Good morning, everyone. Thank you for joining the EDIT-301 clinical update webinar. This webinar is being recorded and can be accessed in the future through this same link or through the investor section of the company's website. After the webinar, the call will be open to Q&A. To ask a question, please click the Raise Hand feature in the webinar portal. As a reminder, various remarks that we make during the presentation today about the company's future expectations, plans, and prospects constitute forward-looking statements for the purposes of the Safe Harbor Provisions under the Private Securities Litigation Reform Act of 1995.
Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC, as updated by our subsequent filings. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change. This webinar will be presented by Editas Medicine's CEO, Gilmore O'Neill, and our Chief Medical Officer, Baisong Mei. I'd now like to turn the call over to Gilmore for opening comments.
Thanks, Christy. Good morning. Thank you to you all for joining us for this webinar presentation of our accumulated clinical experience with EDIT-301. I'm excited to be here today, almost exactly one year after joining Editas, to share these additional clinical data. One year has passed since I joined Editas to lead its transition from a development stage technology platform company into a commercial stage genome editing therapeutics company. Since my arrival, we have demonstrated human proof of concept for two clinical programs. We have launched a new Editas strategy that has sharpened our focus on the execution of EDIT-301 development toward regulatory approval for the treatment of hemoglobinopathies and on the discovery of in vivo edited therapeutics for the treatment of hemoglobinopathies and other inherited diseases.
We have decreased Editas' cash burn, extending our operational runway into 2025, and we have strengthened Editas' leadership team. Since December 2022's data disclosure, we have shared that we want to continue to see rapid correction of anemia to normal physiological hemoglobin levels and fetal hemoglobin levels in excess of 40% that are well above anti-sickling threshold, and a safety profile that is consistent with myeloablative busulfan conditioning and autologous hematopoietic or CD34-positive stem cell transplant, and that treated patients are free of serious vaso-occlusive events. Before I hand over to Baisong to take you through the data, I want to share a few key takeaways from today's webinar. EDIT-301 drives early, robust correction of anemia to a normal physiologic range of total hemoglobin in as early as four months.
EDIT-301 drives robust, sustained increases in fetal hemoglobin in excess of 40%. All dosed participants, 4 RUBY and 1 EdiTHAL patient, have shown successful engraftment and have stopped red blood cell transfusion, and all four dosed RUBY sickle cell patients have remained free of vaso-occlusive events or VOEs since EDIT-301 treatment. The safety profile of EDIT-301 observed to date is consistent with myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. In addition, the trajectory of the correction of anemia and expression of fetal hemoglobin are consistent across EDIT-301-treated sickle cell and transfusion-dependent thalassemia patients at the same follow-up time points. We have seen that ex vivo editing is highly consistent across patient cells, and this gives us confidence that data from additional patients should be similar to what we have seen thus far.
These new data reinforce our belief that we have a competitive product and indeed a product differentiated, thanks to its deliberate design by rapid correction of anemia. What is the impact of these hematological outcomes on a patient? Before I turn it over to Baisong to take you through the clinical data in detail, I would like to share a short video in which Ms. Lee, a participant in the RUBY trial, will describe the impact of EDIT-301 on her life.
Hey, my name is Danielle Lee. I am here to talk about my experience with sickle cell. Having sickle cell has been a part of my life ever since I can remember. I was actually diagnosed while my mom was pregnant with me, and my experiences basically have been throughout my life, anytime I wanted to do something, I had to worry about whether I would get sick or not and end up in a hospital. You know, when I would end up in a hospital, I would have pain crisis. It would be very painful, like, and it would make the most basic everyday functions that most people take for granted. It would make it very hard and very painful for me to do, like, something simple as holding my phone in my hand or going to the bathroom on my own.
Going to the hospital when I was in L.A., I'd have to crawl to my car or, if I'm trying to avoid the hospital, like, just crawling to the kitchen to fix myself something to eat so that I can take medicine or crawling to the bathroom. You know, like, things that most people don't even think about, that was something that I had to think about. I would have to navigate quite often. Even with trying to get my education, it took me nine years to graduate from college because even though I was an honor student, I graduated magna cum laude. The minute that I would get sick, even if I had an A in the class, my teachers wouldn't understand that I was in the hospital and physically cannot come to class.
They would say things like: "Oh, well, maybe you should retake the class when you feel better." I get sick every semester. I'm not gonna feel better, you know, but I still need this degree, and, you know, I still need to pass the class. You know, trying to navigate that took nine years for me to get my bachelor's. When I try to work, I could be doing great at my job, being told by my employer that I'm doing a great job one minute, and then I end up in the hospital, and the next minute, even though they know I'm in the hospital, I'm receiving a text message saying that they're letting me go. You know, I...
It's been a journey, you know, my doctor told me about the RUBY trial, I decided to do it because I want a real chance at living my life to the fullest and pursuing my dreams. Even though it's in the early days right now, I think I made the right decision, and I'm very happy with the prospects of what the future may bring me.
