Editas Medicine, Inc. (EDIT) Earnings Call Transcript & Summary

Great. Good morning, everybody. Thanks for joining us here. I'm Matthew Harrison, one of the biotech analysts at Morgan Stanley. Very pleased to have Editas with us for the next session. Before we get started, I just need to read a disclosure statement. Please note that all-important disclosures, including personal holdings disclosures and Morgan Stanley disclosures appear on the Morgan Stanley public website at morganstanley.com/researchdisclosures. We've got the full crew with us. So we have Jim Mullen, CEO; Mark Shearman, CSO; and Lisa Michaels, CMO. So very pleased to have you all here, and thanks for joining us.

I thought maybe a good place to start as you -- you recently spent some time at Cold Spring talking about some of the newer technologies that you're working on. So maybe just talk a little bit about SLEEK and why you've made some investments there and how you think that differentiates maybe versus other CRISPR technologies out there.

Thank you, Matthew, it's Mark. I'll take that question, and thanks for bringing this up. We're really excited about the technology. So SLEEK is short for SeLection by Essential Exon Knock-in. It's a technology that was developed in-house at Editas, utilizing the AsCas12a nuclease to very selectively and at high-efficiency knock transgenes into a specific locus. We published mostly on the GAPDH locus. Essentially, the technique allows you to get high-efficiency knock-in in a number of different cell types. We published data on iPSC, T cells, NK cells. And in addition to the high efficiency, you also get sort of a selective process because only those cells that have been successfully edited, meaning you get the restoration of the Exon 9 of GAPDH you get survival of those cells and therefore, transgene expression. So, we think this is a really powerful technique that is far superior to other modes of integration -- targeted integration that at least we've seen published, and we've deployed this in our iNK program as well as in our collaboration on the alpha-beta T cell program with Bristol-Myers Squibb. So it's something that we've been working on for a while that has been developed in a pretty sophisticated way and opens up a lot of possibilities for us for knocking in genes into, as I say, the GAPDH locus, but other low side as well, which adds also a factor of tunability to the expression.

Okay. Great. Good. And then one other sort of, I guess, platform question because before we get to some of the program, which I know that people want to focus on is just -- I think for investors, it's hard because there's so much innovation in gene editing, and they hear a lot about prime editing and base editing and CRISPR and other novel enzymes that potentially could be used. So maybe just talk to people about how you see sort of your platform fitting in with the variety of emerging technologies across the space.

So we utilize both the Cas9 and Cas12a nucleases, which I mentioned, that gives us a lot of optionality, whether it's in the recognition of the PAM sequence, whether it's in the nature of the double-strand break that occurs, whether it's direct or staggered. And so, that has been deployed in all of our programs to date. Yes, you're right, there's a lot of innovation taking place generally in this area, whether it's engineering, known nuclease is the way that we did with AsCas12a or whether it's the discovery of other nucleases with different properties, size and so on. I think all of that's really exciting. Obviously, we pay very close attention to all of that, including developments in either base and prime editing. And we have our own thoughts on how we could continue to innovate and participate in this essentially revolution of editing. I think at one point, you have to reduce this to practice, you have to industrialize the CRISPR-Cas systems. I think we have effectively done that now with the programs that we have in or approaching the clinic plus in the pipeline. And so, it's really just balancing the degree to which the new innovations can offer something beyond what you currently have versus reducing to practice what you have and developing the therapies that we're focusing on.

Okay. Great. Jim, just a question, I guess, for you before we put Lisa on the firing line and tell us everything about the upcoming data. You've been -- you took over as CEO. I guess it's been somewhere between 6 and 12 months now. I'm sorry, I don't remember exactly how long. But just give us your updated thoughts on the company, things that have changed, your outlook, now that you've been here for a while. And just to help investors think about what you're focused on from a high-level standpoint?

