For the morning. So maybe let's start there. Welcome to Chardan's, ninth annual genetic medicines conference. And before we begin, let me share the compliance statement, and it covers the presentations today. Our conference presenters have attested and agreed that they will not share or discuss any material nonpublic or confidential information that they are aware
of. Great.
Alright. With that out of the way, welcome everyone to this session focusing on the next wave of technologies and programs in the genome editing space. I'm Gula Lifshitz, a biotech analyst at Chardan. And investors that have been following the genome editing space have probably seen that genome editing works. We have great efficacy for ex vivo and in vivo LNP delivered, liver editing programs among the first wave of programs that we've seen so far.
Again, we saw the clinical data aligning nicely with data from preclinical models. And now as those mature, we're seeing additional waves of programs that are coming through. Some of those are using similar technologies, some are using precision editing approaches, and some with innovation around delivery. But there's also been some ongoing debate regarding the commercial case for some of these one time genome editing therapies across indication types and market sizes. So in this session, we'll discuss how companies are approaching these scientific, clinical, and commercial challenges that are facing the next wave of editing programs.
So I'm joined by our guests. We have, doctor Devin Smith, CEO of Arbor Bio, Gilmore O'Neill, CEO of Editas, Alan Ryan, CEO of Prime, Emma Wang, CEO oh, sorry, cofounder and CTO of Yultech, and Tian Zhu, cofounder and CEO of Gen Edit Bio. Thank you all for joining us today. And maybe to start with, I'll ask each of our participants to briefly introduce themselves and their company's technologies and programs. And maybe let's start on this end.
Good morning, everyone. Thanks for the invitation. It's a great pleasure to be here. My name is Emma Wong. Our CEO couldn't make it, so you get me instead.
Yao Tek Therapeutics is a small biotech company based in Shanghai founded a little more than four years ago. We we focus on development of in vivo genome editing therapies, and we are a little more than four a little more than four years in business. We have four five programs in the clinic, and, hopefully, our first program will interface three development beginning of next year, which is a China, program. And we we we we our our pipeline programs cover indications from, ultra rare disease, with global population global patient population of around, ten thousand people all the way to chronic, cardiovascular disease. So we cover the whole spectrum, And we continue to work on other novel indications and diseases to further explore the potential of gene editing.
Great.
Great. Good morning, everyone. My name is Gilmore Neal, CEO of Editas Medicine. We are a in vivo CRISPR gene editing company and focused entirely on in vivo leveraging LNPs, both targeting LNPs for extra body delivery as well as liver delivery. We are focused on the development of low cost of goods, high efficacy differentiated medicines.
Our lead program EDIT-four zero one upregulates LDL receptor has had significant impact 90% reduction LDL C and is going into the clinic next year with what we hope is a human POC by the 2026. And the beauty of that indication we see is it actually can potentially in the future address a prevalent population, but has niche populations within it that will actually sort of help drive that sweet spot for speed and regulatory comfort in its approval.
Hi everyone. It's Kean. I'm CEO and co founder of Gen Ed Bao. So we are an in vivo genome editing company based in Hong Kong, Beijing, and Boston. So our aim is try to afford, to to provide affordable DNA surgeries to genetic diseases and beyond.
We we have a platform and also pipeline. So our platform includes the proprietary protein delivery vehicle. It's like similar to engineered virus like particle to encapsulate the RNP form of the CRISPR and SGNA. And we also have a versatile editor could do site specific insertion of large fragment. And in pipeline, our first pipeline is eye diseases.
It's called TGFBI mutant corneal dystrophy, which is autosomal dominant, like gain of function mutation diseases. And we have, dosed for patients from IIT setting in China and aim to file IND to FDA on the end of this year and open global Phase onetwo development early next year. And second pipeline is we try to do a site specific insertion of the CAR for in vivo cell therapy. Yeah. Very nice meeting everyone.
Hi. I'm Alan Ryan, CEO of Prime Medicine. We're a company that was founded around prime editing and owned the IP estate around prime editing, which came out of David Lou's lab 29 invented in 2019. Think of this as a as a gene editing technology that can really do any type of edit. So, without going into too much detail, we can actually, using an enzyme, we can transcribe genetic code or base pairs directly into your DNA to make a permanent change.
