On stage, we have the team from Editas Medicine. I'll now pass the mic to their CEO, Gilmore O'Neill, for a short presentation followed by a live audience Q&A. Gilmore, the stage is yours.
Thank you very much, Brian. Good morning, everyone. And also special thanks to J.P. Morgan for all your support. So I'm delighted to be here this morning to tell you about the progress that Editas has made along its path to being a lead in vivo gene editing company. I'm also going to be sharing some exciting new data that we have released this week and really look forward to sharing that with you. And we'll tell you about our plans for this year and going into the next couple of years after that. But before I say any more, I'm just going to pause and point out that I am going to make some forward-looking statements. And I would really encourage you to read our disclosure filings so that you can fully understand the risks that could result in some actual results being different from what we anticipate.
Two years ago, I think on this very stage, although it might be slightly bigger at the time, I actually announced our intent as an editing company to be a leader in in vivo gene editing. This is based on a conviction that in vivo gene editing will transform human therapeutics globally, much to the same degree that mobile smartphones have actually transformed the communications business around the world. I stand by that conviction. I have to say, from a technical point of view, over the last 15 months, we've seen phenomenal validation of the technical and, frankly, clinical efficacy of editing, both in ex vivo programs included indeed by the significant and meaningful clinical data that we saw with our reni-cel ex vivo therapy. We've actually also seen it with multiple readouts for in vivo editing.
Notwithstanding that significant technical success, the field, the gene editing and gene therapy fields in general, have struggled to show a compelling, I should say, investment thesis. And the thesis has been challenged by a number of factors. And we've actually listened very hard to investors, analysts, et cetera, just to try and understand where those problems lie. One, obviously, is that the association in the near term of gene editing with the launch of an ex vivo cell therapy and the commensurate challenges of a recent slow launch, lower total addressable markets owing to the restriction of the segment of patient populations owing to the rigors of transplant, obviously reimbursement challenges, et cetera. But also in the in vivo setting, we have seen launches and, frankly, active clinical trials pursuing competitive indications with already high standards of care addressable by other more established modalities.
There are a number of solutions. Those include, obviously, a focus away from ex vivo to in vivo, a differentiated approach, and the leveraging of CRISPR's capability to actually deliver therapeutics with ambitions, objectives, and effects that are unachievable using other modalities of therapy. I would argue that Editas has that solution. We have actually completed a transition to being a pure in vivo company. While that is necessary, it is not sufficient. In addition, we have positioned ourselves with an absolute focus on functional upregulation as a treatment strategy using our CRISPR editing technology. That actually has been validated by reni-cel, as I'll show you in a little while. We've also solved for delivery beyond the liver, a critical need where we can actually deliver the editing payloads using our proprietary targeted LNP platform to deliver to HSCs and other tissues.
But as we talk about upregulation or functional upregulation, what does that actually mean? I just want to pause for a moment on that and describe what it is, which is first, it is using the editing of regulatory or non-coding elements in the DNA to drive the functional increase in expression and activity of disease-mitigating genes or proteins. And that actually gives a significant advantage because it's not actually trying to do knockdown, which, while CRISPR can do very well, can be addressed with siRNAs, antisense, and even monoclonal antibodies. And it also allows us to comprehensively address, in a mutation-agnostic manner, entire patient populations with genetically defined disease. Now, I would be remiss not to actually mention reni-cel, which has actually demonstrated a significant, and dare I say, 100% complete response rate in treated patients. And in so doing, it has actually validated our functional upregulation treatment strategy.
It has actually validated the use in humans of AsCas12a. It has actually very specifically validated our approach to using or editing the promoter of the HBG1/2 genes to treat sickle cell disease and beta thalassemia. Indeed, our preclinical data, which I'm about to show you for HSC editing, basically demonstrates in vivo HSC editing, which leverages our gene editing expertise and actually additionally provides foundational POC for our targeted LNP platform. That combination gives us the potential to be best in class or first in class for in vivo medicine for sickle cell disease and beta thalassemia. It leverages that reni-cel experience that I've already alluded to. It demonstrates an in vivo capability for our targeting strategy of hematopoietic stem cells with our proprietary LNP.