Thank you, Ms. Lee, for sharing how sickle cell has affected your life and how EDIT-301 has helped you to pursue your dreams. Baisong Mei will now take you through the RUBY study and share the data that support our conclusions.
Thanks, Gilmore. Sickle cell disease is an inherited, life-threatening hematological disorder, which start to cause serious complications in early childhood. This disorder affects millions of people worldwide, including approximately 100,000 people in the United States. Sickle cell disease can result in severe anemia and the sickling-induced blood vessel blockage, resulting in unpredictable and severe attacks of acute pain, stroke, acute chest syndrome, liver disease, renal failure, and shortened lifespan. In low-income countries with no treatment, majority of sufferer will die in early childhood. In the United States, approximately 50% of patients with Sickle cell disease die before forty-five years of age. Allogeneic bone marrow transplantation can cure Sickle cell disease. Less than 20% patient can find matched donors, and there is a risk of graft-versus-host disease, a very serious complication of transplantation with stem cell from another donor.
Other approved treatment show the limited effectiveness and do not address the underlying cause of sickle cell disease, nor do they fully ameliorate disease manifestations. We believe that fetal hemoglobin expression will ameliorate the symptoms and complications of sickle cell disease. In fact, natural genetic variants in the gamma-globin gene promoter can cause hereditary persistence of fetal hemoglobin with high levels of fetal hemoglobin in red blood cells. In sickle cell patients who co-inherit hereditary persistence of fetal hemoglobin, the patients can have a reduction or absence of sickle cell symptoms. In fact, there is a high negative correlation between mobility score and the percentage of fetal hemoglobin in peripheral blood of sickle cell patient. Levels greater than 30% fetal hemoglobin are associated with significant reduction or absence of sickle cell symptoms, particularly vaso-occlusive events.
In addition, the amount of fetal hemoglobin within an individual red blood cell is important. That is called cellular fetal hemoglobin levels. When cellular fetal hemoglobin level exceeds 10 picograms per cell, it is considered clinically meaningful because it prevents that red blood cell from sickling. The choice of CRISPR enzyme and the target for editing to switch on fetal hemoglobin expression matters. AsCas12a is our proprietary, high-fidelity, high-specificity CRISPR nuclease and is very different from the Cas9 enzyme used by others. AsCas12a has demonstrated superior characteristics that increase efficiency of editing and significantly reduces off-target editing when compared to other CRISPR nuclease, including Cas9. Before Editas selected the HBG1/2 promoter as our genomic target for upregulation of fetal hemoglobin, we conducted a comprehensive head-to-head comparison between editing the HBG1/2 promoter versus editing of BCL11A.
HBG1/2 editing in human CD34-positive cells result in greater red blood cell production, normal proliferative capacity, and improved red blood cell health when compared to editing BCL11A. Using AsCas12a to edit HBG1/2 promoter should deliver on our desired drug attributes of correction of anemia and more sustained expression of fetal hemoglobin with high editing efficiency and low off-target editing. The RUBY study has been designed as a registrational study to evaluate the safety, tolerability, and efficacy of EDIT-301 for treatment of severe sickle cell disease. The RUBY study will recruit approximately 40 patients between the age of 18 and 50 years old, who suffer from severe sickle cell disease and has a history of at least two vaso-occlusive events per year for the two years prior to enrollment.
The key clinical assessment include total hemoglobin, fetal hemoglobin, and the resolution of vaso-occlusive events after EDIT-301 treatment. All four patients treated so far in RUBY study has been homozygous of sickle mutation, have suffered a high rate of vaso-occlusive events, with a median annual vaso-occlusive event rate of 4.8 for the two years prior to enrollment. Starting with safety, EDIT-301 was well tolerated by the four patient dose. All patients had successful neutrophil and platelet engraftment, with the most engraftment occurring within one month of EDIT-301 treatment. To date, the safety profile has been consistent with that of myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. No SAE were reported after EDIT-301 infusion. No AE related to EDIT-301 treatment have been observed. The first patient has had a 10-month follow-up. The second patient has had a six month follow-up period after EDIT-301 dosing.
The third and fourth patient had a two, three months follow-up. Importantly, all patients have remained free of vaso-occlusive events since treatment. Last December, we shared that patient one from the RUBY study had normal physiological levels of total hemoglobin by month five after treatment, and the fetal hemoglobin level greater than 40%. This latest data kind of shows that these levels have persisted after 10 months, reaffirms our confidence that this effect is durable. Let me take you through the data. The x-axis represented the follow-up period after infusion of EDIT-301. The y-axis represented the total hemoglobin level and the total hemoglobin value are denoted on top of the bars. The reference range of normal hemoglobin is 13.6 to 18 gram per deciliter for men, and 12 to 14 gram per deciliter for women.
It's marked by the solid bar running across the top of the graph. The hemoglobin fraction are color-coded in each bar, with the fetal hemoglobin fraction represented at the bottom of the bar in orange. Please note that prior to transplant, all patients received blood transfusion. The normal adult hemoglobin from the transfusion is represented by the gray bar. You can see that the transfused hemoglobin washes out after four to five months with disappearance of the gray bar. Patient 1's total hemoglobin reached a normal physiological level of 16.4 gram per deciliter at five months after infusion of EDIT-301. These normal levels of hemoglobin has persisted during the 10-months follow-up.