And so, through that technology, you know, again we can do a whole host of different sort of mutations that can't be addressed through other gene editing approaches and we do that using what we call sort of a modified Cas enzyme. So it's a nickase where you're making a single stranded break. So from a as you think about sort of side effect or off target or other things that can happen, it's a very gentle way to edit the genome. Our programs that we're focused on today are predominantly for liver disease or liver directed programs. So Wilson's disease, which is kind of IND in the first half of next year, alpha one antitrypsin deficiency with an IND mid next year.
We're also working on cystic fibrosis with the Cystic Fibrosis Foundation and ex vivo CAR T cell therapies in oncology and immunology, hematology with Bristol Myers.
Morning. Devin Smith, CEO at Arbor Bio. We, like everyone else here, do genome editing. We are purely focused in vivo ourselves, although we do have partnerships on the ex vivo side as, you know, similar to Prime. We have a two pronged approach as it goes for gene editing.
So, first, we do have a pretty broad platform of editing approaches that were all discovered de novo, so our co founders, Feng Zhong, David Walt, built the company on idea, not on IP, and so we've been able to go out and find novel approaches for editing that allow us to have very small technology so we can, you know, become delivery agnostic. We have a couple of liver programs, and importantly moving out of the liver, we have a couple of programs targeted in the CNS because we feel, you know, are a lot of really cool targets in the liver, but there's also a lot of really cool companies going after the same targets in the liver. And so, for us being able to move outside of the liver is an important sort of step for I think all of us and and doing so as quickly as possible.
Great. So, with that, let's dive into, some of the topics that I mentioned earlier. We'll start with technology. So genome editing has expanded over the last several years. The field now encompasses several different technologies.
There's nucleus editing, base editing, prime editing, epigenome editing, and and other, approaches as well. And, initially, there was a lot of discussion about this as first gen, that's second gen, that's third gen. Now as these technologies start to mature and we're starting to see some divergence in strategy there, what is the latest thinking about how these technologies will coexist and evolve together in this space? Does one supplant the other? Are there opportunities more broadly?
And I'd like to keep this conversational, so maybe you can jump in on this.
Gil? Can I just go and just say that I actually think that, all these technologies I think will coexist in the ecosystem? I think the most important thing I've learned over twenty plus years of drug development in the end is the product. And this is a guy who led the development of DMF as an oral therapy for MS, which was transformative and probably the single biggest medicine that Biogen has ever actually launched. And so and we launched DMF, dimethyl fumarate, just think about the chemistry there in 2013.
So I think it's a really good example of how it's about the product and the profile. I think that the different tools and the way we use CRISPR have strengths and dare I say weaknesses, and what you have to do is you can direct them to places that they can actually have the greatest effect. I think Alan pointed out how Prime can actually make edits. I think the base editing that is also used by Devon and my colleagues. Also, if approvals, you have insertional and obviously we can actually do direct editing of the regulatory elements to functionally upregulate rescue proteins, which could be agnostic to mutations.
So the way we use these technologies and the products we create, I think allows to coexist. I think that's the key area for focus in therapeutics development.
Yep, that makes sense. Anyone else with that?
Yeah, I mean, think that was really well said. I just would add a couple of things. I really agree, I think these technologies will coexist. We kind of look at it as sort of what's the problem you're trying to solve and what's the best tool to take to that problem, but also sort of how differentiated are you to do something with prime editing, you know, that's being done with CRISPR or base editing today. And when we're evaluating a program, we want to look at and say, do we think we can be, obviously you want to be first, if you're not first, are we going to be best?
And oftentimes, as we look at the profiles for certain approaches that we've seen, it could be CRISPR, could be base editing, saying, look, like, this is a pretty good approach, maybe we could have a better off target or something else going on here, but, you know, on balance, we think they're they've solved the problem pretty well and it really wouldn't make sense for us to to develop there. So, you know, I think we all kind of look at it in the same way and I'm gonna agree with Devon as well. I think there's way too many companies going after the same target in many different areas and and, you know, that's a debate we can have as well. But, yeah, I think there's there's a lot of reason for these technologies to coexist. Mhmm.
Yeah. I guess Go ahead, Devin.
Go Go ahead, think, you know, Alan, which is and you mentioned this too, I think the strategies are gonna are diverging, whereas a few years ago it was kind of unclear, right? We're all kind of trying to figure out where things sit, and I think that, you know, ultimately as Gilmore said, it comes down to the product and how do we differentiate what we're doing, and I think as this matures into a true modality, we have to take much more of a modality approach. So, find the right target and then find the right tool or approach that actually can alter that target no matter what it may be, and I think you're starting to see that maturation, which is a normal maturation of a new modality, which is exciting because it's here to stay, it's going to revolutionize patients' lives, not in every disease, but there will be diseases where CRISPR based approaches will revolutionize patients' treatments.
