EDIT - Editas Medicine Inc. (EDIT) EDIT-301 Program Update: RUBY and EdiTHAL Trials Data Update (Transcript)
2023-12-11 17:50:27 ET
Editas Medicine, Inc. (EDIT)
EDIT-301 Program Update: RUBY and EdiTHAL Trials Data Update
December 11, 2023 1:00 PM ET
Company Participants
Cristi Barnett - Corporate Communications & IR
Gilmore O'Neill - CEO
Baisong Mei - CMO
Caren Deardorf - Chief Commercial & Strategy Officer
Conference Call Participants
Jack Allen - Baird
Gena Wang - Barclays
Joon Lee - Truist Securities
Samantha Semenkow - Citigroup
Yanan Zhu - Wells Fargo
Luca Issi - RBC Capital Markets
Phil Nadeau - TD Cowen
Dae Gon Ha - Stifel
Eric Schmidt - Cantor Fitzgerald
Brian Cheng - J.P. Morgan
Jay Olson - Oppenheimer
Jingming Chen - Evercore ISI
Presentation
Cristi Barnett
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. To ask a question, please click the Raise Hand feature in the webinar portal.
As a reminder, various remarks that we make during this presentation 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 to any forward-looking statements, represents 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 would now like to turn the call over to Gilmore for opening comments.
Gilmore O'Neill
Thanks, Cristi. Good morning, and thank you for joining us for this webinar presentation of our cumulative clinical experience with EDIT-301. I'm excited to be here today to share additional clinical data from the RUBY and EdiTHAL studies of EDIT-301.
I joined Editas 18 months ago because I saw a huge opportunity to help transform Editas from a development-stage technology platform company into a commercial-stage genome editing company, and we are well on our way driving towards commercialization with our deliberately-designed management team, our focused strategy, and our groundbreaking science. In the past 18 months, we have formed a new senior management team with a proven track record of drug approvals and with strong domain expertise to leverage cutting-edge gene editing technology. We have focused our strategy to lead asset EDIT-301 and the development of in-vivo medicine making investments based on high conviction targets with a high probability of technical, regulatory and commercial success. Finally, we have increased our business development activities, specifically out licensing our foundational Cas9 intellectual property, and we have a strong cash position to fund these activities.
Finally, I am pleased to share EDIT-301 is now known as renizgamglogene autogedtemcel or reni-cel. Now, since the June 2023 data disclosure at the European Hematology Association or EHA Congress and in our company-sponsored webinar, 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% that are well above the safety threshold, and a safety profile that is consistent with myeloablative busulfan and conditioning, and autologous hematopoietic or CD34+ stem cell transplant, and all treated sickle cell patients, free of vaso-occlusive events or VOEs, and all TDT patients achieving transfusion independence.
Before I hand over to Baisong to take you through the data, I want to share a few key takeaways from today's webinar. Reni-cel drives early robust correction of anemia to a normal physiological range, total hemoglobin in sickle cell disease patients. Reni-cel drives robust sustained increases in fetal hemoglobin in excess of 40%. All RUBY sickle cell patients have remained free of vaso-occlusive events following reni-cel treatment. Reni-cel treated sickle cell and transfusion-dependent thalassemia patients have shown successful engraftment and have stopped RBC or red cell transfusions, and the safety profile of reni-cel observed to date is consistent with myeloablative condition of busulfan and autologous hematopoietic stem cell transplant.
In addition, the trajectory or trajectory of the correction of anemia and expression of fetal hemoglobin are consistent across reni-cel treated sickle cell disease and beta thalassemia patients at the same follow-up time. These new data reinforce our belief that we have a competitive product and, indeed, a product differentiated from other treatments, thanks to its deliberate design by rapid correction of anemia.
But what is the impact of these hematological outcomes on a patient? I would like to share a quote from a RUBY trial participant, a 26-year old man, who shared his experiences with us since dosing. I just want to highlight this particular part. “Before, I had to work so hard at everything. I was a dreamer. Now I can do anything. I feel like myself.” I thank this patient and pride just for sharing the story of how reni-cel has helped him pursue his dreams. And I'd like to thank all patients and trial participants, their families, investigators, study site staff members, our CRO partners, employees, shareholders, and you, as we follow this journey to bring potent new gene editing medicines to market.
Baisong will now take you through the RUBY and EdiTHAL study and share the data that support these findings.
Baisong Mei
Thanks, Gilmore. Sickle cell disease is an inherited life threatening hematological disorder, which has started 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 sickle-induced blood vessel blockage resulting in unpredictable and severe attacks of acute pain, stroke, acute chest syndrome, liver disease, renal failure and shortened life span.
With limited approved treatment options, there’s significant unmet medical need for sickle cell patients. Natural genetic variance in the gamma globin promoter can cause hereditary persistence of fetal hemoglobin, HPFH, with high level of fetal hemoglobin in red blood cells. In sickle cell patients who co-inherit the hereditary persistence of fetal hemoglobin, the patient can have reduction or absence of sickle cell symptoms. 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 total hemoglobin within an individual red blood cell is important. That is called the corpuscular fetal hemoglobin levels. When corpuscular fetal hemoglobin levels exceed 10 picogram per cell, it is considered clinically meaningful because it prevents that red blood cell from sickling. Therefore, based on this nature occurrence, we believe that increased fetal hemoglobin expression will ameliorate the symptoms and complications of sickle cell disease.
