should speculate that it was due to those interactions,
(14:08):
there was a change in strategy.
So actually, Casgevi has now been approved by a conditional.
I think it went in with the hope of getting full and came out with conditional
on the basis of the uncertainty. Which makes sense. It says,
and that's what the pathway is there for.
Yeah, yeah. It'd be interesting to know whether they were recommended to follow
that pathway in the first instance, but we do not know.
I mean, with the amount of risks that are associated with this and the incredible
(14:32):
amount of unknowns, this being the world's first product, now there's precedent.
Things may change in the future for future CRISPR-Cas9 technologies.
But, you know, I think that was probably quite a smart move by the regulator
to have a conditional approval.
There was one combined phase 1, 2, 3 study in limited patients and the approval
was based on interim safety data and analysis that, you know,
(14:56):
the study hadn't finished at that point.
So the concerns over data comprehensiveness, actually, I think are really valid.
And the same happened in the UK as well.
Now, the FDA took a slightly different approach and they approved the indication
separately. So one indication was approved in December, and then I think it
was the beta thalassemia that was approved afterwards in January in 2024.
(15:20):
But they did have a particular route to approval as well, not conditional, but priority review.
Orphan drug designation was granted, obviously, FastTrack and RMAT designations as well.
So the developers did really leverage
the opportunities that were there in existing regulatory pathways.
Yeah, and importantly, there were advisory committee meetings.
As well yeah which you know it's always worth going and having a read of the
(15:44):
transcripts and the slides and things from those they're usually an absolute wealth of information.
And they did have a fair old list of post-marketing requests yes and not unsurprisingly
given all the uncertainties that we've talked around about you know particularly
around some of these these long-term risks the risk of secondary malignancies
in particular which we know is
(16:04):
a particular concern it's a hot topic right now isn't it but I mean just
so exciting absolutely we've got these therapies approved.
And if I were a new person in regulatory coming in looking to one of these projects landed on my desk.
Oh gosh, that would be tough. And I could go and read the SBA and the EPAS,
et cetera, for the Kazjevi review.
(16:25):
But in terms of what other guidance and regulation is out there,
what do we really have, Harriet?
Well, I guess in short, the answer is not much. However, I don't think that
actually does justice to the effort that's going in by the regulators and also industry alike.
Everybody wants to get these technologies as safely to market as possible.
(16:47):
And so there is a lot of collaboration that's happening. In terms of specific
guidance and legislation, there isn't any specific legislation yet.
That will come in the future when we have a bit more precedent and a bit more
knowledge and understanding.
But there is a specific FDA guidance document. They are the first agency actually
to put something out that is solely focused on genome edited technologies.
(17:08):
It's currently draft as is most FDA guidance,
but there is a huge effort by FDA to actually add some colour to what is a relatively
broad and vague guidance,
of course, because these technologies are also different and they are evolving
and there are new technologies coming to the fore as well under that genome
edited technology umbrella.
(17:30):
So very good. I would advise people to look at the guidance and then maybe listen
to the webinar that FDA have put out as well, just again, to add some colour,
answer specific questions by developers. There is this real engagement.
And then of course, you and I had the absolute pleasure of being able to speak to Dr.
Marks from CBER, so director of CBER recently, and he shed some light on where
(17:53):
the agency is going in terms of developing future guidance, not just for genome
edited to technologies but innovative therapies in general and I think you'll
agree it was a real career highlight.
It really was a career highlight absolutely.
And really really enjoyed that so I urge anybody to go and read that interview
because it was incredibly insightful.
So there is this real desire I think by the agencies to actually want to work together.
(18:16):
EMA are doing something similar they have a dedicated working party they've
released a horizon scanning report and that's That's not retrospective of this
approval that was back in 2019.
So, you know, there is real effort by all the major agencies,
at least, that are trying to learn as the developers are.