Indeed, and importantly, it expands the total addressable population, addressing the needs of multiple segments within the sickle cell and thalassemia patient communities. So let's take a look now at the data. We have demonstrated high levels of in vivo HBG1/2 gene editing. And we've achieved that in hematopoietic stem and progenitor cells as well as hematopoietic stem cells using our proprietary LNPs, which have been optimized iteratively over the last couple of years in a novel targeting strategy in mice who have been engrafted with human hematopoietic stem cells. And it's important to remind you that that same mouse model, humanized mouse model, actually predicted the significant and meaningful efficacy of our reni-cel asset. So what does this all mean? Our LNP3 LNP actually has driven and achieved approximately 40% HBG1/2 editing in hematopoietic stem cells.
And that is associated with an induction of fetal hemoglobin in erythroid cells at a level of about 20%, which actually is meaningful. Essentially, what we have is already meaningful levels of editing and fetal hemoglobin expression for the treatment of sickle cell and beta thalassemia. Now, in developing our targeted LNP platform, we have iteratively improved our LNPs. And indeed, we saw significant improvements with an earlier LNP, LNP2. And we're so excited by the order of magnitude that it achieved in improvements in editing that we moved it to the non-human primate, even as we subsequently discovered that it was actually threefold less potent than the LNP3 delivery tool that I actually demonstrate here.
And so in the non-human primate, what we actually saw was a high degree, 80% delivery on the left to hematopoietic stem cells of our editing machine or, sorry, of GFP as a reporter gene. And that translated when we transmitted the editing machinery into an approximately 17% of HBG1/2 editing in hematopoietic stem cells. And it's important to note two things. One, this was after a single infusion. And two, this was actually seen after seven days of follow-up in an ongoing study. And I remind you again that the LNP2 moiety or LNP that we used is actually about threefold less potent than the LNP3. And indeed, that LNP3 now is in a non-human primate, and we're looking forward to sharing data. Now, our ambition extends beyond HSCs. And just last quarter, we announced a collaboration with Genevant to access their liver- tropic lipid nanoparticles.
This preclinical data provides non-human primate proof of concept that validates a high-efficiency genome editing in the liver and the first use of AsCas12a in vivo nuclease delivery to the liver. Indeed, on the left side, you can appreciate that we've seen close to maximum editing within the liver. That translates from an effectiveness point of view or activity point of view in robust reduction of the order of 70% reduction in a serum biomarker that is relevant to disease. In other words, it actually elevated the context of disease. These levels of reduction are significant and meaningful. Now, in the interest of time and space, we have additional data that I'm just going to describe at a high level on our corporate deck on our website.
But in that, in mouse, we actually have demonstrated again that our functional upregulation of a disease mitigating gene is actually significantly effective. In that case, we have upregulated a disease mitigating gene almost fourfold. And that fourfold increase in expression is also associated with a significant increase in activity, again, reducing by about 60% a downstream biochemical serum biomarker that is elevated in the context of disease. And that 60% reduction is likely to be clinically meaningful. Now, I've talked about ambition. And that ambition actually extends even beyond hematopoietic stem cells and liver. I alluded already to our targeted LNP platform, a proprietary platform that we have developed here at Editas. And what that actually comprises is two key components: a base LNP that detargets the liver through a manipulation of its chemistry and the ratios of lipids, and a targeting ligand.
That targeting ligand can actually be switched for the intentional direction of the LNP to specific cell types. What this data slide illustrates in mouse data using a GFP reporter gene is that when we use targeting moiety one, we can very precisely target a cell type, cell type one. You can appreciate that for cell types two and three, targeting moieties two and three actually direct that. For your information purposes, almost an internal control inside here is our HSC targeting moiety. What you can actually see is potent delivery in a plug-and-play way where we can intentionally redirect an LNP well to different cell types.