Yes. So thanks. I actually started it in mid-February, started the role. And you probably remember my first thing to focus on was recruiting a CSO, and I believe I can declare a great success in having brought in a fantastic CSO. But what I was really focused on -- in the early days, it was 2 things, really. I was trying to get underneath and understand kind of where is our -- how strong is the scientific core of the company, but then also try to put in place sort of the thinking, the discipline that I've seen in my past as you go from sort of a research companies through research and development and move on. And I think some of that had been a bit missing with my predecessors in terms of really putting in place some of the disciplines. So a lot of that's been put in place. And it helps because I'm surrounded by people like Mark and Lisa. They have lots of experience in drug development, right? So now, we've got a team that really knows what that movie looks like. So then as I think about where am I going now with this, I'm really starting to ask the question. As we look back -- and you just touched on it a little bit in your question to Mark, as we look back at the beginning of this technology a few years ago, how has it evolved? What have we learned? And what are the new ways that we can apply this technology? And therefore, what opportunities are now available to us that may not have been -- that we may not have thought about in the past, right? So that's a second piece. And then, we've got really our 3 platforms, right? I always call it our in vivo, which is the next thing you're going to quiz Lisa on for the next 20 minutes is in vivo, the ex vivo with sickle cell, which is equally exciting. And then the edited iPSC platform where we're initially focused on the iNK. Those are all sort of very different ways to apply the technology with very different opportunities. And then sort of the last point I would make is really expanding our business development collaborations. So, we've got a very strong collaboration with BMS on the -- in oncology and the T -- alpha-beta T cells, and they've been very active and they continue to expand their use of our technology in their pipeline. We're also looking -- is there a good place to -- is there a good partner there for the iNK because the IO space, as you know, is very competitive and you need a lot of expertise and a lot of throw weight. Those are really the 2 areas. And then I'd say, lastly, Mark and company are really spending a lot of time thinking about alternative delivery technology. So particularly for the in vivo, we focused on AAV heretofore, but we don't need to limit ourselves only to AAV. We think there's some other interesting opportunities there. So that probably gives you a little bit of a sense of where I spend my [ days doing ].

Great. And then maybe before we turn to Lisa, just talk about BizDev a little bit. And I mean, I know you can't tell us specifics, but maybe just in broad strokes, what are the kinds of deals that you're most hoping for? Is this -- is this a specific product collaboration? Is this a platform collaboration? Is it -- I don't know, maybe just give us some sense of the specific items that you're focused on there?

Well, in the oncology space, we do have the relationship with BMS. We'd also like to either broaden that relationship or have another broad relationship around in oncology that allows us to do a bit more collaboration, if you will, to be involved in the development and the manufacturing and potentially participate at some level of commercialization. And in part, that's also looking to continue to build and leverage our platform that we're building out in the iPSC, right? So the editing iPSCs and thinking about other cell types beyond NK. With respect to the sickle cell program, beta-cell program, our view is, or my view is we continue to progress through the clinic on our own. We can very clearly do that. Ultimately, we will want some kind of a commercial partnership outside the U.S., which probably needs you to end up with a mid late-stage development commercial partner along the way. But where we are with moving into the clinic, and that's moving along, I think the best thing to do is sort of wait until probably about this time next year to start to have those conversations after we've developed some clinical data. Yes. So those are sort of the partnerships out and partnerships in would be really looking around technologies that augment the platform, editing technologies and/or delivery technologies.

Okay. Perfect. Thank you. All right, Lisa. So for the first time, you're going to tell us every bit of data. So we don't have to wait until September 29, and we're very pleased with that. But outside of that, maybe you could just, in broad strokes, outline for people, what are we going to get? What should people be looking forward to on the 29th?

