CRISPR Therapeutics AG (NASDAQ:CRSP) Innovation Day Conference Call June 21, 2022 2:00 PM ET
Company Participants
Samarth Kulkarni – Chief Executive Officer
Phuong Khanh Morrow – Chief Medical Officer
Sumanta Kumar Pal – Associate Clinical Professor, Department of Medical Oncology & Therapeutics Research, Co-Director, Kidney Cancer Program, City of Hope
Susan Kim – Vice President of Corporate Communications & Investor Relations
Jon Terrett – Head of Research
Swaminathan Iyer – Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, University of Texas
Alireza Rezania – Senior Vice President, Head of Regenerative Medicine
Conference Call Participants
Raju Prasad – William Blair
Joon Lee – Truist Securities
Liisa Bayko – Evercore
Tyler Van Buren – Cowen
Ted Tenthoff – Piper Sandler
Yigal Nochomovitz – Citi
Tony Butler – ROTH Capital
Gil Blum – Needham & Company
Silvan Tuerkcan – JMP Securities
Cheng Li – Oppenheimer
Elizabeth Webster – Goldman Sachs
Samarth Kulkarni
[Call starts abruptly] Innovation Day. It’s great to see you, many familiar faces and some new ones.
It’s good to get back in this mode. We are 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. And 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 10 years since the first publication elucidating the mechanism of gene editing with CRISPR Cas9 was published by Dr. Jennifer Doudna, Dr. 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 will be the first CRISPR-edited product approved in the world. It’s also hard to believe that it’s been 8 years since the start of the company. In the last 8 years, we made tremendous progress in establishing ourselves as the leading gene editing company.
We made progress across many fronts with 5 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 have prosecuted the CRISPR platform in 4 different pillars: Hemoglobinopathies, immuno-oncology, regenerative medicine and in vivo therapies. We’ve made great progress across all of these verticals. But in each of these verticals, we have a tremendous premium on continuous innovation. And 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. P.K. Morrow, our Chief Medical Officer; Dr. Jon Terrett, our Head of Research; and Dr. Ali Rezania, Head of regen med. Additionally, we’re very privileged to have with us today, Dr. Sumanta Pal from the City of Hope 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 core Director of the Kidney Cancer Program at the City of Hope Medical Center. Joining us virtually today is Dr. Swami 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 2 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.
So without further ado, I would like to now turn it over to our Chief Medical Officer, Dr. P.K. Morrow. P.K.?
Phuong Khanh Morrow
Thanks, Ian 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. And I hope that today, I really convince you about the true progress and the excitement and we’ll take you along this journey with us. So 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 used data from 70 patients across the 2 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 crisis. So 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 were as durable elevations in fetal hemoglobin that allow patients to remain above the transfusion threshold with beta-thalassemia. And also we’re able to maintain their status and avoid vaso-occlusive crises in sickle cell disease. So 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 onetime gene-editing therapy using CRISPR technology.
So 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 2 different approaches. One, through targeted conditioning as well as potentially through in vivo delivery. And I’m going to walk through potential approaches for each of these in the subsequent slides.
So the first is the fact that when we looked at the ability to perform dental targeted conditioning prior to gene editing. We had 4 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. And 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 cKit antibody drug conjugate in which you have a monoclonal antibody targeting cKit 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 cKit-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 aberrate growth of AML tumor. But with the administration of the cKit-ADC, this flattens the curve significantly, pushing growth of the tumor down to near 0. On the right-hand portion of the slide, you can see that a single dose of the cKit-ADC is able to completely deplete functional HSCs in nonhuman primates. And what we’ve been able to see is that we’re able to increase the dosing and further dose the cKit-ADC without increasing toxicity. So 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. And we have several potential approaches for this which I’ve delineated on this trial here — this slide here. On the left-hand side, AAV in the middle, LNP; and thirdly, targeted LNP. And 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.
So 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. And 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.
So 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. And with that, I’d like to then move on to immuno-oncology.
So immuno-oncology is actually very close and dear to my heart and 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. Swami Iyer, who will be online soon. And of course, Jon Terrett and we will be reviewing with you our evolved oncology strategy, the clinical data in providing you new glimpses as well as updates to that data. And thirdly, what research is doing within oncology and beyond. So it’s going to be a pretty packed presentation and I’m sure you’re as excited as I am about it.
So 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 at some key clinical 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 1/3 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. And so for that reason, we are advancing CTX110. We have dosed 15 plus 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. And so 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.
So 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. But today’s 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. So some of them will be familiar to you. So 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. And we’re also — we’ve also knocked out beta-2 microglobulin in order to remove MHC Class 1 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 fracture side of the T cells. So 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. So 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. But 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.
Well, let me start with T-cell lymphoma and we’ll then turn to Dr. Swami 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. So 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 is 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 is a tremendous need for better therapies and safer therapies for this disease state. So for that reason, we wanted to really focus on T-cell lymphomas and hopefully help patients through CTX130.
So with that, I would like to turn this to Dr. Swami 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.
So Dr. Iyer, let me turn to you and I’ll advance your slides.
Swaminathan Iyer
Thank you, P.K. I don’t emphasize the — over empathize the fact that T-cell lymphoma is an area of high unmet need for the petrogenous disease, 30% resized and rate only fixed approvals in this context that CTX130 COBALT new study is making progress. And what I am 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. And this is a data cutoff from 26th April 2022. So this COBALT study is a Phase I dose-finding study. What I’m going to share with you is the data across all of the dose levels. And since it’s a Phase I study, the first part of the study, the primary endpoint of safety and for the dose escalation which is going to come pretty soon, the endpoint is going to be looking at 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’ve had patients who are 65 and above participating in the study. They range from 39 to 78. And more than half of them had an ECOG performance status of 1. And they didn’t — this study didn’t allow anybody with ECOG of 2 and above. Look at the TCL subtypes for the PTCL which is the peripheral T-cell lymphoma which is a very broad category, consisting of external and the leukemic versions. We had patients with AITL angioblastic T-cell lymphoma, ALCL, the ALK negative and ALK positive anaplastic large cell lymphoma and patients with PTCL not otherwise specified. We also had 3 patients with the adult T-cell leukemia lymphoma which is caused by HTLV virus.
