Great. Thanks everyone for being here. My name is Yanan Zhu, and I'm one of the biotech analysts here at Wells Fargo. It's our privilege to have Editas Medicine management team with us for our Fireside Chat here today. With me here are Gilmore O'Neill, Chief Executive Officer, and Baisong Mei, Chief Medical Officer. Thank you, Baisong, thank you, Gilmore, for being here. Thank you very much for having us. Thank you. Great. So I think, if we could, let's dive right into EDIT-301 for Sickle Cell Disease and the ongoing RUBY trial, if that's okay. Wondering how many sites have been opened, how many patients have been enrolled, and how many have been dosed? Baisong? Sure, yeah. Yeah, thanks for the question, Yanan. We shared in June, we already opened 22 sites for RUBY study and have 20 patients enrolled. And since then, we continue to activate more sites and enroll and dosing more patients. So we're very excited about the momentum for the RUBY trial and as well for EdiTHAL trial, too, for the beta thalassemia. We're looking forward to sharing data at the end of the year from our sickle cell and our thalassemia studies. Right. That's, yeah. Yeah. So you reported data previously for, I think, of data that we saw? That is correct. Right. We presented in June at EHA. We presented four patients' data from the RUBY sickle cell study, and in a webinar a couple of days later, we shared those data and data from one of our thalassemia patients in the Editas program. We're really very happy with the data we presented as seeing very robust expression of fetal hemoglobin, in excess of 40% for our first two patients in the RUBY study, with the third and fourth patients following a very similar trajectory. In addition, the first two patients at Month four to five demonstrated a correction of their anemia to normal physiological ranges. The third and fourth patients in the RUBY study followed a very similar trajectory. We also presented 1.5-month data from our thalassemia patient, first patient, in the Editas thalassemia study, and that patient again showed a trajectory of fetal hemoglobin, progression or increase that was very comparable, to that we were seeing in our sickle cell patients. So we're obviously seeing kind of consistent trajectory of fetal hemoglobin, production. Got it. I was wondering, since the presentation of those data, has there been increased interest for participation for these two studies? I'm pretty happy to say yes, and Baisong has had that- Yeah ... sort of personal interaction- Yeah with patients and physicians. Absolutely. We have a lot of interaction. I mean, we're focused on the patient community side. We have significant several-fold increase of the phone calls and emails from patient and the patient community inquiries about the RUBY study after the data release. And actually, the trend continues over the last several months since June. Yeah. Great. That's great, great to hear. Thank you. I think as we think about, you know, going forward, lovo-cel, exa-cel might get approval in the near term, how do you think those treatment centers might allocate patients to commercial versus clinical trial patients? Well, we're actually very confident that we will continue to enroll patients for a number of reasons. Baisong has himself traveled to many sites, interacted with many investigators, and has a much more personal insight into how they're feeling about that. Yeah, I have been traveling many sites over the last several months. I continue to do that. Actually, just at the end of last month, I was at the site also, and they're very enthusiastic to participate in the trial. With the momentum we have, we are very confident about our enrollment, and we do not feel any impact from this commercialization or potential commercialization for both studies. Okay, great. Great. Thanks for the color. At the year-end 2023 data update, how many patients do you think we could see? And in terms of fetal hemoglobin, could we expect that fetal hemoglobin levels in the additional patients to be in line with the level reported previous, in previous patients? Sure, yeah. So we really feel confident that with the data we see released in the last June, the past June, that we are confident that the future patients will have a similar trajectory for the total hemoglobin and the fetal hemoglobin-wise. That is based on not only the clinical data, but almost also the consistency between the clinical observation and our preclinical data. As we probably discussed, as we discussed before, we have a rational design to choose approach of in targeting the HBG1, 2 promoter region, rather than BCL11A, and then also using the AsCas12a as a, as an enzyme to do that with the preclinical data head-head comparison. So now the clinical data actually validate our preclinical findings. Indeed, you know, Baisong and I come from an R&D background, and we're hardcore empiricists. What has made us feel very good about our data, as Baisong says, is not just the consistency that we saw in the trajectory followed by those first four patients that we presented, but indeed, in the webinar and it, you know, on our website, we actually