In addition, this first patient's fetal hemoglobin fraction, as shown by the orange bar, increased from 5% at baseline to 45.4% five months after treatment with the EDIT-301, and has persisted during the 10-months follow-up period. As a reminder, sickle cell patients with 30% fetal hemoglobin may have no sickle cell symptom. Patient one has remained vaso-occlusive event-free since treatment. The increase in total hemoglobin and fetal hemoglobin of RUBY patient two, three, and four follow the same trajectory as patient one. Patient two, three, and four, had six, three, and two months of follow-up, respectively. Patient two, a female, has had a normal physiological level of total hemoglobin and a fetal hemoglobin of 51% since month five, similar to patient one.
For patients three and four, not enough time had passed to show the normalization of total hemoglobin, which tends to occur in month five. This data are encouraging, show that increase in total hemoglobin and fetal hemoglobin fractions of patients three and four are following the same trajectory, seen as in patient one and two at the same time points. If patients three and four should what patient one and two achieved in months five and six, we believe that we can truly differentiate EDIT-301 in this treatment class. Patient two, three, and four have been free of vaso-occlusive events since treatment with EDIT-301. The next question is, do we see similar trajectory when EDIT-301 treats beta thalassemia, an inherited disorder characterized by severe chronic anemia that require repeated blood transfusion?
In May, we have announced that we had dosed the first beta thal patient in our EdiTHAL study. The first EdiTHAL patient experience with EDIT-301 to date resembles that of the first four RUBY patients. The patient had early successful neutrophil and platelet engraftment, and the safety profile has been consistent with that of myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. The first EdiTHAL patient has had only one and a half months follow-up, so not enough time has passed to show the normalization of total hemoglobin. Nevertheless, this data has shown that total hemoglobin and the fetal hemoglobin fraction increase at the trajectory seen in the RUBY patient at this time point. Specifically, patient one has already achieved a fetal hemoglobin fraction of 34%, representing four grams per deciliter, just one and a half months after treatment. A very encouraging result after such a short follow-up.
As you can see in this chart, we have achieved consistent ex vivo editing of around 80% for nine currently enrolled RUBY patients' cell and three currently edited EdiTHAL patients' cell. Patient one through four and patient 10 have been dosed in RUBY and EdiTHAL studies respectively. As shown earlier, all five patients have followed a very similar rate of increase in total hemoglobin and the fetal hemoglobin fraction in patient one and two, both achieving normal hemoglobin level and over 40% fetal hemoglobin by month five of follow-up. The consistency of ex vivo editing and the consistency of the associated clinical outcome, gives us confidence that data from additional patients should be similar to what we have seen so far. Patient enrollment in RUBY and EdiTHAL study remain on track.
We have 22 sites activated and 20 patients enrolled in RUBY study to date, giving us confidence in our ability to dose total of 20 patients by year-end. We have seven study sites activated and five patients enrolled in EdiTHAL study. These data support our initial clinical results shared last December. EDIT-301 drive early, robust correction of anemia to a normal physiological range of total hemoglobin in as early as four months. EDIT-301 drives robust, sustained increase in fetal hemoglobin in excess of 40%. The trajectory, correction of anemia, and expression of fetal hemoglobin are consistent across EDIT-301 treated sickle cell patients and the beta thalassemia patient at the same follow-up time points. All dosed participants, 4 RUBY patients, 1 EdiTHAL patient, have shown successful engraftment, have started red blood cell transfusion.
All four dosed RUBY sickle cell patients have remained free of vaso-occlusive events since EDIT-301 treatment. In addition, we have seen that ex vivo editing is highly consistent across patient cells. This give us confidence that data from additional patients should be similar to what we have seen so far. The safety profile of EDIT-301 observed to date is consistent with myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. Both the RUBY and EdiTHAL studies have strong positive momentum, and the enrollment remain on track. We look forward to sharing more data from more patients and the longer observation from both RUBY and EdiTHAL study at the year-end. I will turn the call back to our CEO, Gilmore.
Thank you, Baisong. As you can see, these data give us more confidence that EDIT-301 is potentially both a competitive product and a differentiated medicine that can give robust clinical benefit to patients with severe sickle cell disease and beta thalassemia. Looking beyond these exciting clinical data to EDIT-301's path to approval and launch, it is important to note that we have significant investment and strong in-house manufacturing capabilities and expertise. We also believe that at the time of launch, the vast majority of sickle cell disease patients will still be waiting to choose the best edited medicine for their treatment. I do want to emphasize that we utilize Cas12a or AsCas12a for EDIT-301. We have exclusive licenses for AsCas12a, and we do not require a Cas9 cross-license to commercialize EDIT-301.