The choice of CRISPR enzyme and the target for editing to switch arm fetal hemoglobin expression matter. Before Editas selected The HBG1/2 promoter as our genomic target for upregulation of fetal hemoglobin, we conducted a comprehensive preclinical study for head-to-head comparison between editing of 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 of BCL11A.
AsCas12a is our proprietary high specificity CRISPR nuclease and is very different from Cas9 enzyme used by others. AsCas12a has demonstrated superior characteristics that increase the efficiency of editing and significantly reduce off target editing when compared to other CRISPR nuclease, including Cas9.
Additionally, our comprehensive off targeting assessment uses multiple orthogonal methods including in silico, biochemical and cellular, followed by verification of candidate sites. This approach in combination with high specificity AsCas12a enzyme, give us confidence in the design of reni-cel to provide high editing efficiency and a low of target editing. Therefore, using AsCas12a to edit HBG1/2 promoter should deliver our desired direct attributes of correction of anemia by increasing and normalizing total hemoglobin and more sustained expression of fetal hemoglobin.
The RUBY trial has been designed as a registrational study to evaluate the efficacy, safety and tolerability of reni-cel for treatment of severe sickle cell disease. Reni-cel trial will recruit an approximately 40 patients with severe sickle cell disease and have a history of at least 2 severe vaso-occlusive events per year for the 2 years prior to enrollment; in addition to safety, the key clinical assessment including total hemoglobin, fetal hemoglobin and the resolution of vaso-occlusive events after reni-cel treatment. Reni-cel continues to show a favorable safety profile and the reni-cel was well tolerated by the 11 patients dosed in the RUBY trial. All 11 patients have homozygous severe sickle cell disease. And during the 2-year prior to enrollment of the RUBY trial, patients had a mean annual rate of severe vaso-occlusive events of 3.9. The mean follow-up period post reni-cel treatment was 6.5 months.
The first 2 patients have had 18 and 15 month follow-up periods respectively. All 10 patients with greater than 1 month follow-up period have success for neutrophil and platelet engraftment after reni-cel infusion: The neutrophil engraftment within one month and platelet engraftment within 1.5 months. To-date, the safety profile has been consistent with myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. No serious or adverse events related to reni-cel treatment were reported after reni-cel infusion.
Importantly, all treated RUBY patients are VOE freely since reni-cel infusion. This slide shows the data from 10 patients with over 1 month follow-up period: Their VOE during the two years before enrolling into the RUBY trial versus VOE after the reni-cel infusion. While the patients have frequent VOEs before the trial, there are no VOE after reni-cel treatment.
This past June, we showed that patient one and two from the RUBY trial had the normal physiological level of total hemoglobin by month five after treatment, and fetal hemoglobin level greater than 40%. As a reminder, fetal hemoglobin level exceeding 30% is considered clinically meaningful reduction or elimination of sickle cell symptoms, particularly vaso-occlusive event. Here we show data from more patients and a longer follow-up period up to 18 months. The data reaffirms our confidence that this effect is durable.
Let me take you through the data. The X axis represents the follow-up time after infusion of reni-cel. The Y axis represents the mean total hemoglobin level and the total hemoglobin values are denoted on top of the bars. The mean total hemoglobin level ranging from 15.1 grams to 16.9 grams per deciliter, five months after reni-cel infusion. All six RUBY's patients who had a five months or longer follow-up period had a normal total hemoglobin level since month five, and maintained the physiological level of hemoglobin during the follow-up period up to 18 months. For reference, the normal total hemoglobin is 13.6 grams to 18 grams per deciliter for men and 12 grams to 16 grams per deciliter for women. It is marked by gray bars running across the top of the graphs.
I mentioned total hemoglobin level at month five because at this time, the transfused blood has been washed out, so that the total hemoglobin level at month five is not confounded by transfused blood. The fetal hemoglobin fraction is represented at bottom of the bar in orange. The fetal hemoglobin level of all patients reached greater than 40% at month four after reni-cel infusion and maintained greater than 40% during the follow-up period up to 18 months. The clinical data thus far reaffirm our belief that achieving sustained normal level of total hemoglobin could be a potential point of differentiation for reni-cel.
Moving to transfusion-dependent beta thalassemia, or TDT. TDT is characterized by severe anemia, hemolysis, severe ineffective erythropoiesis, clinical manifestation appear in infancy, and patient require lifelong regular transfusion for survival. Similar to sickle cell disease, increased total hemoglobin level can also ameliorate the manifestations of TDT and reduce a correction of the anemia. The EdiTHAL study has been designed to evaluate the safety, tolerability and efficacy of reni-cel for treatment of TDT. The EdiTHAL patient experience with reni-cel to date resembles that of the RUBY patients, the increase of total hemoglobin and fetal hemoglobin.
This past June, we shared early data from the first patient with 1.5 months follow-up after reni-cel infusion. Today, I'm pleased to share a data set of 6 EdiTHAL patients. This patient had 1 to 8 months follow-up post reni-cel infusion, with 4 patients being at least 3 months post reni-cel infusion.
EdiTHAL patients treated with reni-cel have demonstrated successful neutrophil and platelet reference and the safety profile has been consistent with that of myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. Following reni-cel infusion, mean total hemoglobin level increased to 13.1 gram per deciliter by month 5 and maintained over the follow-up period up to 8 months, post reni-cel infusion, well above transfusion independence threshold.