And Matthew, I was just laughing to myself sitting here and thinking about how the questions have changed so much since I joined the company last November. Because in last November, the question is, how come you haven't enrolled a patient in the trial. Those were the first questions I was getting asked. And I remind everybody that this was, unfortunately, 1.5 years later, the headline is not quite so big, but this was the very first program that went with an in vivo editing in the human body. And as a consequence of the concerns and the fact this was completely totally new when the study was first conceived, it was conceived primarily as a safety study. It is a dose-limiting toxicity study. It's very similar people are used to seeing oncology where you select the highest dose, which you believe provides some benefit without any causing any problems for the patient. And when the first patient was treated in February of last year, all of a sudden, COVID hit and everything came to a saw. And then the program came back to Editas, where most of my focus for the first couple of months was just trying to get the [indiscernible] moving, and getting patients enrolled. But one of the very first observations that we were able to make is a lot of the theoretical concerns of related safety and the CAS apparatus inside the human body. And one of the concerns was, would you have unexpected inflammation and immune responses against the CAS protein itself. And so, the trial began primarily as a safety study with the intention of just seeing whether or not we could -- we would cause harm rather than good. And the most important thing that we found in the first 2 patients was that we had perfectly adequate safety and the unexpected adverse events did not materialize. So we were able then to modify the protocol, which allowed, at that point in time, only patients who had light perception to be able to enroll in the study. So we were able in January of this year to enroll the first patient actually in the mid-dose cohort, which is the level where we were hoping that we would achieve high enough levels of editing to really start to get some clear signals that something has actually happened in the back of the eye. So the data set that we will be presenting at the end of this month includes those patients that were treated with up to 15 net months of follow-up in the first cohort and includes observations up to at least 3 months in the patients that were treated in the second mid-dose cohort. And the reason why I say that is because of the injection procedure and the fact that the blood is actually put over the area of the eye that we're intending to edit, we know it takes about 6 weeks or so to get to the maximum level of editing. The blood needs to be resorbed, so that we can start measuring efficacy. And so, we're targeting at least being able to present efficacy data through at least 3 months of collection in order to be able to demonstrate both safety, but also to see if we can uncover any signs that editing has actually occurred. And I remind people, the other thing, and so that's one of the real challenges with this particular study is unlike a TTR study or hemophilia or sickle cell disease, we can very easily measure the protein in the blood. In this particular case, we're actually subject to physiologic measurements that are really surrogate measures of editing in the back of the eye that would be indicative that we've been able to get enough protein reconstitution. And so one of the most important things that I'm looking at is to be able to show reproducibility as well as sustained effect in terms of all the measures that we're collecting.

Perfect. Good. All right. So a couple of follow-ups. I guess, first, let's talk about duration of follow-up. How important is that? I mean, I know you touched on needing sort of enough time to get to sort of maximal editing, but is 3 months enough, I guess, is the real question for the patients in the second cohort, or do you need more time to be able to see some of these other biomarkers move?

It's a very good question. And the answer is, I really don't know. We're making -- we're pretty much making an assumption that by 3 months, that would be the very first time point where I would assume I should be able to directly measure something. But the protocol does require the patients to continue for ongoing follow-up. We bring them back for most of the repeated efficacy measures every 3 months for up to a year, and then we'll continue to follow them for 12 months. Because it is a one and done, one of the things that we have as sort of a variable in these patients is how much vision did they have when they entered the trial? And what is their capability of having vision restored? And it may well have a lot to do with what the patient has experienced in the past, what we'll see in the first couple of months. But because of neuroplasticity and the high amount of variability of vision these patients they have had in their life spend, that continued follow-up will be very important to see what the clinical relevance is.

Yes. Okay, good. I want to come back to baseline vision because I think that's important, but just a couple of other direct questions. So obviously, pre-clinically, you could exercise and directly measure how much editing was achieved. You can't do that here. So can you talk about the surrogate markers you're looking at and how you're going to sort of look at those to infer what level of editing might have occurred or if there's a dose exposure relationship?

