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

Good morning, everyone, and 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 Investors section of the company's website. After the webinar, the call will be open to Q&A. [Operator Instructions]. 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, Cristi. Good morning, and 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 1 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 2 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 EDITHAL therapeutics for the treatment of hemoglobinopathies and other inherited diseases. And we have decreased Editas' cash burn extending our operational runway into 2025, and we have strengthened Editas' leadership team. Now since December 2022's data disclosure, we have shared that we would want to continue to see rapid correction of anemia to normal physiological hemoglobin levels and fetal hemoglobin levels in excess of 40%. They are well above anti-sickling threshold and a safety profile that is consistent with myeloablative busulfan conditioning and autologous hematopoietic or CD34+ 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 4 months. EDIT-301 drives robust sustained increases in fetal hemoglobin in excess of 40%. All dosed participants for RUBY and 1 EDITHAL patient have shown successful engraftment and have stopped red blood cell transfusion. And all 4 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. And we have seen that ex vivo editing is highly consistent across patient cells. And this give 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. But 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. [Presentation]

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 will now take you through the RUBY study and share the data that supports our conclusions.

Thanks, Gilmore. Sickle cell disease is an inherited life-threatening hematological destroy, 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 the blood vessel blockage resulting 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 who suffer will die in early childhood. In the United States, approximately 50% of patients with sickle cell disease die before 40 year -- 45 years of age . Allogeneic bone marrow transplantation can cure sickle cell disease, but less than 20% patients can find matched donors and there is a risk of graft with host disease. A very serious complication of transplantation with stem cell from another donor. Other approved treatment shows 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 variance 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 a hereditary persistence of fetal hemoglobin, the patient can have 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 patients. Levels greater than 30% fetal hemoglobin are associated with significant reduction or absence of sickle cell symptoms, particularly by cell occlusive events. In addition, the amount of fetal hemoglobin within an individual red blood cell is important. That is called corpuscular fetal hemoglobin levels. When corpuscular 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 nucleus 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 and nucleus, including Cas9. Before Editas selected HBG1/2 promoter as our genomic target for upregulation of fetal hemoglobin, we conducted a comprehensive head-to-head comparison between editing HBG1/2 promoter versus editing BCL11A. HBG1/2 editing in human CD34+ cells result in greater red blood cell production, normal proliferative capacity and improve red blood cell health, when compared to editing BCL11A. Therefore, using AsCas12a to added 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 age of 18 and 50 years old who suffer from severe sickle cell disease and has a history of at least 2 vaso-occlusive events per year for the 2 years prior to enrollment. The key clinical assessments include total hemoglobin, fetal hemoglobin and the resolution of vaso-occlusive events after EDIT-301 treatment. All 4 patients treated so far in RUBY study has been homozygous of sickle mutation have suffered high rate of vaso-occlusive events with a median annual vaso-occlusive event rate of 4.8% for the 2 years prior to enrollment. Starting with safety, EDIT-301 was well tolerated by the 4 patient dosed. All patients had successful neutrophil and platelet engraftment with the most engraftment occurring within 1 month of EDIT-301 treatment. To date, the safety profile has been consistent with that myeloablative busulfan conditioning and autologous hematopoietic stem cells transplant. No SAE were reported after EDIT-301 infusion. No AE related to EDIT-301 treatment have been observed. The first patient has had 10 months follow-up, the second patient has had a 6-month follow-up period after EDIT-301 dosing. The third and fourth patient had 2, 3 months follow-up. Importantly, all patients have remained free of vaso-occlusive events since treatment. Last December, we shared that patient 1 from the RUBY study had a normal physiological levels of total hemoglobin by month 5 after treatment and the fetal hemoglobin level greater than 40%. And this latest data card shows that these levels have persisted after 10 months, refirms our confidence that this effect is durable. Let me take you through the