So, what are some of the lessons learned from the first wave of therapies that we've seen, some of which have moved on to phase three trials or or the commercial space, and some of which have been deprioritized by some by some of you folks here. What are the lessons learned that you can apply going forward? Anyone?
Sorry, I'm just going to go for forgive me. So I think you actually summarized it very nicely. I think there are a couple of things we've learned on the technical side, which is that these editing tools are incredibly powerful. The technical probability of success in translation pre clinical to clinic is unprecedented, I've already. If you actually look at the rates over the last few years.
The second is you can move actually very quickly. Now, we thought we were moving quickly and then I'm sitting around my colleagues who are moving faster, but that actually shows what's possible with this technology. I think that Tim earlier, Tim Punt earlier in our session talked about the platform capability. In fact, I think the potential for platform for gene editing is very real, and I think that's demonstrated what we've learned over the last few years. I think the other thing that we have learned is the need to focus, which we're all doing, to try and differentiate, you know, really critically differentiate from other products, which I think we are doing.
And then I I think finally to really think about the business case. And I think the good thing is sometimes you just have to spend time working with people to point out that not only can we give a superior product, but that a one and done therapy is viable. And I think it was again very reassuring in the earlier session to hear from Tim Hunt, comments from senior leadership of CMS, which is we actually get the economic argument for a one and done therapeutic. So I think overall that has actually I think that has been an important lesson.
Mhmm. Yeah. I will share that, like we always learn from the, first peers and I think delivery is everything or it's very very important. As previously we see that it is like equally important as, the editor but but I think comparing to the editor but I think it's delivery is really the key. So we have to invest on delivery and the delivery and the editor, they actually have to be optimized together.
Uh-huh. Yeah. Yeah. And I think the indication choice is very important as Gil said, like the technology success may not be necessarily translate to the commercial viability. Mhmm.
And clinical significance is also very important. Yeah. Thank you.
Yep. I mean, maybe staying on the delivery topic, and maybe we can come back to other points after. But I mean, tell you guys are developing this PDV technologies. Can you expand on how that differentiates, and what's different about that versus LNPs?
Sure. Sure. I think the first thing we want to develop the PDV is actually we try to encapsulate the cargo diversity to like a DNA and also the RNP form. So RNP form, in our view, in our company's view is very important to like minimise the off target potential because it's really transient, it's already protein with the astronomy. So that's the, focus aim.
So the, PDV could encapsulate DNA, RNA, RNA form and make it very diverse. And also we can do a lot of engineering work outside, like do glycoprotein pseudotyping and also do antibody conjugation to make it a tissue specific and cell specific like delivery more precisely. And CMC point, it's more leveraging the like lengthy similar process, but we are also accumulating our own CMC in house like know house and also because it's RNP form, so the astronomy has not to be like chemically modified. It's just astronomy and the pain of like optimizing like the novel cast sometimes, I'm not sure if Devon can comment like is the scaffold and chemical modification. So in that form, we have also our own cast delivery platform.
We think this kind of compatibility of the r r and p form could accelerate a novel CAS application.
Yeah. Mhmm. Interesting. So I guess beyond that, LNPs have really emerged as the so far the forerunner for in vivo delivery at to deliver. You know, in your experience, are these all the same or can they really drive a differentiated profile depending on how you design them or what you conjugate to them?
I'll leave that open.
Yeah, I mean, think that they are definitely not, excuse me, all the same. Even, you know, you're looking at a number of different components, maybe five, six components that go into an LNP. You can have a targeting moiety, obviously, that can change tissue specificity. But, you know, probably the most important component is likely what drives most of the toxicity is the ionizable lipid, and there's probably a few different ionizable lipids that have now in different LMPs gone into the clinic, and I think they're gonna have different safety profiles. So, at the end of the day, it really is all about how you're adjusting that mixture and ratios and everything else that's going to dictate the therapeutic index of your LNP, and also, you know, which ionizable lipid you are using.
So, we see extremely different profiles based on the LNP that we're using, and then we benchmark to the best of our ability on what we believe is being used clinically to see what our therapeutic index looks like, and at least so far, against benchmarks it's looked favorable. But, yeah, I think it's a lot of differences is what I would say. Everything is not created equal.