also shared a drug product editing data for the first four RUBY patients, plus an additional five RUBY patients who were yet to be dosed at that time, and for the first EdiTHAL patient, an additional two. So in all, 12 patients, drug product. Obviously, the drug product is individualized for each patient, and what was really striking, in addition to the consistency of the data we saw on the clinical side, we saw a consistent level of editing, high-level editing, you know, roughly between 80%-90%, at consistent levels across the edited drug product. All of those things come together and give us a confidence, notwithstanding that statement about being empiricists, that we are actually going to continue to see that consistent replication of data by the end of the year into the future. Got it. So does the replication also apply to the high or normalized total hemoglobin level? Well, we actually believe so. As Baisong Mei said, when you actually line up that consistency in trajectories in the clinic, you line up that consistency of editing, in the drug product, and then you look at the deliberate design and selections or choices we made, using AsCas12a, in a high-efficiency enzyme to target the gamma globin promoter, that we actually expect or, you know, anticipate seeing that consistency continue. Great. Great. Great to hear. Thank you. Do you plan to report additional efficacy measures beyond fetal hemoglobin, such as the hemolytic markers at the year-end data readout? Well, what we're actually planning to do is we'll actually talk more about what we will be sharing, the number of patients of data we'll have later, but at a time sooner and closer to the actual disclosure of those data. Got it. Got it. Do you continue to think that total hemoglobin normalization is a differentiation from CRISPR's exa-cel? I guess, you know, through your continuous dialogue with investigators in the field. Yeah, I think- Yeah. That's... Well, let me start, and then Baisong, who has been speaking a lot to investigators, but we do actually see the normalization or correction of anemia as a potential differentiator. It was a deliberate part of the design. We selected the gamma globin promoter as our target rather than the BCL11A for the very simple reason that we believed, and then our non-clinical data showed that you got better red cell output, red cell health, and red cell longevity, all pointing towards a correction of anemia. And obviously, anemia itself is an independent risk factor for end organ damage. Those two things tied together really would suggest that this will have a meaningful effect on the physiological parameters for end organs, including cardiorespiratory, etc. Then Baisong can tell you about how investigators are thinking about it and also more maybe a little about how we're thinking about our clinical trial and collecting additional data. Yeah. Yeah, certainly. Thank you, Gilmore. I think maybe I can back up a little bit for, you know, treatment in rare disease and devastating disease perspective. And Gilmore and I work on many, several different rare disease in, before life. When you get into the new disease area, which have less treatment options and no cure options in there, you focus on most important symptom. In this case, for example, sickle cell, you're talking about vaso-occlusive events. But sickle cell clinical manifestation is much more beyond vaso-occlusive events, right? They have end organ damage, the anemia, fatigue and pain and all those in there, too. So I think exa-cel have demonstrated excellent data to be able to actually manage the VOE, and patient symptom-wise. Then we're thinking about to say, "Can EDIT-101 do more than that, right? In addition to VOE, can we correct the anemia?" And as Gilmore mentioned, anemia is actually important, that factor for end organ damage, among other symptoms in there, too. So that's kind of the direction we're looking into. We hope that in the community together, keep improving the standard of care for those patient population. So I think that's the direction we're trying to go. You know, at a very high level, patients, you know, visually complain about fatigue. It's a dominant symptom when you ask patients about what they suffer from day to day with a Sickle Cell Disease, and drivers of fatigue include pain, but actually also anemia. In fact, anemia is a classical etiology for fatigue, and actually also can limit exercise tolerance and the activities of daily living. And the good news is that within our clinical program, we are collecting patient-reported outcomes, which include domains that focus on these things. Yeah, just kind of add on that is also we have interaction with investigators and KOLs. They're also very pleased to see the correction of anemia with our patients, and, so they have experience with other several people before, and they feel that it's really good that we see the correction of anemia for those patients. I think that's an important piece of which I think you asked, myself and Baisong Mei about how investigators are thinking now when they actually see potentially differentiated hematologic parameter and what