It's great to see many familiar faces and some new ones. It's good to get back in this mode, where we're all meeting in person again, and hopefully the brunt of the pandemic is behind us. As you all know, it's been an eventful couple of weeks for us at CRISPR Therapeutics. We had our oral presentations for both CTX001 and CTX130 at the EHA conference in Vienna. On the heels of that conference, we're very excited to have you all here today and provide you a comprehensive update on our pipeline and showcase the depth and breadth of our pipeline as well as our platform.
Before we begin, we will be making forward-looking statements today, and I encourage you all to go to our website or our SEC filings to get a full list of our risks and uncertainties, and also spend a moment on the disclosures for our guest speakers today, Dr. Swaminathan Iyer and Dr. Sumanta Pal. It's hard to believe that it's less than ten years since the first publication elucidating the mechanism of gene editing with CRISPR-Cas9 was published by Dr. Jennifer Doudna and Emmanuelle Charpentier, and here we are standing today on the cusp of a BLA filing for CTX001, or exa-cel, in hemoglobinopathies. If it gets approved, it would be the first CRISPR-edited product approved in the world. It's also hard to believe that it's been eight years since the start of the company.
In the last eight years, we've made tremendous progress in establishing ourselves as the leading gene editing company. We've made progress across many fronts with five different clinical programs, over 500 employees, a state-of-the-art GMP facility, and over $2 billion in the balance sheet, which puts us in a position to be at the leading edge of the CRISPR-based revolution to transform medicine. I want to take a moment to acknowledge and thank all our employees, our partners, and our investigators in helping us reach this stage, and we feel well-positioned for the future. As you all know, we've prosecuted the CRISPR platform in four different pillars, hemoglobinopathies, immuno-oncology, regenerative medicine, and in vivo therapies. We've made great progress across all these verticals, but in each of these verticals, we have a tremendous premium on continuous innovation.
That's what we want to describe to you today, is both the success of the lead programs in these verticals, but also the innovation that comes behind it, not to mention all the improvements we're making on the platform. Joining us today for this update from CRISPR Therapeutics are Dr. PK Morrow, our Chief Medical Officer, Dr. Jon Terrett, our Head of Research, and Dr. Alireza Rezania, our Head of Regen Med. Additionally, we're very privileged to have with us today Dr. Sumanta Pal from the City of Hope National Medical Center, who is the principal investigator on our CTX130 RCC trial.
Many of you may already know, but Dr. Pal is an internationally recognized leader in the area of genitourinary cancers and is a Co-Director of the Kidney Cancer Program at the City of Hope National Medical Center. Joining us virtually today is Dr. Swamy Iyer from the MD Anderson Cancer Center.
Dr. Iyer is a world expert in hematologic malignancies and is a principal investigator on our COBALT lymphoma trial, and we're very pleased to have him here with us today. In terms of the agenda, we will begin by talking about our progress in hemoglobinopathies and immuno-oncology, and follow that up with Q&A for those two sections, after which we'll have a short break and then move into our presentations for Regen Med and in vivo, followed by additional time for questions. Without further ado, I would like to now turn it over to our chief medical officer, Dr. PK Morrow. PK?
Great. Thanks, Sam, and it's really great to meet you all for the first time. I'm really excited to join the CRISPR Therapeutics team, and one of the reasons that I was truly motivated to join this team was the ability to really join in developing transformative gene therapies. I hope that today I'll really convince you about the true progress and the excitement, and we'll take you along this journey with us. I'll start first with the hemoglobinopathy strategy, and what better slide than to start with exa-cel. I think you all are very familiar with exa-cel, but exa-cel is our gene therapy targeting and editing and increasing hemoglobin F, resulting in potentially functional cures for patients with sickle cell disease and beta thalassemia.
Recently, this data was presented as part of a late-breaking abstract that occurred at the European Hematology Association in Vienna, Austria, and was presented by Dr. Franco Locatelli. We released data from 70 patients across the two disease states of sickle cell disease and beta thalassemia, and what we found was that there were incredibly encouraging findings here. You can see on this slide that 42 out of 44 patients who had previously been transfusion dependent with beta thalassemia became transfusion independent, and all patients with sickle cell disease became free of vaso-occlusive crises.
I think it's honestly an amazing achievement by this therapy, and it's due to the fact that we were able to achieve early as well as durable elevations in fetal hemoglobin that allow patients to remain above the transfusion threshold with beta thalassemia and also were able to maintain their status and avoid vaso-occlusive crises and sickle cell disease. As I mentioned, just an incredibly encouraging and delightful thing to be able to respond and to present to you today. We believe that exa-cel has the potential to be the first approved durable one-time gene editing therapy using CRISPR technology. What do we need to then address? Well, as you can see from the very top portion of the slide, exa-cel now currently would be able to address approximately 30,000 patients with sickle cell disease as well as with beta thalassemia.
However, we believe that we can further augment and increase the reach of this program by several fold by two different approaches. One, through targeted conditioning, as well as potentially through in vivo delivery. I'm going to walk through potential approaches for each of these in the subsequent slides. The first is the fact that when we looked at the ability to perform gentle targeted conditioning prior to gene editing, we had four different criteria. One was a very specific on-target potency for the program. Two, limited off-target toxicity. Three, rapid clearance. And four, scalable manufacturing.
We believe that we have actually looked at or developed and are developing a promising approach with what you see on the right-hand side of the slide, which is a c-Kit antibody drug conjugate in which you have a monoclonal antibody targeting c-Kit, which is linked to a DNA alkylating toxin with limited toxicity. I'm going to present to you some of the preclinical data related to the c-Kit ADC. On the left-hand portion of the slide, you can see a xenograft model featuring an AML tumor. Now, without any treatment, as you can determine, the black line indicates the aberrant growth of the AML tumor. With the administration of the c-Kit ADC, this flattens the curve significantly, pushing growth of the tumor down to near zero.
On the right-hand portion of the slide, you can see that a single dose of the c-Kit ADC is able to completely deplete functional HSCs in non-human primates. What we've been able to see is that we're able to increase the dosing and further dose the c-Kit ADC without increasing toxicity. I think this is a promising approach to further harmonize delivery therapies for gene editing as well as potentially deliver and augment the reach of exa-cel. Beyond that, though, we have a dream, and the dream is actually to be able to administer gene editing without conditioning at all. We have several potential approaches for this, which I've delineated on this slide here. On the left-hand side, AAV. In the middle, LNP. And thirdly, targeted LNP.
What I'll do is actually walk through some of these approaches with you to give you an understanding of the promise that we're seeing in these approaches. First of all, we've actually taken advantage of some of the natural tropism of the AAV by doing a dual AAV vector to deliver Cas9 and guide RNA, and we've been able to achieve 60% editing in these mice. This is pretty exciting. Also, what's also exciting is the fact that with our secondary engraftment studies, we've shown preservation and durability of these edits, which implies that we may be targeting the true long-term hematopoietic stem cells. Ultimately, as I look across the hemoglobinopathies pipeline, I'm very encouraged. You start with the clinical encouraging efficacy seen with exa-cel, which could be the first approved gene therapy using CRISPR-Cas9.
Moving beyond that, we want to truly continue to harness the safety and the efficacy of gene editing through both conditioning regimens as well as through in vivo editing. With that, I'd like to then move on to immuno-oncology. Immuno-oncology is actually very close and dear to my heart. I'm going to be partnering with a number of folks on this presentation and discussion. One, Dr. Monty Pal, who is just to my right, Dr. Swaminathan Iyer, who will be online soon, and of course, Jon Terrett. We will be reviewing with you our evolved oncology strategy, the clinical data, and providing you new glimpses as well as updates to that data, and thirdly, what research is doing within oncology and beyond.
It's going to be a pretty packed presentation, and I'm sure you're as excited as I am about it. We'll start with CTX110, which was really our pioneer in allogeneic CAR T therapies. We had a recent very productive meeting with FDA related to RMAT in which we held to align on some preclinical and CMC questions. While we recognize that the CD19 targeting landscape is very competitive, we also recognize that there continues to be an unmet need in this landscape, as evidenced by the fact that up to one-third of patients who are eligible for auto CAR Ts are unable to receive them due to manufacturing difficulties, disease progression, and other areas that can be addressed by the administration of an allo CAR T. For that reason, we are advancing CTX110.
We have dosed 15+ patients in consolidation cohorts, and we're looking at optimization of the dosing for CTX110. Furthermore, I will share with you today the fact that we have also developed a next-generation program called CTX112 with additional potency edits, which will be discussed by Jon Terrett shortly. Now, turning to CTX120, I think many of you are very aware of CTX120. It's our BCMA-targeting allogeneic CAR T. This program has had some encouraging responses that are dose-dependent, and it has a very tolerable safety profile. But we're also very cognizant about the high threshold for efficacy within the BCMA myeloma landscape, especially with the recent approval of Carvykti. What we have determined to do is to pivot from CTX120 to our next-generation program that will incorporate additional potency edits engineered to further improve efficacy and durability of response.
We do plan to submit some of the data from CTX120 as part of a future scientific publication. I've talked to you about CTX110 and CTX120, and those I believe are really the pioneers, right, for CRISPR in terms of allogeneic CAR T therapy development. Today is innovation day, so let's talk a little bit more about an area that we would love to spotlight with you in terms of the innovation that's happening at CRISPR and how we're bringing that innovation to the clinic every day and that's CTX130. CTX130 is our allogeneic CAR T that has a number of edits that I'll review with you in detail today. Some of them will be familiar to you. For example, on the right, we have the removal of the T cell receptor in order to eliminate GvHD.
We are targeting CD70, which I'll talk about the target to you shortly. We've also knocked out beta-2 microglobulin in order to remove MHC class I and increase functional persistence. What's kind of cool about this CAR T and very innovative is the fact that we've also edited out the CD70 from the T cells in order to avoid fratricide of the T cells. That's a very novel edit that we believe is actually unique to our program and we believe may help to further improve and support the efficacy of this program within both solid and liquid tumors. Why CD70, and why am I focusing on this so much?