I think the other thing that's becoming clear is that everything I agree with everything that Alan just said. I think the other issue is we're finding that you do have to do some tweaks. The difference change is not necessarily in the individual components. There are elements there, but it's actually in the totality.
Right.
Because the LNP sometimes and the sort of the chemistry etcetera has to be modified in the context of the target that you're working with. I still think there's substantial room there for it to be used for a platform once
Right. You've actually just going say that
Once notwithstanding that, once you've actually developed it for a given target tissue and target, know the simplicity, the simple pieces that you can modify 20 nucleotides on a guide RNA and essentially should be able to reference in theory, not just from a regulatory point of view, the safety experience, the CMC etc, but actually also very importantly it will substantially diminish the amount of, and this is the beauty of the LNP, the amount of investment that you will have to do for process development, analytics development for your second, third and fourth indication. So the platform isn't just about a regulatory designation, it's very much about the level or degree of investment you have to make for the next indications, and that matters in selection of indications because the cost to value ratio changes. Know that first indication of the cost of value is going to be different, that numerator and the is going to be different, as you go into your second and third indications. And I think that is actually something that I think potentially can enable acceleration, and it also means that we can actually increase our ambition, the level of ambition and the value creation we can do, not just for moving from rare to more prevalent diseases, but frankly moving from rare to ultra and supporting ultra rare diseases.
Mhmm.
I think that as you move from it's interesting because you if you use the same LNP and you use Cas nine or you do a Prime Edit or you do a Cas 12 or base whatever it is, it's not one size fits all, even with the same LMP because the mRNAs are vastly different in length, the guides are vastly different in length, and so the you have to find the right stoichiometry between the guide and your editing machine, whatever you're putting in within each LMP, so it is there is quite a bit of, I guess, art to the sciences as Gilmore said, but then once you've got that, and if all you're changing is really just the guide element, then then it is very plug and play like at that
point. Mhmm.
Got it. So there's some optimization, but really not nearly as much as it would be for starting a different product, de novo, that was entirely different technology.
I think just one point to add though, because I think it's an important one, is, you know, we've now seen multiple examples clinically where we can very safely get to the liver. Right? And so, we've seen that now with multiple times with CRISPR, base editing, and hopefully soon prime editing. So, we're we're in a very different place today than we were three or four years ago Absolutely. In terms of we now know we can deliver to that tissue and hopefully other tissues will open up.
But that's a, you know, pretty important, I think, inflection point that we've come to in the sector for gene editing.
Yeah. Emma, what about you guys? You have multiple programs in the clinic now. How are you leveraging that platform capability to move quickly?
Yes. When I started working in this field, it was all about vaccines. Right? And the vaccine, mRNA, the payload echo echo what Devin just said that the payloads tend to be shorter, and it's the I m, LNP LNP's. Now now in gene editing, we are mostly dosing IV and with larger payload more two different RNAs, instead of one.
And the formulation has had there's a lot of optimization work on the formulation. And and, on top of that, different, ionizable lipid had lipids, they have different tropism. Some some perform better in the liver, some perform better in in in muscle, in in t, in in HSE. We we see all that. We can confirm.
And and I I think what, from our experience, we've been very lucky that we we have one of the few clinically validated, formulation, already in used in in in several of our programs, and that helped a lot, for us when it comes to communication with FDA. For example, it has helped to, for example, to to to save a lot of nonclinical studies in NHP in mice in long term durability study. And and as well when when when we communicate with with the KOLs and PLs, PPs in in the clinical on the clinical development side, the the PIs tend to be more willing to to take a risk, knowing that, this part of the product has been validated, in the clinic. So definitely there's a platform techno there's a platform advantage. On the CMC side, we know our formulation very well.
We know there's there's good predictability, in in manufacturing as we always know what it takes. We have we have the people, the the facility, the instruments, and the process, definitely. And and the stability stability study, people don't often talk, well, it takes a long time to generate data, and then we could also leverage some of the the data as well.
It sounds like there's a lot of synergies across the Absolutely. Multiple programs. That makes sense. So, Devin, you guys, as you mentioned, are doing some CNS programs where their AAV is the more mature delivery technology. Can you talk about how you've approached that part of the delivery equation for those type of programs?