the downstream effects will be and impact will be on patients. Got it. Very helpful. For the year-end data, what might be the forum? Would you be targeting ASH or? So we've kept our options open, and we'll share more of that, more detail, closer to the time. You know, for EHA, we presented both at EHA and a webinar, in last December. We did a webinar. We'll make sure that people are notified in adequate time so that everyone actually can see the data. But we're really excited, looking forward to showing those data. Great. Great. Maybe a curious question here about definition of severe VOC. There is a little bit of a controversy when ICER put out its report comparing lovo-cel, exa-cel, and said the criteria is a little different. One is more lenient, the other is more stringent, or, or at least the company's claimed as such. Mm-hmm. I was wondering, what's your take on that, and what's the stringency of your severe VOC definition? So this is something that, you know, Baisong and I have lived through our earlier careers in defining outcome measures and so on. And we've talked a lot about this, but Baisong, you have some insights to share. Yeah. Yeah. I mean, when I look into our definition of VOE, as well as lovo-cel and exa-cel, I think they are very consistent in general, that one is clinical symptom and one is require medical attention. So that's kind of the generally consistent there. There's still, you can see between lovo-cel and exa-cel, there's slightly difference in there, and so I think that's just generally consistent. And with what we have is that also require clinical, severe clinical symptom and medical attention. And we have, you know, when we develop our protocol, we have a lot of engagement with our investigators who have been in multiple different trials before, as well as KOLs. So we're very comfortable with our definition on that too. I mean, that's very important for the, for this definition because you're gonna use that definition as your inclusion and exclusion criteria, right? Then you'll use the definition for your primary endpoint in this case. I think that's certainly, I can see that attention to these, but I think it's generally consistent. Yeah, so we see a general consistency across, and then as long as there's a consistency within a protocol of what the definition is before and the definition is after- Yeah ... that really minimizes or, takes away any, any risk to the integrity of the study or the interpretability of the data. We believe with the broadly, shared, commonalities of, or overlaps with those definitions, it will still enable physicians, patients, not really payers, to actually, you know, understand the impact of the therapy. I think another important point that's, which is really important to take, is that the patients that we're enrolling in our studies are very severely affected by their disease. Indeed, we require a minimum of two events per year in the two years prior. Our patients more than exceed that. These are patients who are manifestly, visibly, profoundly impacted by their disease, and you match that against the large impact, I mean, the super impact of these, potent therapies. There really is not going to be any difficulty in actually seeing the benefit that we can give to these patients with these therapies. Got it. I was wondering also, are you still on track to engage the FDA on the sickle cell program in second half of or in the remainder of this year? What would be your focus for the meeting, and when might we hear about the outcome of the meeting? We are definitely on track, as you know, I should say, a fundamental rule that we have is that if we say we're going to do something, we're going to make sure we do it. And that's been true for a number of things, and this is one of them. And Baisong, you have obviously some- Yeah- updates here. We're absolutely on track on that. And, so we, you know, from clinical perspective, there we are thinking about get alignment with FDA with the registrational package and study design and everything in it too. So we are very much, this will be our topic in there too. And we are also very interested to see the AdCom information coming from exa-cel, which will also give us more information on that end, too. So overall, we, you know, this is an important half of the year for us with our own individualized interactions with the agency. But actually, also, I think it's going to be a very valuable experience for all of us, to actually see the AdCom on October 31st, for exa-cel. Yeah, I was going to ask you what might be focusing on at the AdCom and how that inform your development strategy? So I think there'll be two focuses, if you like broad categories. Obviously, this is the first time a therapeutic using CRISPR technology is being approved, which, by the way, it's worth pointing out, that's 10 years. Within 10 years of the publication of the original idea, which is a phenomenal timeline from a new technological idea to approval, almost unprecedented. And so we learn a lot about the FDA's views around, and indeed, the expert's view around, the benefits and the risks of CRISPR based editing. And