So we're all learning as we go along. It is important to say,
(18:38):
though, there's lots of guidance that exists that isn't specific to genome-edited
technologies, but is still applicable.
So ultimately, there are elements of genome-editing products.
Are essentially advanced therapies or regenerative medicines
or gene therapies depending on where you are in the world and the
use of viral vectors for example there's plenty of
(18:59):
guidance and legislation out that relate
to that and that's the same is true for genome edited products that
utilize viral vectors as an example or modified cells
so it's not a complete desert it's
not a of vacuum yeah and it's
interesting and i i i do feel as if we've heard more
from the fda on this topic but i don't think
(19:21):
we should read that as as you said that the european regulators aren't engaged
in this and you've had some really good interactions through the innovation
task force for example where you had a lot of engagements oh absolutely and
i think that's a really great point to make actually katherine because there
is this real desire by ema and and MHRA as well, to learn.
And leveraging existing pathways like the Innovation Task Force actually is
(19:45):
a wonderful way to be able to educate the agency as well as learn from them.
And they're really engaged in that. So yeah, for anybody that is thinking about
developing these technologies, I would definitely advise,
certainly from our experience, it's been a great way to interact,
build that relationship,
start to educate, and then hopefully further down the line, when you do get
(20:08):
to your clinical trial applications and then beyond, it will pay dividends because
it's not a foreign concept anymore.
So, yeah. And that's often the case with new technologies coming through.
The developers are often really the experts and agencies do want to learn.
They do want to learn and they do want to understand.
So what's next? Oh, gosh.
(20:29):
Where is all of this going? I wish I had my crystal ball. Well,
you're in regulatory, so you are supposed to have one. Does no one tell you?
Hence the PhD research, I think, so I can try and help to advise people in the future.
But ultimately, it's the same as anything innovative, isn't it?
As experience with these types of technologies and products grow,
then agencies will develop regulatory guidance to support developers based on
(20:54):
their knowledge and understanding,
which will continue to evolve potentially new regulatory
pathways and specific pathways or processes might
come to the fore and may be leveraged but
things to watch out for I think you know ultimately as we've said benefit risk
is key here there's no getting away from that and the benefit risk in genome
edited technologies is so skewed that we really need to know a little bit more
(21:17):
about off-target effects and you know that's not going to be quick it's not
it's not And what we know right now,
sort of delivering the product and then having a few months of data is not necessarily enough.
You know, these side effects could be long term. If we're changing someone's
DNA, there is the possibility that it could be decades down the line before
(21:38):
we actually see something.
So long term follow up is key. And there are some sort of specifics now from
FDA, particularly asking for 15 years follow up.
EMA are likely to follow suit. Their guidance is a little bit older,
so hasn't specifically called out genome-edited technologies yet,
but certainly watch this space.
And I think there needs to be a continued collaboration, really,
(22:00):
more so for these types of products and technologies than anything else before,
because the benefits are potentially so great.
But the risks are too. And we don't know what we don't know.
Precisely. It's the uncertainty, isn't it? Yeah, absolutely.
But an incredibly exciting space, Harriet.
(22:21):
It feels like a good thing to do a PhD on. Yes. So we should do that.
Absolutely. So that's happening at the moment. So as I said,
I hope very much to be able to share some of that research, maybe in a future
podcast as we learn a little bit more.
Absolutely. I think given the rate that things are happening in this area,
we should absolutely get you back in to discuss this at
least once more in the future and see where we're
(22:43):
at watch this space watch this space well thank you so
much Harriet that's been an absolutely fascinating introduction was it okay
on the other side of the on the other side of the room well we'll let the listeners
decide I guess but absolutely it was it was great really wonderful and as you
said a good introduction I hope there's so much more that we could cover but
not in the the timeframe that we have.
(23:04):
And I think there's lots of exciting developments. So do watch this space.
We'll be talking about it more in the future. Definitely.
Fantastic. Thank you very much, Harriet. Thank you, Catherine.
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