Yeah. I mean, think we think about, you know, the liver, think is is is pretty well validated, I think, on delivery and on the ability that editing works. We know it works in the liver, and it's durable, and there's a clear regulatory path, even in The US, and that's been established I think over the last couple of years. And, you know, as we thought about where do we wanna go and how do we continue to differentiate, You know, our technology is very small, it can fit into AV whether we're doing complex editing with different effectors or excisions, insertions, whatever it may be. And so, it allows us allowed us to really think creatively about where else we could go.
And the CNS is really, you know, it's the next big horizon I think in our industry, and we can access the CNS with AAVs today. And so, from our perspective, it's finding the right indication where you can balance the learnings but also sort of the risk benefit of an AAV delivering an editor. And so, we centered in on ALS, where you can access the spinal motor neurons, where the risk reward there is reasonable, looks unfortunately a lot like a pancreatic cancer or some other really deadly cancer with no treatment. And so, it is an opportunity we feel to potentially deliver value to patients, but also de risk how do we move outside the liver into a new organ with gene editing. And, you know, it's I'm sure it will have all sorts of unforeseen interesting challenges and opportunities as we do so, but it is that the time is right and it's the opportunity I think to really move beyond the liver.
So we're doing that.
Great. So maybe let's shift gears and talk about the commercial and business case for gene editing therapies. As we've already talked about several times here, we've seen some impressive human efficacy data for the clinical stage, programs. But often time when I talk to investors, some of the debate centers not on the science, but on the commercial prospects either because a program is advancing in a very rare disease or a subset of patients, or it's a less rare disease where there are some available therapies, and the question is the extent of unmet need or demand, for example, in the cardiovascular space. So how do you make the commercial case for one time gene editing within your pipeline indications and some examples to or data to support that would be great.
I'll I'll start on that just to you know? So we did announced a partnership with Chiesi Pharmaceuticals a couple weeks ago for our lead program which is for an ultra rare pediatric liver indication. And, you know, in all of our indications we decided we have to be first in class, particularly when you're in the rare space because as you every patient you dose, your pool shrinks and goes down to zero, which is great for patients. It's a little more difficult when you think about the commercial aspects of it. But I think as as we have the conversation with Casey, they have a very large rare disease group, they understand the commercial model, they understand the rare disease space and they It's nice that they You know, to have a partner that is dedicated, understands it and understands the commercial opportunity.
And I think, you know, I'll be honest, I've had investors say, Well, why would you want a one and done therapy? How do you monetize that completely? And, you know, I mean, the response is, Well, why don't you call the Wall Street Journal and tell them that? Because I'm sure the entire Is there anyone here who doesn't want their child or their family member be treated one and done? And the commercial model, you know, it will work because we've seen that before.
If you have a therapy that's transformational and it works, it will be commercially successful. And so, think we will demonstrate that. I think there's, you know, Intellia is probably gonna be first up on the in vivo side and, you know, I have full confidence they'll be successful because these therapies transform patients' lives.
I think just to add or build on what Devon has said, I think one of the things that, you know, I think we need to share and have people fully understand is that we are differentiated. You know, our approach has been to think about saying, what's the space that we can work in or we have the right to work in with CRISPR? And we decided to say we will function up regulate. And I'll come back to knockdown because there are advantages there too, but we have decided to focus on functional upregulation, but we're not happy, I think Devon actually alluded this way, it's not sufficient to be mechanistically differentiated. That's great, that's just cool.
But what you have to do is create a product. And so we also said that we must have products and develop products that are going to differentiate in efficacy. So, with our LDLR program, we believe that a 90% reduction LDL C is meaningfully differentiated from other targeted approaches. And indeed, you know, we've a lot of data have been generated over the last decade or plus to show that the long term benefits of significant reductions in LDL translate into very meaningful and very rapid onset reductions in risk of cardiovascular disease, which we have to remember is a substantial burden. And within that on healthcare and even and as I said earlier, within that population there are subpopulations which are truly refractory and in a smaller size that enables to we believe move rapidly through the regulatory space and actually have a create a meaningful business on which we can build into a larger prevalent populations.
I think the other piece I would just return to is that one of the things we've seen with editing in the clinical data to date, which I think is sometimes buried or lost because everyone focuses on the mean response. But if you actually look at the variability of the clinical response in edited patients, it's much narrower than you see for other therapeutic modalities. And why does that matter? That matters because when you think about it, it means that the responder rate is going to be higher. And I think that's a really important distinction that sometimes is lost because people are so focused on that single number in the middle, the mean.