data. The X axis represented the following-up period after infusion of EDIT-301. The Y axis represent the total hemoglobin level and the total hemoglobin value 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, is 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 representing the bottom of the bar in orange. Please note that prior to transplant, all patients receive 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 4 to 5 months with the disappearance of the gray bar. Patient's first total hemoglobin reached a normal physiological level of 16.4 gram per deciliter at 5 months of the infusion of EDIT-301. These normal levels of hemoglobin has persisted during the 10 months follow-up. In addition, these patients -- this first patient fetal hemoglobin fraction as shown by the orange bar increased from 5% at baseline to 45.4% 5 months after treatment with EDIT-301 and has persisted during the 10-month follow-up period. As a reminder, sickle cell patients with 30% fetal hemoglobin may have no sickle cell symptoms. Patient 1 has remained vaso-occlusive event free since treatment. The increase in total hemoglobin and fetal hemoglobin of RUBY patient 2, 3 and 4 follow the same trajectory as patient 1. Patient 2, 3 and 4 had 6, 3 and 2 months of follow-up, respectively. Patient 2, a female, has had a normal physiological level of total hemoglobin and fetal hemoglobin of 51% since month 5, similar to patient 1. For patients 3 and 4, not enough time have passed to show the normalization of total hemoglobin which tends to occur in month 5. However, this data are encouraging show that increase in total hemoglobin and fetal hemoglobin fractions of patients 3 and 4 are following the same trajectory seen as in patient 1 and 2 at the same time point. If patients 3 and 4 showed what patient 1 and 2 achieved in month 5 and 6, we believe that we can truly differentiate EDIT-301 in this treatment class. Patient 2, 3 and 4 have been free of vaso-occlusive events since treatment with EDIT-301. So the next question is, do we see similar trajectory when we -- when EDIT-301 treats beta-thalassemia and inherited disorder categorized by severe chronic anemia that require repeated blood transfusion. In May, we have announced that we had dosed the beta-thal patient in our EDITHAL study. The first EDITHAL patient experience with EDIT-301 to date resembles that of the first 4 RUBY patients. The patients have early successful neutrophil and platelet engraftment and the safety profile has been consistent with that of myeloablative busulfan conditioning and autologous hematopoietic stem cells transplant. The first EDITHAL patient has had only 1.5 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 fetal hemoglobin fraction increase at the trajectory seen in the RUBY patient at this time point. Specifically, Patient 1 has already achieved a fetal hemoglobin fraction of 34% representing 4-gram per deciliter, just 1.5 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 9 currently enrolled RUBY patient cell and 3 currently enrolled -- 3 currently EDITHAL -- EDITHAL patient cells. Patient 1 through 4 and patient 10 have been dosed in RUBY and EDITHAL studies, respectively. As shown earlier, all 5 patients have followed a very similar rate of increase in total hemoglobin and fetal hemoglobin fraction in patient 1 and 2, both achieving normal hemoglobin level and over 40% fetal hemoglobin by months 5 of follow-up. The consistency of ex vivo editing and the consistency of the associated clinical outcome gives us confidence that the 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 a total of 20 patients by year-end. In addition, we have 7 study sites activated and 5 patients enrolled in EDITHAL study. In summary, 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 4 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 beta-thalassemia patient at the same follow-up time points. All those participants 4 RUBY patients, 1 EDITHAL patient have shown successful engraftment, have start red blood cell transfusion. And all 4 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 gives 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 the myeloablative busulfan conditioning and autologous hematopoietic stem cells 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 longer observation from both RUBY and EDITHAL study at the year-end. Now I'll 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 a 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 and meaningfully size 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 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. And 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, and we are happy to answer questions. Thank you.

We will now take your questions. Gilmore, Baisong are also joined by our Chief Financial Officer, Erick Lucera, to answer questions. [Operator Instructions].

[Operator Instructions] Our first question comes from Joon Lee from Truist.

Congrats on the impressive data. How much of an overlap is there between RUBY and EDITHAL sites and the sites that are enrolling for exa-cel and for those sites with overlaps, how are physicians and patients going about deciding whether they want to get exa-cel versus EDIT-301? And I have a follow-up question.

