Great. Welcome, everyone, to the next session here for the Cardiometabolic Day. Happy to have the Cellectis team, who just went through a recent interesting transition, and excited to have André Choulika , CEO, Arthur Stril, CFO and CBO, and Adrian Kilcoyne , CMO, and have them do a presentation. With whatever time is left over, we can do a short Q&A. Feel free to throw in any questions from the audience. Great. André , take it away.
Thank you very much, James. Good morning, everyone, and thank you very much for your attention. We will present Cellectis, which is developing in vivo gene editing, in this conference. We are a listed company. Cellectis has been founded as a gene-editing company. Since inception, we have been, I think, one of the first, if not the first company, that pioneered gene editing in this industry. Gene editing intervenes in the cell at the genome level, and it allows to do many type of modification, essentially shutting down the expression of a gene, activating a gene, or eventually repairing or modifying the sequence of a gene that can be either repaired or altered. Since the discovery of gene editing, gene editing has transformed science numerous ways, specifically from the scientific standpoint. A lot of the life science field have integrated gene editing as one of the main tool.
Today, we can agree that 21st century gene editing is going to be a major paradigm shift in the way people are going to be treated in medicine. When you think about all the diseases we have, for example, cancer, diabetes, obesity, neurological disorder, anything, immunity, if you are more susceptible to infection or not, or longevity, everything is the result of specific polymorphism and aberrant gene expression that leads to sensibility to diseases. It could be infectious diseases or other type of diseases. The basic logic of gene editing with these polymorphisms that every human being has, is fix the gene, and then you fix the disease. We have two pathways for gene editing. The first one was ex vivo, collect the cells, edit them under GMP condition, ex vivo, outside the body, and reinfuse them back in the human body.
This is the example of CAR T-cell, for example, in oncology or autoimmune diseases. In vivo is a different type of thinking, and this has been the recent paradigm shift in the industry. Deliver the editor directly in the body by injection, and the editor will go in the right tissue, silence, activate, or repair the target gene. Building our own ex vivo leadership to advance the next frontier is the target for Cellectis, moving into in vivo gene editing. What is in vivo gene editing? How does it work? In vivo gene editing is made by intravenous injection, but potentially it could work also by subcu, but today it is done by IV.
Single IV injection that goes inside the body, for example, goes inside the liver, goes inside the cells of the liver, and edit very specifically a gene that will make a meaningful modification that will last in the patient. If you want to think about the product, what is the product? This is the product, messenger RNA coding for a gene editor and lipid nanoparticle. Many of you probably saw a drawing like this. It's remember something, I guess. It is a COVID vaccine, like LNP was messenger RNA, messenger RNA coded, for example, for the S protein. Here it codes for the gene editor. It's one injection in this case that will go edit the gene with a long-lasting effect. We have taken the decision to push forward two preclinical candidates in dyslipidemia, and these two preclinical candidates will go into clinic very soon.
.HEAL-101, which is a messenger RNA plus an LNP, is targeting APOC3 in severe hypertriglyceridemia. The second one is .HEAL-201, same thing, messenger RNA plus LNP, very similar, but target this time PCSK9 in severe hypercholesterolemia. They're very well-validated target, APOC3, PCSK9, super well-known. Single IV injection offering potential of a long-lasting effect. Let's go to .HEAL-101, and now I'd like to pass the word to Adrian, that will give you more the idea from the indication. Adrian?
Yeah. Thank you, André. Our initial indication we decided on was severe hypertriglyceridemia. APOC3 has been traditionally very difficult to target, and while there has been some developments in this area, this is still an area of very significant unmet need. One of the big clinical issues related to this severe hypertriglyceridemia is these patients have a higher risk of acute pancreatitis, which is a very severe and potentially recurrent disease. Therefore, long-term control of these triglycerides is incredibly important. While there is some associated cardiovascular risk, of course, the main issue for these patients is the risk of acute pancreatitis, recurrent pancreatitis, and the pursuant poor quality of life and limited treatment options that are available to these.
When we're targeting this patient population, we believe that as a gene-editing therapy that can give you potentially long-lasting efficacy for these patients that do need lifelong therapy, we chose patients that are obviously very high risk of pancreatitis, those with 880 mg per deciliter or those patients greater than 500 who've had prior pancreatitis. We know both of these populations are at very high risk of a first episode of pancreatitis or recurrent pancreatitis. This is a very large patient population. 1 million- 2 million patients across the U.S. and EU would fall into this category. But in order to give you a broader view of how we've had our, what we consider our unique approach to offering a potentially long-lasting one-and-done therapy, André, you can give some details on the gene editing approach we've taken, including the preclinical data.