Now this is devastating disease and there’s absolutely no therapies out there which are reliably producing responses [indiscernible] seem to work but for the most part, most patients die of this disease. And from the patient characteristics involved in the study, 2/3 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 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. And note, this study also allowed the second infusion of CTX130 if the patients did not achieve a CR or the CR that they achieved, eventually the disease progressed and including patients with CR, a stable disease, whether investigator thought, there’s 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 for the constructs. And you can see the peak expansion in concentration was 80.9 per microgram of the DNA but the time to peak expansion was 8.5 days. And at the bottom panel, you see the peak expansion concentration in dose level 4 which is where we — probably will focus on in the near future is that there’s initial dip and you can see these still expand enormously for the first 28 days.
Next slide, please. This is a safety profile since the primary endpoint is safety. And it’s the allogenic CAR, so you’d expect potentially to monitor for things like GvHD, tumor lysis syndrome because it’s pretty effective. And also the 2 special events with any CAR-T therapy which is the cytokine release syndrome and the neurological events described as ICANS. And there was no TLS, no hemolysis syndrome, no GvHD and the CRS were Grade 1 to 2 and ICANs were Grade 1 to 2 and all of them were reversible. And if you look at the treatment-emergent SAEs and there are a few details to it. If you look at it the infections, the Grade 3 infections in 4, Grade 1 to 2 tumor hemorrhage during a biopsy, Grade 3 syncope, Grade 3, pre-syncope and there’s a patient with Grade 3 HLH which was noticed in the patients with disease progression at day 51, also a patient with grade 3 drug eruption and all the patients with grade 1 to 2 ligament sprain with the exception of 1 patient with infections with Grade 3, all other treatment-emergent SAEs were not going to be related to the CTX130.
There was a patient with William’s syndrome eventually at sudden death in the context of a lung infection which is deemed unrelated to CTX130 after extensive analysis in the study. 3 cancers are diagnosed in patients with the CTCL post treatment. And 1 patient had EBV-associated lymphoma which is like post-transplant lymphotropic process which actually resolved on count recovery, the same patient had squamous cell carcinoma and another patient with the invasive ductal carcinoma. These last 2 skin cancers, squamous and ductal breast carcinoma were resected with the curative intent. And none of these are deemed related to CTX130.
Next slide, please. And this is the efficacy data. And mind you, this is a Phase I but you can see the efficacy data with a very promising responses with 70% overall response rate when 30% complete response rate, all seen in dose level 3 and above. On the left-hand panel, you can see this overall response rate is not only 30% CRs but 40% PRs. And 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 a stable disease is very meaningful. We have a 90% disease control rate. On the right-hand side, if you break them down into disease sites, the PTCL subset for overall response rate of 80%, with 40 CRs, 40% PRs and overall response rate of 80% with a disease control rate. For the CTCL, the overall response rate is 60% with CRs with 40% PRs and 100% disease control rate.
Next slide, please. And this waterfall plot shows that these responses are observed across all compartments. So T cell lymphoma is a multi-compartmental disease, including the lymph nodes, the bone marrow, the skin and the blood and 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 compartment, the skin and green, the lymph nodes in blue and the blood in red and it’s very impressive responses.
Next slide, please. This swimmer 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 5 of the patients. And you can see the median or the time response has not been reached, the 2 patients who are successfully bridged to a stem cell transplantation at the time of the data cutoff. So it looks very promising. We’ve not seen any CAR-T do something like this and especially in T-cell lymphoma.
And I think this is the last slide. I’m going to hand over to P.K. and happy to answer any questions. Thank you for your time.
Phuong Khanh Morrow
Can you guys hear me okay? Okay. Perfect. So thank you. That was exceptional. So I want to just kind of go through briefly how we plan to or hope to change the paradigm in T-cell lymphoma. You could see on the right-hand portion of the slide. We really summarized for you the variety of therapies for T-cell lymphoma. And there’s quite a few I could see people putting glasses on. So that’s an indicator of the number of therapies. But also what you can also see, unfortunately, is the fact that they’re associated with poor response rates. And also, 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.
And so what we feel is a — 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 onetime dose CAR-T at this time.
Now we are looking at potential consolidated dosing to look at redosing with CTX130 and we are also looking at a potential next-generation CTX130, called CTX131 which incorporate further potency edits. But 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.
So, now I’m going to pivot and talk about solid tumors briefly. I’m going to start with just talking a little bit about renal cell carcinoma. If you 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. And the reason for that clearly was the high levels of CD70 expression that we’re seeing with renal cell carcinoma tumor samples but 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 1 in every 5 patients is actually able to survive to 5 years after the diagnosis of metastatic renal cell carcinoma. And many of these patients, almost half of them are primary refractory to their initial therapy. So 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. And so we started 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 is also the Co-Director of the Kidney Cancer Program at the City of Hope. Dr. Pal?
Sumanta Kumar 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 time frame. And I truly feel that CAR-T cell therapy has transformative potential in this space. I’m going to 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.
And just to walk you through initially the demographics of this population and 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 3 prior therapies in this cohort with up to 6 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 a 100%.
In discussions with my co-investigators who I met often during the conduct of the 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 to 2 CRS. We didn’t incur any grade 3 or greater CRS events. We did have 3 patients who had SAEs coded related to CTX130 and all of these fell into that Grade 1 to 2 CRS category.
We did have 3 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, that event was incurred.
So I’m very excited to share with you the efficacy data here. And in particular, I want to highlight what you see in row 1 there which is a complete responded 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. But 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 diseases of 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 for 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 going to 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 some dermal 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 and 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. And 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 centimeters 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. And then at month 3, that actually deepened to a complete response and that complete response has actually maintained at its 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 has 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. And so he’s really enjoyed a very, very exceptional quality of life since that time. So again, I just want to reemphasize my vigor for this data and I look forward to seeing what’s on the horizon.