Thanks, Joon, for your 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 good knowledge in this field and understanding the gene editing and gene therapy. And it's really their efforts, really helps drive the program forward along with our other investigators.

I think, Joon, 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. And indeed, 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.

And yes, the rate of enrollment is impressive. What's your goal for the year-end? Again and -- is that something that, I think you could exceed based on the current rate of enrollment?

Joon, 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. And we're very happy with the current enrollment because that actually puts us on track with 20 patients already enrolled, and that enables us to ensure that patients are prepared for transplant, are able to have their cells, their CD34+ cells collected and edited and released in time for dosing.

And last question. And is that number something that you think would be sufficient to submit to the FDA for possibly approval in sickle cell?

I think what we've said is that this 20 patients is a clinically meaningful cohort and the benchmark for what might be necessary, may actually be judged by looking at recently filed BLAs, and I will say, obviously, that we will -- we'll be engaging with the agency to finalize and discuss what is the size of the package and the data set that they'd like to see. But as I say, you can look to the current benchmark or recently filed BLAs.

Our next question comes from Greg Harrison from Bank of America.

Sorry about that. This is [ Mary Ken ] on for Greg. I'm going through the data here. I guess, could you add additional color to the editing decisions behind using HBG 1 and 2? And how this could potentially translate into patient outcomes? And maybe when do you expect to see these outcomes?

Well, thanks very much for your question. I think the key point, 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 BC11A editing strategy with editing of the HBG1/2 and what we saw in those comparing studies was that editing HBG1/2 promoter close to that -- or actually within the deletion that is the most common cause of hereditary persistence of 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 physiologic or normal ranges in the clinic, and we have seen that. So we are very happy with the clinical consistency of the data with the nonclinical data and its support of the original hypothesis for selecting HBG1/2 promoter as a target.

Our next question comes from Phil Nadeau from Cowen and Company.

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 a reduction in vaso-occlusive events to be differentiated from the other gene editing or gene therapy approaches or maybe more consistent expression of fetal hemoglobin. What clinical differentiation profile do you think would be necessary for physicians to look at 301 as the most superior...

Thanks, Phil. I'm going to have Baisong answer the question. Baisong?

Yes. Thanks, Phil. Thanks for your question. So we are currently already looking to the clinical differentiation on that. We're looking from 3 category of things. And one is from hematological parameters and the lab values, for example, the total hemoglobin and among others. And then the second would be looking for the end organ damage and we have this endpoint to capture that. And then the third one, of course, is very important is actually patient report outcome and quality of life. And as Gilmore mentioned, we're starting to see the direction of differentiation by seeing the normalization of total hemoglobin. And with this normalization of total hemoglobin with a high-level expression of fetal hemoglobin, we'll see that it will change the patient life and the patient already reported they have more energy after the treatment and can do a lot of things, they never could be able to done before. And also, we're looking for -- and organ damage, as you know that the anemia as well the sickling will have end organ damage and then we -- hopefully, that we will see that clinically -- the normalization of the correction of anemia as well as the high-level fetal hemoglobin and will have to -- in view of the end organ damage. So we are starting to see that direction, we'll continue 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 physiologic levels of normal hemoglobin. And as Baisong says, that is an important factor in predicting end organ health as well as patients' quality of life. Indeed, data suggests that degrees of anemia are associated with different degrees of risk to end organ health. And so this is something that we are looking at in our trials. And indeed, we have our PROs or Patient Reported Outcomes built in, and we'll be looking to the near- to long-term benefits in the clinic from this return to physiologic normal levels of hemoglobin.

That's very helpful. And then one last question for us. In terms of the benchmarks necessary for FDA filing and approval that you referenced, would you expect the requirements to change should a genomic medicine be approved before you submit. I guess we're all kind of curious about why it's so good, a priority review in sickle cell disease and a standard review in beta-thal where there's already 1 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 1 in the market.