Well, first of all, CD70 is a unique target in the sense that it's expressed to a high degree in certain tumors such as T-cell lymphomas, renal cell carcinomas, and other hematologic and solid tumors. The nice thing is it's very minimally expressed in healthy tissues, reducing the likelihood of off-target toxicity. What's also really important about this target is that, as I mentioned, because it does help us to potentially cross that divide for CAR Ts from liquid tumors to solid tumors. It's kind of that holy grail that we've all focused on in many ways. Let me start with T-cell lymphoma, and we'll then turn to Dr. Swaminathan Iyer also to spend some time talking to you about this disease state as well as about the updated data from our COBALT lymphoma trial.
You can see here on this slide the fact that CD70 expression is very high in T-cell lymphomas. T-cell lymphomas are really this very heterogeneous group of diseases, and if you look at overall in all of the T-cell lymphomas, about 85% of the T-cell lymphomas have a median 40% surface expression of CD70, so pretty high. But the other common thread across these lymphomas is the fact that there's a severe unmet need for this population. You're talking about a disease state with significant morbidity and mortality and for which the current oncology guidelines past first-line therapy truly just recommend a clinical trial. That indicates that there's a tremendous need for better therapies and safer therapies for this disease state. For that reason, we wanted to really focus on T-cell lymphomas and hopefully help patients through CTX130.
With that, I would like to turn this to Dr. Swaminathan Iyer, who is our principal investigator for the COBALT lymphoma trial. Dr. Iyer is actually joining us from his clinic. He's a very busy man. He is a professor of medicine in the Lymphoma/Myeloma department. He's also a treasured colleague due to his passion in advancing the science for T-cell lymphoma patients. Dr. Iyer, let me turn to you, and I'll advance your slides.
Thank you, PK. I overemphasize the fact that T-cell lymphoma is an area of high unmet need, such a heterogeneous disease, 30 different disease sites and with only 6 approvals. In this context, CTX130, the COBALT-LYM study is making tremendous progress. What I'm going to share with you in the next few slides is the data that we just presented at EHA in Vienna a couple of weeks ago. This is the data cutoff of 26th April 2022. This COBALT-LYM study is a phase 1 dose-finding study of
What I'm gonna share with you is the data across all of those levels. Since it's a baseline study, the first part of the study, the primary endpoint is safety. For the dose escalation, which is gonna come pretty soon, the endpoint is going to be looking at the efficacy as well. What you see on this slide is the patient demographics on the left-hand side. You can see the patient characteristics. The median age is 65, so you had patients who are 65 and above participating in the study. Range from 39 to 78. More than half of them had an ECOG performance status of 1. This study didn't allow anybody with the ECOG of 2 and above. Look at the T-cell subtypes.
For the PTCL, which is a peripheral T-cell lymphoma, which is a very broad category consisting of nodal, extranodal, and the leukemic versions. We had patients with AITL, angioimmunoblastic T-cell lymphoma, ALCL, ALK-negative and ALK-positive anaplastic large cell lymphoma, and patient with PTCL not otherwise specified. We also had 3 patients with the adult T-cell leukemia lymphoma, which is caused by the HTLV virus. Now, this is a devastating disease and there's absolutely no therapies out there which are reliably producing responses. Zidovudine and interferon seem to work, but for the most part, most patients die of this disease. Of this patient characteristics involved in the study, two-thirds of them had skin involvement, about 30% had blood involvement, and 20% had bone marrow involvement.
The entry criteria for the study with the CD70 expression was 10%, equal to 10% or above. You can see that majority of them, 90% of them, had CD70 expression level, about 90% between the range of 20 and 100. Note, this study also allowed the second infusion of CTX130 if the patients did not achieve a CR or if the CR that they achieved, eventually the disease progressed and including patients with PR stable disease where the investigator thought there was a clinical benefit by giving the second infusion. 5 patients received the infusion. On the right-hand side, you see the pharmacokinetics data, and these were, ddPCR data for the constructs.
You can see the peak expansion concentration was 80.9 per microgram of the DNA, and the time to peak expansion was 8.5 days. At the bottom panel, you see the peak expansion concentration in dose level four, which is where we probably will focus on in the near future. There's initial dip and then we can see these cells expand enormously for the first 28 days. Next slide, please. This is a safety profile since the primary endpoint is safety. It's an allogeneic CAR, so you'd expect potentially to monitor for things like GvHD, tumor lysis syndrome, because it's pretty effective. Also the two special events with any CAR T therapy, which is the cytokine release syndrome and the neurological events described as ICANS.
There was no TLS, no tumor lysis syndrome, no GVHD, and the CRS were Grade 1-2, and the ICANS were Grade 1-2, and all of them were reversible. If you look at the treatment emergent SAEs, and there are a few details to it. If you look at the infections, the Grade 3 infections in four, Grade 1-2 tumor hemorrhage during a biopsy, Grade 3 syncope, Grade 3 pre-syncope, and there is a patient with Grade 3 HLH, which was noticed in a patient with disease progression at day 51. Also a patient with a Grade 3 drug eruption, and also a patient with a Grade 1-2 ligament sprain.
With exception of 1 patient with infection with Grade 3, all other treatment emergent SAEs were not found to be related to CTX130. There was a patient with HLH syndrome, eventually had sudden death in the context of a lung infection, which is deemed unrelated to CTX130 after extensive analysis and study. 3 cancers were diagnosed in patients with CTCL post-treatment, and 1 patient had EBV-associated lymphoma, which is like the post-transplant lymphoproliferative process, which actually resolved on count recovery. The same patient had a squamous cell carcinoma and another patient with invasive ductal carcinoma. These last two skin cancers, the squamous cell and an invasive ductal breast carcinoma were resected with a curative intent. None of these were deemed related to CTX130. Next slide. This is the efficacy data.
Mind you, this is a phase 1, but you can see the efficacy data with very promising responses with 70% overall response rate and 30% complete response rate, all seen in dose level 3 and above. In the left-hand panel, you can see this overall response rate. Then not only 30% CRs, but 40% CRs. If you look at the disease control rate and stable disease, it does play an important role in T-cell lymphoma. Even though it's not in the criteria of response, several agents have shown that stable disease is very meaningful. You have a 90% disease control rate.
On the right-hand side, if you break them down into disease sites, the PTCL subset had overall response rate of 80% with 40% CR, 40% PRs and overall response rate of 80%, with a disease control rate. For the CTCL, the overall response rate is 60% with CRs of 20%, with 40% PRs and 100% disease control rate. Next slide, please. This waterfall plot shows that the responses are observed across all compartments. T-cell lymphoma is a multi-compartmental disease, including the lymph nodes, the bone marrow, the skin, and the blood. Since you have 30 different varieties potentially that could participate, if you map the responses across all compartments, you can see the responses across all the compartments.
The skin in green, the lymph nodes in blue and the blood in red. It's very impressive responses. Next slide, please. This swimmer's plot actually gives you the most important information in terms of the meaningful responses that you expect to see with CTX130. There are several ongoing responses with five of the patients, and you can see the median or the time to response has not been reached. Two patients were successfully bridged to a stem cell transplantation at the time of the data cut off. It looks very promising. We've not seen any CAR T do something like this, and especially in T-cell lymphoma. I think this is the last slide I'm gonna hand over to PK, and happy to answer any questions.
Thank you for your time.
Sure. Can you guys hear me okay? Okay, perfect. I thank you. That was exceptional. I wanna just kinda go through briefly, how we plan to or hope to change the paradigm in T-cell lymphoma. You can see on the right-hand portion of the slide, we've really summarized for you the variety of therapies for T-cell lymphoma, and there's quite a few. I can see people putting glasses on, so that's an indicator of the number of therapies. also you can also see unfortunately is the fact that they're associated with poor response rates. also, you know, what's not delineated on the slide is the fact that there are significant toxicities such as peripheral neuropathy and others, which are very difficult to manage in this highly refractory population.
You know what we feel is, now that you've seen our data, this data has demonstrated a 70% overall response rate at dose level 3 or higher, accompanied by a 30% complete response rate. This is across all compartments: blood, lymph, bone marrow, skin, and that's accompanied by a fairly tolerable safety profile for a one-time dosed CAR T at this time. Now, we are looking at potential consolidative dosing to look at redosing with CTX130, and we are also looking at a potential next generation, CTX130 called CTX131, which will incorporate further potency edits.
You can even see with this current data, with a response rate of 70% with a very favorable toxicity profile, why we're very encouraged about the potential for CTX130 to really make a difference in the lives of patients with T-cell lymphoma. Now I'm gonna pivot and talk about solid tumors briefly. I'm gonna start with just talking a little bit about renal cell carcinoma. Recall from the previous slides that that was the other trial that we were focusing on. We had COBALT lymphoma and COBALT renal cell carcinoma. The reason for that clearly was the high levels of CD70 expression that were seen with renal cell carcinoma tumor samples. Also the other rationale, quite frankly, is the fact that this continues to be a disease state with a significant unmet need.
You can see on the slide that less than one in every five patients is actually able to survive to five years after the diagnosis of metastatic renal cell carcinoma. Many of these patients, almost half of them, are primary refractory to their initial therapy. For these findings, we believe that if we could find a regimen that was effective and safe, we could really make a big difference in the lives of renal cell carcinoma patients. We embarked on this trial called the COBALT-RCC trial, and I have the delight of transitioning this to Dr. Monty Pal. Dr. Monty Pal is, as Sam mentioned, a renowned expert in renal cell carcinoma. He's passionate about therapies for renal cell carcinoma, and he's also the co-director of the Kidney Cancer Program at the City of Hope. Dr. Pal?
Great. Thank you, Dr. Morrow, for the very kind introduction. I really appreciate that. I have to tell you, I've been treating patients with renal cell carcinoma for 16 years now. I've seen lots of ups and downs in terms of drug development over that timeframe, and I truly feel that CAR T-cell therapy has transformative potential in this space. I'm gonna walk you through the results of the COBALT-RCC cohort on behalf of my co-investigators. Very excited to share this data with you here. Just to walk you through initially the demographics of this population, it's what you might anticipate for patients with advanced RCC. The median age of the population was around 65. It's a male predominant population. As stipulated in the protocol, the majority of patients had advanced disease at the time of study entry.