then in the context of the disease, sickle cell itself, we'll, I get a very good sense of how people are thinking about risk-benefit, both from the FDA briefing and from the experts on the committee. And then we'd be very interested in the specifics, particularly around outlier analyses, the impact on total hemoglobin, and any what are the adverse event experience and risk-benefit calculus that the sponsor, FDA, and AdCom are thinking about? Yeah. Just to add on that, this is like the impact from our view is actually beyond sickle cell itself, right? Mm-hmm. It's actually the first time that we use the, CRISPR editing technology, that we are in the new era to actually change the chromosome of human, human cells to be able to cure the disease. So we're looking forward to that, and also very, much to see that, you know, in general, the regulatory environment is encouraging innovation, too. So we're excited about that. Got it. Very helpful. Could you comment on whether you're planning on requesting RMAT or BTD designation for 301? Yeah. So we are certainly considering multiple options on the different designation, regulatory designation. For example, we have orphan drug designation for both. We have pediatric rare disease designation for both, RUBY and EdiTHAL. We're certainly looking for other designations, and we will share the information when we have that update. We embrace the potential use of all the mechanisms that the FDA has made available- Mm-hmm. - to enable us to, you know, advance these, this product. Got it. Effectively as possible. As effectively as possible, sorry. Right. Yeah. Got it. Got it. Any thinking or update on the ex-US regulatory front? So the way we're thinking about it is that, What I would say is, if you were to describe the strategy we present or rolled out, last January, is one of simplicity and focus. And we're a small company, and we want to be sure that we focus our attention, resources, mind share, as effectively as possible. So we are focusing on, North America. We are, applying and running our clinical trials in North America. We have said before that a partner certainly is a significant potential upside for us in that they would enable us, as long as the partner has, and the partner we kind of look for, would want, would have a large footprint, would enable us to expand the availability through development, commercialization of 301, beyond the coastline of North America. Right. Right. Right. That leads into perfectly the next question, any partner interest on the program? And from your perspective, what is the right time, and what is the right structure? Yeah. So the way we look at partnerships are that, we see that certainly as a, you know, potential upside, for us as a company and also for patients around the world who are waiting for something as exciting as, EDIT-301 to treat their hemoglobinopathies. The type of partner and the timing, really, as I said, really, we want a, a large partner with a big footprint, that can actually, develop, and commercialize, beyond, North America. With regard to timing, the timing is actually, you know, there is a, a, a rather large window. Obviously, it really is going to come down to the, perfect convergence of comfort with our data. You know, one of the things that's really evolved over the last year, beyond just our generating clinical data, showing potential differentiation, but actually also more clarity around where we can see a BLA on the horizon. You know, as Baisong Mei has said, we are on target to have dosed 20 patients by the end of the year. That is a meaningful clinical... That could lead to a meaningful clinical efficacy data set. If you look at the efficacy cohort that has been accepted by regulators on both sides of the Atlantic, we're looking at an efficacy data set of about 17 patients with approximately 15-18 months of follow-up data. So you can actually see that that horizon is there. So we have all those elements, and then obviously, the perfect balancing of the commercialization plans, etcetera. So we see a window. I think it's a broad window, and I think ultimately the terms we would be interested in and the kind of structure would really come down to one that's going to optimize the availability, the access, the commercial journey, for patients around the world. Got it. Got it. Has there been any initial interest or interactions? Well, we have had. Obviously, there is always some interest in our programs. Our programs have generated interest, really, quite broadly, over the last year or so, particularly as we're moving it forward. But we would only talk about any specifics, if and when we would actually have- Got it. - a deal with a partner. Got it. Got it. Let's talk about the CRISPR patent interference case. Can you review the next steps for this interference case? Have oral presentation been scheduled yet? What is the next milestone that we should be watching for, and when is the CAFC decision expected? Yeah. So there's a lot to unpack there. So let me start at a high level, and first of all, say that, you know, we are exclusive licensors for the Cas9 and Cas12 IP from Broad Institute of