Now, this actually represents significant progress and really underpins our conviction that our pivot to in vivo, our pivot to functional upregulation of disease mitigating genes, and our desire to be able to deliver to different cell tissues or types in an intentional way are very robust. What this actually puts us on track, and I'll summarize it in a little while, is that our HSC targeting program, our liver functional upregulation program, are on track for INDs in the middle of this year. And it's our intention to also announce and nominate a third cell type that we can actually address with our targeting LNP. Now, obviously, this is a lot of progress, but we have to ask the question, how do we pay for this? So with the reorganization that we actually carried out just last month, we have extended our cash runway at Editas into Q2 2027.
That is based on a conservative model that does not acknowledge the possibility of potential upside from non-dilutive financing through our foundational IP. I just want to emphasize that just in the last year, we raised approximately $80 million in a non-dilutive manner through the single sublicensing to Vertex to enable the launch of Casgevy. Essentially, the combination of the value from that deal upfront, plus the monetization with a DRI deal that we announced in the second half of last year to bring in the payment stream over the following 10 years essentially gave us that $80 million. It's a really wonderful example and validation of both the validity of our foundational IP and also the value and its utility and an upside way of potential non-dilutive funding.
I do want to emphasize also that our partnerships really validate our science as well as the IP estate value and validity. What are our plans for this year, and how do they actually feed into the next three years or so? This year, as I've kind of hinted at, but I want to summarize here, we're going to declare two in vivo development candidates in the middle of 2025. We intend to establish one additional target tissue or cell type for targeting using our targeted LNP. We will obviously present in vivo preclinical editing data in more detail and as it evolves at future scientific meetings. We're obviously going to look for that potential upside I've alluded to already for deriving revenue from our foundational IP.
But all of this is actually really to support a longer-term ambition to submit at least one IND or clinical trial application by mid-2026, begin at least one human clinical trial in the second half of 2026. So we'll be dosing there and actually intend to have human proof of concept by the end of 2026. And that gives us the potential to have pivotal studies in late 2027. In addition to that, based on the data we've showed you for our targeted LNP platform, we can expand, along with our upregulation strategy, the range of diseases that are addressable with that strategic or therapeutic strategic approach. So in summary, Editas is well positioned to deliver to the investment thesis that has been troubling the editing field over the last couple of years. We are a pure in vivo company, and we've completed that transition.
We have a differentiated approach focused on functional upregulation of disease mitigating genes. We have solved for the delivery problem that enables us to actually go to multiple cell types in an intentional way and beyond simply the liver. We have a cash runway that extends into Q2 2027 with no additional upside, but the potential for that available to us. And we are well positioned to fund ourselves to human proof of concept in late 2026. We look forward to sharing more information and data as we progress. And I just want to say that we're incredibly grateful to you for your support. We're incredibly grateful to patients, physicians, and our scientists for the phenomenal work we are doing in progressing this exciting technology to transform human therapeutics.
Thank you. We'll start the Q&A session.
For those of you who are in the audience, if you have any questions, you can raise your hand. We have a runner on the floor. For those joining us virtually, you can submit questions on the portal. Gilmore, maybe just for those who are joining us virtually, maybe you can introduce the team that you have on the stage today.
Thanks very much, Brian. So I am joined on my left by Erick Lucera, our Chief Financial Officer, and Linda Burkly, our Chief Scientific Officer, who has been a phenomenal leader in advancing and building that accelerator momentum on our pipeline.
Great. Oh, there's one question.
Hi. Thanks for the talk. I just have a question regarding the LNP delivery platform. So as I--oh, I'm here. Sorry. Maybe I should introduce myself also a bit. I'm Way. My name is Way. I'm based in Boston.