So what I know from the non-clinical work is that the concentration of the product that was delivered in both the mouse and the primate models did correlate to definite measures of how many cells were edited, as well as some correlation to protein reconstitution. So I'm having to, at this point in time, put a lot of faith in our models in both in the mouse and the non-human primate to predict that we're going to achieve similar things in the human. I've actually moved away from at this point in time trying to measure it in terms of percent editing because it's really not relevant anymore. At this point in time, it really is what level of editing is required and how many cells does a patient have that did need to be corrected to then actually result in some sort of clinical signal. We know that the direct outcome of our editing is to restore the outer nuclear layer. So we are looking and we are continuing to follow-up in a progressive manner, being able to image the back of the eye. It's probably not a sensitive measure of what we're able to do, but certainly being able to show increased thickness there would be a nice positive finding that would correlate to something that we would actually be able to show. The second one, of course, is retinal when these patients have photoreceptors that aren't really responding to light. And so, various different measures where we can actually shine light in the eye, both for patient reported as well as objective measures to see whether or not we can change responses to light when they're put on the back of the eye and whether the patient can even perceive those. Those all for me would be indicative that editing has occurred, but they probably will not correlate to an explicit 10%, 15%, 20% or 30%. And at the end of the day, that probably doesn't matter because what we're shooting for is that next higher level of can we actually measure changes in how patients perceive vision themselves. And that may well be just seeing different color flashes on the screen, or it may actually get down to more meaningful measures such as some improvement in terms of the range of vision, changes in their actual measured visual acuity or even something as simple as being able to maneuver at different levels of light where a patient may do very well in bright light and because we've modified the effect on the cones, they may actually be able to do better in dimmer situations. All of those are being collected because at the end of the day, this is sort of an exploratory evaluation of which those best measures are going to be as well as trying to correlate them in some combination of something meaningful to the patient.

I want to come back to baseline vision. And I guess the other thing is, how should investors look at the data in the context of the baseline vision of the patients? Because -- and I think you touched on this, but presumably, patients that had no or little life perception that enrolled in the study, it's going to be very difficult to get them to see significant clinical response, but maybe that's not the right way to think about it.

No, it's an interesting question. I do know that in terms of at least proof-of-concept, the expectation is that we're going to restore some sort of function in the back of the retina. The challenge in this particular disease is that most of these patients have lost their vision very early in life. We know the majority of them are actually diagnosed in infancy. They're found within the first couple of years of life. And so, there's a possibility they've never actually experienced meaningful vision. And so, one of the challenges that we do face in this is whether or not their brain has the ability to translate the signals of vision to something more meaningful. So there's a lot of variability as to when they've had their maximum loss of vision. But we are -- what we're trying to do is that because it was a safety study, the first patients enrolled are those sentinel patients who only have light perception or slightly better vision. Once those patients have demonstrated safety at each dose level, protocol is relatively open in terms of enrolling patients with different levels of blindness, but better-seeing eyes. And that allows us to explore a little bit better whether better-seeing eyes would have a more comparative -- would have a comparative or even better benefit than those who have LP. So at this point in time, I only have 6 patients really treated where we have that much -- where we have follow-up data. And it's a little bit too early to discern which patient population is the one that would be best treated with the treatment.

Okay. Last question, and then I want to make sure we spend some time on sickle cell. But what's the path forward from this data? What happens next in terms of -- do you continue to enroll more patients here? Or how many more -- I mean, I know you can't answer exactly, but like just talk to people broadly what the path forward is and how to think about this program.

This is still a complete total go. We have completed the planned dosing in the mid-dose cohort. We have already started enrolling the patients in the planned high-dose cohort. And because after the IDMC evaluation that we had the summer based upon the safety in the mid-dose adult cohort, we're also now enrolling pediatric patients. So like I said, we continue to explore higher dose levels as well as going to the younger age groups, and we're just progressing forward at the moment.

Okay. Great. Perfect. Can we talk about sickle cell? I guess there's 2 questions here. So one, there are obviously other sickle cell programs, both with gene therapy and gene editing. So what do you think is your differentiation or potential differentiation here? And then just remind people about how quickly you think you can move this program ahead.