Thank you very much, Adrian. You will come back. The indication, as Adrian described, is hypertriglyceridemia with high risk of pancreatitis. The target, super well known, APOC3. It is not that much a druggable target because the protein is super small, so most of the time it is being validated with antisense oligonucleotide, ASOs, or RNAi, because you need to shut down the expression of APOC3, and it is th e only way to do it so far. Currently, we are developing what is called a TALE base editor . I will walk you through it. The goal is one single injection, and you reduce for a long period of time triglyceride and the risk of acute pancreatitis, and we have interesting data. I will walk you through it. This is how a base editor works. .HEAL-101 is a base editor.
It goes inside a cell, and it will find exactly the APOC3 gene, bind to it, and will convert a C into a T. There is no DNA break, and this is a change in the gene that when you look at the gene, the structure of APOC3, we are hitting exon 4, and we will do this edit to exon 4, which will introduce inside a gene a stop codon. Then the protein that is made is disabled. This protein will be degraded, and the APOC3 is not expressed. When you look at the data, the messenger RNA shuts down the gene very clearly, and there is absolutely no deletion or any kind of chromosomal aberrations. When you look at all the potential off-targets, you see that no off-target is hit by the .HEAL-101. Only the on site is modified at close to 80%.
How that translates into data, the frequency of APOC3 editing goes from 40%- 80%. However, you see the quantification of APOC3 secretion from the cell translate into an enhanced reduction of APOC3 secretion. That translate, of course, like you have a precise editing of APOC3 in humanized mice, so these mice are, like you remove the liver of the mice, and then you put a human liver inside. Then, so you see that there is no deletion or anything that would happen in the gene. You only have a very targeted base editing in vivo. You see that there is a meaningful decrease in expression of APOC3, and then, of course, a drop in triglycerides.
One of the thing that is interesting is these mice are not really sick, so we took a transgenic mice that have tens of copies of human APOC3, the human APOC3 gene, because .HEAL-101 works only on human genes. Then you see that there is APOC3, there is 70% decrease in the baseline. When you look at the triglyceride, we drop up to 76% decrease in the expression, in the presence of t riglyceride in the blood. This is a really meaningful change. Now let us go walk you through .HEAL-201. Same thing, Adrian, can you introduce this indication, please?
Absolutely. On the spectrum of dyslipidemia, you have on one side hypertriglyceridemia, which we are approaching with APOC3. But on the other end of the spectrum, we have hypercholesterolemia, which we all know is related to increased cardiovascular risk. Now, on the face of it may seem that this is a very well-served patient population with multiple therapies available. But the reality is that a very large proportion of patients fail to reach their goals. There is a number of reasons for that, from suboptimal therapy, but also compliance with therapy. We did extensive market research when we were looking at the place for a gene editing therapy within this, and it was very clear that addressing this with PCSK9 is really important.
Clinicians also immediately, with the potential for a gene editing therapy with potentially long-lasting efficacy, they could see a very clear positioning of this within the patient population. Because the patients who are very highest risk, probably greater than 60% lifetime risk of cardiovascular disease, those patients need the reassurance of durability of response. So we have identified a very key group of patients. Younger patients are a particular group that have been identified. Those who have genetic disease, premature cardiovascular disease, and continue to have elevated LDL-C despite maximal therapy. Again, this is a huge patient population. Even by targeting the very highest risk population that would really be the right patients for a gene editing therapy, the patient group is between 1 and 2 million patients across the U.S. and the European Union.
But again, our approach is differentiated and different, and André , you will take us through that.
Thank you very much, Adrian. So same as Adrian said, severe hypercholesterolemia, target PCSK9. Everyone knows very well PCSK9. It is a very well-targeted, validated target. However, the way PCSK9 has never been addressed is through epigenetic silencing of PCSK9. I will walk you through this also. It is the same thing, one-time treatment for durable lowering of LDL-Cs and reduced cardiovascular risk. I will take you also through the preclinical data. So what are TALE epigenetic modulator? A TALE epigenetic modulator will not modify the sequence of the DNA. There is no DNA sequence change. However, it will epigenomically affect the PCSK9 domain and shut down the expression of a gene without altering anything. So we have two TALE binder that will go on the PCSK9 and will methylate and acetylate the structure of the chromatin, and PCSK9 will be turned off. No change in the DNA sequence.