I'm working for an RNA delivery technology company. We are a startup, which is less than two years old. So that's why I'm very interested in your LNP delivery technology. I'm thinking because if I understood correctly, you use proteins, right, to conjugate on the LNP for targeting. Is that correct?
Actually, I didn't specify the targeting ligand. There's a certain agnosticism. The way this is developed, it can be agnostic to the targeting ligand. We haven't specified either the ligand, the ligand chemistry, or indeed the targets. But the key thing is that we have a scalable conjugation technology that enables us to take that base LNP detargeting the liver and conjugating a ligand, whichever ligand we think is best to target a specific or desired cell type.
I see. Thank you.
Actually, about the scalability, because I also talk with other companies who do similar things for extra hepatic targeting. And scalability manufacturing is always a challenge because part of it is LNP. Part of it is actually, like you said, a ligand is a protein. So there are quite some challenges there to try to solve that. Thank you.
So obviously, we're eminently conscious of challenges. And these are areas that companies have struggled with in the past, historically. What I would say is that we're actually very happy with the progress we're making at sort of research level scale and beyond. In our organization, we have built both internal expertise and actually also engaging with external sort of an outsourced model, our ability and capabilities for scaling for the clinic.
Thank you.
Great. Maybe just--oh, there's one question in the back as well.
Hi.
I'm just wondering, as far as your LNP delivery technology, are you protected against any lawsuit between Immunovant and BioNTech, depending on how that turns out? Is that going to affect your intellectual property and your ability to use this mechanism?
Yeah. So we've actually, obviously, done our searches around that. And we are confident and obviously have built protection around our technology.
I guess just to kickstart my questions is, over the year or two, I think I even came to your Boston office, and we had this discussion about the quote unquote "functional upregulation" aspect of your approach, right? So how do you think about that, focusing on functional upregulation now that you virtually hit the strategic reset button not too long ago? So can you just kind of help us frame focusing on functional upregulation and what the potential looks like?
Let's say if we come back to the story three, four years from now, how would that look like?
Well, let me start sort of addressing at a strategic level. I do want to be very clear that our intent, as announced two years ago, was to drive this company to be a leader in in vivo. And I don't want to describe. I would not characterize our acceleration to that point of being pure in vivo as a strategic reset. That essentially has always been our long-term objective.
Obviously, we move things faster when we actually saw not only the progress in the science and our ability to basically target different cell types using our proprietary targeting LNP platform, but actually also the fact that we were able to, both in hematopoietic stem cells and in the liver, drive the upregulation both of expression and activity of disease-modifying or mitigating genes. From the point of view where we look in the long term, in the next few years, one of the things that's extraordinarily powerful about the use of human genetics in selecting our targets is that in both cases that we've described here, the first is obvious because we've described before reni-cel, we have used naturally occurring variants in the human genome that have been associated with mitigation of biological and clinical adverse events
In the case of our targeting of the promoter of HBG1/2, we actually leveraged the natural experiment, if you will, of hereditary persistence of fetal hemoglobin, which we co-inherited with the genetic predisposition to sickle cell disease or beta thalassemia significantly mitigates that pathology. Indeed, we've proven with reni-cel that that intervention with an editing approach can suppress the complications of that disease and indeed correct anemia. In the context of our liver target, we again found a natural human experiment that essentially did the same thing. We targeted regulatory elements of that gene, again, based around the observation of variants that actually drive that to get that effect. I think you're going to see more of that.
I think the other thing you expect to see in the long term will be how we select diseases by also requiring or aspiring to having biomarkers that are readily measurable in humans that can actually drive an early readout. You're going to see us focusing on diseases where there is a segment of the patient population that is actually, at the very minimum, refractory to any kind of treatment. Obviously, in general, we are looking to areas where the standard of care may still leave substantial gaps, but where that refractory segment may actually allow an approval in an aggressive timeline based on the benefit-risk profile, but then would also enable one to expand into a larger set of segments of that population without actually having to create a new molecule or new treatment strategy.
Yeah.