While on the subject of Editas' intellectual property, it is worth noting that Editas controls valuable foundational Cas9 patents from the Broad Institute and Harvard University that cover the use of Cas9 in human therapeutics. These are some of the patents that we believe are most important for developing human therapeutics. Only a fraction of which, represented in gray, are currently involved in the ongoing interference process. We are always ready to license these to companies needing them to develop Cas9-based human medicines and have done so already. In closing, clinical execution and the path to commercialization for EDIT-301 are the top priorities for us. We are on track to achieve our goal of dosing 20 RUBY patients by year-end, a meaningfully sized patient cohort. We plan to engage with the FDA in the second half of this year.
We remain on track to provide additional data from the RUBY and EdiTHAL trial by the end of 2023. We remain focused on driving enrollment and dosing in the RUBY and EdiTHAL trials. We remain confident that we have not just a competitive product, but that we have a differentiated medicine that can give robust-.
Clinical benefit to patients with severe sickle cell disease and beta thalassemia, and has the potential for clinical differentiation in the long term. We are well positioned to drive EDIT-301 to regulatory filing and approval. Finally, I thank all patients, their families, the investigators, study site staff members, our CRO partners, and employees as we follow this journey to bring potent new gene editing medicines to market. Thank you very much for your interest in Editas, we are happy to answer questions. Thank you.
We will now take your questions. Gilmore and Baisong are also joined by our Chief Financial Officer, Erick Lucera, to answer questions. Please use the Raise Hand feature to join the queue.
We will now begin the Q&A session. As a reminder, please select the Raise Hand feature at the bottom of the Zoom interface to be placed in the virtual queue. Once it is your turn to ask a question, we will call on your name and ask you to unmute yourself. Our first question comes from Joon Lee from Truist.
Hey, congrats on the impressive data, and thanks for taking our questions. How much of an overlap is there between RUBY and EdiTHAL sites and the sites that are enrolling for exa-cel? For those sites with overlaps, how are physicians and patients going about deciding whether they want to get exa-cel versus EDIT-301? I have a follow-up question.
Thanks, Joon, for our question. This is Baisong. Yes, we do see our investigators have experience with other gene therapy experience in this disease area, and we do not have the specific number by the overlap, but these are the investigators that will have a good knowledge in this field and understand the gene editing and gene therapy, and it's really their efforts really helps to drive the program forward, along with our other investigators.
I think, you know, Joon Lee, one of the key things is that we are very happy with what we've seen with regard to enrollment. Our investigators are optimistic that they will continue to be able to enroll. Indeed, you know, a very good concrete metric is that we have enrolled 20 patients already, and that reflects a doubling of enrollment just since we rolled out our strategy at the beginning of the year.
You know, yes, the rate of enrollment is impressive. What's your goal for the year-end again? You know, is that something that I think you could exceed based on the current rate of enrollment?
Joon, what we, what we've guided to is that we intend to dose or have dosed 20 patients in the RUBY study by the end of the year. We're very happy with the current enrollment because that actually puts us on track with 20 patients already enrolled. That enables us to ensure that patients are prepared for transplant, are able to have their cells, their CD34-positive cells collected and edited and released in time for dosing.
Last question, is that number something that you think it would be sufficient to submit to the FDA for possibly approval in sickle cell?
You know, I think what we've said is that this is. You know, 20 patients is a clinically meaningful cohort, and the benchmark, you know, for what might be necessary, may actually be judged by looking at recently filed BLAs. I will say, obviously, that we will, you know, we'll be engaging with the agency, you know, to finalize and discuss, what is the size of the package and the data set that they'd like to see. As I say, you can look to the current benchmarks of recently filed, BLAs.
Thank you. I'll hop back on the queue.
Our next question comes from Greg Harrison from Bank of America. Feel free to unmute to ask your question.
Oh, sorry about that. Hi there. This is Mary Keeling for Greg. Thanks for taking our question and going through the data here. I guess could you add additional color to the editing decisions behind using HBG1/2 , and how this could potentially translate into patient outcomes? Maybe when do you expect to see these outcomes? Thank you.
Well, thanks very much for your question. I think the key point is. Let me answer the latter part of your question first, which is: When do you expect to see the impact of selecting that in the clinical data? We actually are seeing it. The intent was to maximize the total hemoglobin response and correct anemias in the original selection of the target. The preclinical data actually empirically compared a BCL11A editing strategy with editing of the HBG1/2. What we saw in those comparison studies was that editing HBG1/2 promoter, you know, close to that, or actually within the deletion that is most common cause of hereditary persistent fetal hemoglobin, did indeed show superior red cell output from bone marrow, better red cell health and better red cell longevity.
We anticipated or believe that that would result in a normalization and correction of anemia, with the production of hemoglobin at physiological or normal ranges in the clinic, and we have seen that. We are very happy with the clinical consistency of the data with the non-clinical data and its support of the original hypothesis for selecting HBG1/2 promoter as a target.
Great. Thank you very much.
Our next question comes from Phil Nadeau, from Cowen and Company.
