Hey, everyone. I'm Alex Kelly. I'm one of the biotech associates on Phil Nadeau team. Thank you so much for joining us for this fireside chat with Editas Medicine as part of our 45th annual TD Cowen Healthcare Conference. Joining us from the Editas team, we have Gilmore O’Neill, the CEO of the company, and Erick Lucera, the CFO. It's a pleasure to have you both here.
Great to be here. Thanks very much, Alex.
Great. I'd like to start off relatively broadly. Gilmore, if you could maybe give us a brief overview or state of the company for Editas. What are Editas's biggest strengths, biggest challenges, and what does the company really need to do over the next 12 to 24 months to create value?
Thanks very much, Alex. Is that my phone?
Let me just sign to that.
Sorry about the noise there or the sounds. Editas is a pure in vivo focused CRISPR editing company. We have a targeting LNP delivery technology, which enables us actually to go after a number of tissues and deliver our editing machinery. We have humanly validated editing machinery with our own proprietary As Cas12a enzyme. Indeed, we actually also have clinically validated our use of Cas9 in humans as well. We have a robust targeting LNP delivery system, as well as an editing machinery. That gives us a lot of flexibility and optionality. We are focused currently on two lead assets. One is targeting hematopoietic stem cells using a target that's been validated by us with our previous ex vivo reni-cel asset in humans.
We actually also have a liver target, which is our lead liver target, which we haven't disclosed yet, but essentially is like our HSC target focused on functional regulation. That basically means that we dial up the volume or amount of a protein that's expressed that can mitigate or reduce or eliminate the effects of a disease, much like increasing the amounts of fetal hemoglobin essentially can, at the right levels, and we saw this with reni-cel, cure or totally control the complications and symptoms of sickle cell disease. That is what we are right now. We have very good and robust technology. We're making substantial progress speedily on our in vivo. Our strengths really center around our deep know-how, our experience, particularly in the sickle cell and TDT clinical space.
We have meaningful and important IP, which is valuable not just to us, but valuable to others who need it to enable their products. From an opportunity point of view, we basically have a set of ambitious timelines. We shared those at a previous meeting earlier this year, where we are targeting having those lead assets going to DC, so two DCs in the middle of the year. We plan to have at least one asset in the clinic in the middle of 2026 and are targeting human proof of concept by the end of 2026. With that, we actually have a cash runway that extends into Q2 2027. Overall, we actually feel we're well positioned from a technological point of view, from a strategic and operational point of view, and from a finance point of view.
Great. Thank you. You recently announced that you'd be discontinuing development of the reni-cel program in sickle cell disease and transfusion-dependent beta thalassemia. Can you just comment on the underlying rationale there? Was that decision primarily driven by the data itself, or was it more so driven by market considerations?
It was actually driven by a convergence of two key things. I think the first thing on a very positive point of view was that we've actually made substantial progress in advancing our capabilities to target or do in vivo delivery to hematopoietic stem cells of our editing machinery. That, by the way, was supported by what was incredibly exciting data with reni-cel. From a human proof of concept, it was incredibly robust. We effectively saw 100%, dare I say, complete responses for the patients that we had treated with reni-cel. I say we had the convergence of significant progress in moving to in vivo. The other was essentially that the cost of capital for progressing the reni-cel to approval and commercialization really just became extraordinarily high. It was that combination of events that drove us to make this decision.
It is worth pointing out that two years ago, we announced that the ultimate goal of Editas was to be a leader in in vivo editing. I will say that, if I may, and we may come back to that later, an important piece or strength for our organization is our focus, our laser focus on clearly differentiating how we use CRISPR as a therapeutic, and more specifically, how we use it to go after indications or methods that cannot be replicated by other technologies. We are essentially functionally upregulating disease mitigating proteins. We're not knocking things down. The reason we're not doing that is because siRNAs, antisense oligonucleotides, indeed, antibodies can antagonize the protein.
We feel that the real strength for us and the real potential differentiation and value creation is to focus on functional upregulation, which is what we're doing now with our pipeline.
Okay. Thank you. Just to follow up on that, could we maybe, I mean, I'd like to dig in, I guess, a little more on your in vivo editing technology. Could you maybe outline that platform and what are the key points of differentiation between you and other competitors in the space, like Beam or Intellia?