What's really important to bear in mind as we look at the results is the heavily pretreated population that we were looking at. You can see that there was a median of three prior therapies in this cohort with up to six prior treatments. As Dr. Morrow had mentioned, renal cell carcinoma tends to be a highly CD70 expressing disease. We saw a range of CD70 expression in our study, but the median value sat at 100%. In discussions with my co-investigators, who I met with often during the conduct of this study, we were really impressed by the safety profile of this regimen. As you can see here, we encountered no DLTs in the course of the protocol so far. We've had no instances of tumor lysis syndrome, no infusion reactions, no HLH, no ICANS, no GvHD, and no secondary malignancies.
About half of patients had grade 1-2 CRS. We didn't incur any grade 3 or greater CRS events. We did have three patients who had SAEs coded related to CTX130, and all of these fell into that grade 1-2 CRS category. We did have three patients who had significant adverse events of infection. I'll point out that all of these were deemed to be ultimately unrelated to CTX130. I'll point out as well that we did have a patient who had a pneumonia with a grade 5 dyspnea event, but very importantly, that patient had actually progressed beyond CTX130 and was on next line of therapy at the time that event was incurred.
Now I'm very excited to share with you the efficacy data here, and in particular, I wanna highlight what you see in row 1 there, which is a complete responder to therapy. To my knowledge, this is the first time that we've seen a complete response in renal cell carcinoma with an allogeneic CAR T-cell. Very, very exciting, and I'll share with you some details of this case on the next slide. What I also wanted to highlight is we had a substantial stable disease rate as well. You can see that 10 patients in this cohort of 14 had stable disease as a best response to therapy. Beyond this, typical PK was seen with a peak time to expansion at a median of day 10 with a peak concentration of 3,500 copies per microgram.
Again, to summarize here, the disease control rate overall was 79% in this cohort and again in this population of heavily pretreated patients, and I can't underscore that enough. I think that this data is quite compelling. Now, I'm gonna walk you through some of the details of the patient that incurred a complete response here. This was a patient in my practice, in fact, and this was a 64-year-old gentleman who was actually diagnosed with clear cell renal cell carcinoma back in 2017. This patient actually had a relatively aggressive disease phenotype. He had subdermal metastasis, and that usually implies a very poor prognosis. The patient was treated with Cabozantinib and Atezolizumab, a study that I was leading at the time. The patient ultimately developed a partial response to therapy.
He did ultimately progress on that regimen, though, with lesions in the lungs and the pleura. If you can make it out on the right-hand side there in the top panel, I'm showing you one of the lesions there in the paravertebral region that measured around 2 cm in size. What was so impressive to me as we started the patient on CTX130, at day 42, you see a near complete response, a very deep PR at that time. Then at month three, that actually deepened to a complete response, and that complete response is actually maintained at his most recent imaging at month 18. Not only that, I think the complete response in and of itself was quite impressive to me.
Beyond that, this patient's really been able to remit a lot of the toxicities that he and other patients have with chronic therapy for advanced renal cell carcinoma. The current paradigm includes chronic therapy with tyrosine kinase inhibitors, with checkpoint inhibitors, and this patient, for instance, had all of those standard toxicities, hand-foot syndrome, diarrhea, fatigue, et cetera. He's really enjoyed a very, very exceptional quality of life since that time. Again, I just want to reemphasize my vigor for this data, and I look forward to seeing what's on the horizon. For that, I'll turn it over to Jon. Thank you.
Thank you. Thank you, PK, Monty, and Swami. It's pretty amazing as a research lead to see these products get in the clinic, have such clear patient benefit, and be able to use what we're seeing in the clinic and in research to map out what comes next. We validated using CRISPR in the CAR T space with CTX110. You've seen prior data on that. You saw T-cell lymphoma a couple of weeks ago, and we have a solid tumor complete response out 18 months. What do we do next to unlock the full potential of CRISPR in this space? We can go to novel edits to improve the performance of our CAR Ts, and we can look at novel targets. When we think about novel edits, we've really focused down onto potency. Why do we do that?
We've seen activity of CTX110 and 130 as described here, where there is that 28-day period of pharmacokinetics that you can see. Within that, we are seeing durable responses. If we can increase the activity of our CAR Ts in that period, we should be able to kill more cancer cells, and the responses last longer. If you think back to the autologous experiences within Yescarta and other therapies, you'll see that CAR Ts quite often are gone by three months, but the responses go on for years. If MRD negativity can be achieved early on, that correlates strongly with a long-term durable response. Getting in early with very potent cells, getting rid of as much cancer as possible is clearly a way forward.
We went through CRISPR screening and empirically combining different edits with each other to come up with what we think is a very unique pair of edits. They may not be unique in their names, but this pair together does something that I haven't seen in terms of a combination of knockouts and improving potency. The first one here listed is Regnase-1. If you knock that out, the T-cells just last longer. The CAR T-cells last longer. They stay central memory phenotype for longer. What Regnase-1 normally does is degrade mRNAs for proteins that CAR T-cells and T-cells like to use to keep going, like cytokines and BATF. The second one, TGF beta R2, will be more familiar to people that think about solid tumors and avoiding, you know, suppression signals in the tumor microenvironment, which is quite often TGF beta. We get these two edits.
By themselves, they do good things to CAR T-cells. Together, it's rather dramatic. Here's a demonstration of that. This may look like a regular xenograft model. You've got no treatment in the black squares and then treatments in the different colors. This is actually a second tumor. We've already, in these mice, put an established tumor on one flank and cleared that tumor with either CTX130 or 130 plus TGF beta, 130 plus Regnase, or 131, as we're calling it, which is 130 plus the Regnase and TGF beta receptor knockouts. Here we've enrolled new mice, put on a different tumor, this ACHN model. CTX130 does show some tumor growth inhibition, but those cells are exhausted. They're not killing anymore. They're not really expanding much anymore.
Adding the individual edits, either TGF-beta or Regnase, you can see in the other color, the triangles, that they suppress the tumor, but it starts growing. In green, CTX131 just goes along the x-axis. Those tumors never take off. They are rejected. What do we do next? We put a tumor back on the initial flank, a different one again. This whole study, we start with a H1975 lung tumor, so pay attention to that. We've spoken about renal cancer, but CD70 is in many different tumor types. We get complete eradication of the tumor, including with CTX130. We challenge with ACHN, CTX131 rejects it. We challenge again with CTX131 with Caki-1 cells, and they reject it. Only one dose of CAR T was given right at the start of this study. No further doses were given.
The only re-challenging was different tumors. Importantly, we can take CAR T cells out after those re-challenges. We see them expand again, and they are central memory and phenotype. They have not gone to terminal effectors. We wanted to try and enumerate how much better is CTX131 than 130 in this context, so we did a dose titration study. CTX130 clears the tumors quite nicely at a 1 million dose. At a 0.1 million, 100,000 dose CTX130 does not clear the tumors. There's a bit of tumor growth inhibition. CTX131, we did a million of that as well, but it just wiped out the tumor so fast it wasn't important here. 0.1 million, a 100,000 dose of CTX131 completely clears these tumors.
There's a bit more to it if you reflect back to the previous slide. They kept going through two more tumors. We can say on a dose-by-dose, we're about 10x more potent with CTX131 than CTX130, but there's a lot more to it than that. Clearly, we're very excited about these 2 edits. They do something very, very dramatic, and we're progressing next-generation CD19, CTX112, and next-generation CD70, CTX131 towards INDs this year. Building on that further, those generation 2 CAR Ts have up to 6 edits, which we can do with our current technologies. If we wanted to go further, and this is where the platform comes in that Sam was highlighting earlier, we've been very busy looking at base editors, trying to find a high-efficiency base editor by screening multiple different species.
We're comparing off-target versus on-target on the left, and you want to be in the top left. There are two green dots, which are our preferred base editors with the preferred profiles, and then on the right-hand side, we started making CAR T cells. The knockout you can see are 95% efficient. When we're knocking in a CAR, we're still gonna go with a double-strand break and CRISPR-Cas9 and do a single site insertion. We're not gonna go and do random insertion of a lentivirus when we've done so much work to control everything else. Going back to what PK said, CD70 was a risk. Everyone followed CD19, BCMA. There's been multiple stories with people saying solid tumors with CAR Ts is different. It's highly toxic.
You've probably seen some of those reports, and as you've heard, particularly from Monty, in the renal cell carcinoma space, it's quiet. The patients like it. They don't want to be taking drugs every week that make them feel bad. What do we do with all of those learnings? We prioritize some novel targets, we compare them with our new edits, and we're trying to accelerate these novel targets going beyond CD70. We're not gonna be copying other people's targets so much. We want to get fast readouts on these, and we're partnering with academic centers to get some readouts in the autologous setting where we're not having to build a whole manufacturing scale and then potential conversion to the allogeneic setting. Two of these that are ongoing towards the clinic, CD83 in hematologic malignancies and Glypican-3 in hepatocellular carcinoma, CD83 with the Moffitt and Glypican-3 with Roswell Park.
These cancer centers will put the manufacturing together, initiate the phase one trials, and CRISPR Therapeutics retains the commercial rights. Here is the updated pipeline, including what I've just told you all. We're very excited about our next gen edits, but don't forget we're really excited about 110 and 130. With consolidation dosing and the dose responses we've seen and the safety tolerability and clear patient benefit, why would we stop those? We're gonna bring along CTX131 and CTX112 as quickly as we can. You all know about our Nkarta collaboration. We saw pretty good data with their CD19, so we're excited to do a CD70 CAR NK with potency edits. CTX121 was mentioned earlier. We're revamping that program. It will obviously include potency edits, and we have other CAR Ts that we've disclosed previously.
I just told you about CD83 and Glypican-3, which we're gonna prosecute in the clinic with partners and find out. I will end there and pass it back to Sam.
Thank you, Jon, and thank you also to PK, and particularly Dr. Pal and Dr. Iyer for taking time out of their busy schedules to be with us here today. What we're gonna do now is because of the, you know, we wanna be respectful of the time for Dr. Pal and Dr. Iyer, we will do Q&A for the hemoglobinopathies and the immuno-oncology section now, and then take a short break and then come back, and do the Regen Med and in vivo sections. Susie here will direct questions. If you have any questions, please raise your hand.
You can state your name for-
Sure. Raju Prasad, William Blair. Thanks for the presentations. Sam, can you just talk a little bit about the c-Kit ADC and the in vivo strategy in the context of the Vertex partnership? I think it'll be interesting to kind of delineate, you know, some of the stuff that's in-house versus what Vertex is doing. Thanks.