As a reminder, average total hemoglobin level at or above 9 grams per deciliter is considered transfusion independent for TDT patients. The increased total hemoglobin level is driven by rapid and robust increase of fetal hemoglobin expression. After reni-cel infusion, the mean fetal hemoglobin level rapidly increased to 9.4 grams per deciliter at month 4, remained high over the follow-up period. Excitingly, this data showed that total hemoglobin and fetal hemoglobin increased their trajectory in RUBY patient at the same time point.
In summary, this data reconfirmed our initial clinical results study in June. Reni-cel drives early robust correction of anemia to a normal physiological range of total hemoglobin in sickle cell patients. Reni-cel drives robust sustained increase in fetal hemoglobin in excess of 40%. All RUBY sickle cell patients have remained free of vaso-occlusive events following reni-cel treatment. Reni-cel treated sickle cell and beta thalassemia patients have shown successful engraftment of stopped red blood cell transfusion. And the safety profile of reni-cel observed to date is consistent with myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant.
In addition, the trajectory of correction of anemia and expression of fetal hemoglobin is consistent across the reni-cel treated sickle cell disease and beta thalassemia patients at the same follow-up time point. Both the RUBY and EdiTHAL trials have strong positive momentum. We look forward to sharing more data from more patients and longer observation of both RUBY and EdiTHAL studies in mid-2024.
Finally, I thank all patients, their family, investigators, 35 staff members, our CRO partners, employees, shareholders and you, as we're following this journey to bring potent new gene editing medicine to market.
Now, I'll turn the call back to our CEO, Gilmore.
Gilmore O'Neill
Thank you, Baisong. As you can see, these data give us even more confidence that reni-cel has the potential to be a competitive product and the potential differentiated medicine that can give robust clinical benefit to patients with severe sickle cell disease and beta thalassemia.
In closing, clinical execution and the past commercialization for reni-cel are top priorities for us. We are on track to achieve our goal of dosing the 20th RUBY patient in the January time frame, and we remain on track to present a substantial clinical data set to sickle cell patients mid-2024.
On the regulatory front, we are also pleased that the FDA granted Regenerative Medicine Advanced Therapy or RMAT designation to reni-cel for the treatment of severe sickle cell disease in October. To further enable commercialization on the manufacturing front, we've ensured our ability to scale reni-cel manufacturing both for clinical trial supply as well as ensure commercial measures. We remain confident that reni-cel has the potential to be not just a competitive product, but 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 reni-cel to regulatory file approval.
Gilmore O'Neill
Thank you very much for your interest in Editas, and we are happy now to answer questions. Thank you.
Question-and-Answer Session
A - Cristi Barnett
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. We will call on you and ask you to unmute yourself. Our first question comes from Jack Allen from Baird.
Jack Allen
Congratulations on the data. Very interesting dataset here. I guess maybe, one question I had was around the thoughts on total hemoglobin as it relates to remaining within the normal range for the given genders. I know that some of these patients are -- have different normal range maybe just depending on if they're male or female. Are you seeing that all the patients are remaining in their normal range? And if not, is there any risk to overexpression of total hemoglobin? And then I have a quick follow-up as well, if I may.
Gilmore O'Neill
Thanks very much, Jack, for your question. I will warn you that owing to the ASH, we're in different sites, and so I will be, how should I say, overseeing or facilitating questions, but I'm going to pass this question to Baisong Mei, our Chief Medical Officer.
Baisong Mei
Yes. Thank you, Gilmore. Thanks, Jack. Thank you for the question. So as I mentioned, at month 5, we have 6 patients reach month 5 or longer. And all those patients are in a different gender. They are within the normal range of their specific reference range.
Jack Allen
And then just a brief follow-up -- sorry. Go ahead.
Baisong Mei
You had another question about overexpression. Just wanted to follow-up on that. No, we do not have a concern about overexpression on these patients.
Jack Allen
And just a brief follow-up, I know it's a very exciting time in the CRISPR cell therapy space. I'm sure you guys have seen the recent approvals. I was wondering if you had any overarching remarks as it relates to the approvals. And I know there are some IP dynamics as it relates to CRISPR Cas9, and products in the U.S. I'd love to hear any thoughts you have as it relates to these updates?
Gilmore O'Neill
Yes. Definitely, Jack. We'd be delighted to. Listen, we share the excitement of everybody involved. This is a fantastic moment in time, most particularly for sickle cell warriors. But it's also a very exciting time for programmed genome editing, and more specifically using CRISPR-based technologies with a significant step with this first approval of a CRISPR-based medicine. Frankly, it validates our own approach to approval and differentiation in this context.
And then with regard to the IP situation, we have consistently expressed our desire and interest to sub-license our Cas9 technology to enable these medicines and their approvals. Now we talk to many companies about Cas9 licenses, but we do not discuss any specific conversations until there is a signed agreement.
Jack Allen
Got it. Great. Well, congratulations again on the progress. This is very exciting time in this space.
Cristi Barnett
Our next question comes from Gena Wang from Barclays.
Gena Wang
Thank you. I have three quick questions. The first one -- or the first two are a little bit technical questions. First one is regarding the cell collections for sickle cells. What is the average cycles you need to do in order to collect sufficient cells for sickle cell disease program? And the second question is regarding the fetal globin. What is the sweet spot regarding the percentage of the fetal globin, over 60% or would that be too high or any concern -- safety concern there? And then lastly, very quickly, I just wanted to ask, after recent approvals of Lyfgenia and Casgevy last Friday, any updated thoughts on regulatory path?