And for that, I’ll turn it over to Jon. Thank you.
Jon Terrett
Thank you, P.K., 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 recent search 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. So 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 on to potency. And why do we do that? We’ve seen activity of CTX110 and 130, as described here, whether there is that 28-day period of pharmacokinetics that you can see. And within that, we are seeing durable responses. So 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-T is quite often are gone by 3 months but the responses go out years. If MRD negativity can be achieved early on, that correlates strongly with a long-term durable response. So 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 to something that I haven’t seen in terms of a combination of knockouts and improving potency. So 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 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 back.
The second one, TGFBR2 will be more familiar to people that think about solid tumors and avoiding suppression signals in the tumor microenvironment which is quite often TGF-beta. So we get these 2 edits by themselves, they do good things to CAR-T cells together, it’s rather dramatic.
So 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 1 flank and cleared that tumor with either CTX130 or 130-plus TGF-beta, 130 plus Regnase or 131 as we calling it which is 130 plus the Regnase and TGF beta receptor knockouts. So 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 TGFBR or Regnase, you can see in the other colored 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 flag, a different one again. So this whole study, we start with H1975 lung tumor to pay attention to that, we’ve spoken to about renal cancer but CD70 is in many different tumor types. We get complete eradication of the tumor, including with 130. Then we challenge with ACHN, 131 rejects it. We challenge again with 131 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 are given. The only rechallenging was different tumors. Importantly, we can take CAR-T cells out after those rechallenges, we see them expand again and they are central memory and phenotype. They have not gone to terminal effectors.
We wanted to try and numerate how much better is CTX131 than 130 in this context. So we did a dose titration study. CTX130 plays the tumors quite nicely at 1 million dose. At a 0.1 million, 100,000 dose CTX130, does not clear the tumor, there’s a bit of tumor growth inhibition. CTX131, we did 1 million of that as well but it just wiped out the tumor so fast, it wasn’t important here. 0.1 million, 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 to more tumors. So we can say on a dose by dose, we’re about 10x more potent with 131 to 130 but there’s a lot more twit than that.
So clearly, we’re very excited about these 2 edits. They do something very, very dramatic and we’re progressing next-generation CD19, CTX112, our 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 but if we wanted to go further and this is where the platform comes in as Swami highlighted earlier, we have been very busy looking at base editors trying to find a high efficiency base editor by screening multiple different species, by comparing off-target versus on-target on the left and you want to be in the top left.
So there are 2 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 knock-out you can see at 95% efficient. When we’re knocking in a car, we’re still going to go with a double-strand break and CRISPR/Cas9 into a single site insertion. We’re not going to go into random insertion of a lentivirus when we do so much work to control everything else.
Going back to what P.K. 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’ve prioritized 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 going to 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 I trials and CRISPR Therapeutics retains the commercial rights.
And 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 going to bring along CTX131 and CTX112 as quickly as we can.
You’ll all know about our Nkarta collaboration. We saw pretty good data with their CD19. So we’re excited to do with 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. And I just told you about CD83 and Glypican-3 which we’re going to prosecute in the clinic with partners and find out.
I will end there and pass it back to Sam.
Samarth Kulkarni
Thank you, Jon. And thank you also to P.K. and particularly Dr. Pal and Dr. Iyer for taking time out of their busy schedules to be with us here today.
What we’re going to do now is because of the — we want to 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. So, Susie here will direct questions. If you have any questions, please raise your hand.
Question-and-Answer Session
Q – Raju Prasad
Sure. Raju Prasad, William Blair. Sam, can you just talk a little bit about the ADC and the in vivo strategy in the context of the Vertex partnership? I think it will be interesting kind of delineate some of the stuff that’s in-house versus what Vertex is doing.
Samarth Kulkarni
Yes. Thank you, Raju, for that question. As you can tell, we’re extremely excited about the data from Axi-Cel. I think it’s — we have data over 75 patients and see 31 of 31 sickle patients have that transformative effect is just unbelievable a few years after we started the program. I think we have — we obviously think that can be a very competitive product and address the needs of significant population of patients but we want to keep innovating. And with the ADC on — for genital conditioning agents, this is — 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 genital conditioning. But I think many of those have been optimized for different settings, mainly for AML settings. And what we wanted to do here is develop an ADC with a profile where there is very fast clearance, so you don’t have any impact on the drug product.
And so we started our own program here. Vertex also have their own programs around genital conditioning agents. And ultimately whichever one pans out, we can actually apply it to Axi-Cel. And 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. We think it may take 4 to 5 years. So Axi-Cel has a good runway with the current conditioning agent before new conditioning agents come into play.
And then with the in vivo editing, 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. And we actually have a collaboration with the Gates Foundation to develop these, ultimately make therapies available globally. But it will take longer on the time scale to get in vivo editing of HSCs.
Joon Lee
Joon Lee from Truist Securities. A couple of 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 Axi-Cel? And the second question is, have you shown — or are you able to show clonality data using — similar to what beta-cell [ph] have to show in your product? And I have a follow-up on CK — ADC.
Samarth Kulkarni
We may allow you for 2 questions, Joon. So I’ll address the first 2 questions you asked. And we have more time for Q&A later. I think the first question you asked around the allo transplants, 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. I think the first recommendation for a lot of these patients with severe sickle cell is to get a match transplant, if you can find a match. But that is not a good proxy for the commercial potential for Axi-Cel because if you had more matches, you’d see a lot more allo transplants happening. We just can’t find the matches. I think with Axi-Cel, I think that proves the 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’re just — can’t deal with their disease at all. The pain, the VOCs, et cetera. But I think with an opportunity to have something like Axi-Cel, that just opens up the opportunity. And I think we’ll see capacity expand in hospitals and the infrastructure expand to allow for many more transplants.