I think the benchmark is always a very good place to look. I think we're going to learn a lot about the FDA's evolution of its thinking as it reviews edited autologous therapies for treating hemoglobinopathies and we will maintain our ongoing dialogue with the agency as we look forward. Some of those questions you've asked are probably better opposed to our colleagues in Bluebird and Vertex. But 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 at that benchmark. And at least say that, that gives us a broad view of what would be required. And certainly, I think that benchmark gives us a sense of what the size of the trial and the data set would be and the follow-up time.

Our next question comes from Jacques Villefranc from Stifel.

This is Jacques on for Dae Gon. 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. And I have a follow-up.

Yes. Thanks,Jacques. So absolutely, we're actually very pleased to see that hemolysis mark by markers see that close to getting into the normal or close to normal for all the patients we observed, especially for the first 2 patients. Then the set in -- the third and fourth patient already in the same direction, but of course, a little bit early. We will be sharing more data when we have more information together.

Great. And then a follow-up here. So on editing levels, can you comment on patients 2 and the editing in the peripheral blood nucleated cells. Just curious to see whether what they're editing was beyond the 4 months? And then as part of your editing measurements, do you run any translocation or chromosomal rearrangement experiments?

Yes. Maybe I start with your second part of the question first, and we have done the sequencing of those ex vivo editing cells, we have not find any translocation or off-target editing that as we've seen so far. And for your first part of that, we are very pleased to see that all the 4 patients have very good editing level for the -- from the data from the nucleated peripheral-blood cells. And we do see a little bit slight variation, for example, the second patient, and the first month data is just slightly lower than the other 3 patients, but actually really getting up on the subsequent testing assays. So we just -- we do not view that as a significant with variation among this patients and how this patient -- how those edited cells be getting to peripheral-blood.

Our next question comes from Lisa Walter from RBC.

Great. 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. And also at what time point would you hope to be able to capture differentiation and end organ damage? And I have a follow-up.

Yes. Thanks, Lisa, for the question. Certainly, we are looking to -- from multi-organ systems on the health of those patients. And from a central nervous system and kidney and pulmonary and cardiovascular functions that we'll be able to see the function of this organ change over course. And there's no specific timeframe that -- and not sure how this change will happen. But within the normalization of total hemoglobin and the high-level fetal hemoglobin. We are optimistic that we will be able to see the difference in the end organ damage.

That's helpful. And then just maybe another observation on the engraftment timeline. 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.

Yes. Thanks, Lisa, for the observation. We are also very pleased to see the early engraftment from both neutrophil and platelet perspective for all the 4 patients, actually 5 patients we've seen so far, including the EDITHAL patient, and we are very pleased to see that. And it may be related to the editing strategy. And of course, and it's 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.

Our next question comes from Rich Law from Credit Suisse.

This is Grace on for Rich. I have 2 questions today. The first one is about exa-cel also updated -- have updated data at EHA in both at SCD and TDT. Do you see any room for a clinical improvement to those results since not all patients are VOC-free or transfusion independent?

So thanks very much, Grace, for your question. It's always -- one has to be very careful on commenting on the people's data. Obviously, they know their data very well. I think there are some appropriate questions you could post 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 nonclinically demonstrated a higher and better improved red cell output from bone marrow, better red cell health and better red cell longevity. And indeed, in the clinic experience to date, we have actually seen that borne out where the clinical data are consistent with nonclinical data, seeing robust normalization to physiologic ranges of total hemoglobin as well as a strong fetal hemoglobin response.

And the second part to my question is, the FDA only granted priority review to exa-cel for SCD but not TDT. Likely due to Zynteglo already approved in TDT? Do you see FDA here getting more stringent as the unmet need in these conditions decreases over time when more products get approved?

I think the only thing I can say is it's very hard to speak for the FDA. I will tell you this, in my experience and Baisong's experience, priority review is not necessarily tied to the standard of care. And particularly when we're talking about rare diseases with innovative products. But I really say it's very hard to comment on where the FDA is thinking or how it actually is thinking along these lines. But we will be engaging with them. And well, 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 301.