Yeah. Thank you, Raju, for that question. As you can tell, we're extremely excited about the data from exa-cel. I think it's we had data for 75 patients, and to see 31 of 31 sickle patients have that transformative effect is just unbelievable, a few years after we started the program. I think, we obviously think that can be a very competitive product and address the needs of significant population of patients, but we wanna keep innovating. With the ADC for gentler conditioning agents, we started an in-house effort because obviously there are many companies that are also working on these agents, whether it's naked antibodies or ADCs for gentler conditioning. I think many of those have been optimized for different settings, mainly for AML settings.
What we wanted to do here is develop an ADC with a profile where there's very fast clearance, so you don't have any impact on the drug product. We started our own program here. Vertex also have their own programs around gentler conditioning agents, and ultimately, whichever one pans out, we can actually apply it to exa-cel. In fact, that applies not just to our programs, but also to any other programs that other companies may be pursuing. Ultimately, it's very beneficial to expand the patient population, and we can access the agent even if it's developed by someone else. You know, we think it may take 4-5 years, so exa-cel has a good runway with the current conditioning agent before any new conditioning agents come into play.
With the in vivo editing, you know, it's still early and there's a lot to be figured out here, but to get 60% editing with the dual AAV and HSCs is quite remarkable. We actually have a collaboration with the Gates Foundation to develop these, ultimately make therapies available globally. It will take longer on the timescale to get in vivo editing of HSCs.
Thanks.
Thanks. Joon Lee from Truist Securities. A couple quick ones on sickle cell and beta thalassemia programs. In the real world, what percentage of those who have matched donor actually undergo bone marrow transplant? And is that or is that not a good proxy for the commercial potential of exa-cel? And the second question is, have you shown or are you able to show clonality data using similar to what, you know, beta cell had to show in your product? And I have a follow-up on c-Kit ADC.
All right. We may just allow you for two questions, Joon. I'll address the first two questions you asked. And we have more time for Q&A later. I think you know the first question you asked around the transplants. You know, there's about 200-odd transplants that happen in the U.S. every year, and a lot of it's because you don't find matches. You know, I think the first recommendation for a lot of these patients with severe sickle cell is to get a matched transplant, if you can find a match. That is not a good proxy for the commercial potential for exa-cel because, you know, if you had more matches, you'd see a lot more allo transplants happening. We just can't find the matches.
I think with exa-cel, I think that proves a foundation for what patients are looking for, and then they go through allo transplant, even with the risks that come with allo transplant because they just can't deal with their disease at all. You know, the pain, the VOCs, et cetera. I think with an opportunity to have something like exa-cel, that just opens up the opportunity, and I think we'll see exa-cel capacity expand in hospitals and the infrastructure expand to allow for many more transplants. I think on the clonality data, I think you know that is more a specific question for lentiviral-based products and retroviral-based products. I don't think it applies as much to CRISPR, where we have such deterministic editing with every time we manufacture.
That's one of the, you know, great advantages we have with CRISPR is that the predictability of manufacturing, the reliability is a lot greater than viral manufacturing methods. We'll go to the next question. Here.
Hi there. Liisa Bayko at Evercore. I think I'll ask Joon's question on. I just wanted to understand, like, really what's the progress and with the field on this idea of gentle reconditioning regimens? And for your program specifically, what are the next steps? Just trying to understand, you know, a little bit more granular on tangible next steps and what's going on in the field.
Yeah.
It just seems like this concept, but a little bit obscure what everyone's up to. I think it's an important potential lever, obviously.
Yeah. I'll start, and I'll see if Jon wants to add any comments. I think, you know, three or four years ago, there was a lot of hype about gentler conditioning agents. Several companies developed agents, and it was, you know, everyone thought it was gonna come very quickly. It's taken a lot longer because it's you know, when you're dealing with HSCs, you really wanna you know there are many different populations of HSCs. It's not clear what you're depleting. The markers of long-term HSCs is not fully understood. That's something we've learned through our manufacturing process. You know, we characterize these cells quite a bit and understand all the subpopulations.
That's why we wanted to have our own agent to sort of optimize around what we're trying to solve for, which is sickle cell and thalassemia mainly, not as much in the cancer indications. Now we have looked at all the other options out there in terms of antibodies or ADCs that have been developed. In fact, we've looked at. We are using our own toxin for this that we think is more appropriate for this indication. It's a less toxic conjugate. I think in terms of the path forward, I think we will hopefully move into IND-enabling studies. Then you do have to try these in the relevant indications, and particularly AML, where it's most relevant, before you apply it directly into clinical trial.
There is a little bit of time before we bring this to bear. But, you know, what's exciting is if you can, you know, show the re-engraftment or engraftment of new drug product in mouse models or NHP models at a higher rate, then it gives us a lot of confidence that we can then apply it in human models for sickle cell and thalassemia. Jon, is there anything you'd like to add?
I would obviously. There was a gap in what everyone else was doing. When we saw this particular thing that we're trying with this toxin hasn't been done, and it's kind of the most appropriate one. We went for it, but as Sam was saying, if someone else fixes it's kind of okay, you know? We didn't wanna leave that gap there, for sure.
Tyler?
Great. Thanks very much for the presentations. Tyler Van Buren from Cowen. Two quick ones, hopefully. Can you tell us the latest on the sickle cell BLA filing? Vertex earlier this month said clarity should come in the coming months. I guess, you know, the discussions are related to follow-up. If you don't need to have all of the patients evaluable for the primary endpoint at 12 months, what percentage of patients do you think need to be evaluable to file? Then the second is on RCC. Really exciting to see that CR, or complete response, but obviously the next question becomes, how can we see more complete responses? You noted the tenfold increased potency with CTX131 . Does that increase expansion as well?
'Cause I think I saw 3,500 copies, which is a little bit lower than what you see in heme malignancies, and would that not make the safety worse?
Tyler, thanks for that question. There are two parts to the question, one on exa-cel and one on RCCs. I'll have Dr. Pal and Jon comment on the RCC question. On sickle cell and thalassemia, I think, you know, we're continuing to have discussions with the regulators. I think one of the advantages of having an RMAT designation is you can have continuous discussion with the regulators in the U.S. We also benefit, quite frankly, from the PRIME designation in Europe. You know, Vertex and us are aspire to file by the end of this year. I think on the EMA, we've completed a lot of the discussions, and we're confident that we can file by the end of the year for both thalassemia and sickle cell.
I think with the FDA, we're continuing discussions. I think it, you know, the discussions are two parts. One is the CMC-related discussions, and the other is around the number of patients and what the follow-up needs to be. I think on the CMC front, again, you know, having this commercially ready process from the get-go really helped us. I think that helps us answer a lot of the questions that the regulators may have. That, you know, there's still work to be done. You have to do complete process characterization around every starting material, around different components, et cetera. We feel confident that we can get there. I think on the clinical front, you know, I think, again, you have to put it all in the context of the data, right?
I think now that we have disclosed the data and we've done the data cut, we'll have more discussions with regulators. It's hard for them to comment even when they haven't seen data, and the only data they'd seen were a handful of patients. Let's take sickle. The last data cut was seven patients. I think we will have more information, and we hope to update you as soon as we have more information, and we'll provide that guidance. So far, I think we're trending nicely, at least on the European front. As for RCC, you know, I'm personally if you asked someone three years ago, "Will you see a full complete response in a solid tumor with a CAR T?" Forget allogeneic, autologous.
The answer was, you know, "No way, unless you get a Nobel Prize." Here we are talking about a complete response with an allogeneic CAR T three years later. We're quite excited about it, but maybe I'll first turn it over to Jon to talk about the expansion with CTX131 and the potency, and then Dr. Sumanta Pal to contextualize all of this.
Yeah, the peak expansion you saw was the average. We've had higher ones than that in the RCC trial for sure. We expect the dose for CTX131 to be significantly lower than CTX130 and potentially to have a slower burn to get there. That's certainly seen what we've seen in the mouse studies. That titration study we showed you, the lower doses clear the tumor and you just don't see this big expansion going on. Pre-clinically, I don't think it's a problem on what we've seen to translate into the clinic. What we've seen in the 130 trial, we've seen bigger expansions. I think on the whole T cells being a bit higher. I don't know, Monty, if you have any other comments.
No, no. Your points around wanting more responses are well taken. I see the same. You know, having said that, you know, I would just underscore the fact that in this heavily pre-treated population, these stable disease events are quite meaningful. This offers patients some respite from chronic toxicities from therapy and, you know, as we plan to ultimately publish this data around, you know, patients in this context, I think we'll see that there's some meaningful pauses in systemic treatment that we're able to afford folks in this setting. The stable disease rates I think are quite compelling.
Yeah. I think Monty, if you can further expand on that. I think a stable disease is not a stable disease like any other therapy because, you know, these patients come off therapy, if you wanna make that, you know, expand on that comment as well.
Absolutely. It really does invoke a bit of a pause. The reason why I think this is such a paradigm shift potentially in renal cell carcinoma is that, you know, right now everything that we offer post-front line is purely palliative and reflects a chronic treatment, whether it's a TKI, whether it's a novel HIF inhibitor, whether it's a checkpoint inhibitor in many cases. You know, these patients just remain on therapy for the long haul, and they're just constantly exposed to toxicity burden. In the context of this study, I've had more than a handful of patients who have been able to come off of systemic treatment, really enjoy a far superior quality of life.
Thank you, Dr. Pal. Ted?
Thank you. Thanks. Ted Tenthoff from Piper . Two quick questions, if I may, sticking with your two questions. Firstly, for T-cell lymphoma, are there other CAR-T programs in T-cell lymphoma, and what kind of data have they shown? Then the thing that I saw from the T-cell lymphoma that I think really maybe will carryover interesting to kidney is the repeat dosing, and it really looked like the best responses were seen in the T-cell lymphoma patients who were re-dosed. What does that profile look like or what could that look like in kidney, and what are the steps to actually bring repeat dosing into the solid tumor setting? Thanks.