I think on the clonality data, I think that — it’s 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. And that’s one of the great advantages we have with CRISPR is that the predictability of manufacturing, the reliability is a lot greater than viral manufacturing methods. So, we’ll go to the next question.
Liisa Bayko
Liisa Bayko with Evercore. I think I’ll ask Joon’s question on — I just wanted to understand like really what’s the progress with the field on this idea of genital conditioning [ph]. And for your program, specifically, what are the next steps? Just trying to understand a little bit more granular on tangible next steps and what’s going on in the field. It just seems like this concept but a little bit obscure, what everyone is up to. And I think it’s an important potential lever, obviously.
Samarth Kulkarni
Yes. I’ll start and I’ll see if Jon wants to add any comments. But I think 3 or 4 years ago, there was a lot of hype about genital conditioning agents. Several companies developed agents and was — everyone thought it was going to come very quickly. It’s taken a lot longer because it’s — when you’re dealing with HSCs, you really want to — 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. And that’s something we’ve learned through our manufacturing process. We characterize these cells quite a bit and understand all the subpopulations. And 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 are — 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. But I think in terms of the path forward, I think we’ll hopefully move into IND-enabling studies. And then you do have to try these in the relevant indications and particularly AML, where it’s most relevant before you apply directly into clinical trial. So there is a little bit of time before we bring this to bear. But what’s exciting is if you can show this — show the reengraftment or engraftment of new drug product in mouse models or in HP 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?
Jon Terrett
There was a gap to what everything else was doing. And when we saw this particular thing that we’re trying with this toxin hasn’t been done, it is kind of the most appropriate one. So we went through it. But as Sam was saying, if someone else fixes it, it’s kind of okay. But we didn’t want to leave that gap there, for sure.
Tyler Van Buren
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. And I guess the discussions are related to follow-up. So if you don’t need to have all of the patients evaluable for the primary endpoint of 12 months, what percentage of patients do you think need to be evaluable to file? And 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 increase potency with 131. So does that increase expansion as well? Because 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?
Samarth Kulkarni
Yes. So Tyler, thanks for that question. There are 2 parts to the question, one on Axi-Cel and one in RCCs. I’ll have Dr. Paul and Jon comment on the RCC question. But on sickle cell and thalassemia, I think 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 benefited, quite frankly, from the prime designation in Europe. And Vertex and us are aspired 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 the discussions are 2 parts: one is the CMC-related discussions and the other is around the number of patients and what the follow-up needs to be. And I think on the CMC front, again, 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 there’s still work to be done. You have to do a complete process characterization around every starting material, around different components, et cetera but we feel confident that we can get there. I think on the clinical front, 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 7 patients. So 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. But so far, I think we’re trending nicely, at least on the European front. As for RCC, I’m personally — if you asked someone 3 years ago, will you see a full complete response in a solid tumor with a CAR-T, forget allogeneic autologous, the answer was no way, unless you got a Nobel Prize. And here we are talking about a complete response with an allogeneic CAR-T 3 years later. And so we’re quite excited about it. But maybe I’ll first turn it over to Jon to talk about the expansion with 131 and the potency and then Dr. Paul to contextualize all of this.
Jon Terrett
Yes. The peak expansion we saw was the average. We had higher ones than that in the RCC trial, for sure. We expect the dose for 131 to be significantly lower than 130 and potentially to have a slower burn to get there. And that’s certainly 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. So preclinically, I don’t think it’s a problem on what is to translate into the clinic. And what we’ve seen in the 130 trial, we’ve seen bigger expansions. I think on whole, T cells being a bit higher. I don’t know, Monty, if you have any other comments.
Sumanta Kumar Pal
No, no. Your points around wanting more responses are well taken, certainly I want to see the same. Having said that, I would just underscore the fact that in this heavily pretreated population, these stable disease events are quite meaningful. This offers patients, some respite from chronic toxicities from therapy. And as we plan to ultimately publish this data around patients in this context, I think we’ll see that there’s some meaningful positives in systemic treatment that we’re able to afford folks in the setting. So the stable disease rates, I think, are quite compelling.
Samarth Kulkarni
Yes. And I think — and Monty, if you can further expand on that, I think a stable disease is not a stable disease like any other therapy because these patients come off therapy. If you want to make that — expand on that comment as well.
Sumanta Kumar Pal
Absolutely. Absolutely. So it really does invoke a bit of a positive. The reason why I think this is such a paradigm shift potentially in renal cell carcinoma that right now, everything that we offer post frontline is purely palliative and reflects a chronic treatment, whether it’s a TKI, whether it’s a novel inhibitor, whether it’s a checkpoint inhibitor in many cases, these patients just remain on therapy for the long haul. They’re just constantly exposed to toxicity burden. So in the context of the study, we’ve had — I’ve had more than a handful of patients who have been able to come off a systemic treatment, really enjoy a far superior quality of life.
Samarth Kulkarni
Thank you, Dr. Pal. Ted?
Ted Tenthoff
Ted Tenthoff from Piper. So two quick questions, if I may, sticking with your two questions. Firstly, for T cell lymphoma. Are there other — I should know this but are there other CAR-T programs in T cell lymphoma? And what kind of data have they shown? And then, the thing that I saw from the T cell lymphoma that I think really maybe will carry over 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 redosed. So 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?
Samarth Kulkarni
Yes. Thank you, Ted. To your first question and I’ll ask Dr. Iyer to comment on the second part of the question and P.K. as well but to the first question, there aren’t too many other cell therapies in T cell lymphomas. The only other therapy is in autologous CAR-T targeted towards TRBC1 and TRBC2 that reported some data, preliminary data, at EHA. But 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 was — that had an accelerated approval 10 years ago and never had confirmatory approval. Gosh, we’re dealing with brentuximab but there’s so much neuropathy that we always — patients always come off of it. We’re dealing with romidepsin, where there’s so much nausea, so much vomiting, it’s just very hard to keep patients on it. And so they 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 want to make some comments around the competitive landscape or what options there are for patients in T cell lymphomas.