First of all, I think when we talk about the space, we really actually do not talk about competitors. We actually think about how can we actually create meaningful value for patients and investors and shareholders. That is a very important point I want to make because we are actually all trying to achieve something similar in creating meaningful value. I think the way we are actually trying to differentiate across the entire, dare I say, biopharma space is really by actually using CRISPR technology in a way to do things that other technologies cannot do. Like I said, siRNA can knock things down. Antisense oligonucleotides can knock things down. Monoclonal antibodies or small molecules can antagonize the effect of proteins. We want to move away from that, and we have, and we are with our approach to functionally upregulating proteins that can mitigate disease.
An example of that is fetal hemoglobin, where functionally increasing the levels of fetal hemoglobin mitigates or completely controls. In our hands, in our ex vivo reni-cel program, we completely controlled effectively the symptoms and complications of sickle cell disease by functionally upregulating fetal hemoglobin, which is a very wonderful example of a disease mitigating protein. We're using a similar approach in our lead liver program, where we're actually functionally upregulating protein that can actually mitigate the effects and complications of a disease. That is one key piece of our differentiation. The other approach is to actually ensure that as we choose that approach, we actually go after diseases where there is a significant unmet need, where there are effectively white space or really a real place where we believe we can create a meaningful and differentiated value proposition for patients and for the market.
Another thing that's very important to us as we move forward is we choose and select diseases where there are biomarkers. That is, easily measurable physiological or pathological biomarkers that we can actually measure and can see will change rapidly or early, so we can get early readouts. Obviously, one of the things that we actually favor also is using those diseases or graft diseases where the biomarker is not just validated in humans, but can actually be replicated in animals, so we can actually significantly de-risk as we move into the clinic.
Finally, another way we actually de-risk our selection of targets, particularly in the context where you want to differentiate from other therapies, where you do not have the luxury of pharmacologic validation of the target, is that we are using right now the power both of our computational biology group and our genetics group, as well as the incredibly well-curated and increasingly large human biobank data sets to identify natural human variants that we could replicate. In other words, what do you mean by that? There are many proteins or genes where natural human variants can actually increase the level of protein. A very good example of that is hereditary persistence of fetal hemoglobin, which if co-inherited with sickle cell disease or thalassemia, mitigates the phenotype. That was how we thought about using the HBG1/2 promoter target.
We're using a similar approach for our other programs, including the lead liver program.
Okay. Thank you. That's very helpful. You recently shared preclinical POC data for your in vivo approach. That showed efficient editing and functional upregulation of genes across a range of tissue types and animal models. I'd like to walk through each of these data sets. The first data set showed robust editing at the HBG1/2 locus and upregulation of fetal hemoglobin in mice engrafted with human HSCs. Can you just walk us through these results and their implications?
Sure. Happy to. I think one of the first things, one thing I just want to add before I even go there is that you very rightly said that we've actually demonstrated or shared data on multiple targets across multiple tissues. The reason I highlight that is because our objective and the goal we set for ourselves publicly at the beginning of last year was that we would do it with one indication in one species. We actually did it across multiple indication groups and multiple species. That gives you a sense of the pace at which we are moving preclinical. That's the first thing. Specifically to your question, we used a mouse model, which enables you to engraft or essentially place human-derived CD34 positive or stem cells into their bone marrow. In other words, those cells are in the niche in the bone marrow.
What we delivered was a series. We actually presented data showing a series of increasingly potent targeted lipid nanoparticles to deliver our editing machinery to the HBG1/2 locus or loci in those cells. What we saw was with our LNP2 that we saw a 10% efficiency in editing, which was already a log increase over what we had seen before and others had seen before. More recently, and again, we shared the same data at the same time, but more recently, we had derived data with a further optimized LNP, so-called LNP3, where we were seeing an excess of 30% editing of those human stem cells in the mouse bone marrow. That was actually really exciting and very meaningful.
Okay. Yeah. Thank you. You also recently shared data in HSCs, again, but this time it was in monkeys. Can you walk us through those results as well?
Yeah. We were so excited by when we saw the LNP2 at 10%. Remember, that's three-fold less than what we saw with LNP3, that we actually moved that LNP2 formulation into non-human primates. After seven days, and it's important to highlight that in non-human primates, you can actually evaluate or assess the state of their marrow, their bone marrow, and interrogate it without sacrificing the animals. Those animals are still alive and continue to be followed. At seven days after a single injection, we saw a mean of 17% editing. So 10% in the mouse, 17% in non-human primate, and ongoing follow-up with these animals beyond seven days of follow-up. We will be moving our LNP3 into non-human primates, and we look forward to sharing more data in the middle of the year on that.