That translates the same way. It is not the base editor, but it is just an epigenetic modifier. Transcription is totally shut down very specifically, and you see that the PCSK9 protein is turned off very rapidly by .HEAL-201 compared to the mock, and that lasts over time, like many days after. One of the things we can ask is these epigenetic modulator can affect the rest of the transcriptome in the cell, so upregulate or downregulate other genes. You see that we have done a full transcriptome post .HEAL-201 treatment, and we show that the only gene that shows a meaningful downregulation besides all the gene inside the genome is only PCSK9. So there is no change in the rest of the transcriptome. All the genes is expressed in the cell but PCSK9.
Same thing when you take, for example, the mice, we remove the liver and put a human liver in there because it is a human gene, then what you obtain is a long-term and very r apid and durable decrease of PCSK9. One of the things that you have to keep in mind is that epigenetic modifications or the epigenetic imprinting in the human body is lasting for whole life in general, and is something that could potentially last for a long period of time for PCSK9. It depends on the level of reproduction of these cells and the durability of the epigenetic modification. With that, I would like to pass it again to Adrian to walk you through the clinical development plan.
Thanks, André. I will first talk you through the .HEAL-101 clinical development plan. You will see some consistency in how we have approached both these indication, in that each is composed of two phases. The first phase is focused on accelerated generation of first-in-human data, and that will be via an investigator-initiated trial in China. It is important to understand that this IIT, investigator-initiated trial, will be run under the new regulations which came into effect in May this year in China, which requires a fairly significant preclinical package before first-in-human data. You have already seen some of the promising preclinical data, which has been shared by André. It is also important to highlight that there will be parallel IND and CTA preparation activities, which are ongoing with a seamless transition from that initial investigator trial, in China to a phase I-b/II study, which will have a global footprint.
It is also important to understand that, as many people will know, triglyceride levels are a validated endpoint for these clinical trials. Because this is a primarily pancreatitis-driven indication, there is no requirement for a cardiovascular outcome trial. Obviously that has an important implication in terms of our path to market, what our phase II programs will look like, and of course, the time it takes for us to generate revenues. In summary, we have got a quick first-in-human data. I will talk about the timelines in a little while, what you will expect over the coming year. But if we go to the next trial, we will share a similar approach to .HEAL-201. .HEAL-201 similarly has an aggressive path to first-in-human data through an investigator-initiated trial in China. It will be looking at severe hypercholesterolemia, as we have discussed earlier.
Again, there's a significant body of patients who fail to achieve their target despite the available therapies. As I said, ongoing parallel activities in terms of IND and CTA, and we will be going with a global footprint for phase I-b/II, and that will be in those younger high-risk patients, those with severe genetic hypercholesterolemia, and of course, those patients, as we discussed earlier, with severe premature cardiovascular disease. Again, the LDL-C is a validated surrogate marker accepted by both FDA and EMA for approval. Now let's understand what you will expect emerging over the next period of time in terms of our timeline. When we talk about .HEAL-101 first, as you have seen, we have already generated significant preclinical data. We are finalizing our IIT enabling activities and ongoing interactions with the regulatory authorities.
We plan to start in Q1 of 2027 our investigator-initiated trial, which will be focusing obviously on safety and tolerability, but importantly, we will be capturing efficacy data. It's important to understand that the center we're working with, we're doing extensive modeling to allow us to start at a safe but effective dose of the product. This should lead us to a data readout in the second half of 2027. This data is important because it will show us two things. One, it will show us the efficacy, which we've seen from the promising preclinical data. Towards the end of 2027, we'll also start to see the emergence of the durability, which is really a unique aspect of this product. Durable efficacy, which again, we will start seeing by the end of the year.
When we think about .HEAL-201, w e have a similar path, but it's staggered by about four months. Whatever happens in .HEAL-101, four months later, you should see the emergence of similar with .HEAL-201. That means that we are ongoing with our IIT enabling activities, and the dose escalation phase through the IIT in China will start in the second half of 2027, with the first readout starting in the first half of 2028. Again, importantly, towards the latter part of the first half of 2028, we should start to see the emergence of the durability of response that we anticipate will be a unique characteristic of this program. There are obviously parallel activities in terms of ensuring our manufacturing is capable of supporting global demand for the product.
Again, expect really the key milestones for us are in Q1 2027, we will start our first study with a data readout in the second half of 2027. For .HEAL-201 in the second half of 2027, we will start the study with initial readouts in the first half of 2028. With that in mind, I will hand back over to André, who will give you an overview of what we consider to be our world-class gene editing capabilities.