Our next question comes from Jay Olson from Oppenheimer.

Congrats on these results. 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? And then also any feedback that you got from KOLs at EHA and how you expect this updated data impact the enrollment of your study?

Yes. I'll answer the first question and pass the second question to Baisong regarding the KOLs. With regard to the BLA acceptance, this is actually a very exciting day for the field. What we're actually seeing is a CRISPR-based medicine, is 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, great day for CRISPR-based medicines. With regard to the read-through, I think it kind of sets a benchmark for the kind of data set size or size of data set, a 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 certainly was our hypothesis, and now this recent acceptance suggests that we're well within the range of the benchmark for the kind of data set or cohort size that the FDA would like to see. And then Baisong on, maybe talk about KOL reaction to the data at EHA.

Yes. Thanks, Jay. Yes, the -- actually, we see a very positive feedback in the KOL from EHA. And all the KOLs we spoke with, they're impressed with the results and about the consistent results and our different approach. And they say they give confidence to themselves as we have 20 patient about joining the study. So that's very, very pleased to hear. And one KOL also comment that Editas has been doing extremely well on our enrollment for both RUBY and EDITHAL study, and we just also very good to hear. And we are on target to dose 20 patients by year-end. And so with all this new data, certainly will help us to achieve the goal.

Our next question comes from [ Toni Dang ] from Barclays. We'll go to the next person and we can return to Tony. So next, we'll hear from Yanan Zhu from Wells Fargo.

Congrats on the data. 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, erythrocyte count and/or hemoglobin. Does the improvement on normalization of these markers correlate with total hemoglobin levels?

Thanks for the question, Yanan. This is Baisong. Yes, we are looking to multiple hemolytic biomarkers, including particular size, counts and percentage, including LDH, the bilirubin then have -- those biomarkers. And we see that, of course, we have 2 patients with a longer follow-up period and the other 2 have a shorter follow-up period. And we see all those biomarkers going close to normal already normalized. And so we're very pleased to see that, and we'll continue to monitor this patient. And so this is consistently our observation of the total hemoglobin as well as the high level of fetal hemoglobin.

Got it. Great to hear. Patient 3 and patient 4 seems to have higher transfused blood at baseline than patient 1 and 2. Could you perhaps give some color on what underlies this difference in baseline transfusion blood levels?

Yes. Thanks, Yanan, and you have a very good observation. Indeed, that patients 3 and 4, they actually have red blood cell exchange rather than blood cell transfusion. So therefore, actually, most of the hemoglobin in the baseline that we're taking from the transfused blood, that's hemoglobin. And then the first 2 patients actually were given red blood cell transfusion rather than exchange. So that's the difference we've seen so far. Very good observation, Yanan.

But what we don't believe is that, that is having -- we'll have a significant impact on the data that we're seeing. And indeed, we're very happy in patients 3 and 4 to see the consistent or rather to see that the trajectory of fetal hemoglobin expression that they are showing at 2 and 3 months follow-up or 3 and 2 months follow-up, respectively, really is very consistent with what we've seen in our first 2 patients.

Yes. Maybe I'd just add on that, Yanan, and we discussed on that before is the baseline level of the sickle cell patient is a very tricky point. It's much different from other clinical trial, you have baseline value in there, but that baseline has been impacted by many different things, and that's the observation too, yes.

Our next question comes from Madhu Kumar from Goldman Sachs.

So really, we have 2 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 a lovo-cel? And then my second question is on a kind of deeper level about hemoglobinopathies space. So earlier in the year, you highlighted this kind of 3-pronged strategy of EDIT-301 busulfan, EDIT-301 with milder conditioning and in vivo editing of hematopoietic stem cells. So given the kind of rapid recruitment like kudos to you all on that. On for EDIT-301 with busulfan, how are you thinking about kind of the pace of recruitment for that program versus kind of dive into development for milder preconditioning and in vivo editing.