Yeah. Thank you, Ted. To your first question, I'll ask Dr. Iyer to comment on the second part of the question, and PK as well. To the first question, you know, there aren't too many other cell therapies in T-cell lymphomas. The only other therapy is an autologous CAR-T targeted towards TRBC1 and TRBC2 that reported some data, preliminary data, at EHA. Generally, this is an area where not just are there no cell therapies, there just aren't any therapies out there. I think the comments we got at EHA from investigators were, "Gosh, we're dealing with something that had an accelerated approval 10 years ago and never had confirmatory approval. Gosh, we're dealing with Brentuximab where there's so much neuropathy that patients always come off of it.
We're dealing with Romidepsin where there's so much nausea, so much vomiting, you know, it's just very hard to keep patients on it." There just aren't. It's a very barren field, and I think Dr. Iyer will talk about that. Dr. Iyer, if you're still on the line, maybe you wanna make some comments around the competitive landscape or what options there are for patients in T-cell lymphomas.
Of course, Sam. I think it's one of the last frontiers for developing cellular therapy in lymphomas. Part of the reason why it's been so hard is, you know, it's because the T-cell fratricide that you normally see with autologous products. In addition to the TRBC1 that you mentioned, CD5 is also being considered as a target. Right across the street from us, Baylor is conducting that study. Although I should say that's limited to nodal lymphomas and not necessarily to the CTCL.
What is special about this in working with this, and I should say initially, when you do a study, it's always a promise, but when you see the results, it actually looks very satisfying and fulfilling to know that for a complex disease that spans multiple compartments, you're actually seeing responses across all compartments. There are other CAR T in development. We're very early on, like CD7, but the biggest problem there is fratricide. That being said, I think moving on to the second part of the question, I think we did show the data of second infusions in about five patients with final data cut off. Clearly, we have seen CRs in patients who received one, just one response.
One of the patients that I presented at EHA two weeks ago was this gentleman with transformed MF who couldn't even walk, had a lesion oozing from the leg and with an mSWAT of close to 100. With one treatment, went on to achieve a CR and is still in CR at this time, now four months later. It's not necessarily that you do require two treatments in this. Of course, it's a small patient cohort. You can't generalize this. There might be patients where you might need multiple doses. I think that's being tested, as Dr. Morrow had alluded to earlier. There are patients for whom I think one treatment may perhaps be more than sufficient. I think this is what the study moving forward will show us.
Yeah. Thank you, Dr. Iyer. I think the other part of your question on redosing, Ted, you know, we have seen benefit. In fact, you know, benefit could come either from very long durability in these T-cell lymphomas from multiple doses or single dose, or by the way, if you get them to transplant, it's not a bad outcome for these patients because, you know, the allo transplant is one of the highest potential options in terms of curative options for these patients. Even if you get them to that setting, it's actually quite good outcome for the patients. You know, finally, I think for what does that mean for RCC. We are actually now, and Dr. Pal and other investigators are now putting in place the redosing paradigm into the RCC trial.
Now, we, you know, we obviously wanna show more data from this trial, and I think what we discussed with all the investigators is that we wanna do it at a scientific meeting, given the importance of the first allo CAR-T in solid tumors. We will show additional data on the RCC trial, including patients that have gotten a redose. The more to come there. Maybe a couple more questions before we take a break. I see Yigal right in front of me here. Sorry.
Great. Thanks, Sam. Yigal Nochomovitz at Citi. I just had a question on the dosing ladder for RCC in the T-cell lymphoma. I think if I saw correctly, it was the same dosing ladder for both diseases. Was that done just out of simplicity for operational simplicity, or was there some reason to believe that, you know, the same dosing range would be appropriate for two very different diseases?
I'll start and then see if anyone wants to add any comments. I think, you know, a lot of it is just understand, you know, the regulators are also learning as we go along in terms of what these cell therapies do. You know, I think we, you know, we had sort of an unfortunate death in a different trial with the CAR-T in solid tumors, and I think people just wanna be a little more cautious. So I think the original assumption we had was that we could go with even higher doses in solid tumors, right? But I think given sort of how we're trying to bring all these to patients safely, we're starting more conservatively. So that's the reason for the same dosing ladder, but it's a good question.
Okay. Then if Dr. Iyer is still on the line. I'm just curious what you think about the dosing. Do you believe you should go for multiple doses now or maybe push the dose even higher beyond DL4?
Dr. Iyer.
Great question. I think, as I alluded earlier, there might be patients who will need multiple doses. You heard about trying to improve the longevity of the allo product. I think one of the big questions is who are transplant candidates? Because it is so exciting that we talk about transplants as the best curative option, but in reality, less than 10% actually make it to transplant. When you have a product like this for a young patient, and it's going to be a life-saving bridge to transplant, and whether it's one or two treatments or more.
To that, I think we are investigating this multiple dosing of possibilities and particularly making sure when somebody has to get to a transplant, you get them to the complete remission state. If it's one infusion gets you to, you know, maybe 1 or 2 or 2.5 compartments control, I think you want to have complete response in all the compartments. Multiple dosings perhaps is one way to go for this transplant-eligible patient. For the non-transplant-eligible patients, I think one of the things because the follow-up is so short, and I think if you have patients who are able to have great prolonged response time, and they're not transplant eligible, and it's very well tolerated for the most part, I think that's one way of keeping the disease under control for a long time.
I think future follow-up will help us understand if it's at all unique. I think we're looking forward to that.
Just to add to that, just briefly, I think what we've seen is some deepening of responses with those second doses. What we're trying to determine now is which are the patients who are most warrant a second dose and the timing of that, right? We've looked at, for example, day five redosing, day 35. We're looking at first, one, you know, that triangulation of timing. Which patient characteristics, you know, warrant a second dose in order to provide a deepening of response to either get them to CR or to bridge them to transplant.
Yeah. Thank you, PK. Thank you, Dr. Iyer and PK. We wanna keep on time, so we'll do one last question. I see Tony over there, and then we'll have more time for Q&A post the second session. We just wanna be respectful of Dr. Iyer and Dr. Pal's time.
Thank you very much. Tony Butler, ROTH Capital . Jon, I wanted to just stay on the duration comment you made. With the two additional edits that you've been able to demonstrate, the question is. I mean, let's be fair. What sometimes this word duration gets maybe overused. We just need enough pharmacological pressure on the tumor in order to get the appropriate phenotype, which would be obviously no tumor. The question really is that going to be sufficient, do you think? Then obviously you're gonna say yes because that's what you've deduced from. Here's the issue. Is it duration is the question, but do you need something else beyond the CAR to help in killing? Maybe an ADCC mechanism or something else beyond that? Thanks.
Jon, do you wanna take that question?
I'm gonna say yes 'cause you said I could if it's enough. No, but it's a fair question. I mean, these two edits were determined empirically given the toughest challenges that we could think of and compared to anything else. As long as the antigen is there, they're gonna keep killing the tumor cells, as you saw with a, you know, with a second re-challenge. I think maybe one of the places where there's gonna be help is antigen escape. I think that's another reason why you wanna get as much of the tumor as early as you can. You don't wanna be tickling it for months given, you know, it the opportunity. From what I've seen, these things are gonna kill as many tumor cells are there once they get there.
Yeah. Thank you, Jon. I think, Tony, you know, obviously we have some ADCC approaches in the NK cell, NK CARs, so we'll have to see how the data emerge and what that tells you. I think some things we just don't know until we see the data. At this point, I think the CAR axis probably acts as a primary axis, and unless it's a heterogeneous tumor and we've had CD19 negative escape sometimes, right? I think the CAR is the primary way we're gonna try and attack the tumor at this point. Thank you for all the questions. I'm sure there are more questions here, and I missed some of you.
Why don't we do this, which is we'll take a very short 5-minute break and come back at 3:15 P.M., and try to make up some time during the presentations for the Regen Med and the in vivo sections and leave a little more time for Q&A for the second half. I really wanna thank Dr. Pal and Dr. Iyer for taking the time to be with us today and for, more importantly, for leading our clinical trials in these important indications where patients have great unmet need. Thank you all. We'll take a 5-minute break and come back. We will start again here for the second part of our session. Thank you for all the engagement and the questions for the hemoglobinopathies and immuno-oncology.
You saw the extent of innovation that's happening in both those franchises, and now we'll talk about our regenerative medicine franchise. I'd like to invite Dr. Alireza Rezania to take the podium.
Thank you, Sam. Very excited to be here. My name is Alireza Rezania. I lead the Regen Med franchise at CRISPR. Let's see. I'm very excited to share with you our regenerative strategy as well as our progress we've made. Unlocking the potential of regenerative medicine is hereby combining the breakthroughs in pluripotent stem cell technology as well as CRISPR genome editing. This is indeed our vision, that combination of these two platforms will enable a new class of replacement therapies for both rare as well as common diseases. Treatment of type 1 diabetes using cell therapies is our first application of RegenMed platform for the simple reason that the proof of concept clinical data is already out there in the form of islet transplantation.
The field recently celebrated a 20-year anniversary of the Edmonton Protocol, where investigators at University of Alberta infused cadaveric human islets via portal vein into liver of type 1 diabetic subjects, resulting in significant number of patients becoming insulin independent. This was coupled with elimination of glucose excursions. You can see an example of that in the figure on the left-hand panel, a patient pre-transplant and on continuous glucose monitoring, you can see the excessive glucose excursions despite being on the best treatment. What happens afterwards when they get the islet infusion? Those glucose excursions essentially eliminated. It's very well known that these glucose excursions are what leads to complications of diabetes. Despite this remarkable success, this approach has been limited by two main reasons. One is that there is a scarcity of islet tissues.
Many of these patients who became insulin dependent require two islet infusions or more. Essentially, we have an issue with scalability of cell source. The other one is that they have to be on chronic immunosuppression, right? Chronic immunosuppression carries with it significant risks that are well known and also requires patient compliance. There have been many instances where a patient didn't adhere to the immunosuppressive regimen, and they lost graft function. The last thing I'll mention is that chronic immunosuppression really limits the patient population to very severe type 1 diabetes phenotype. We typically have hypoglycemia unawareness. How are we gonna solve these two main challenges? Our approach is to use gene-edited stem cells that can really enable much broader applicability than what's already been shown with islet transplant.
Regarding addressing the scalability and cell source, three years ago, we partnered with ViaCyte, a world leader in generating pluripotent stem cell-derived pancreatic cell, essentially addressing the scalability of the cell source. Regarding chronic immunosuppression, this has been a challenge that the field has been grappling for the past couple of decades. One of the main areas that people have focused on is to use essentially a physical barrier, where essentially you are separating your grafted cells from the host immune response with a hope that will allow the cells to thrive. Despite significant research effort and investment in that approach, there has not been a clear clinical benefit established. What is our approach?