Thank you, Adrian. Cellectis has been a gene editing company from the get-go, and we have a very differentiated gene editing platform. First of all, let's look at our gene editing companies, and there are not that many technologies that can allow to do in vivo gene editing because you need to recognize a very long site and with a very high specificity. Essentially, there is meganucleases, there is zinc finger nucleases, CRISPR, and TALEN. Cellectis covers many of the TALEN essentially that are developed for .HEAL-101 and .HEAL-201. Beside the binders, you can have the effectors, can cut DNA with a nuclease, you can edit the base with the base editor, do epigenetic modification, or have a transcription factor. Look at the comparison and Cellectis check all the boxes in there.
.HEAL-101 is essentially the base editor, while you have .HEAL-201, which is epigenetic modifiers. Competition essentially trying to target essentially one or two type of effectors. The strengths into this positioning is a very broad gene editing toolbox. The thing is that makes us strong, essentially TALE are, we believe, the most powerful technology because it binds only to DNA, a TALE, without nicking DNA, which is the case of other technologies. So no snap in DNA. The precision is to the base pair, don't have that much of a constraint of a PAM sequence, and the size of the recognition site is 32 base pair. So it's four to the 32 in term of cryptology and how powerful and the recognition site can be.
That gives them the unique advantages, which are it can target any gene modalities and change them, and also you can do hybrid tool combinations. Sometimes if you snap or cut DNA at two places, then you can have potentially some chromosomal aberrations or genotoxicity, et cetera. If you don't overlap between cutting or modifying genes, that allows you to do very interesting hybrid tools and combos into this. We'll stop here. As we said, .HEAL-101, APOC3 in severe hypertriglyceridemia. First in human H1 2027, data disclosure H2 2027, .HEAL-201, PCSK9. Severe hypercholesterolemia, it's like H2 2027, H1 2028. The partnerships that we have, AstraZeneca, Servier, and Allogene, and Iovance are continuing as they were. No change in this space.
It allows us to have a very broad surface of interaction, especially in the cell therapy space that we keep an eye on, and an implication with, that is very deep with our partner. The cash runway is into second half of 2028. Everything that is our internal cell therapy development, lasme-cel and eti-cel, there is like we're moving for partnerships, and we're currently relying all our organization towards the two priorities that we showed up here. Now I would like to open to Q&A session. Thank you very much.
Yeah. Perfect. Thank you. We are just about up on time, but maybe just a real quick one. I think investors obviously appreciate PCSK9, APOC3 very well-validated. We kind of know what proof of concept looks like there. I think also investors, especially with some of the recent data, are really appreciating the size of the LDL-C market and what PCSK9s are doing now and all the tailwinds. Probably the biggest question, and I think in the context of Arrowhead and Ionis, is in the SHTG market, what does that look like? I think specifically the question investors have with these oligos that are launching or about to launch is what the priority of treating trigs and pancreatitis is in the context of what maybe is a metabolically complex patient with multiple other comorbidities.
Just curious your thoughts quickly on expectations for those drug launches and also just sort of how you will slot into the market with those other options around.
Adrian, do you want to take this question?
Yeah. Well, for the APOC3, again, you are right, a very well-validated market. Again, we have done extensive market research in this area, seeing what is the need for a gene-editing therapy, and the message is very clear. Based on the target product profile that we have, they believe this would be the go-to product for severe hypertriglyceridemia. Because many of the available therapies need redosing, and these are often young patients redosing for life with $50,000- $70,000 per year. It is a fairly significant cost level for these patients. So they believe new patients, very clear. This probably, if we can show the level of efficacy and durability that we anticipate, that would be a best-in-class product that they say they would be happy to adopt. In terms of, there is another question, I suppose, is around the existing patients that are already doing really well. These are good therapies.
These work, their efficacy is incredibly well. Is there a potential to switch existing-
Oh, like it's freezing. Maybe I can say one thing-
-patients who are doing very well on their current is depending on what the emerging data. Oh, sorry. Go ahead, André .
Yeah. You froze for a moment. One thing people have to keep in mind, like in vivo gene editing is gene surgery, and you have to take it in the same way surgery is taken. People take pills for the rest of their life, for example, when they have prostate problems, or you can fix the prostate problem by surgery and get remain, come back as normal and be free of taking any kind of pills with an improvement in your quality of life. Second thing, for example, when people have a breast cancer potentially mutation, like in BRCA, there is the choice of going for mastectomy before the cancer develops. This is very brutal surgeries. Or, for example, for sight, et cetera. It's becoming now part of the "I'll fix the problem for the rest of my life.
I don't want to deal with taking drugs for the rest of my life.
Yeah.
Here it's the same thing for PCSK9 and APOC3. Do you want to take a drug for the rest of your life, or you prefer to take one gene surgery and over?
Yeah. No, totally makes sense. All right. We're just up on time, so I appreciate you guys taking the time to join us, and thanks everyone for listening in.
Thank you.