Morning. Thanks for taking our questions, let us add our congratulations on the data. Just a couple of follow-up questions to the questions that were previously answered. In terms of clinical differentiation, Gilmore, we're curious to get your thoughts on what would be clinically meaningful for patients and physicians. Do you think you'd need to see long-term reduction in vaso-occlusive events to be differentiated from the other genetic thing or gene therapy approaches, or maybe a more consistent expression of fetal hemoglobin? What clinical differentiation profile do you think would be necessary for physicians to look at EDIT-301 as the most candidate?
Yeah. Thanks, Phil. I'm going to have Baisong answer the question. Baisong?
Thanks, Phil. Yeah, thanks for your question. We are currently already looking into the clinical differentiation on that. We're looking for from three category of things, and one is from hematological parameters and the lab values, for example, the total hemoglobin and among others. The second one would be looking for the end organ damage, and try where we have this endpoint to capture that. The third one, of course, is very important when the actual patient report outcome and quality of life. As Gilmore mentioned, we're starting to see the direction of differentiation by seeing the normalization of total hemoglobin.
With this normalization of total hemoglobin, with a high level expression of fetal hemoglobin, we'll see that it will change a patient life and patient already reported they have more energy after the treatment and can do a lot of things that they never could be able to done before. Also, we're looking for end organ damage, as you know, that, the anemia, as well as the sickling, will have end organ damage. Hopefully, that we will see that clinically, this normalization of the correction of anemia as well as the high level of fetal hemoglobin, and will help to eliminate the end organ damage. We are starting to see that direction. We're continuing to look more.
Thanks, Phil, and thanks for asking the question because I think the key point, obviously, is that we designed and chose the HBG1/2 promoter deliberately to differentiate, and amongst other things, drive that return to physiological levels of normal hemoglobin. As Baisong says, that is an important factor in predicting end organ health as well as patient's quality of life. Indeed, you know, data suggests that degrees of anemia are associated with different degrees of risk to end organ health. This is something that we are looking at in our trials. Indeed, we have our PROs, our patient-reported outcomes built in, and we'll be looking to the near to long-term benefits in the clinic from this return to physiological normal levels of hemoglobin.
That's very helpful. One last question from us. In terms of the benchmarks necessary for FDA filing and approval that you referenced, would you expect those, the requirements to change should a genomic medicine be approved before you submit? I guess we're all kind of curious about why exa-cel got a priority review in sickle cell disease and a standard review in beta thal, where there's already one genomic medicine approved, and wondering whether that has any implications for ultimately what the requirements for approval are of these genomic medicines when there's already one on the market.
You know, I think benchmark is always a very good place to look. You know, I think we're going to learn a lot about the FDA's evolution of its thinking as it reviews edited autologous therapies for the treatment hemoglobinopathies. We will maintain our ongoing dialogue with the agency as we look forward. Some of those questions you've asked are probably better posed to our colleagues in Bluebird and Vertex. What I would say is that from a benchmarking point of view, it is not unreasonable, it's actually very plausible for us to look to that benchmark and at least say that that gives us a broad view of what would be required.
Certainly, I think that benchmark gives us a sense of what the size of the trial, and the dataset would be, and the follow-up time.
That's very helpful. Thanks for taking our questions. Congratulations again.
Thanks very much, Phil.
Our next question comes from Jacques Villefranc from Stifel.
Hi, this is Jacques on for Dae Gon Ha. Congrats on the progress. A couple from us. First, you qualitatively mentioned markers of hemolysis showing a trend of improvement or normalization. Any additional comments there on that? That would be helpful. I had a follow-up. Thanks.
Yeah. Thanks, Jacques. Absolutely, we actually very pleased to see that hemolysis marked by markers, see that getting close to getting into the normal or close to normal for all the patients we observed, especially for the two first two patients. The third and fourth patient, already in the same direction, but of course, a little bit early. We are share more data when we have more information together.
Great, thanks. A follow-up here. On editing levels, can you comment on patient two and the editing in the peripheral blood nucleated cells? Just curious to see whether what their editing was beyond the four months. As part of your editing measurements, do you run any translocation or chromosomal rearrangement experiments? Thank you.
Yeah. Maybe I'll start with your second part of the question first. We, you know, have done the sequencing of those ex vivo editing cells. We have not found any translocation or off-target in editing that as we've seen so far. For your first part of that, we are very pleased to see that all the four patients have very good editing level for the data from the nucleated peripheral blood cells. We do see a little bit slight variation, for example, the second patient, that the first month's data is just slightly lower than the other three patients, but actually really getting up on these subsequent testing assays.
We do not feel that is significant with, you know, just variation among this patient and how this patient, How those edited cells be getting to peripheral blood.
Got it. Thanks. Very helpful, and, congrats on the progress.
Thank you.
Our next question comes from Lisa Walter, from RBC.
Oh, great. Thanks for taking our questions. This is Lisa on for Luca. First one, maybe for Baisong. Just wondering if you can add more color on using end organ damage as an endpoint. Could you give us more detail on how this would be captured, either as a primary, secondary endpoint in RUBY? Also, at what time point, would you hope to be able to capture differentiation and end organ damage? Thanks, I have a follow-up.