We like to take the approach of multiplex genome editing at a cellular level to avoid the need for long-term immunosuppression, as well as introduce new edits that go beyond immunoevasion, address cell fitness and as well as functionality. Earlier this year, along with our partners at ViaCyte, we launched the first clinical trial of its kind, which essentially is addressing immunoevasion. This is a phase one safety trial. Our approach regarding product strategy is multi-staged, starting with 210, progressing to 211, and landing on 212. Our ultimate goal is to make a gene-edited pancreatic beta cell that does not require any chronic immunosuppression or a device. We refer to that as VCTX212. That's at the earliest stage of development. With VCTX210, we've entered the clinic.
This is a safety trial, and we'll address immune evasion, and really will inform on two eleven design. Two eleven is introduces additional edits that we'll talk about in a subsequent slide that really promotes cell survival and fitness. We are on track to file a CTA for 211 later this year, and this, to our view, will really represent, in the clinic potential for a functional cure. What are the edits? 210 , VCTX-210, and, by the way, we are very excited. It's the first time we actually introducing the edits. I know we get these questions often. VCTX-210 has four edits, while VCTX-211 has six edits. We have the same four edits that are in 210 plus two additional ones. We categorize these in two buckets. One is the immune evasion bucket, and the other one is cell fitness.
In the immunoevasion bucket, we are removing MHC class one by knocking out B2M. We're introducing PDL1, a very well-known molecule, to induce some level of tolerance by inhibiting antigen-specific T-cell proliferation. Also lastly, we're introducing HLA-E to further dampen immune response via the NK cells. Regarding cell fitness for 210, we are knocking out thioredoxin interacting protein, also referred to as TXNIP. TXNIP inhibits thioredoxin, so by knocking out TXNIP, we can essentially relieve thioredoxin to act fully and to dampen oxidative and ER stress. A major reason why beta cells have failure is because of oxidative and ER stress. Lastly, for 211, we're introducing two novel edits. One is called A20, also known as TNF alpha-induced protein 3 that induces graft acceptance as well as protection from cytokine-induced apoptosis.
MANF, that stands for mesencephalic astrocyte-derived neurotrophic factor that enhances beta cell proliferation as well as protection against inflammatory stress. In sum, 210 has four edits, and 211 has six edits. How do we know these cells actually can protect, these edits can be protected in a setting of allogeneic rejection? We test them in a battery of in vitro assays as well as in vivo models. You can see here addressing the adaptive immune arm by looking at T cell response. These are mismatched T cells that we simply ask the question, what is the difference between unedited and edited 211 edited cells in response to a mismatched T cell proliferation assay? As you can see, unedited cells definitely trigger the T cell response as predictable.
However, 211 cells did not elicit any T cell proliferation. It was actually lower than T cells alone. We've tested multiple T cell donors as well as whole PBMCs from healthy donors as well as from type 1 diabetic PBMCs, and we see very similar response. Regarding the innate arm, specifically looking at NK cell killing, we see we compare 211 edits versus unedited, and that's compared with controls. Cancer cell line that which has Class I knocked out, as expected, the cancer cell line definitely triggered NK killing because it has no B2M, no Class I. However, 211 edits did not elicit any NK killing. Again, we've looked at many different NK donors. Taking this to the next step and testing it in a humanized mouse model.
In this particular humanized mouse model, we have reconstituted the T cell, B cell, and NK cell, as well as the neutrophil cell compartment. It is pretty robust humanized mouse model. We ask a simple question, is there a difference between unedited and edited in terms of survival and durability? As you can see, putting unedited pancreatic precursor cells, and we measure that by measuring bioluminescence intensity, there's a dramatic drop post-transplant a few weeks later. Versus in VCTX211 edited cells, we don't see that drop at all. The bioluminescence intensity stays constant. This gives us confidence that our edits are making a difference, at least in this in vivo as well as humanized mouse model. What about potency?
In order to test for potency, we transplant these cells in a diabetic rat model, and we compared unedited versus edited cell population, and we were delighted to see that our edits actually make a meaningful difference. On the left-hand panel, you see looking at C-peptide production. C-peptide is a biomarker for insulin. When proinsulin gets processed, we get insulin and C-peptide produced in equimolar fashion. You can see about 3x fold increase in C-peptide production compared to unedited population. Further, we looked at two of the cardinal features of beta cells. One of them is glucose responsiveness, the other one is how they respond to exogenous insulin. In case of C-peptide production, in terms of when we look at glucose response, we fast the animal, and then we give them a bolus of glucose.
You can see in the middle panel, there is a 13x fold increase in C-peptide production shortly after giving the bolus of insulin, essentially check-marking one of the main features of beta cells, GSIS. On the last panel, we're showing what happens if you give them too much insulin. We give them exogenous insulin injection, and you can see the cells are appropriately shutting down C-peptide production. In sum, we think these features will allow for consistent glucose homeostasis. How do these graphs look? You're seeing here cross-sectional images of what these cells between the lumen of these devices look. On the top panel, we've provided the arrow to help orient you where the device membrane is, and then between the lumen of the device is where the cells reside.
This is many months post-transplant. I just wanna highlight that these graphs are highly vascularized. Vascularization and close proximity of beta cells to blood vessels is a really critical feature for maintaining their function. Next, we see in another image, where we've stained for endocrine hormones, in this case, insulin and glucagon. Insulin is stained in pink, and glucagon is stained in brown. There's a predominance of beta cells within the lumen of these devices. The ratio is about 2 to 1. Lastly, we stained for PDL1, one of our knockins, and this is what's very important for us. We have to make sure our knockins are retained post-differentiation. We're putting these in embryonic stem cells and pluripotent stem cells. These cells definitely, once they differentiate, there's chromatin remodeling going on.
We wanna make sure there's no silencing of those knockins. Indeed, we don't see that six-month post-transplant. We were delighted to see that. Then lastly, we tested the ability of the cells to normalize blood glucose in a chemically induced diabetic rat model. We give the animals beta cell toxin called STZ, and you can see on the left panel, the blood glucose, as expected, shoots up. The animals are put on insulin treatment, just very much mimicking what happens in the clinic. Then a few weeks later, we transplant the cells with the device. You can see, after 12-16 weeks, there's normalization of blood glucose, and this is very much in conjunction with the significant increase in C-peptide we see on the right-hand panel.
This slide summarizes our pipeline in terms of the VCTX programs. Let me just re-emphasize the main point I started. The era of gene-edited pancreatic beta cells is here, and we have progression of multiple products starting with VCTX210, which breaks new ground with our partner at ViaCyte looking at immune evasion. This is a safety trial. We've been making really good progress with VCTX211 with gene edits that confer additional cell fitness and functionality to these cells. Then ending with VCTX212, we're gonna be incorporating new edits in VCTX212. At some point down the road, we'll disclose what those edits are, that in our view can address type 1 diabetes as well as insulin-requiring type 2 diabetes.
With that, I'm gonna hand it off to my colleague, Jon Terrett, to talk about our exciting in vivo platform. Jon?
Thank you, Ali. It is exciting to move to our fourth pillar in vivo, and probably show the most comprehensive data we have in this area. Our strategy for in vivo therapeutics is to progress from gene disruption to whole gene insertion and correction. Gene disruption is tractable with current technologies and offers a set of potentially 10-20 very meaningful therapeutic opportunities. However, it is fundamentally limited by the fact that the majority of the genes cannot be eliminated permanently safely. Similarly, base and prime editing have a finite set of opportunities where disease is caused by a single point mutation or a small mutational hotspot. The vast majority of monogenic diseases are caused by mutations throughout a multi-kilobase region, and therefore require gene insertion and correction.
Over the past five years, we have established a powerful messenger RNA LNP-based platform for gene disruption, starting with the liver. Our plan is to advance a broad portfolio of therapeutic programs based on this platform, which will form our entry into in vivo therapeutics. In parallel, we have advanced gene correction and insertion using validated AAV and LNP technologies, and are moving a hemophilia A program towards the clinic. We are working to extend gene correction and insertion into novel technologies that could allow HDR independent AAV-free formats for whole gene correction. Some data. As just stated, we have put together the relevant platform pieces to enable high efficiency direction of genes in the liver, including an acceptable off-target and safety profile. Those elements are the LNPs, the guide RNAs, and the Cas9 mRNA.
This slide shows the clear dose response in terms of in vivo editing that we observe in non-human primates. You can see that the editing rates plateau at about 70%, which is totally in line with anything else you've looked at from other companies, and normally corresponds to a 90% knockdown in the protein when we look at the plasma or serum. We're taking advantage of a well-established translational research and development engine to advance a broad portfolio of wholly owned programs making use of this mRNA LNP platform. These programs have significant synergy, given that the only thing that changes from one program to the next is the guide RNA. The LNP and the mRNA are shared across programs.
We're advancing more programs to non-human primate proof of concept stage, from which we will choose programs to enter the clinic sequentially, as well as potentially access partnership opportunities, given that this area is completely unencumbered for CRISPR. The first place we decided to deploy our gene disruption platform is in cardiovascular disease. Listed here are three gene targets where there's deep evidence through natural human genetics that significant clinical benefit can be achieved through long-term lowering of target protein levels. There is a clear development path by targeting severe disease and then expanding into the very large patient populations at risk of atherosclerotic cardiovascular disease. Gene editing for these targets represents a paradigm shift to one and done therapy, and avoids the risk of poor compliance and inconsistent knockdown that may be provided by other therapeutic modalities.
With that strategy and platform in mind, we've very quickly gone to lead candidates for a couple of these programs. CTX310, it has a number now, targeting ANGPTL3. As you can see on the left, we've got the dose response in the protein knockdown that we saw with the editing. It goes across the programs. The 3 mg per kg group at 90%, 1.5 mg per kg practically there as well. The corresponding reduction in serum triglycerides at 1 month. We have studies running longer than this that show this protein knockdown stays with the animals through multiple months, and we're progressing CTX310 to the clinic in 2023.
