Exploring Genome Editing Technologies in Drug Development

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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. 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. 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 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.

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. 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. 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, 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. 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 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 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 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

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. 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. 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 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 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 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 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. 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 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?

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. 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. 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 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 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 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 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 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

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 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. 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. 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, 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. 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. 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 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 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, 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 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, 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. 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 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 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.

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. 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.

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. 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 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. 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, 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 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 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 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 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. 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 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 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 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, 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. 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 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. 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. Music. Thank you for listening to Conversations in Drug Development, the podcast series brought to you by the team of boys.

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