Overall, we're very pleased with the progress that we're making and the data we're seeing as we move from mouse engrafted with human stem cells to monkey.
Two of those three monkeys experienced editing that fell slightly short of the predicted therapeutic level of 20%. What are you doing in terms of optimization to ensure you achieve supratherapeutic editing levels in subsequent experiments?
Yeah. I think the key point is I'll just rearticulate it. We actually had continued to optimize that LNP. So that's actually, or as I say, had already achieved a threefold higher degree of editing in the mice compared to the LNP2, and that's moving into monkeys. The other thing you need to know about that sort of LNP2 monkey experiment, that is ongoing. We are actually continuing to evaluate what the outcomes there would be, but we would anticipate continued increases in editing levels. Obviously, we look forward to sharing that in the future.
Great. Kind of beyond HSCs, you've also shared that data showing in vivo editing in liver cells. Could you just walk through that relevant data in monkeys and what type of target were you using there?
Yeah. I'm not going to share the target yet, but we're hoping to share that target in the middle of the year when we talk about those two DCs that we're talking about in the middle of the year, which we've set as sort of our goals and our objectives for the year. What I can tell you is that we used an LNP delivery system to the liver that enabled us to achieve high levels of editing in the monkey. Very importantly, we actually also saw, we did similar experiments in the mouse. What we were actually able to see was that by, again, editing regulatory elements of not the coding part of the gene, but non-coding regulatory elements, we could actually increase the levels, significantly increase the levels.
We actually saw a 4x increase in the levels of the protein we want to actually raise. That was associated with a greater than 60% reduction in a critical biomarker. What I would say is both the increase in the protein levels and, very importantly, the reduction in the biomarker, which is actually one of those ones that translates to humans and is predictive of human outcomes, was actually in the meaningful range, the clinically meaningful range.
Okay. The editing level you achieved in the liver was 64.9%. You said that was close to your reported theoretical maximum liver editing efficiency of 70%. Just curious how you derived that figure.
It's actually basically based on the we're targeting hepatocytes. The liver is about 70% hepatocytes and 30% other cell types, including endothelium or lining of blood vessels, epithelial linings of biliary vessels, et cetera, and obviously connective tissue cells. 70% of hepatocytes is really your theoretical maximum. It's based on that ratio of 70% - 30% hepatocyte to other cell types.
Okay. Great. In a bit more detail, could you walk us through that data in mice that showed functional upregulation and biomarker reduction that was using an undisclosed target?
Yeah. I'd be trying to summarize it. The way I think to look at it is we saw a 4x increase in the expression of the protein that we wanted to dial up. That 4x is meaningful. We would expect meaningful for looking at the literature, et cetera. Very importantly, to validate that further, we saw that greater than 60% reduction in a biomarker. That biomarker is actually relevant to pathology. That level of reduction is predictive of clinical benefit, meaningful clinical benefit.
Great. Lastly, you also showed data in mice highlighting the ability of your targeted LNPs to effectively deliver GFP to three extrahepatic cell types. Can you maybe comment on those results and what do they say about the plug-and-play potential of your LNP technology?
Yeah. Happy to. Plug-and-play is a term that we used for two things. You can plug or play your guide to determine which gene you actually want to target. In our targeted LNP technology, we essentially have created a carefully curated combination of lipids in our lipid nanoparticles that de-target the liver. We think that's important because we want to reduce the levels we deliver to the liver to reduce toxicity and, frankly, to increase the efficiency of the delivery, reduce the doses you need to do, and actually reduce cost of goods overall. We have de-targeted the liver.
What we have from a point of view of plug-and-play to get to different cell types is we have a conjugation chemistry that we use to attach different targeting moieties or ligands or molecules that will actually direct that lipid nanoparticle, which is not going to the liver, and get it to go to the cell you desire. We have a ligand that brings it to hematopoietic stem cell. We have ligands that take it to other cell types that we have not shared. The point is that with that conjugation chemistry, you can basically plug and play different ligands to go to different cell types. It was very exciting for us to see our ability to deliver high levels of GFP to those cell types. Obviously, in the context of hematopoietic stem cells, we have gone much further than that.