Gilmore O'Neill
Yes. Thank you very much, Gena. So with regard to the cell collections, I am going to pass that question to Baisong, and then I will facilitate the other two questions. So, Baisong, just the average number of cycles for cell collections.
Baisong Mei
Yes. So we are very happy with our cell collection cycle. We actually have a specific optimization for the apheresis process and have on-site support for the apheresis in the study site. We are doing very well but we have not shared the specific average cycle publicly on that, but we are doing very well and very happy to see the results.
Gilmore O'Neill
And with regard to the fetal hemoglobin question you asked, Gena, around the sweet spot and is there a level that is too high? And I am going to ask Baisong to address that. And, of course, in many ways, you can actually look to the co-inheritance of hereditary persistence of fetal hemoglobin, particularly in the context of thalassemia where you see very high percentages without apparent -- with actually with benefit and without apparent adverse effect. Baisong, if you want to build on that?
Baisong Mei
Yes, thank you, Gilmore. So, Gena, yes, that's certainly a very interesting question because we want to see the sickle cell and beta thalassemia doing differently. So for sickle cell location, really is we are try to prevent sickling with the increased amount of fetal hemoglobin. So the knowledge we have so far is primarily based on two things before. One is hereditary persistence of the fetal hemoglobin; and the other one is related to the hydroxyurea. But now, of course, we have data from our study as well as other study-wise, we have a better understanding. So certainly, there is a positive correlation, that 20% you start to see the impact and 30% you have better one, but now we actually see 40% that really give good results. Then we are further to see exactly, as you said, whether 60% is necessary or not or whether it is benefited, remain to be seen, but we are happy to see that the higher fetal hemoglobin level give us better benefit at this point.
Gilmore O'Neill
And thanks very much, Baisong. And then, Gena, your third question is around any updates on the regulatory pathway? We are thinking about post these critical approvals. Indeed, we see this approval as a validation of our strategy. As Baisong said, we continue to enroll. We are on track to really be in a position with that good momentum on dosing and recruitment to present a substantial dataset in the middle of 2020-2024 and benchmarking by the original exa-cel BLA accepted by the FDA, including their original efficacy dataset of 20 patients with 16 months follow-up. We believe this validates a line of sight to a BLA in 2025.
And it's probably worth reminding as well that the FDA granted us RMAT in October, even while they were reviewing the exa-cel datasets, really confirming a remaining unmet need per the regulation that oversees RMAT granting. Obviously, that was based on their review of our current clinical data at the time. So again with that view with also the RMAT granting us opportunities or increased amount of opportunity to engage with senior FDA officials, further increases our confidence in a timely review.
Cristi Barnett
Our next question comes from Joon Lee from Truist.
Joon Lee
Thank you, and congrats on the very strong data. In the press release, you see that the reni-cel can be clinically differentiated. Can you point to a specific data point supporting this? And can you share some specifics on how editing the promoter differs from enhancer in terms of mimicking the hereditary persistence of fetal hemoglobin? One of the slides actually had a list of things that were better with promoter editing versus the enhancer editing. I'm just really curious what you're referring to?
Gilmore O'Neill
Yes. Thanks very much, Joon. With regards to the clinical differentiation beyond the hematologic parameters we have presented today, let me pass the question to Baisong who will talk about how our clinical trial is designed. Baisong?
Baisong Mei
I think when we clinically study the EDIT-301 and reni-cel in the sickle cell patient, we're looking to three category of endpoints for the potential differentiation. As I mentioned earlier that the normalization or correction of anemia could be a potential differentiation point. And with that in mind, we are looking, of course, for hematological parameters to see the difference in there. But more importantly, we're looking to see the end organ function after the advent of treatment from cardiovascular, pulmonary, liver, renal functions too.
Another important category we're looking into that is patient reported outcome, because that anemia can really impact patients' quality of life, right? So we all know that when we go to high altitude, we have short breaks. So that's kind of the indication. We're short of oxygen in our system, which is related to anemia. And also end organ function, there are already literature in the macro analysis, say, for the sickle cell patients, that level of total hemoglobin is related to the end organ functions. So that's kind of the directions we're looking to that from a differentiation perspective.
Gilmore O'Neill
And then Joon, you asked us just about how our targeting the gamma globin promoter directly as opposed to the BC11A suppressor might differentiate. Well, I think the key thing beyond just the clinical data is that our nonclinical data showed in a head-to-head comparison that targeting the gamma globin promoter as opposed to the B7a suppressor would actually result in -- and did indeed result in increased red cell output longevity and health in a nonclinical model. We presented those data a few years ago. Obviously, one can speculate about the underlying mechanism beyond the empiric observation. One possibility is that directly targeting a single suppressor may have less impact than targeting the promoter itself where you can actually essentially interdict or interfere with both trans as well as cis elements that might impact the promoter and its impact on downstream expression.
Cristi Barnett
Our next question comes from Samantha Semenkow from Citi.
Samantha Semenkow
At ASH, there's just been a lot of discussion on how to ensure sickle cell disease patients are able to access these gene editing therapies, following the recent approvals. The conversation is relevant for reni-cel too. First, what is your view on the feasibility and expected trajectory of building the necessary structure to administer these gene therapies or gene editing therapies? And second, what if anything can Editas do now to help prepare the market for when you potentially launched reni-cel commercially?