Yeah. Thanks, Lisa, for the question. Certainly, we are looking to from multi-organ systems on the health of those patients. From central nervous system and kidney and pulmonary and cardiovascular functions that we'll be able to see the functioning of this organ change over course. There's no specific timeframe that in the literature on how this change will happen. Within the normalization of total hemoglobin and the high level of fetal hemoglobin, we are optimistic that we will be able to see the difference in the end organ damage.
Thanks. That's, that's helpful. Just maybe another observation on the engraftment timelines. I know the RUBY trial is still maturing here, but the data so far, it appears that the time to engraftment is a bit faster than exa-cel. Just wondering if you noticed the same thing and perhaps what implications, if any, that faster engraftment could mean in terms of efficacy, safety, or overall quality of life for patients? Thanks.
Yeah. Thanks, Lisa, for the observation. We are also very pleased to see the early engraftment from both neutrophil and platelet perspective for all the four patients, actually five patients we've seen so far, including the edited patient, and we are very pleased to see that. It may be related to the editing strategy. Of course, these are early days for us to comment, but we're looking forward to see more data, and we're very pleased to see the data so far.
Thanks so much for taking our questions.
Thank you, Lisa.
Our next question comes from Rich Law, from Credit Suisse. Feel free to unmute.
Morning. Thanks for taking our question. This is Grace Hahn for Rich. I have two questions today. The first one is about exa-cel also updated, like, had updated data at EHA in both SCD and TDT. Do you see any room for clinical improvement to those results, since not all patients were VOC free or transfusion independent?
Thanks very much, Grace, for your question. You know, as always, one has to be very careful on commenting other people's data. Obviously, they know their data very well. I think there are some appropriate questions you could pose to them about where they can see improvements. What we can actually say, again, is that we made deliberate decisions when we selected our target and designed our construct. We decided to use AsCas12a as an enzyme that is differentiated from Cas9. We chose the HBG1/2 promoter over BCL11A, because we hypothesized and then non-clinically demonstrated a higher and better improved red cell output from bone marrow, better red cell health, and better red cell longevity.
Indeed, in the clinic experience to date, we have actually seen that borne out, where the clinical data are consistent with that non-clinical data, seeing robust normalization to physiologic ranges of total hemoglobin, as well as a strong fetal hemoglobin response.
Thank you. That makes sense. The second part to my question is, the FDA only granted priority review to exa-cel for SCD, but not TDT.
L ikely due to Zynteglo already approved in TDT. Do you see FDA here getting more stringent as the amendment need in these conditions decreases over time when more products get approved?
I think the only thing I can say, it's very hard to, you know, speak for the FDA. I will tell you that in my experience and Baisong's experience, you know, priority review is not necessarily tied to the standard of care, and particularly we're talking about rare diseases with innovative products. I'd really say it's very hard to comment on where the FDA is thinking or how it actually is thinking along these lines. We will be engaging with them, and we'll obviously these will be one of the things or some of the matters that we would engage with them on as we think about the path to regulatory approval for EDIT-301.
Yeah. Thank you.
Thanks very much.
Our next question comes from Jay Olson from Oppenheimer.
Hey, congrats on these results, and thank you for taking the questions. Can you just talk broadly about any read-across from FDA's acceptance of the exa-cel BLA and the priority review in sickle cell disease? Also, any feedback that you got from KOLs at EHA, and how you expect this updated data to impact the enrollment of your study?
Yeah. I'll answer the first question, then pass the second question to Baisong regarding the KOLs. With regard to the BLA acceptances, you know, this is actually a very exciting day for the field. You know, what we're actually seeing is a CRISPR-based medicine. It's the first CRISPR-edited medicine to be filed with the FDA, and to see that acceptance, I think, is a significant boost for the entire field, and it's a great day for patients, a great day for CRISPR-based medicines. With regard to the read-through, I think it kind of sets a benchmark for the kind of dataset size or size of dataset, and follow-up that the FDA would be looking for.
Obviously, that's subject to our interactions with them, but it's worth reminding you that we have enrolled 20 patients in the RUBY study and are on track to dose 20 patients by the end of the year, which it certainly was our hypothesis. Now, this recent acceptance suggests that we're well within the range of the benchmark for the kind of dataset or cohort size that the FDA would like to see. Then, Baisong, maybe talk about the KOL reaction to the data at EHA.
Yeah. Thanks, Jay. Yes, we actually received very positive feedback on the KOL from EHA. All the KOL we spoke with, they're impressed with the results and about the consistency of the results and our different approach. They said they give confidence in themselves, as well to their patient, about joining the study. That's very, very pleased to hear. One KOL also comment that Editas has been doing extremely well on our enrollment for both RUBY and EdiTHAL study, and which is also very good to hear. We are on target to dose 20 patient by year-end, and so with all this new data, certain will help us to achieve the goal.
Great. Thanks for taking the question.
Our next question comes from Tony Deng, from Barclays. Tony, your line is open. Feel free to unmute and ask your question. Maybe we'll go to the next person, and we can return to Tony. Next, we'll hear from Yanan Zhu from Wells Fargo.