I would add one thing, which is, I think, which is important, which is that this strategy for upregulation is a strategy that lets us go for first-in-class and best-in-class indications because it gives us the path to a differentiated pipeline. Rather than going after knockdown approaches that others are pursuing, which is well addressed by established modalities, we can develop first-in-class and best-in-class indications where we can go after targets that others cannot go after or devise editing approaches that may be better outcomes than other approaches. So I think the path that we're seeing is a path to first-in-class and best-in-class indications.
As you think about your sickle cell beta thalassemia pipeline, I think when you look at the gene editing field, I think there's always that pushback of going for indication that have been historically the risk.
That's been the approach for a lot of the gene editing companies, and I think getting credit from an investor perspective has been difficult, right, in the last year or so. How do you kind of frame your perception of the market opportunity, particularly around sickle cell and beta thalassemia? I mean, I know that you have done a lot of work in the past while developing reni-cel, so how do you think about an in vivo approach today, and as we kind of think through how big the market opportunity is, if you can help us with that, that would be super.
Yeah. I'd be happy to. I think the key thing is that by moving to an in vivo strategy, you've already significantly altered the benefit-risk profile.
The challenge for cell therapies, even edit cell therapies, is that they are intimately tied to the requirement to use chemotherapeutic, example, busulfan conditioning therapeutic, which is toxic. It causes significant morbidity in the acute and sometimes the long term, and actually also creates, basically destroys fertility. So overall, that risk is eliminated already by in vivo. That immediately enables you to expand into multiple segments within the sickle cell and beta thalassemia patient population and actually significantly enlarges what we would call the eligible or treatable or addressable population within the United States. You see a tenth of up to 80,000 patients could be amenable. And globally, because of the simplicity of the therapeutic, instead of using a very complex patient journey, we're talking about an infusion, which can be delivered in almost any healthcare system, you massively expand the global footprint.
And even just in the context of the U.S., E.U., and GCC or Gulf states, for example, even there, you're talking about potential expansion to about three million patients. I think there was one other thing I just wanted to address. You talked about the de-risking of a target. And in many ways, historically, de-risking has been driven by pharmacological de-risking. And I think the point I was trying to make earlier in the presentation was that somewhat historically in the field, there has been a tendency in the field to go after pharmacologically validated targets. The issue, of course, if it's pharmacologically validated, there's another modality that can already address that. What we actually have shifted to, and actually we've built that in-house expertise, is to actually leverage the incredible trove of human genetics that actually de-risk targets.
And the two examples I've already given about the de-risking by hereditary persistence of fetal hemoglobin as that as a target. And then without going into the details, another, again, human variant that de-risks that liver target are essentially a key part of our approach to both de-risk, but actually address diseases that cannot be addressed by other modalities.
Maybe just kind of stepping back just to build on what you just said, right? We're expecting another tissue theme in the not-too-distant future. Just how do we think about liver plus tissue expert now, right? How do we think about your thinking around best-in-class or first-in-class? Just how do you kind of balance both too? Because you also want to make sure that this is not a risky asset in your portfolio. So how do you kind of balance both too?
Well, actually, I'm glad you asked that question because that's addressing or identifying a third cell type. So we have liver. And then with our targeted LNP, our proprietary targeting LNP platform, we have HSCs. And then we would have a third cell type. What that actually gives us is an increased optionality that is both from a strategic and therapeutic way very valuable for actually managing risk within our portfolio.
Just going back to one of the audience questions earlier around the targeted LNP, I think it's interesting to think of your approach as not just from a genetic manipulation standpoint to target the exact DNA location, right? There's also LNP targeting approach. How mechanistically can you manipulate LNP? It would be great to kind of walk through maybe just conceptually what are the key components that are important to you to develop these new targeted LNP approaches.