Swaminathan Iyer
Of course, Sam. I think it’s one of the last frontiers for developing cellular therapy in lymphomas. And part of the reason why it’s been so hard is because the T cell factor side that you normally see with autologous products, in addition to the TRBC1 that you mentioned, CD5 has also been 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 and 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. And there are other CAR-T developments but very early on like CD7 but the biggest problem there is [indiscernible].
That being said, I think moving on to the second part of the question, I think I did — we did show the data of second infusions in the worst 5 patients with [indiscernible]. But clearly, we have seen CRs in patients who received 1, just 1 response. And 1 of the patients that I have presented at EHA 2 weeks ago was this gentleman with transformed MF, who couldn’t even walk, was — had lesions oozing from the leg and with an mSWAT of close to 100 and with 1 treatment went on to achieve a CR and is still in CR at this time, about 4 months later. So it’s not necessarily that you do require 2 treatments. And of course, it’s a small patient cohort. We can’t generalize it. There might be patients that might need multiple doses. I think that’s being tested, as Dr. Morrow had alluded to earlier. But our patients for whom, I think, 1 treatment may perhaps be more than sufficient. And I think this is what the study moving forward will show us.
Samarth Kulkarni
Thank you, Dr. Iyer. And I think the other part of your question on redosing, Ted, we have seen benefit. In fact, 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 the allo transplant is one of the highest potential options in terms of curative options for these patients. So even if you get them to that setting, it’s actually quite good outcome for the patients.
And then finally, I think for — what does that mean for RCC? So we are actually now — Dr. Pal and other investigators are now putting in place the redosing paradigm into the RCC trial. Now we obviously want to show more data from these — from this trial. And I think what we discussed with all the investigators is that we want to do it at a scientific meeting given the importance of the first allo CAR-T in solid tumors. So we will show additional data on the RCC trial, including patients that have gotten a redose. So more to come there.
Maybe a couple more questions before we take a break. I see Yigal right in front of me here. Sorry.
Yigal Nochomovitz
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. So was that done just out of simplicity for operational simplicity? Or was there some reason to believe that the same dosing range would be appropriate for 2 very different diseases?
Samarth Kulkarni
I’ll start and then see if anyone wants to add any comments. I think a lot of it is just understanding the regulators are also learning as we go along in terms of what these cell therapies do. I think we had sort of an unfortunate death in a different trial with the CAR-T in solid tumors. And I think people just want to 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 letter but it’s a good question.
Yigal Nochomovitz
Okay. And 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?
Samarth Kulkarni
Dr. Iyer?
Swaminathan Iyer
Great question. I think, as I alluded to earlier, there might be patients who will need multiple doses. And you heard about trying to grow the longevity of the allo product. And I think one of the big questions is the two are transplant candidates. Because if it’s so exciting that we talk about transplant as the best curative option but we can, in reality, less than 10% actually make it to transplant. But 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 1 or 2 treatments or more. And so to that, I think we are investigating this multiple dosing possibilities and particularly making sure wherein somebody has to get to a transplant, you get them to the complete remission state. So if it’s 1 infusion gets you to maybe 1 or 2 or 2.5 compartments control, I think you want to have complete response in all the compartments, so multiple dosings. Perhaps there’s one way to go for this transplant-eligible patient.
For the non-transplant-eligible patients, I think one of the things — because a 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. And I think future follow-ups will help us understand that it’s all you need and I think we’re looking forward to that.
Phuong Khanh Morrow
And just to add to that just briefly. I think what we’ve seen with some deepening of responses with those second doses. And 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? So we’ve looked at, for example, day 5, redosing day 35. And so we’re looking at, first, one, that triangulation of timing which patient characteristics warrant a second dose in order to provide a deepening of response to either get them to CR or to bridge to the transplant.
Samarth Kulkarni
Yes. Thank you, P.K. Thank you, Dr. Iyer and P.K. We want to 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 want to be respectful of Dr. Iyer and Dr. Pal’s time.
Tony Butler
Tony Butler, ROTH Capital. Jon, I wanted to just stay on the duration comment you made. With the 2 additional edits that you’ve been able to demonstrate, the question is, I mean, let’s be fair, what you — 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. So the question really is, is that going to be sufficient, do you think? And obviously, you’re going to say yes because that’s what you’re [indiscernible]. But 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?
Samarth Kulkarni
Jon, do you want to take that one?
Jon Terrett
I’m going to say yes because you said I could. Is this enough? No but it’s a fair question. I mean, these 2 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 going to keep killing the tumor cells, as you saw with secondary challenge. I think maybe one of the places where there’s going to be help is antigen escape. And that’s — I think that’s another reason why you want to get as much of the tumor as early as you can. You don’t want to be tickling it for months given the opportunity. But from what I’ve seen, these things are going to kill as many tumor cells are there once they get there.
Samarth Kulkarni
Yes. Thank you, Jon. I think, Tony, obviously, we have some ADCC approaches in the NK cell — NK CARs. So we’ll have to see how data emerge. And what that tells you, I think, some things we just don’t know until we see the data. But at this point, I think the CAR access probably acts as a primary access. And unless it’s a heterogeneous tumor — and we’ve had CD19 negative escape sometimes, right, unless it’s a heterogeneous tumor, I think the CAR is the primary way we’re going to try and attack the tumor at this point. But thank you for all the questions. I’m sure there are more questions here and I missed some of you. But why don’t we do this which is we’ll take a very short 5-minute break and come back at 3:15 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 want to thank Dr. Pal and Dr. Iyer for taking the time to be with us today and for — more importantly, for being — for leading our clinical trials in these important indications where patients have great unmet need. So, thank you all. We’ll take a 5-minute break and come back.
Samarth Kulkarni
So we will start again here for the second part of our session. Thank you for all the engagement and the questions in the — for the hemoglobinopathies in immuno-oncology. Saw the extent of innovation that’s happening in both those franchises.