Yes. Thanks very much, Madhu. So with regard to question 1 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. Besides growing their capacity to meet the commercial demand will actually take time as well as adjusting to a commercial edited drug paradigm and obviously, payer negotiations and decision-making about access will be an issue that will have to evolve over the next few years. So I think patients will have more data. They will have partnerships with their physicians as they look at the data as they evolve. And what excites us is that 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 hemoglobins that we're seeing early on. I think the next thing is -- and 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 our strategy in general and the 3 prongs, thanks for recognizing that the pace of recruitment for 301. We've been certainly very pleased with that. And I think it reflects how we redeployed capital with the reorganization of the company to building our CMC capacity and recruiting. How does it impact our view of milder conditioning and in vivo? Well, we believe, if I may start at the end, that in vivo editing for hemoglobinopathies, 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 very well-funded health care 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. And then with regard to milder conditioning, we are looking to milder conditioning and continue to evaluate that. We see that as sort of a medium-term way to essentially reduce the burden of conditioning and immunosuppression in patients and thus increase the overall or total eligible patient population. But 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.

Our next question comes from Steven Seedhouse from Raymond James.

First, I just wanted to ask about hemoglobin kinetics and whether for Editas 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 bonafide flatlining and stability at peak of hemoglobin.

Thanks very much, Steven, for your question. 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 nonclinical data set when it comes to actually stability. So yes, our follow-up, our longest follow-up is now 10 months, but 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 nonclinical data sets. I think the final piece will really -- we will actually see the evolutions in the FDA's thinking over the next few months as they review what we would see, so 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 day-to-day measurements of hemoglobins can actually show some mild variability. And so one should anticipate that. But 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 nonclinical data sets that we generated.

Okay. And another question I just wanted to ask separately on leukocyte count post transplant. Could you comment on that? And did that recover and remain in the normal range for at least the 2 patients with 6 or more months of follow-up. And the reason I ask is because the 1 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. So 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?

We have not shared all the details yet, but we are very happy to see these hematological parameters for all those patients we have those in so far, and there's no concern from our end.

Yes. And I think with regard to exa-cel patients, you probably have to talk to -- we don't have enough data to be able to comment that at all. But 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. And the only thing I would say at the end is that, 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. And 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 nonclinical data as well what we've seen to date in our clinical data set.

Our next question comes from Samantha Semenkow from Citi Group.

I wondered if you could share a bit more detail on the definition for what is an edited cell. Do both HBG1 and 2 need to be edited for definition? And instead on both alleles or is 1 site and 1 allele sufficient? And then just following up on that, how should we think about your editing level 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?

Yes. Thanks, Sam, for your question. From the clinical data of editing is the number of alleles being edited and percentage of allele being edited. And towards your question in there, for example, if we have 80% of allele being edited, that is possible -- that it's very possible that more than 80% cells has been edited in there too. So that's the editing level. We are 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. And 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.

Yes. And I would add, Samantha, that 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. And I think very importantly, sometimes they say, the proof is in the pudding. We are actually looking at consistent editing levels, which actually translate in our human patients into I would say, consistent trajectories for expression of fetal hemoglobin, normalization of total hemoglobin to the physiological normal range. And indeed, that experience reflects what we've seen in the nonclinical setting, with a correlation between editing and the expression in vivo in our nonclinical set. So 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 what we call very exciting data suggesting that we certainly, at the very minimum, have a competitive product and are looking to differentiate with the normalization of hemoglobin to physiological ranges.

That's very helpful. And 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 are -- do you expect with more patients that you'll see consistent editing across both diseases?

We do not consider that we have lower editing efficiency for beta-thal patients. Our sample size is not small. But in general, it's consistent around 80%. There are always a little bit of variation when you're executing these different editing [ loss ] lines. But 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.

There are no further questions at this time. That concludes today's event. Thank you for joining. You may now disconnect.