MIT and Harvard. The Cas12 is the enzyme that we are using and focusing on internally for our pipeline. Cas9, we don't have programs in Cas9 in our development or our pipeline, but that IP would be required for others using Cas9 technology for human therapeutics. With regard to interference, some of that IP, not all of that IP, is subject to interference. There is other IP that is also needed that is not subject to interference. Apropos the interference, we have already had three reviews: two by PTAB, one by the appeals court. The last appeal is now going through or working its way through the appeals court, the Federal Circuit. Oral hearings have not yet been, or oral presentations have not yet been scheduled. But notwithstanding that, we would anticipate that the resolution will occur in early to mid-2024. And finally, we have prevailed in the last three, and, you know, we're optimistic and confident, indeed confident, that we will prevail again. Got it. If the PTAB decision is indeed favorable, what are your plans in terms of licensing and economics? Would the potential economics be different for a sickle cell-related license versus a non-sickle cell license, given that you are competing directly in the sickle cell space? Well, let me just clarify one thing about the impact on interference on, you know, doing deals. The key thing, first of all, is we are the patent holders. We have prevailed in every interference decision to date and therefore are in a position to license, and indeed, we are licensing. In fact, you would see one of those deals was announced just a couple of weeks ago, or had taken a licensor for their portfolio. So we are continuing to do licenses. With regard to the actual details of licenses, we would only disclose those once, if, and when we've actually finalized those and would be obviously, we'll talk about them then. Okay, great. Perhaps, just to cover the base for TDT, and the EdiTHAL study. So I was wondering, I think you said you plan to provide a clinical update to that program by year end 2023. I'm wondering, does that mean clinical data? And if so, you know, roughly how many patients can we expect, and what would be the benchmark for total hemoglobin, for your program? Do you also expect a higher total hemoglobin compared with competitor programs? Well, let me address that second part, and then I'll ask Baisong to talk about what we're going to update. With regard to our expectations, we presented the first patient from our first beta thalassemia patient for the EdiTHAL study in June. We just showed a month and a half of follow-up data, and that patient's hematologic data really followed a very favorable trajectory and was very absolutely consistent with what we were seeing with our sickle cell patients. That gives us a lot of, you know, confidence that we will see a very meaningful impact from our therapeutic. We look forward to sharing that at the end of the year. With regard to what we are going to share at the end of the year, Baisong, might want to give a- Yeah, yeah. So we shared one patient data in June for EdiTHAL. Certainly, we have more patients dosed so that in year end, we're going to have a longer follow-up for this first patient and additional data for the additional patients in there, too. And we should be similar for the RUBY study, too. Yeah. We'll have, like, longer follow-up for patients we have done before, released before then, additional patient dose in that, too. We're going to have the package in there. And certainly that when we have even 45 days of data, you know, one and a half months data in... for the EdiTHAL, we already see significant increase of the fetal hemoglobin level, right? In the beta thal, they're all actually... They don't have a sickle globin. They are all in the fetal globin level. We're very pleased to see the data about the first patient. Got it. Got it. Do you expect the gamma globin target approach could produce higher fetal hemoglobin in TDT patients compared with the BCL11A? Yeah. That, in fact, was indeed the attempt or the intent of the original design, which was to generate a robust, very durable fetal hemoglobin expression, but actually also increase red cell production. Because in the end, hemoglobin rather red cell is, you know, the hemoglobin has to be packaged in red cells. So the overall intent of design, which was universal across sickle cell and thalassemia, was to have a robust red blood cell output with the associated robust fetal hemoglobin output. So what that means is that our intent is to have a very robust total hemoglobin response, which will be driven by fetal hemoglobin, as Baisong quite correctly says. As I say, with the consistency of the data that we saw with that first patient, our non-clinical data and then, the consistency of the editing of the drug product, again, we feel that we are going to see a very robust hemoglobin response. Got it. Maybe let's talk about additional pipeline efforts. I think one of the efforts you have touched on is milder conditioning or in vivo- Mm-hmm ... therapy for sickle cell. Yeah. That, obviously, that's a very exciting area and, leading to even greater