And now we’ll talk about our regenerative medicine franchise. And I’d like to invite Dr. Ali Rezania to take the podium.
Alireza Rezania
Thank you, Sam. So very excited to be here. My name is Ali Rezania. I lead the regen med franchise at CRISPR. Let’s see. And I’m very excited to share with you our regenerative strategy as well as our progress we’ve made.
So unlocking the potential of regenerative medicine is here by combining the breakthroughs in pluripotent stem cell technology as well as CRISPR genome editing. This is indeed our vision. The combination of these 2 platforms will enable a new class of replacement therapies for both rare as well as common diseases. So treatment of type 1 diabetes using cell therapies, our first application of regen med platform for the simple reason that the proof-of-concept clinical data is already out there in the form of allo transplantation. So the field recently celebrated a 20-year anniversary of Edmonton protocol, where investigators at University of Alberta infused cadaveric human islets via the portal vein into the liver of type 1 diabetic subjects, resulting in significant number of subjects becoming — 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. And what happens afterwards when they get the islet infusion? Those glucose excursions essentially eliminated. It’s very well known that these glucose excursions is what leads to complications of diabetes. Despite this remarkable success, this approach has not — has been limited by 2 main reasons. One is that there’s a scarcity of islet tissues. Many of these patients who became insulin-dependent required 2 islet infusions or more. So essentially, we have an issue with scalability of cell source.
The other one is that they have to be on chronic immunosuppression, right? And chronic immunosuppression carries with it significant risks that are well known and also requires patient compliance. There has been many instances that the 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 and awareness.
So how are we going to solve these 2 main challenges? Our approach is use gene editing 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 last couple of decades. And one of the main areas that people are focused on is to use essentially a physical barrier. Essentially, you are separating your grafted cells from the host immune response with the hope that, 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.
So what is our approach? We like to take the approach of multiplex genome editing at a clonal level to avoid the need for long-term immunosuppression as well as introduce new edits that go beyond immune evasion, address cell fitness and as well as functionality. So earlier this year, along with our partner, ViaCyte, we launched the first clinical trial of its kind which essentially addressing immune evasion; this is a Phase I safety trial.
Our approach regarding product strategy is multi-staged, starting with 210, progressing to 211 and landing on 212. Our ultimate goal to make a gene-edited pancreatic beta cell that does not require any chronic immunosuppression or a device. We refer that — to that VCTX212, that’s at the early stage of development.
With VCTX210, we’ve entered the clinic. This is a safety trial and will address immune evasion and really will inform on 211 design. 211 introduces additional edits that I will talk about in a subsequent slide that really promotes cell survival and fitness. We are on track to file the CTA for 211 later this year. And this, to our view, will really present in the clinic potential for a functional cure.
So where are the edits? So 210, we see TX210 — by the way, we are very excited. It’s the first time we actually introducing the edits. I know we get this questions often. So VCTX210 has 4 edits, while VCTX211 has 6 edits. They have the same 4 edits that are in 210 plus 2 additional ones. We categorize these in 2 buckets: one is the immune evasion bucket and the other one is cell fitness. In the immune evasion bucket, we are removing MHC class I by knocking out B2M. We introduce in PD-L1, a very well-known molecule, to induce some level of tolerance by inhibiting antigen-specific T cell proliferation. And 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 failures is because of oxidative and ER stress.
And lastly, for 211, we’re introducing 2 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 neutropic drive factor [ph] that enhances beta cell proliferation as well as protection against inflammatory stress. So in sum, 210 has 4 edits and 211 has 6 edits. So how do we know these cells actually can protect — these edits can be protected in a setting of allo rejection? So we test them in a battery of in vitro assays as well as individual models. So 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, can — what is the deficit in unedited and edited, 211 edited cells in response to a mismatched T cell proliferation assay?
As you can see, our unedited cells definitely triggered a T cell response as predictable. However, 211 cells did not elicit any T cell proliferation. It was actually lower than the 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 a very similar response.
Regarding the innate arm, specifically looking at NK cell, killing. We see — we compare 211 edits versus unedited and as [indiscernible] controls, cancer cell line which has class I knocked out. As expected, the cancer cell line definitely triggered NK killing because he has no B2M, no class I. However, 211 edits did not elicit any NK killing. And again, we have 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 recasted it the T cell, B cell and NK cell as well as the [indiscernible] cell compartment. So it’s is pretty robust humanized mouse model.
And we asked a simple question, is there a difference between unedited and edited in terms of survival and durability? So as you can see, putting unedited pancreatic [indiscernible] cells and we measure that by measuring bioluminescent intensity. There’s a dramatic drop post-transplant a few weeks later. Whereas in 211 edited cells, we don’t see that drop at all. The bioluminescent intensity stays constant. So 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, the transplant these cells in diabetic rat model and we compared unedited versus edited cell population. And we were delighted to see that our edits will actually make a meaningful difference. So on the left-hand panel, you’re looking at C-peptide production. C-peptide is a biomarker for insulin. So when proinsulin is processed, we get insulin and C-peptide produced in equal mode or fashion.
So you can see at about 3x fold increase in C-peptide production compared to unedited population. Further, we looked at 2 of the cardinal features of beta cells. One of them is glucose responsiveness. The other one is how they respond to exogenous insulin. So 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. And you can see in the middle panel, there’s 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.
And then on the last panel, we’re showing what happens if you give them too much insulin. So we give them the insulin — exogenous insulin injection. And you can see the appropriate — cells that are appropriately shutting down C-peptide production. So in sum, we think these features will allow for consistent glucose homeostasis.
So how do these graphs look? So you’re seeing here cross-sectional images of what these cells between the lumen of these devices look. So on the top panel, we provided the arrow to help orient you where the device membrane is and everything, the lumen of the device is where the cells reside. This is many months post-transplant.