Yeah, sure. I can speak to that. So I think there are a few aspects of the LNP platform that we've developed that were important to seeing the success that we have for the targeted LNPs. I mean, first, we worked on optimization of the base LNP itself. And that required changes to the composition of the LNP. I think many people realize there are four components. There are multiple components to the LNP. And we needed to make optimizations to those various components in order to follow a principle that I think is in the field of detargeting the liver in order to change the biodistribution of the LNP to favor what our goal was. We also needed to add a targeting moiety to promote the uptake of this base LNP to the cell type of interest. And our first cell type of interest was the hematopoietic stem cell.
So there's a combination of getting the base formulation that one wants and then also getting the targeting moiety selection. You also have to have a conjugation chemistry that is satisfactory. So there are many different things that you have to combine in order to get this to be successful. Selecting the targeting moiety has a lot of nuances as well. So those are the various components, as best I can share them. I think we've combined all of those pieces to get this very, very, we're very excited about the level of editing we're getting in with our targeted LNP in the hematopoietic stem cell and our ability to swap the targeting moiety to get it to other specific cells. So I think we've basically validated this notion that we have a plug-and-play base LNP platform.
What is a potential new tissue type that you're thinking of?
All I can say is nice try, Brian. We actually have said that we've expressed our intent to share that with you in the middle of the year. And we're actually very confident of our path to that. But I will tell you that these are, as we move forward, it's obviously going to be a balance of viability, but also, very importantly, its validity and utility in actually expanding the therapeutic potential of our functional upregulation therapeutic strategy.
Oh, there's a question from the audience.
The question about the dose on the targeting LNPs, in the animal type embryo, you're using similar doses to the liver. Are you using similar doses to the liver, or are you seeing benefits from the targeting as you're going to the HSC? Yeah.
We're currently not really sharing the dosing levels that we're using across the different studies, but in the future, we will be doing that.
But I will say that we have been very happy with the tolerability within our non-human primate and mice.
Yeah. And the dose levels we're using.
Yeah.
Can you remind us the strength of your IP estate? And how are you planning to potentially monetize estate?
Well, I'll start, and then I'll ask Erick to build on the monetization strategy. So we actually feel very good about our IP foundational estate. And I think it's important to emphasize one thing, that we have a robust IP estate which is exclusively licensed from the Broad Institute of MIT and Harvard. I will say that some of that estate has been subject to interference, but most of that estate has not been subject to interference.
With regard to the interference, we have actually consistently prevailed, or rather, the Broad Harvard MIT have consistently prevailed at PTAB, and in the first run through the Federal Circuit Appeals Court, there is an outstanding decision there, but we actually feel very confident about the decision, and I think it's also very important to emphasize once again that we already have, from a monetization point of view, brought it before I pass to Erick, but from a validation point of view, we actually obviously licensed that IP in a sub-license that was necessary to enable Casgevy's launch, but Erick, with regard to the monetization strategy.
Thanks, Gilmore, so with respect to the monetization strategy, we really want to work with potential partners to find a solution that fits everybody's needs.
So if you look at what we did in the last year, on the one end with respect to a smaller company where we took a more traditional biobucks approach, and then on the larger end with respect to Vertex, we took something that allowed them a lot more flexibility with how they manage their P&L statements. So we're willing to take each situation based on what other companies want to do in terms of their capital needs or their P&L needs. And as you know, there's probably about 100 programs in development that need this freedom-to-operate license. About half of them are with 10 or so companies. And we look forward to having conversations with those folks and have had conversations consistently over the years.
Can you remind us just, is there a specific time frame in the stage of development of other genetic products that will be most suitable to start having that discussion with you?
It's a great question. I'd say there's really two bookends where you see the most activity. I think with early-stage companies where venture capitalists are looking to check the freedom-to-operate box, and then obviously, as you get close to commercialization, that research and development safe harbor goes away, and when you get into the stormy seas of approval and violating that willful intent and treble damages, you start seeing high levels of interest to get that settled before the first commercial sale.
Great. I think that's all the time we have. Thank you so much for your time today.
Thank you for having us.