Hey, thanks for taking my questions, and congrats on the data. Just first question is to follow up on a previous answer. Could you provide some additional details on hemolytic markers, such as which marker have normalized and in which patients? I'm thinking about LDH, reticulocyte count, and/or hemoglobin. Does the improvement or normalization of these markers correlate with total hemoglobin levels?
Yeah, thanks for your question, Yanan. This is Baisong. Yes, we are looking to multiple hemolytic biomarkers, including reticulocyte counts and percentage, including LDH, the bilirubin, those biomarkers. We see that, of course, we have two patients with a longer follow-up period, and the other two have a shorter follow-up period, and we see all those biomarkers going close to normal, already normalized. We're very pleased to see that, and we'll continue to monitor this patient. This is consistent with our observation of the total hemoglobin, as well as the high level of hemoglobin F.
Got it. Great to hear. Patient three and patient four seems to have higher transfused blood at baseline than patient one and two. Could you perhaps give some in- color on what underlies this difference in baseline transfused blood levels?
Yeah. Yeah, thanks, Yanan. You have very good observation. Indeed, that patients three and four, they actually have red blood cell exchange rather than blood cell transfusion. Therefore, actually, most of their hemoglobin in the baseline that we taking from the transfused blood, that's adult hemoglobin. Then the first two patient actually get red blood cell transfusion rather than exchange. That's the difference we've seen so far. Very good observation, Yanan.
What we don't believe Will have a significant impact on the data that, you know, we're seeing. Indeed, we're very happy in patients three and four to see the consistent, or rather, to see that the trajectory of fetal hemoglobin expression that they are showing at two and three months follow-up, or three and two months follow-up respectively, really is very consistent with what we've seen in our first two patients.
Yeah. Maybe I just add on that, Yanan, we discussed on that before, the baseline level of the sickle cell patient is a very tricky point, is much different from other clinical trial. You have baseline value and in there, their baseline has been impacted by many different things, and that's your observation, too. Yeah. Thank you.
Got it. Thanks, Baisong, and thanks, Gilmore.
Thanks very much, Yanan.
Our next question comes from Madhu Kumar from Goldman Sachs.
Hey, can you guys hear me?
Yes, we can, Madhu.
Okay.
Yeah.
Thanks for taking our question. Really, we have two questions. The first one is, obviously, it's early days, but how are you thinking about the kind of patient who would choose EDIT-301 over, say, exa-cel or lovo-cel? My second question is on a kind of deeper level about hemoglobinopathy space. Earlier in the year, you highlighted this kind of three-prong strategy of EDIT-301 busulfan, EDIT-301 with milder conditioning, and in vivo editing of hematopoietic stem cells. Given the kind of rapid recruitment, like, kudos to you all on that, for EDIT-301 with busulfan, how are you thinking about kind of the pace of recruitment for that program versus kind of diving into development for milder preconditioning and in vivo editing?
Yeah, thanks very much, Madhu. With regard to question one and how patients will actually choose, I think the key point is that we believe that the vast majority of patients will actually still be waiting to make their choice by the time we approve. Why do we think that? Basically because of natural patient hesitancy. Sites growing their capacity to meet the commercial demands will actually take time, as well as adjusting to a commercial, you know, edited drug paradigm. Obviously, payer negotiations and decision-making about access will be an issue that will have to evolve over the next few years. I think patients will have more data, they will have partnerships with their physicians as they look at the data as they evolve.
You know, what excites us is that, you know, the current data for us, shows that we have, at the very minimum, a very competitive product, and indeed a potentially differentiated product, with the normalization of hemoglobin that we're seeing early on. I think the next thing. I think also we will actually see an evolution of that patient population as people get more comfortable with this kind of medication. We may see younger patients, et cetera, actually leaning in as well, as they get more comfortable with the therapies. With regard to hemoglobinopathies and their strategy in general and the three prongs, you know, thanks for recognizing that the pace of recruitment for 301.
We've been certainly very pleased with that, and I think it sort of reflects, you know, how we redeployed capital with the reorganization of the company, to, you know, building our CMC capacity and recruiting. How does it impact, you know, our view of milder conditioning and in vivo? Well, we believe, if I may start at the end, that in vivo editing for hemoglobinopathies, you know, will be an important, and truly transformational, change in the use of programmable CRISPR genome editing. Simply because it will actually eliminate many of the constraints, the needs for a, you know, very well-funded healthcare system, transplant centers and apheresis. You can eliminate all of those, and obviously, busulfan conditioning, with in vivo editing is certainly the way we see it.
With regard to milder conditioning, you know, we are looking to milder conditioning and continue to evaluate that. We see that as sort of a, you know, a medium-term way to essentially reduce the burden of conditioning and immunosuppression on patients, and thus increase the overall or total eligible patient population. As I say, in vivo is, I think, the way to really truly open up the and maximize the eligible patient population for editing for the treatment of hemoglobinopathy.
Great. Thanks very much, everybody.
Thanks, Madhu.
Our next question comes from Steven Seedhouse, from Raymond James.