But a mean plus or minus one is a very different value proposition for a mean plus or minus 10, because that means that you know when you're talking about, and this is important for lifelong therapies, if you're thinking about you know how health systems and payers are going to look at that, they need to see a high responder rate or a low number needed to treat rate. And so that's a really important piece and something that I think is being missed or I shouldn't say that, but it's important that we emphasize and highlight so people actually see that.
Yeah. Think commercial viability and clinical significance are very important and we have to think about it earlier. Although like for our first programme, it's just in IT stage and hasn't start initiate a global phase onetwo trial, but we will, like interview with our KOL, like the physicians and to understand the truly unmet medical need and the clinically significance it potentially could provide and even thinking about the pricing strategy earlier because the like the current what is the current standard of care, what is the pricing and how can we like save how many standard of care and what is the pricing strategy and what is the COGS of our therapy and yeah, yeah so those factors all will count. I
should have said that, sorry my apologies, One one thing I left out and you said it, but I just want to really emphasize it is that there is a reason why all of us sitting up here are you know, certain for systemic use have moved to nanoparticles. Obviously, if you move into enclosed spaces as Tian and Devon have too, you can actually get your cost of goods low. And that's important because ultimately it's not just about popular shapes, it's about margins. And actually getting the right margin, getting the cost of goods low enables you to get the margins right for something that is going to actually deliver value to healthcare systems, very importantly change patients lives, but actually also create a viable business. And I think that was one of the things that we struggled with the beginning with because we were using incredibly high COGS delivery technologies like cell therapies, with vanishingly low margins, which were basically making people incredibly anxious.
So, think moving to a simplified systemic delivery using LNPs with low cost of goods or focal delivery with low cost of goods, high margins is actually going to be something that's really going to is actually transforming the business case.
Yeah, I completely echo that. And I just want to add, in the gene and cell therapy space probably, genetic and cargo delivered by a non viral approach is the option with the highest chance of commercial viability, you know, given the extremely low cost of goods Mhmm. Order of magnitude, lower cost of goods. Mhmm. And I I think that's the where the field is going.
And That's fine. And personally, I don't think it's it's ethical to make black boss blockbuster drugs costing millions of dollars as to for rare disease patients. Especially in our experience, many of these patients and their families are not doing well economically to start with. And without mature payer system like The US and EU, the vast majority of the global population have no chance to access, you know, the the benefit of of gene editing without, with with the current price tag. Mhmm.
So so nonviral is is is, I I believe, so far the only way, the only way to go, for for the global south.
Yeah. Yeah. There's absolutely cost and COGS advantages both for the you know, from a pharmacoeconomic standpoint and for, you know, an investment case standpoint. Alan, did you have something to say? You look like you're about to say something.
No. No. I mean, I I would just say these are transformational therapies, which the world really hasn't seen these types of things before. Right? I would say this is very differentiated from gene therapy, which would be the only kind of close chlorate and it's too different.
So, to me, this is going to transform patient treatment over the coming years and decades. And the commercial, it's going to be a I don't worry kind of how these companies are going to do commercially because I just think we're just scratching the surface of what we can do. I think from an investor standpoint, you know, at some point you you gotta see it before you believe it. Right. And because it's so new, they just have to understand how that's gonna work.
But the last thing I'll say is it's all about the business model. Right? I think many of the companies started out and just kind of worked everywhere and for I'll say the market maybe forced a
lot of us to
really focus on the right commercial opportunities for the right reasons. And I would say companies today, are more disciplined. I think everything that companies are going after, if you look at pipelines today, they're typically, you know, now really focused on where can we be successful commercially.
Great. In the last minute or so, any closing thoughts for where you think the space is going and and what we should look out for in the next few years? Again, keep that open. I I
think you're going to see multiple approvals. I think you're going to see multiple launches and and I think that what's the other thing I want to say, I think you're actually going to see what Alan just said is people are going to see what they need to see to believe. And I think after the first wave of high technical success and some commercial challenges, I believe that the sort of the payer landscape is actually evolving and we'll have had a chance to sort of say, oh hang on, oh so this is coming, this is real and we'll adjust because you know historically sometimes those systems have lagged behind the technology and the therapeutic launch. So, I actually think the next five years are going to be incredibly exciting in the space, not just technically, but actually just from a point of view of showing the true robust business viability of this approach to therapeutics.
Yep. Great. I see we're getting the flashing times up sign so I think that brings us to the end of our session. So thank you all again for participating in for the fantastic discussion.