We have actually demonstrated that we can actually deliver editing machinery. That editing machinery can achieve already clinically meaningful and likely increasingly clinically meaningful levels of editing to hematopoietic stem cells for a target that we have already proved in humans is incredibly meaningful for the treatment of sickle cell disease or thalassemia.
Great. Just curious what the next steps are for your in vivo program. What milestones can we expect in 2025 and beyond? How are you thinking about bars of success there?
Yeah. Our milestones really are to deliver two DCs in the middle of the year, in the middle of 2025. Obviously, we'll be sharing data then. In 2026, our intent is to be in the clinic, certainly by the second half of 2026, with a first in human proved and kicking off in the middle of 2026, targeting human proof of concept by the end of 2026. Those are the critical milestones. I think some of the bars I've actually already talked about, which are essentially targeting levels of clinically meaningful levels of editing and actually also downstream biomarker success or change. In our liver program, I've highlighted that looking at that 60% reduction is actually really important. In the context of hematopoietic stem cell editing, we have a sense of what is clinically meaningful.
The bar based on our evaluation of the literature on allogeneic transplantation is that somewhere between 20%-30% editing of the cells, hematopoietic cells, is actually going to be meaningful, clinically meaningful, and highly likely to control or eliminate occlusive events and other complications for sickle cell disease. That, by the way, is based not on just pulling it out of the air. That is based on carefully curated literature review for allogeneic transplant, where obviously healthy cells have been transplanted to individuals with sickle cell disease, for example.
Okay. It's helpful. Thank you. It appears that one of the initial indications you'll be focusing on will be sickle cell disease along with beta thalassemia. Is there any meaningful read-through from the reni-cel program here? What can those prior results tell us about the probability of success there?
Yeah. I think the read-through, there are several read-throughs. The first is that AS Cas12a, which is our proprietary high-fidelity, high-efficiency enzyme, has been validated in humans and has really behaved extraordinarily well or performed very well. The second is that the actual guide RNA that we're using to target the HBG1/2 promoter for our in vivo program, we've actually already validated again in humans with clinical readouts. We believe that that actually there's significant important read-through. Obviously, in addition, sort of more on the softer side is we have robust relationships with patients, advocacy organizations, as well as the clinical trial sites and experts around the world.
Great. I think you touched on this earlier, but why do you see your approach of targeting HBG12 locus and using the As Cas12a enzyme as superior to competitor approaches, which use BCL11A and Cas9?
Essentially, we hypothesized that it would be superior, probably likely because not only could you actually get robust functional increases or upregulation in the levels of fetal hemoglobin, but we actually also hypothesized that you would actually correct anemia, which is an important comorbidity, if you will, of sickle cell disease. I'm just going to focus on sickle cell disease. Indeed, we actually expected that robust fetal hemoglobin upregulation to have a substantial impact on potentially creating superior outcomes from a hemoglobin and anemia correction point of view in thalassemia. That was our hypothesis. We actually saw that in vivo in preclinical animals. I would say that we actually validated that hypothesis completely when we went actually into humans.
We actually saw robust functional upregulation of fetal hemoglobin, robust control of vaso-occlusive events, and this was, I think, an important what I would say differentiation correction of anemia in our sickle cell patients and very robust high levels of total hemoglobin levels in thalassemia patients.
Okay. You've mentioned that outside of sickle cell and beta thalassemia, you're aiming to use your in vivo functional upregulation approach against an undisclosed liver target. How are you approaching this program and what could be some interesting disease areas?
What I would say is that from a how we're approaching again is that functional upregulation using natural variants in the human biobanks to essentially de-risk and validate those targets, increasing also telling us degrees of levels that we need to achieve. That's one approach. When you talk about disease areas, obviously, the beauty of the plug-and-play nature in the context of liver of the guide is once we've actually got a robust clinical data set, we can change 20 nucleotides on the guide and change the spacer targeting. We can across the genome and therefore then more rapidly pivot to additional indications.
Within the context of undisclosed targets, we've been very clear that in addition to all the other elements I've highlighted about translatability, early readout biomarkers, human validation at a genetic level, we're also very interested in looking beyond just rare disease, but actually looking at segments of patient populations where the benefit-risk and unmet need is so robust that you have a clear, a very simple benefit-risk argument. We have a potential to move beyond that segment, post that first approval, if you will, through life cycling without having to change a new molecule. The beauty of it is we can actually expand within the context of a molecule while getting the benefits of a more rapid approval mechanism.