Following quickly behind another protein in this area that doesn't need any introduction, although we put a reminder on the left-hand side, very simply, the more Lp(a) in the serum, the higher the risk of cardiovascular disease. Again, we've quickly gone to a lead candidate. You can see the protein reduction again happening very, very quickly. Here we've got data shown out to day 57 with a 92% reduction at 3 mg per kg. What you see at 1.5 mg per kg, if you take the graph on the left and you say, "What does that mean in reduction?" You're well into therapeutic benefit, even at 1.5 mg per kg.
For both of these programs, we expect the doses in humans to be lower than we're seeing in cynos, and that has been consistent across publications from other companies in these areas. Moving to the gene disruption, as stated, the vast majority of monogenic diseases are gonna require gene correction or insertion, and we're using validated LNP and AAV technologies to achieve this in liver, starting with our hemophilia A program, where we'll share some data shortly. To progress beyond this format, we've established a dedicated group within CRISPR, which we're gonna call CRISPR-X. This group will work internally and scan the external environment for cutting-edge technologies for in vivo editing. One example is emerging technologies that could allow DNA-independent, all RNA-based gene correction. I'm sure you've seen the publications and some of the hype.
These technologies are currently limited by low efficiency and specificity, and that's the point of CRISPR-X, is to look at all of these things going on and develop the ones that are better suited for therapeutic use. Some data around our hemophilia A program. We've been looking for suitable safe harbor loci. I was gonna say better, but it changes with the gene you're looking at, the protein you want to express, how much of that protein you want, how easy it is to get the right post-translational modifications. So again, we're scanning the genome, and what you can see, editing in green and active protein in blue for Factor VIII on the left, it's not a linear correlation. The cells have to be happy producing that much protein and putting the right post-translational modifications on it.
You can see that loci one, two, and three, they don't edit as well as the albumin locus, but they produce more amounts of active protein. We take that information, and we're putting it into programs like Factor VIII hemophilia A on the right, and you can see that we are out 100 days with therapeutic range, normalized range of Factor VIII by this targeted insertion mechanism. To summarize, this slide shows our new in vivo pipeline. We're advancing a broad portfolio of gene disruption programs based on our powerful mRNA LNP platform, starting with the cardiovascular targets. Our hemophilia A program is progressing as a first targeted insertion effort using a combined LNP AAV approach. Additional undisclosed and partnered efforts round out our in vivo portfolio, which seeks to exploit the full breadth and potential of CRISPR-based gene editing.
With that, I'll hand it back to Sam for some closing remarks.
Thank you, Ali and Jon. I hope this presentation gives you an appreciation for the full magnitude of innovation that's happening within CRISPR. If I just recap what we talked about today, in hemoglobinopathies, we're very proud of what we've achieved with exa-cel, and we're in pole position within that indication with editing-based approaches. We wanna protect what we built there and quickly follow that up with gentler conditioning agents and in vivo editing, although that'll take some time, in a way where we remain at the forefront of that field in providing cures to patients with sickle cell disease and beta thalassemia.
Beyond that, in oncology, I know it's a competitive space, and there are a lot of different companies with different approaches, but what we've been able to do is not just put our initial programs in play, we're able to learn from the initial programs and come up with what we think are the two best synergistic edits that we can find out there for potency. You know, you've seen many different labs, many different companies go for some of the obvious edits, like inserting cytokines. You know, there's edits around persistence that some people have done. But what we've seen from our data with CTX110 or from other CAR T data, we think that having early deep responses can lead to durable cures or remissions in many different settings.
With that in mind, we put in play the strategy where we have the two synergistic potency edits, and we're seeing, you know, at least in preclinical data or in manufacturing, the greater level of expansion, you know, the greater potency, rechallenge models, and we're very excited to put these in play. At the same time, we're executing on 110 and 130 to bring them to the clinic and bring them to approval, and we have the benefit of having RMAT designation, and/or other designations that help us in terms of regulatory development. What do we see in regenerative medicine? You know, we weren't gonna go innovate in a serial fashion. I think what we're doing is parallel innovation at a very rapid pace, given that we've invested in a platform where we can manufacture the iPS cells.
We put not just 210 in play, which by the way is dosing patients right now, and we're in the clinic, and we hope to have data, you know, for a set of patients that shows whether these cells are immunoevasive or not. We're not resting there. We wanted to quickly iterate with edits that again, are not very obvious unless you do very large scale empirical screening to find edits that make these cells more robust, and we have all the IP protection around these edits, make these cells survive longer, and that ultimately should get us to a point where we've actually enabled a beta cell replacement as a cure for diabetes, not just type 1 diabetes, but also type 2 diabetes. This is the first time we're talking about in vivo.
You know, we were sort of cast as an ex vivo company for a bit of time, but we've been working on in vivo in the background. I think what we have is one of the most powerful mRNA plus LNP technology that we showed data for. I think we can see very high levels of gene disruption at doses that are comparable to what other companies may have shown. I think with our balance sheet and our ability to translate very quickly and develop in the clinic, we're gonna have multiple programs in play with the in vivo, which all have some synergies between them. As Jon mentioned, all it changes the guide in some cases.
We're going not just for some of the more obvious targets, we also have behind that some other indications that cover both rare and common diseases. Ultimately, again, we don't wanna stop there. We wanna go and improve our platform with whole gene insertion and whole gene correction that ultimately opens up a whole new set of applications for gene editing. If we can do in vivo gene correction or gene insertion, there are tens of diseases we can go after, and that just doesn't stop at the liver. We're also doing improvements in delivery. You saw that we have an undisclosed ocular program, for instance, with LNPs. We're going into, with LNPs into other disease areas that really opens up the space for us. The level...
You know, if you ask me over the last seven years that I've been at CRISPR, I'll say the level of energy and excitement that we feel today is the highest it's ever been at the company. You know, we're all very excited about the innovation that we're putting in play. We're very excited about the possibilities, what gene editing can do, and I know there's very different macro winds that are blowing that may orientate towards value or different, risk-off mindsets, but innovation is the key, and that's what our ethos is. It's innovation that matters that you see on the wall over there, and we'll continue to innovate in parallel fashion across these different franchises, and we hope to bring transformative medicines to patients over the next few years, and we're here as a company that can be the next Genentech within biotech.
We'll stop there and go to the second part of our Q&A. Thank you very much, and I already see some hands up in the air, but maybe Gil, you start us off.
Thank you for taking our questions. Gil Blum from Needham & Company. Is it okay to still ask questions from the previous section?
Sure.
Um-
We wanna focus on this section, but please go ahead, yeah.
Only Gil. No one else.
I'm the only one who gets it. Just a quick one on T-cell recovery. We saw really interesting data with CD70. I'm just curious how rapidly did the patient's own T cells recover following treatment considering there were some infections?
Yeah. I'll start, and I think, you know, these are data that we wanna present, additionally, in publications going forward. Overall, I think the infection rate was quite low if you look at the data from a high level. We don't have Dr. Iyer on the line anymore, but I'll turn it over to PK and see if you wanna make any comments around T cell recovery or the level of infections that we see.
Yeah. You're spot on. There were infections that we're seeing, but recall also that we're talking about actually a disease state that has significant skin involvement. We have patients, many of them who have a high predisposition for superficial infections as well as additional other infections. The level of infection that we've seen, first of all, we did not find the majority of them to be related to CTX130, as you probably saw. This was confirmed with our investigator. Secondly, it's also the fact that they actually do not rise above the noise that's seen with T-cell lymphoma in the natural history of this disease.
Thank you. I'll continue the trend of asking two questions. Do you think the use of a kind of a transplanted device for the regenerative medicine portion of the portfolio does that reduce potential risks involved when going after diabetes mellitus?
Yeah. Let me start and see if Ali wants to add anything, which is, I think we obviously have two strategies. I think, you know, there have been questions before about directly injecting the cells versus the device approach, and I think they both have a lot of potential. I think the device approach is more relevant to type 1 diabetes setting. You know, I think if to truly get to a scalable type 2 diabetes drug, you probably need to have injectable cells. In the type 1 diabetes setting, as we're starting off, I think there's so much to learn about these cells. You know, I think we want these cells to find their niche in the patient, be protected, but then expand and grow and thrive in that environment.
I think the perforated device design that was developed by ViaCyte, I think allows for that. There have been patients who've actually had very meaningful glucose glycemic control using those devices. Also, they're retrievable in case we need to learn more about the cells. You know, that gives us a great sense of what's happening with the cell subtypes, you know, what other infiltrations there may be from other types of cells in there. There are many advantages with starting with the device, which is why we're going with the device approach for type 1 diabetes. Ali, anything to add?
Yeah. Thank you, Sam. I think you covered the bases, and I also highlight two recent seminal publications from the ViaCyte team summarizing their recent clinical data, over 30 subjects transplanted with the same similar device to what we will be testing or are testing, and they don't see any safety issues. For us, safety matters most, right? Because this is. You're not talking about a cancer patient who has two or three months left. You're talking about someone who has diabetes, right? We wanna make sure we are extra cautious. For that in mind, we thought that, you know, having two arms, where one will focus on device and another a little bit later on in terms of addressing with VCTX212, which is a little bit higher risk because we are planning to infuse in the liver, and we can't retrieve.
For us, that safety margin in the device is really important. That's why we're starting with that. Yeah.
Yeah. Silvan?
Great. Thank you. Silvan Türkcan from JMP Securities. Congrats on the progress with T1D . Quite interesting. There, the device is important and I think the colleagues' advice that have shown that you need to have infiltration of immune cells, but also blood vessels, and there may be regions where you have lots of cells engrafting and regions where they're not engrafting. Could you just speak a little bit to how do you make that or have a more homogeneous outcome? Maybe a second question that's more open-ended. About in vivo editing, just a general strategy question for CRISPR. We've seen a lot of these targets before made by other companies.
What is it that you can bring to these targets, you know, based on the progress that you've already made with Cas9 that you know could help you excel here?
Yeah. Thank you, Silvan. Ali, I'll turn to you for the first question around the device.
Sure. It's a great question. Indeed, you know, that was observed, and you highlighted that in their publication as well. They noted that. This is why we are very jazzed about VCTX211, because they have introduced new edits that really improve that early cell survival as well as cell fitness, and also their functionality. That was not the case, obviously, under the population. We're really hopeful that really is gonna move the needle in terms of the percentage of the device that's filled with functional beta cells.