Hi, good morning. Thanks so much for taking the questions. First, I just wanted to ask about hemoglobin kinetics and whether for EDIT-301 and from your perspective, what you think regulators are looking for in terms of stability of the hemoglobin levels that you're seeing? If, like, even a decay from the peak you're achieving of 1 or 2 grams per deciliter would be tolerated by regulators, or if you really need to see sort of bona fide flatlining and stability at peak, of hemoglobin?
Thanks very much, Steven, for your question. You know, what I would say, first of all, is that we're actually very happy with what we've seen to date in our patients and in our non-clinical dataset when it comes to actually stability. Yes, you know, our follow-up, our longest follow-up is now 10 months. We are actually very happy to see that maintenance of total hemoglobin and fetal hemoglobin fractions. We actually also saw something similar, and we're not surprised because we saw it in our non-clinical datasets. I think the final piece will really be. We will actually see the evolutions in the FDA's thinking over the next few months as they review what we would see sort of as those benchmark BLAs when it comes to stability.
I think the only one thing I want to highlight for you as you look at the data is just be aware that, you know, day-to-day measurements of hemoglobins can actually show some milder, mild variability, one should anticipate that. What I will really end with is that we are very happy with the stability that we've seen to date in our clinical subjects and patients, and with the stability that we have seen in the non-clinical datasets that we've generated.
Okay, thanks for that. Another question I just wanted to ask separately on leukocyte count post-transplant. Could you comment on that, did that recover and remain in the normal range for at least the two patients with six or more months of follow-up? The reason I ask is because the one sickle cell patient for which we have data that's published for exa-cel did have declining leukocyte counts at each successive measurement to actually below normal range at month 12. I'm curious if that's maybe a function of gene editing or if that's an artifact or maybe a feature of that product. Thanks.
We have not shared all the detail in yet, but we are very happy to see these hematological parameters for all those patients we have dosed so far. There's no concern from our end.
Yeah, I think with regard to, you know, exa-cel patient, you probably have to talk to. We don't have enough data to be able to comment on that at all. As Baisong says, we're very happy with the engraftment kinetics that we have seen for leukocytes as well as platelets, and happy with the maintenance of those. The only thing I would say at the end is that, you know, there are reasons why we chose, and I think articulated our reasons for choosing an AsCas12a enzyme combined with the targeting of the HBG1/2 promoter. All of those are elements that we actually believe are driving what we have seen, and we're so happy to have seen in our non-clinical data, as well, what we've seen to date in our clinical dataset.
Thanks so much. Congrats on the early results.
Thanks very much, Steven.
Our next question comes from Samantha Semenkow from Citigroup.
Hi, good morning. Thanks very much for taking our questions. I wondered if you could share a bit more detail on the definition for what is an edited cell. Do both HBG1/2 need to be edited for your definition, set on both alleles, or is one site and one allele sufficient? Just following up on that, how should we think about your editing levels so far in comparison to competitor products using Cas9 in terms of both that definition as well as variability we've seen with a competitor? Thank you.
Yeah. Thanks, Sam, for your question. From the clinical data of gene editing, is the number of alleles being edited and percentage of allele being edited. Towards your question in there, too, for example, if we have 80% of allele being edited, that is possible. It's very possible that more than 80% cells has been edited in there, too. So that's the editing level. We're very happy to see the edited level for all the patients, not only the high editing of around 80%, but the consistency among all the patients. That's why we feel confident that we will be able to see the similar data from the future patients and with this editing consistency and clinical consistency outcome.
Yeah. I would add, some of that, you know, we are, we are, it's hard to comment on others' editing efficiency simply because we're not quite clear how they actually assay or measure that. We're very happy with our assays and the analytics that we use. I think very importantly, you know, sometimes they say the proof is in the pudding. We are actually looking at our, you know, consistent editing levels, which actually translate in our human patients into, you know, how would you say, consistent trajectories for expression of fetal hemoglobin, normalization of total hemoglobin to the physiological normal range. Indeed, that experience reflects what we've seen in the non-clinical setting, with a correlation between editing and the expression in vivo, in our non-clinical set.
Overall, we believe that the unique combination of AsCas12a, our high potency, high fidelity enzyme with the targeted HBG1/2 promoter and these editing levels is leading to, you know, what we call very exciting data, suggesting we certainly, at the very minimum, have a competitive product and are looking to differentiate with the normalization of hemoglobin to physiological ranges.
Thank you. That's very helpful. Just a quick follow-up, is there any biological reason why the editing efficiency could be lower in beta thalassemia versus sickle cell disease for EDIT-301? Do you expect with more patients that you'll see consistent editing across both diseases?
Thanks. We do not consider that we have a low editing efficiency for beta thalassemia patients. Our sample size is now small, but in general, it's consistent around 80%. There are always a little bit of variation when you execute in these different editing laws wise. We see the consistency among the patients within the disease as well, between sickle cell and beta thalassemia, and we are looking forward to see more data from our end, too.
Got it. Thank you very much.
Thank you, Sam.
Thanks very much. Thank you.
There are no further questions at this time. That concludes today's event. Thank you for joining. You may now disconnect.