At the same time, we can actually also expand beyond once we've validated that delivery by essentially tweaking or changing the guide RNA sequence and move into new indications.
Great. Thank you. Do you have any plans to pursue kind of alternate approaches beyond functional upregulation?
The beauty of CRISPR is that it is a very powerful tool. It can be used in a number of different ways. Each one of those approaches has its strengths and weaknesses. There are areas where it is fit for purpose for different, where I say, disease areas or genetic lesions. The power of functional upregulation, which is our primary focus currently, is that it's clearly highly differentiated. Very importantly, it can actually embrace or target the totality of a disease population, whereas some of the other approaches where there is a diversity of genetic lesions for a given disease may actually have to walk across or correct different pieces, which requires a more complex clinical trial and discovery approach. All very valid. Don't get me wrong.
Our focus on functional upregulation allows us to actually cover a panoply or be agnostic to a given genetic lesion within the context of a genetic disease.
Thank you. I'd like to pivot to IP for a second here. In December 2023, Vertex and CRISPR licensed your Cas9 IP following Cas9's approval in sickle cell disease. Do you view this deal as establishing a new precedent in the field of genetic medicine? Will the majority of future Cas9 approvals lead to similar licensing deals?
Eric, I've dominated the airwaves here. I'm going to let Eric address that.
Yeah. Thanks for the question. We've done a number of Cas9 licenses in addition to what we've done with Vertex. Going back to our deal with Bristol Myers , we did a deal with Vora Biotech. I think what we try to do is take a real bespoke approach to structuring deals that work not only for us, but also for them. I'd say what we saw with Vertex was what we would expect in terms of a freedom-to-operate license for someone that's about to be launching a product. Whereas if something's earlier in development, there's obviously going to be some amount of discounting for time value of money and probability of success. It's really a range of options.
Okay. How many of those development stage programs could potentially require a freedom-to-operate license? Also, maybe across how many companies do you think those programs are?
We think there's about 100 programs in development, half of which are at about 10 companies, which I'm sure you know and love.
If you could maybe just walk through expectations in terms of how you think these deals might impact Editas's revenues moving forward.
Yeah. I mean, without commenting on any specific deals, I'd say the way we think about it is that any traditional freedom-to-operate license, whether it's Kabili or the Dyax phage display, is sort of a low single digit. We look at a range of consensus estimates from which to apply those royalty rates to. We discount it at a market rate currently around 10%. That's sort of what the economic pie is. We just sort of think about how do we divide that up in terms of upfront milestones or annual payments.
Again, without going to specifics, you asked how does this impact our revenues. Obviously, one of the things that Eric and the leadership team was actually finding a way not just to set the precedent of the Vertex deal, but then actually to further monetize it in an accelerated way through the deal that we did with DRI, which I think was a very important additional leverage.
We were able to monetize the annual license payments with DRI.
Very helpful. Yeah. It looks like we're about to wrap up here. In this final minute and a half, is there anything else that you'd like to bring up in the pipeline or more broadly that you think investors should know?
I think the key thing is that with our focus on in vivo, I think that puts us in a very robust position, particularly with the goals to have DCs in 2025, human POC by end of 2026, and cash into Q2 2027. I think that puts us in a good position, notwithstanding the environment in which we are living today. I think the only other point I want to emphasize is that we're very conscious of what a market and what the commercial opportunity has to be. Obviously, you have to have a large public health impact. That way, you create value for patients and shareholders. I do want to say one thing about particularly as people look about sickle cell disease with thalassemia, we believe, and I think many believe, that there is a real market there.
There is a real need for patients to get significant impact. We believe that this in vivo approach is the right medicine to bring forward and really has substantial opportunity to reach a far greater number of patients because the benefit-risk profile is going to be very different from a cell therapy requiring busulfan. Actually, it is also much simpler. You do not have to harvest cells or transplant. You basically can use healthcare systems across the nation and across the world because you are talking about an injection or an infusion, not a complex one-year journey for the patient. I just want to make that a very important point to emphasize as a way to show how in vivo can really be a significant game changer as we bring CRISPR therapeutics to really bad diseases.
Great. Gilmore, Eric, thank you so much.
Thank you very much. Thanks for having us. Thank you for.