I just want to 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 across another image where we’ve stained for endocrine hormones, in this case, insulin and glucagon insulin stained in pink and glucagon stained in brown. And there’s a predominance of beta cells within the lumen of these devices. The ratio is about 2:1. Lastly, we stained for PD-L1, one of our knock-ins. And this is what’s very important for us. We have to make sure our knock-ins are retained post differentiation. We’re putting these in MBR stem cells and pluripotent stem cells. These cells definitely vastly differentiated. There’s chromatin remodeling going on. So we want to make sure there’s no silencing of those knock-ins. And indeed, we don’t see that 6-month post-transplant. So we were delighted to see that.
And then lastly, we tested our ability of the cells to normalize blood glucose in a chemically induced diabetic rat model. So we give the animals a 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. And then a few weeks later, we transplant the cells with the device. And you can see that after 12 to 16 weeks, there’s normalization of blood glucose and this is very much in conjunction with the significant increase in peptide you see under right-hand panel.
So this slide summarizes our pipeline in terms of the VCTX programs. So let me just reemphasize the main point I started, the era of gene-edited pancreatic beta cells is here. And we have a 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 and have been making really good progress with VCTX211 with gene edits that confer additional cell fitness and functionality to these cells. And ending with 212, we are going to be incorporating new edits in 2012. At some point down the road, we disclose what those edits are. That, in our view, can address type 1 diabetes as well as insulin-requiring type 2 diabetes.
So with that, I’m going to hand off to my colleague, Jon Terrett, to talk about our exciting in vivo platform. Jon?
Jon Terrett
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 to 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 in prime editing have a finite set of opportunities where diseases caused by a single point mutation or a small mutational hotspot. The vast majority of monogenic diseases are caused by mutations throughout a multi-killer based region and therefore, require gene insertion and correction.
Over the past 5 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.
So some data. As just stated, we have put together the relevant platform pieces to enable high-efficiency disruption 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 nonhuman primates. You can see that the editing rates plateau at about 70% which is totally in line in 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 1 program to the next is the guide RNA. The LNP and the mRNA are shared across programs. We’re advancing more programs to nonhuman 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 fully unencumbered for CRISPR.
The first place we decided to deploy our gene disruption platform is in cardiovascular disease. Listed here are 3 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 represent 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 mgs per kg group at 90%, 1.5 mgs per kg practically there as well. The corresponding reductions serum triglyceride at 1 month and 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 really need any introduction, although we put a reminder on the left-hand side, very simply, the more LPA in the serum, the higher the risk of cardiovascular disease. So again, we’ve quickly gone to a lead guide. 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 mgs per kg. What you see at 1.5 mgs per kg, if you take the graph on the left and you say, what does that mean in reduction, you’re well into therapeutic benefits, even at 1.5 mgs 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 going to 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 are going to call CRISPRX. 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 CRISPRX, 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 going to 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-translation 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-translation modifications on it. So you can see the loci 1, 2 and 3, they don’t edit as well as the albumin locus but they produce more amounts of active protein. So 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 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.
And with that, I’ll hand it back to Sam for some closing remarks.
Samarth Kulkarni
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’ve talked about today. In hemoglobinopathies, we’re very proud of what we achieved with Axi-Cel and we’re in pole position within that indication with editing-based approaches. We want to protect what we built there and quickly follow that up with genital conditioning agents and in vivo editing, although that will 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 2 best synergistic edits that we can find out there for potency. You’ve seen many different labs, many different companies go for some of the obvious edits like inserting cytokines. There’s edits around precisions 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.
And with that in mind, we put in place the strategy where we have the 2 synergistic potency edits and we’re seeing, at least in preclinical data or manufacturing, the greater level of expansion, 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? We weren’t going to 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. So we’ve 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 for a set of patients that shows whether these cells are immune evasive or not but 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 first time we’re talking about in vivo. 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. And I think with our balance sheet and our ability to translate very quickly and develop in the clinic, we’re going to have multiple programs in play with in vivo which all have some synergies between them.
As Jon mentioned, all he changed is the guide in some cases. And then 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. But ultimately, again, we don’t want to stop there. We want to 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. So we’re going with LNPs into other disease areas that really opens up the space for us.
So, the level — if you ask me over the last 7 years that I’ve been at CRISPR, I will say the level of energy and excitement that we feel today is the highest it’s ever been at the company. 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 wins that are blowing that may — oriented 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 will 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.
So we’ll stop there and go to the second part of our Q&A. So thank you very much and I already see some hands up in the air. But maybe Gil, you can start us off.
Question-and-Answer Session
Q – Gil Blum
Gil Blum from Needham & Company. Is it okay to still ask questions from the previous section?
A – Samarth Kulkarni
Sure. We want to focus on this section but please go ahead, yes.
A – Susan Kim
Only Gil, no one else.
Q – Gil Blum
I’m the only one who gets it. So just a quick one on T cell recovery. So 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.
A – Samarth Kulkarni
Yes, I’ll start. And I think these are data that we want to present and additionally in publications going forward. But 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 P.K. and see if you want to make any comments around T cell recovery or the level of infections that we see.
A – Phuong Khanh Morrow
Yes, so you’re spot on. There were infections that were seen. But recall also that we’re talking about actually a disease state that has significant skin involvement. So we have patients, many of them who have a high predisposition for superficial infections as well as additional other infections. And so this — the level of infection that we’ve seen, first of all, we do not find the majority of them to be related to CTX130, as you probably saw. But else — and this was confirmed with our investigator. But then 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.
Q – Gil Blum
And I’ll continue the trend of asking 2 questions. So do you think the use of kind of an ex — not ex vivo but a transplanted device for the regenerative medicine portion of the portfolio, does that reduce potential risks involved when going after diabetes mellitus?
A – Samarth Kulkarni
Yes. Let me start and see if Ali wants to add anything which is, I think we obviously have 2 strategies. I think 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 in the Type 1 diabetes setting. I think to truly get to a scalable Type 2 diabetes drug, you probably need to have injectable cells. But in the Type 1 diabetes setting as we’re starting off, I think there’s so much to learn about these cells. 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. And I think the perforated device design that was developed by ViaCyte, I think, allows for that. And there have been patients who have actually had very meaningful glucose glycemic control using those devices.