Gilmore O'Neill
Thanks very much for that question, Samantha. What I'm going to do is actually ask our Chief Commercial Strategy Officer, Caren Deardorf to answer that.
Caren Deardorf
Yes. Thank you. Thanks, Sam and just want to add to Gilmore, the congratulations to bluebird and Vertex. It really is a great time in the field. So I look at this from 2 ways. One is definitely kind of the long-term perspective on having these life transforming therapies available in a really critical population. And then there's also the short-term of how do we get to a place where these patients have the access they need. And as you point out, there are a number of considerations. What I'll say is there are definitely sites available today. But in my experience launching SPINRAZA, when we look at things like CAR-T in general, when a drug is approved, a lot of work happens and starts then. So a lot of centers who anticipate and would like to get involved, often can't build the infrastructure, hire the staff, coordinate with their CFO and their C suite to make sure it's possible.
So I think that we will see that there is work to be done across the physician community, who we're hearing great things. But again, it will take a little bit of time across the payer community, which we also think will get there but it will be slow. Government can work somewhat slowly. But between the government payer and the commercial payers, we believe that there is a huge cost savings and value proposition in therapies.
And then thirdly, the patient community and the education there. So I think that we will see may be a slow start, but I think we will see eventually a very sizable opportunity in a way to get to these patients.
In terms of what we can do, we're already engaged with the patient community through advocacy, doing a lot of listening, engaging, understanding what they need and with sites, not just our own sites, but also other KOLs to really understand what are some of the areas that they need support, or how are they going to go ahead and build. So we are actively involved in those conversations. That will continue over the next years as we think about, hopefully, bringing reni-cel to the market.
Cristi Barnett
Our next question comes from Yanan Zhu from Wells Fargo. Your line is open. Feel free to unmute.
Yanan Zhu
Thanks for taking our questions and congrats on the data. So I was wondering, in speaking about the greater -- potentially greater total hemoglobin compared with exa-cel as you mentioned, how much higher do you think in the eyes of the sickle cell physicians would equate to a clinical meaningful difference? Is it 1 gram per deciliter or 2 grams per deciliter? I think, currently, the data suggest increment in that range. I just wonder about as you gather data and talk to treating physicians, what is the view that you are hearing? And I have a couple of follow-up. Thanks.
Gilmore O'Neill
Thanks very much, Yanan. So I would ask Baisong to answer that question.
Baisong Mei
Yes. Thanks, Yanan, for the question. As I mentioned earlier that their literature already demonstrate that increased total hemoglobin level is very important for sickle cell patients. And so we are pleased to see that we will be able to normalize total hemoglobin. And then -- so then how much higher, I would say, from, like, two angles. One is that, just generally from a hematology perspective, normal hemoglobin with anemia that certainly will have different clinical outcome of that. And then from sickle cell specifically, they’re already evident to say every gram of deciliter change will make a difference. There are several, actually, review articles on that end, and also that the -- if I put, trans and then the Oxbryta approval is based on actually 1 gram per deciliter of total hemoglobin increase for the approval. So certainly, that is a general consensus that normalize hemoglobin and also increase of 1 gram or more will be substantial.
Gilmore O'Neill
Thank you very much, Baisong.
Yanan Zhu
Thank you, Baisong and Gilmore. That's very helpful. And then I see that, one patient had a AE of polycythemia. Could you talk about that? Is that associated with a particularly high fetal hemoglobin expression, and whether that's resolved? Thanks.
Gilmore O'Neill
Yes. Thanks very much, Yanan. Baisong?
Baisong Mei
Yes. Happy to answer the questions. So we do have one patient actually have a slightly higher-than-normal range of total hemoglobin and transiently, and that has been since resolved quickly.
Yanan Zhu
Got it. Any understanding of the transiency of this kind of reaction? Is that stem cells trying to repopulate the bone marrow niche and showing fluctuation? Or -- I wasn't sure about the transient nature, any thoughts there?
Gilmore O'Neill
Baisong, I think…
Baisong Mei
Go ahead Gilmore.
Gilmore O'Neill
No. Sorry. I was going to pass that. Just Baisong, if you'd like to just address that, obviously, as we -- this was a transient single event and the patient has remained within normal. But, Baisong, I think you were going to…
Baisong Mei
Yes. And this is a transient occurrence, and this is something we take this also very seriously. We have extensive investigation and also discussed with IDMC, and then this patient has been resolved actually 6 months ago. So we actually have data for that patient and normalized for 6 months.
Cristi Barnett
Our next question comes from Luca Issi from RBC Capital Markets.
Luca Issi
Two quick questions. One, maybe circling back on the prior questions on cell numbers, can you just talk about what's the minimum number of CD34 positive hematopoietic stem cells that you need as a starting point to manufacture reni-cel? I found it interesting to learn on Friday that bluebird bio needs close to 20% less cells than actually CRISPR according to their label. I believe it's 16.5 million cells for one and 20 million in cells for the other. So I was just curious if your number is closer to the bluebird bio’s number or the CRISPR number? any color there, much appreciated. And then the second one, in a scenario where you actually get approved for both beta thalassemia and sickle cell disease, do you anticipate to receive one or 2 PRVs?
Gilmore O'Neill
Thanks very much, Luca. With regard to question one, we haven't actually disclosed the starting number of cells that we are using right now. Baisong, I don't know if you just want to add, just make -- give clarity, we certainly have shared the range of cells that we administer. But Baisong, if you want to add any more to that?