Yeah. To the second question on in vivo, I think, you know, there's different levels to look at that strategy. One is, you know, I think, we've seen data in the last year or so which shows that in vivo gene editing can be done safely and can be done at high efficiency for gene disruption, right? So all of a sudden the new frontier is open, and not only have we seen that, we saw that the data translate really well from NHPs to humans, and in fact you may need a lower dose in humans than you may need in NHPs. You know, so all of a sudden for us it was pedal to the metal on in vivo platform in general. Why cardiovascular targets?
You know, you've seen a lot of companies go after cardiovascular targets, whether it's antibodies, RNAi or siRNA, and the first question you can ask is, there's so much competition, why are you going into it? But one of the big things you've seen with these indications is a compliance issue, an adherence issue. You know, I think even with the antibodies, while it's a reasonably large growing category now with the antibodies, you know, you still see a lot of patients falling off from therapy from a compliance standpoint. When you can have a one and done solution that is shown to be safe based on natural history data, that can be very powerful. Mindsets are changing around these therapies. Even the last three years, think about how far we've come around acceptance of CRISPR-based medicines or editing.
You know, I think in early days of dosing thalassemia and sickle cell, we had to do so much more education, and now we've dosed, you know, over 75 patients in that indication alone and over 150 patients in cancers. It's changing very rapidly, and having not only that, but also the ability to develop in very severe indications, which PK has identified with the whole team, where we can get to a regulatory path and approval but then broaden it very beyond that, is quite attractive. I think that's the logic behind starting there, but we also have a number of rare diseases where we're going after as well. Ted, since I'm looking in that direction.
Thanks, Sam. Can you hear me or?
Yes.
Okay. You know, I really agree with the last point you made. First I'm gonna make a comment and then two questions. You know, you're seeing the same exact thing right now with siRNA, where, you know, originally it was relegated exclusively to orphan diseases, and now obviously with PCSK9, so you're I think you're following a tried and true path here, which is, you know, really being shown right now in practice. I totally agree with what you said at the end. Two questions. What kind of in vivo editing efficacy can you achieve? And are there different percentages for the LNPs versus AAV? And then my second question was just is there any reason the Vertex partnered programs are footnoted versus highlighted on the in vivo pipeline slide?
I'll start with the second part of your question and thEn go to Jon to comment on the editing efficiencies. Obviously, the editing efficiencies are very different based on gene disruption versus gene correction and what modality you're using. You know, there's no reason we're not bullish about the Vertex programs, it's just that we've talked about that a lot before, given that's been the focus of many questions, and we just wanted to highlight other things we're doing outside of perhaps the DMD program and the DM1 program. You know, we're actually making progress on the DM1 program. We had a milestone payment from Vertex not too long ago on the DM1 program.
We are pushing forward, but a lot of the work now is with Vertex in terms of the manufacturing and scale-up associated with DMD and DM1. In terms of the editing efficiencies for LNPs, Jon?
Yeah, I mean, if you mean in the liver, we saw that the 70%, right? Those are just punch biopsies, so it's probably more like 90%. I think every company sees that plateau. The other part that guides us to that is you can see the 1.5 mg/kg, it kind of nearly gets there with some, and then the 3 mg/kg just tightens it all up. If we think about other tissues, you saw we got the 60% going way back to the AAV stuff that PK spoke about earlier with the AAV, and it'll be a significant part of CRISPR-X to also find targeting to other tissues. I think that's a significant part is not just the technology for the editing, but how to edit tissues other than liver.
Yeah, I think, you know, obviously, we haven't shown any of the data today, but we are looking at other organ systems. You know, LNP, obviously a lot of LNP get taken up in the liver, and that's the primary place you can edit with LNPs. If you know, the eye is an interesting option where you can use LNPs. You can get LNPs past the liver without tox and get into certain organ systems with targeted LNPs, where we conjugate certain recognition moieties on top of the LNPs.
I think that's one of the advantages we've had right now is, you know, we're on the offensive with platform development, where a lot of companies are being on the defensive, and we continue to push really hard on achieving very high delivery, which then leads to very high editing efficiencies. We also wanna innovate in terms of the type of editing we do. You know, I think delivering DNA-based templates is a little harder than RNA-based templates. Can we use RNA templates and use a different conjugated editing machinery where we can get very high efficiencies? A lot behind the scenes here, and we hope to do these kinds of events often so we can be, you know, very open kimono about all the things we're doing and working on.
Go ahead. Tony?
Wait, who?
Yeah.
Sorry.
Hi. Richard Law from Credit Suisse. I also have a question from the previous session. Looking across the redose patients for CTX130 and other allogeneic CAR-T programs, how do you compare the safety data for redosing versus the initial dose? Is there any redosing learning that you can take from redosing to consolidation dosing?
Yeah, very good safety profile, but I'll let PK expand on the question.
Yeah, thAt's spot on. You know, we've had such a profoundly positive safety profile, and we haven't seen any new safety signals with redosing. I would say that, you know, ultimately, you know, we haven't seen it any negatives with actually redosing patients. The only question is, you were alluding to, is what learnings can we gain from the current programs in terms of the appropriate timing of dosing and which patients would benefit most? That data we're still actually gathering at this time.
Generally a very tolerable profile. That opens up.
Yes.
Redosing maybe more than twice.
Yeah.
Okay.
Hello, Cheng Li, Oppenheimer. Thanks for taking the question. I also have to go back to the previous section, so two for me.
All right.
For the exa-cel, I'm just wondering, can you comment on the patient diversity in the trial and basically how to maximize patient access, especially I think the disease disproportionately affects patients in the U.S. and also have pretty diverse geographical distribution. For the allo CAR T part, I guess my question is, how are you thinking about the treatment sequencing, say for CTX110 in the context of like auto CAR T, bispecific, and some other novel agents? Thank you.
Great. Thank you. I'll answer both questions briefly, just sensitive to time here. I think on exa-cel, I think, you know, you're right in that this sickle cell obviously affects a certain segment of the population, which is distributed, you know, more incidence in certain states within the US and in certain countries in Europe. I think what we've done actually is try to recruit patients within those regions to get sites ready for these transplant procedures, ultimately with the view of having an effective commercial launch, right? I think we have done that. I think you'd be surprised in Europe there's a lot more sickle cell incidence than people imagine. It's not just thalassemia.
There's quite a bit of patient need for sickle cell among the major European countries in addition to transfusion-independent thalassemia. Again, we've tried to get sites on board our trials across all these different geographies to ensure that we are preparing them for what could potentially be an effective launch hopefully once we're approved. On the second question, PK, do you wanna address that?
Yeah. We're actually looking at a variety, honestly, of sequences. I can't actually tell you definitively which one we're going to be choosing. We've met with opinion leaders and oncologists and investigators and discussed with them, where can we have the greatest benefit? Obviously, some have suggested things like going after allogeneic CAR T. I would say that right now what we really need to do is further analyze our data and see where we combine sequence or combine or even sequence. Honestly, combinations, you know, with other therapies is not out of the question either.
Yeah, I think it's a very difficult question to answer. I think there's, you know, you have bispecifics, you have auto CAR T. You know, recently you've seen interesting data. You saw data for a bispecific in frontline higher risk, for instance, right? The things are moving up in the, you know, in the different treatment lines. Again, bispecifics and auto CAR T are ultimately using the endogenous T cells from the patient, and not all patients have good immune system to work off of. I think allo CAR T ultimately can leapfrog a lot of these therapies.
I think especially if you have more potent allo CAR Ts, eventually the flexibility that you have with the amount of doses available, off-the-shelf nature, single dose, all that is gonna come into play at some point, and it's gonna be superior, I think, to bispecifics or auto CAR Ts. But only time will tell on that. Maybe we'll do one last question. Go ahead. Yeah, Elizabeth.
Hey, it's Elizabeth Webster on for Salveen Richter at Goldman Sachs. Maybe kind of a bigger picture question is that now we have kind of a lot of visibility onto the breadth of the pipeline, and I know you have plenty of cash, so what's your strategy for pipeline prioritization on the forward?
Yeah. Thank you. Thank you, Elizabeth. I think that's one of the benefits we have or the strong position that we have here with CRISPR. We have a very strong balance sheet on the back of, you know, frankly, success with exa-cel that allowed us to capitalize on that and build sort of for the future, and I think we're gonna leverage that. I think we are gonna take risks and be aggressive across all these programs. Now, ultimately, we don't need to take all these programs to full approval ourselves. You know, I think what we've seen is also a very prolific business development team at CRISPR Therapeutics, both in the buy side and the sell side. I think for some indications like cardiovascular, I think there is a lot of interest from Big Pharma.
You know, I think that's an area where Big Pharma sees that can be of huge value, not just in the U.S., but globally. You've seen, you know, the interest in immuno-oncology go up and down in Big Pharma. I think that's the nature of Big Pharma. Sometimes you have, you know, a lot of interest, but then and things change. But there, overall, there's still an oncology is a key focus for a lot of the big pharma companies, and they are all recognizing that they need to build cell and gene therapies. They can't just stay out of the game. You know, that's one of the things is if they don't go into it or dive into it, you know, feet first, they're just gonna be left out.
That's not just the U.S. pharma companies, it's Japanese pharma companies and other pharma companies as well. I think you are gonna see interest. I think for us, you know, obviously we don't wanna get into a point where we're burning so much cash that we create a dilution spiral. We're very sensitive around equity raises in the market and dilution. I think we're carefully titrating with the bias towards being more aggressive in times like these when everyone else is defensive. I get the signal that we're out of time, and we wanna be respectful for all the people that are on the webcast as well. I can't tell you how thankful I am for all of you for being here. It's great to get back to this model of interaction.
I think you all have an important role in keeping companies honest, but also in stimulating us to do the right things and be more aggressive and actually allocate capital efficiently. I appreciate all the questions that you all have, you all had, and look forward to further interactions. At this time, I think we have, Susie, a small reception outside, and Susie will direct us all there for those who wanna stay and chat, and we'd love to chat with you all further. Thank you again. We're very excited about the team at CRISPR. We're very excited about the pipeline at CRISPR.
Most importantly, we're excited about the ethos of innovation, and that's what carries us forward and keeps us excited every day, and look forward to sharing more updates with you going forward. Thank you very much.