Well, I guess I'll start with the first question. That was the second half of the question, and that is we're actively moving forward. We actually have already screened a number of different patients, and we're in the process of putting them through the steps to allow them to go to [ for research ], so that we can edit the cells. That's all going forward at the moment. And I'm just waiting for when I have the go-ahead to be able to treat my first patients in the study. So well just moving forward on that one. As to the potential differentiation, I think one of the things that's been really kind of fun for me to watch and again, how the questions have changed since November of last year where I was being asked [ that you ] so far behind bluebird, I think you even have a chance. And I think what the lesson learned from that one is that it's still early days across all the various different programs. I'm very impressed actually by the data that's come out from CRISPR Vertex. I think what it does is it suggests that the gene editing approach likely will be superior in this place, and we are right there in that horse race in order to move forward in the program. Where we differentiate from a lot of the programs is actually in our target for the inducement of hemoglobin F production. CRISPR Vertex has been targeting BCL11A as well as some of the other competitors have done and doing in this place. We're targeting because we're using the Cas12. We're able to actually target the hemoglobin B locus in an effective and efficient manner. And the value of hitting that target is that we are able to limit what is kind of a physiologically proven and safe target, basically making persistent -- hereditary persistent fetal hemoglobin production. We think there's a couple of different advantages to this one. And the first one is, at least in terms of some early data in comparison to BCL11, we do appear to be able to get higher levels of hemoglobin F. But I think also more importantly, and people are becoming more aware of is there are potential risks related to safety on which targets that you go for and how -- what level of fidelity that you have and all making sure that you don't have off-target effects. And I think by our targeting hemoglobin B locus as in mimicking something that's been well-established and it is associated with no disease in humans naturally proven so to speak. I think we have a distinct advantage that will become apparent over time.

Okay. And then I guess, just to remind everybody, you need to have some assay validation that has to occur with this program, just to remind people around time line for that? And what's that -- what removing that or resolving that will have any impact, if at all, on the clinical program?

Well, it doesn't have any impact on the clinical program now. This was always perceived to something that we needed to do in an ongoing fashion. It's not limiting my ability to move forward to patients, and we have a clearly defined plan for the assay validation, which we intend to be able to present to the agency, so that we have, quite frankly, what we're really looking at is a clinical trial that could be used for registration purposes.

Okay. And then I guess last question while we're on 301, just beta-thal, right? I think you still need to file a separate IND for that. So just remind people, if you're on track for that and how people should think about progression in thal versus sickle cell?

So we're just looking to get the IND submitted. We're still targeting the end of this year, and hopefully, we'll start enrolling patients relatively promptly next year.

Okay. Great. So we got a couple of minutes left. Maybe we could just broadly talk about iPSCs because I think that's obviously pretty interesting and a lot of work on NK cells. So maybe just the vision there and how you think about your cell line versus some of the cell lines that are in -- products that are in the clinic and what the clear sort of differentiation is for you?

Maybe I can take that. So really, the iPSC platform is taking advantage of what I described earlier, which is both the AsCas12a nuclease activity and the SLEEK technology. So our goal really is to try to address or to customize an iNK cell, which addresses what would be currently considered some of the limitations, specifically around persistence. And so, we're using a combination of knockout and knock-in technologies to come out with a series of edits. We haven't disclosed the exact combination. But in our corporate deck, you can see a couple of examples of the knockouts that we've made and then coming up at the ASH conference, we have some additional abstracts and presentations indicating some of the knock-in strategies. So people will get a sense of the direction we're going in here, and it's really a combination of a number of different strengths that we have to produce a customized iNK cell that we hope would be superior in both ADCC, CLING as well as persistence and potentially also targeting. So, that's where we're currently at. We will present or disclose more information on this program in 2022, but it's really an exciting allogenic approach for really a potential range of solid tumors, for sure.

Okay. Great. Good. Well, Jim, Lisa, Mark, thank you for being here. Thanks for the time. Very much appreciate it.

Thanks, Matt. It's a pleasure. Take care.

Bye.

Bye.