Baisong Mei
Yes. So the dose of the reni-cel treatment, it's based on the experience, had many years for allogeneic transplant, so that's kind of the generally used case field. So we actually have a final minimum 3 million cells per kilo for treatment with additive cells.
Gilmore O'Neill
But I think the other thing I just want to add, Luca, is that we are very happy with the efficiency of our enzyme. And one of the reasons that we actually chose to develop our program using AsCas12a is because amongst other things, the high efficiency of this engineered enzyme. And we've been very happy to date with the efficiency of our editing. And then with regard to your second question, sorry, could you restate that for me?
Luca Issi
Happy to. Just curious about whether, if you get approved for beta thalassemia and sickle some disease, do you anticipate to receive one priority review voucher or two?
Gilmore O'Neill
Yes. Frankly, that would be a matter of review with the FDA. Obviously, there's substantial upside if you get that. And obviously, we have seen some interesting precedent set with the granting of a PRV for exa-cel. But I think we'll have much more clarity as we get closer to an approval. But, really, it's a matter of review with the agency.
Cristi Barnett
Our next question comes from Greg Harrison from Bank of America.
Unidentified Analyst
This is Mary Kate on for Greg. Thanks for taking our questions and hosting the event today. Just a quick question on just how is enrollment going since the cutoff from the data here? And then, do you expect any impact on enrollment given the recent approvals in the space? Thank you.
Gilmore O'Neill
Thanks very much, Mary, for your question. I'll ask, Baisong to answer the question on the continuing enrollment that we're seeing. And, frankly, he can also comment on our belief that we do not expect to see an impact on enrollment, indeed have not seen it with the approval. Baisong, over to you.
Baisong Mei
Yes. Thank you. Thanks for the question. So we have a strong momentum for the clinical trial enrollment and the movement in that. And we shared that in early January on the earning call, we already had 27 patients enrolled at that time, but since we enrolled additional more patients on that too. We do not see any impact that about the approval of these 2 or the other beti-cel for example, approved last year, and we are still seeing very strong reaction from community, and we still see a lot of interest from study sites and patients. What I would say is that the data -- the more data we share, and we actually see a lot of positive response, right, so we in that -- since -- for example, last June, after we released the data, our inquiry increased about 10-fold over that period right after that -- the data sharing. So we expect that the data we have now, we're going to have even more possible results, reactions to the trials.
Cristi Barnett
Our next question comes from Phil Nadeau from TD Cowen.
Phil Nadeau
Good afternoon. Thanks for taking our question and allow us to add our congratulations on the data. Two from us. First, on the efficacy side. When could we first see some of that end organ function data that you've mentioned? Do you think that you'll have that available in mid-2024 at the next update, or will that require longer term follow-up?
And then the second question, again on differentiation. You've focused the differentiation on efficacy and efficacy measures. Talking to physicians, the safety profile of these agents is a big hurdle to adoption. Is there any way to differentiate on safety or is -- since most of the adverse events are due to the preconditioning, is it difficult to differentiate meaningfully without changing the preconditioning regimen? Thank you.
Gilmore O'Neill
Thanks very much, Phil. I'm going to answer question two and then pass question one to Baisong dealing with end organ functional data and the timing of such sharing.
With regards to the safety profile, obviously, we take safety extraordinarily seriously. Indeed, that was one of the reasons that we elected to move forward with the AsCas12a, which is not just a high efficiency enzyme, but actually is a higher fidelity CRISPR enzyme. And indeed, we felt that choice was further validated during the discussion at the AdCom when we heard the agency's view of the importance of monitoring off target editing.
And, indeed, at that agency AdCom, we actually also were, say, very gratified to see how comprehensive our off target editing package is relative to what the agency was discussing at the AdCom. And so we actually certainly do believe that, that does give us another potential for differentiation with our product.
Then with regard to end organ functional data, let me pass that to Baisong.
Baisong Mei
Yes. Thanks, Phil, for your question. Regarding the differentiation, we feel the end organ function can be an important point for differentiation, benefiting from the normalization of total hemoglobin and correction of anemia. As I mentioned before, there are actually reports that the normalization will help the patient and end organ function.
And then relate to outcome and when we will be able to see the benefit, and this is actually still unknown area for us to explore. So there are relatively limited data on that. But there are publications about from allogeneic transplant for sickle cell patients, and they see the improvement of central nervous system, they see improvement in cardiovascular system, and actually at this ASH, there are several abstracts talking about allogeneic transplant outcome. So we will together learn more about that. I cannot share a specific timeframe, but we are monitoring to this very closely and looking forward to share more data in the future.
Cristi Barnett
Our next question comes from Eric Schmidt from Cantor Fitzgerald. Eric, your line is open. Feel free to unmute. Okay. We can come back to Eric. Let's go to take a question from Dae Gon Ha from Stifel.
Dae Gon Ha
Thanks for taking our questions. Can you hear me okay?
Gilmore O'Neill
Yes. Thank you very much, Dae Gon.
Dae Gon Ha
Great. Congrats on the progress, and the update today. Maybe, a quick clarification question before I dive into my two questions. On the clarification part for the sickle cell data, can you confirm that the one with the 18 month follow-up is a male? And for the TDT data set for the 1 out to 8 months, what genotype was that particular patient?
Gilmore O'Neill
For that clarification, Dae Gon, I am going to hand that to Baisong.