opportunity than- Yeah. ... what's already been a very big opportunity for the - Yeah Busulfan. Yeah ... bone marrow transplant, Yeah mediated- Yeah - therapy. From your vantage point... Are there, you know, you have internal effort, but I believe you also mentioned you're also looking at the development of the field, right? What's your sense of what might be the next breakthrough, or what's the most interesting technology internally or out there? And could the out, you know, the breakthrough actually come from in the just go right into in vivo editing without needing a milder conditioning in transition? Well, let me start at the end, and say that really what we're all trying to do ultimately is continue to expand the population that can actually use a frankly, curative, and I do that with air quotes, but a curative therapeutic, which is going to eliminate, with a single treatment, the symptoms and the complications of two really dreadful diseases. The very first thing we're all doing is essentially already expanding a patient population that can use the drug by moving beyond allogeneic. So if you actually think about the severe, the prevalent patient population in just the United States, just to keep it simple, you know, estimates from various, analysts and companies go between 20 to 30+ thousand patients who are suffering from the disease and waiting for therapy, who would be eligible, for a transplant, in that the benefit risk would be positive for them. Of those, about 10%-15% can find a well, adequately matched donor, which basically means that our therapeutic will already—these therapeutics already, with the limitations of Busulfan and the rigors it creates, already expands that, you know, patient population tenfold, you know, to really address the needs of most of that 22-35 thousand patients. So that's already a big step. If you look at in vivo, in many ways, in vivo is a wonderful way to eliminate the burden on the patient from the point of view of apheresis and transplantation. It actually also reduces the burden on the healthcare systems, where you don't have to worry about capacity build for your transplant centers. And the huge use of personnel and resources to bring these patients through sort of that sort of so-called vein to vein time from identification and initiation of apheresis, manufacturing, editing, and transplantation, and support post-transplantation. So then if you actually go and say, "Well, how can we further expand?" So in vivo kind of really is the ultimate expansion. And I think it's something that we've already started. You know, we have some early work. What I do want to call out, just in passing, and I return to it, is that we're delighted, we were delighted to announce, nearly five weeks ago, that our Linda Burkly had joined us as our Chief Scientific Officer, and she comes aboard as a critical catalyst to our in vivo work. One part of which we've already highlighted, with our work on HSC in vivo editing, with a validated enzyme in humans and a validated target in humans. With regard to milder conditioning, there have been a number of approaches. What is interesting is that we're really using an approach that was developed decades ago. I think the space is interesting. It has been challenging because you're always dealing with the tension of adequate conditioning, trying to make... minimize the impacts and the adverse effects, while ensuring that you adequately condition and create spaces or niches in the bone marrow for the infused drug product to actually, colonize and, mature and proliferate in. So there are a number of approaches. We have looked across, the landscape, and we actually believe that many of the evolutions in that space, CD117, for example, is one approach, would have a generalized impact across the field, because when a transplant center embraces a milder conditioning regime, it's going to generalize its use across an indication. So that's really how we think about it, right now. Got it. Very helpful. Thank you. Lastly, I was wondering if you can talk about your cash, cash runway and what major value creation catalyst could have been or will have been achieved by the end of that cash runway? So, our cash runway extends into Q3 of 2025, and that is a combination of the simplification and focus of our strategy, and a successful raise just last June, on the heels of 301 data. From a base case point of view, our future catalysts we look forward to are sharing the 301 data moving forward. As I said, an efficacy. We will have dosed 20 patients by the end of the year, which really suggests an efficacy cohort that at 18 months follow-up could be a meaningful cohort in mid-2025. And if you actually line up that with our cash runway to 2025, some critical base case catalyst events around our 301 data that makes us actually feel very good about that. In addition, there's potential upside, you know, a partnership around 301 and obviously, you know, a recognition and realization of some of the value in our IP. Got it. Thank you so much. I think that concludes the session. Thanks, Gilmore. Thanks, Baisong. Thanks very much, Yan. Lovely to talk.