Baisong Mei
Yes. For the RUBY study, the patient with 18 months follow-up is a male patient. And for the EdiTHAL patient, the two patients with longer follow-up are also male patient.
Gilmore O'Neill
I think the question Baisong was around the genotype.
Baisong Mei
Yes. They actually are beta-zero, beta-plus.
Dae Gon Ha
Okay. Thank you for the clarification. For my actual questions, I guess with the Lyfgenia and the Casgevy approvals, I wanted to get your strategic take on this. Do you see the strategic rationale of activating or enlisting some of these Casgevy or Lyfgenia QTCs to kind of give these investigators early notion of differentiation of EDIT-301? Or will you be looking into sort of skirt that and go after sites that are non-participating as QTCs? And then last question. We saw quite a bit of disparity on the pricing disclosure 2.2 for Casgevy, 3.1 for Lyfgenia. I wanted to get your take on sort of the COGS, I guess, side of the calculus. How are you thinking about that as you are developing EDIT-301? How much of a wiggle room is there as you kind of see these two precedents that are coming to the market? Thanks so much.
Gilmore O'Neill
Thanks very much, Dae Gon. Let me just answer the last question, and then I will ask Caren just to begin to share her preliminary thinking about how we think about qualified a transplant center in engagement, et cetera. So, yes, we did see that disparity or difference in pricing disclosure. It is very early days yet for us to be thinking about our pricing. And we have not shared our COGS yet, but would look forward to doing that at an appropriate time.
And with that, Caren, I might ask you just to address -- share some of your thinking, preliminary thinking around how we're thinking around QTCs going forward as a -- how to say, a rapid follower with a potentially differentiated product.
Caren Deardorf
Where I'll start is with the sites that we already have. We have about 25 sites that have really good distribution across the country, as well as utilizing some of the strongest thought leaders and centers who can do both the sickle cell care and the transplant care as well. So we already feel very good about our footprint starting there. There I'm sure it's quite a bit of overlap with the clinical trial sites for the other therapies and their QTCs.
So I think it's not necessarily about going after their QTCs. I think we all probably have a pretty similar strategy in looking at where the majority of patients are, how are they distributed across states, how are the Medicaid and the various payers going to move? How quickly will they move? And all of that, we're taking into consideration. But again, starting with gaining the experience through reni-cel sites that we have in place today. And we'll continue to evaluate that. And I'm sure we'll update you as we go along.
Gilmore O'Neill
Thanks, Caren. I'm conscious of time, and I'm worried I think we a few more people with questions, and it might be important just to make to see if we can try and focus the questions. Sorry about that. Sorry to be the bad man -- bad guy.
Cristi Barnett
For our next question, we'll turn to Eric Schmidt from Cantor Fitzgerald.
Eric Schmidt
Maybe quickly just on this single case of grade 2 polycythemia vera. Was there any medical intervention required? And then two, I guess I'm just biologically very curious. It seems like 2 different things are going on in sickle cell versus beta thal biologically. You're getting a lot more hemoglobin F production in beta thal than in sickle cell, yet the total hemoglobin is quite a bit lower or somewhat lower in beta thal versus sickle cell. Do we understand what's going on there biologically?
Gilmore O'Neill
Thank you very much, Eric. And I will I ask Baisong just to clarify on the single event of polycythemia, which was not a vera, which is a primary event. But, Baisong, over to you.
Baisong Mei
So this patient had a transient higher total hemoglobin level during this visit. And the major intervention was that at the time actually the patient -- because the patient had a pulmonary embolism -- thrombosis before, so the physician feel that even though the level was not very high, but did phlebotomy to reduce the total hemoglobin level. And the one important thing, of course, is the nuance for patient management is actually this patient was considered even though they have high total hemoglobin level and these patients consider actually iron deficiency.
So keyword before this event was to put iron supplement before this event. And then after the start the iron supplement and this patient has since been abnormal for the past 6 months.
Gilmore O'Neill
Thanks very much, Baisong. And then I think, Eric, you asked a question around the relative levels or expression of fetal hemoglobin in the context of sickle cell disease versus beta thalassemia. And I think, while it's always dangerous to speculate, there is no doubt that these are -- these diseases are different biologically. And obviously, as we move this medicine forward and it interacts with the biologies of these different patients, we will gain additional insights. Baisong, I don't know if you have anything to add to that.
Baisong Mei
Yes. I do want to add a couple of things in here, right. So one is that, the patients with 5 months follow-up has really robust total hemoglobin level around 13 grams per deciliter, well above the transfusion dependence and is very complete with the results. And two is that the transfusion-dependent beta thalassemia is different from sickle cell actually because this transfusion-dependent beta thalassemia, they have very low total hemoglobin level. It's like below 7 grams per deciliter. So they have the difference between from a pathophysiology perspective.
And as I mentioned earlier, we are very happy with the data, and we're looking forward to more data come from longer follow-up and more patients.
Cristi Barnett
Our next question comes from Brian Cheng from JPMorgan.
Brian Cheng
Can you walk us through how the patient journey is to get on reni-cel? And, I guess, whether there is any key difference versus exa-cel today? And what is the current vein to vein time as you now have a handful of patients in both trials? And I guess as you look forward to next year, how do you think that vein to vein time will improve over time?
Gilmore O'Neill
Thanks very much, Brian. Let me start very quickly before handing to Caren as we were thinking about the evolution of our patient journey and how that will translate from our clinical trial experience to the commercial space.
With regard to the vein to vein time, certainly, the sickle cell patient, our experience has been, as we've shared before, about 5 to 12 months. And not surprisingly, it can be shorter with beta thalassemia patients largely because you can use double agents to mobilize them and therefore get higher yields in the apheresis.
Well, with that, I might ask Caren just if she'd like to comment on just the evolution of her preliminary thinking about what that journey will look like in the future and how we're thinking about that.
Caren Deardorf
Yes. Thanks, Brian. I'm actually going to be very quick and then have based on comment more on from a clinical trial perspective. I'd say there is a somewhat artificial path within the clinical trial where there are more steps. So I would anticipate, what we do today will translate, we'll be able to find places to optimize. But Baisong, do you want to comment just on the steps and…?
Baisong Mei
Yes. I mean, I think, Brian, you're very familiar with this. So we actually have this -- after the eligibility, we have these apheresis, that's collected cells and manufacturing cells and then dosing. And then one of the major factor is, for example, the patient conditionings because those are severe sickle cell patients. And before they had reni-cel treatment, they could have all kinds of different safety and the worst event before the treatment because they are severe patients. So that's kind of one part of that. And the other part is actually patient scheduling because this is a very, very, involving study and require not only a patient commitment but a caregiver's commitment. So as Gilmore mentioned, we actually do see room to optimize it, but certainly, if they are, this is because of nature of severe disease that devastating disease were hit.
Gilmore O'Neill
Brian, just the final thing is that, we have actually evolved our processes and brought in best practices as we move the trial forward, and look forward to talking about more of that in the future at appropriate time and seeing how and describing how it will ultimately impact the commercial journey for patients using reni-cel.
Cristi Barnett
Our next question comes from Jay Olson from Oppenheimer. Your line is open. Feel free to unmute.
Jay Olson
Congrats on these results, and thank you for the update. Can you comment on the opportunity to treat younger sickle cell patients with reni-cel? And separately, are you collecting any biomarkers for hemolysis, like LDH? Thank you.
Gilmore O'Neill
Yes. Thanks very much, Jay. What I am going to do is ask Baisong to talk about how we are moving on the treatment of younger patients. And I can confirm that we are collecting markers of hemolysis. And Baisong could probably talk to you about -- at a high level, as we shared at the ASH poster, about where we are seeing very positive trends there. Baisong, over to you with regard to the opportunities to treat younger patients.
Baisong Mei
Thanks, Jay. We certainly have a plan for expand this study to the younger patients, and we will expand it to adolescent patient first, before we go to under 12 pediatric patients. So we are well underway for that and so that's our plan. And then in terms of the hemolysis marker, we just need to collect the LDH and radicular size, as you mentioned, about that. And we are very happy to see the data we have seen so far. I mean, our data set is still small, but we are very happy to see, as we put in the poster that those parameters either normalize or have a significant improvement. So we are very happy to see what the data looks like so far.
Cristi Barnett
And our final question will come from Jingming Chen from Evercore.
Jingming Chen
Hi. This is Jingming on for Lisa. Thanks for taking our question. Just curious, we know fetal hemoglobin binds to oxygen better than the regular hemoglobin. So do you really think we need normal level of total hemoglobin to have normal functions? Thank you.
Gilmore O'Neill
Thanks very much for your question. I am going to ask Baisong to address that. And in many ways, we partially address that with some of the empiric observations seen with hereditary persistence and indeed our own experience at the clinic to date. But Baisong?
Baisong Mei
Yes. Thanks for the question. So actually, there are probably two aspects of that, right? So one is to say, look, to prevent sickle cell patients, you do need certain level of that, whether it is the high, the better and how much we need, that's kind of one topic of that. And then the other one is actually, yes, the fetal hemoglobin has high affinity to oxygen than the adult hemoglobin and then what level is necessary. So based on our data, of course, other data -- other people’s study data that higher level of total hemoglobin or high percentage of fetal hemoglobin since in patient, been doing very well. So, there's no concern to be have a higher fetal hemoglobin per se. And so that's kind of the knowledge we have so far. It's not only for these trials, but also for the hereditary persistence of fetal hemoglobin patients demonstrate that in the beta thalassemia patients.
Gilmore O'Neill
And it is worth pointing out that the question is quite apt, considering the relative affinities of fetal hemoglobin and adult hemoglobin, but it's worth noting that the affinity of options for hemoglobin is also modified by adaptive mechanisms, including 2/3 DPG, pH, oxygen tensions, etcetera, in the tissues. But the good thing is, is that we are seeing, essentially, very good outcomes in our experience and the hereditary persistence of fetal hemoglobin experience, particularly where you're looking at it in the co-inherited with thalassemia, where fetal hemoglobin is the dominant, these patients are doing very well. Or I shouldn't say patients, these people with that coincident inheritance do very well.
Gilmore O'Neill
So I think that was our last question. So I just want to thank all of you for your interest and dialing in. We are very excited by the data we're able to share with you. We're happy with the momentum, and we look forward to giving you further updates, and obviously, look forward, to being able to share a substantial dataset in the middle of next year. Take care.
Cristi Barnett
Ladies and gentlemen, this concludes today's call. Thank you once again for your participation. You may now disconnect.
For further details see:
Editas Medicine, Inc. (EDIT) EDIT-301 Program Update: RUBY and EdiTHAL Trials Data Update (Transcript)