And also, they’re retrievable in case we need to learn more about the cells, that gives us a great sense of what’s happening with the cell subtypes, what other infiltration. There may be from other types of cells in there. So there are many advantages we’re starting with the device which is why we’re going with the device approach for Type 1 diabetes. But Ali, anything to add?
A – Alireza Rezania
Yes. Thank you, Sam. I think you covered the basis. I also highlight 2 recent seminal publications from the buy-side team summarizing the 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. And for us, safety matters most, right? Because this is — you’re not talking about the cancer patient who has 2 or 3 months left, you’re talking about someone who has diabetes, right? So you want to make sure we are extra cautious.
So with that in mind, we thought that having 2 arms, where one, we focus on device and another a little bit later on in terms of addressing the CTX212 which is a little bit higher risk because we had plant in infused in the liver and we can retreat. So for us, that safety margin in the device is really important. That’s why we’re starting with that.
A – Samarth Kulkarni
Silvan?
Q – Silvan Tuerkcan
Silvan Tuerkcan from JMP Securities. Congrats on the progress with TD 1, 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 we have lots of sales and grafting in regions where they’re not in grafting. So could you just speak a little bit to how do you make that or have a more homogeneous outcome? And maybe a second question is more open ended. About the in vivo editing, just a general strategic 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 based on the progress that you’ve already made with Cas9 that could help you excel here?
A – Samarth Kulkarni
Thank you, Silvan. Ali, I’ll turn it to you for the first question around the device.
A – Alireza Rezania
Sure. It’s a great question. So indeed, that was observed and you highlighted that in their publication as well, they noted that. So that is why we are very jazzed about VCTX211 because we have introduced new edits that really improve that early cell survival as well as sell fitness and also their functionality. That was not the case, obviously, with unedited population. So we’re really hopeful that really is going to move the needle in terms of the percentage of the device that’s filled with functional beta cells.
A – Samarth Kulkarni
Yes. And to the second question on in vivo, I think there’s different levels to look at that strategy. One is, 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 an NHPs. So all of a sudden for us it was pedal to the metal on in vivo platform in general. So why cardiovascular targets, 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’re seeing with these indications is a compliance issue and an endurance issue. I think even with the antibodies, while it’s a reasonably large growing category now with the antibodies, you still see a lot of patients falling off from therapy from a compliance standpoint. And what you can have of 1 and done solution, that is shown to be safe based on natural history data, that can be very powerful. And mindsets are changing around these therapies. Even the last 3 years, think about how far we come around acceptance of CRISPR-based medicines or editing. I think in early days of dosing Thalassemia and sickle cell get to do so much more education.
Now, we’ve dosed over 75 patients in that indication alone and over 150 patients in cancers. So it’s changing very rapidly and having not only that but also the ability to develop in very severe indications which P.K. has identified with the whole team where we can get to a regulatory path and approval but then broaden it beyond that is quite attractive. So I think that’s the logic we have started there but we also have a number of rare diseases where we’re going after as well.
Ted?
Q – Ted Tenthoff
Can you hear me? Or…
A – Samarth Kulkarni
Yes.
Q – Ted Tenthoff
Okay. I really agree with the last point you made. So first, I’m going to make a comment and then 2 questions. But you’re seeing the same exact thing there with siRNA, where originally was relegated exclusively to orphan diseases and now obviously with PCSK9. So I think you’re following a tried and true path here which is really being shown right now in practice. So I totally agree with what you said at the end. So 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 partner programs are footnoted versus highlighted on the in vivo pipeline slide?
A – Samarth Kulkarni
I’ll start the second part of the question and then go to Jon to comment on the editing efficiencies. Obviously, I think efficiency is very different based on gene destruction versus gene correction and what modality you’re using. But 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 was — that’s been a focus of many questions. And we just wanted to highlight other things we’re doing outside of perhaps the DMD program and DM1 program. We’re actually making progress in the DM1 program. We had a milestone payment from Vertex not too long ago on the DM1 program. So 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. But in terms of the editing efficiency or LNPs, Jon?
A – Jon Terrett
Yes. I mean if you’ve been in the liver, we told the 70%, right? And those are just punch biopsy, so it’s probably more like 90%. I think every company sees that plateau. The other part of the guide just add is you can see the 1.5 mgs per kg, it kind of nearly gets there with some and then the 3 mgs kg just tied it all up. If we think about other tissues, you saw we got the 60% going way back to the AAV stuff that P.K. spoke about earlier with AAV and it will be a significant part of CRISPR X to also find targeting to other tissues. I think that’s a significant part, it’s not just the technology for the editing but how to edit tissues other than liver.
A – Samarth Kulkarni
Yes, obviously, we haven’t shown any of the data today but we are looking at the organ systems. And LNP, obviously, a lot of LNP get taken up in the liver and that’s the primary place you’re going at it with LNPs. But 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. So I think that’s 1 of the advantages we’ve had right now is 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. But then we also want to innovate in terms of the type of editing we do. I think delivering DNA-based templates is a little harder than an RNA-based template. So, can we use RNA temperate and use a different conjugated editing machinery where we can get very high efficiencies? So a lot behind the scenes here and we hope to do these kinds of events off and so we can we can be very open kimono about all the things we’re doing and working on.
Go ahead, Tony.
Q – Unidentified Analyst
Rich [ph] from Credit Suisse. I also have a question from the previous session. So looking at the — 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? And also, is there any redo learning that you can take from redosing to consolidation dosing?
A – Samarth Kulkarni
Yes. Very good safe profile but I’ll let P.K. expand on the question.
A – Phuong Khanh Morrow
Yes, that’s spot on. So we’ve had such a profoundly positive safety profile and we haven’t seen any new safety signals with redosing. So I would say that ultimately, we haven’t seen any negatives with actually redosing patients. The only question as 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. And that data, we’re still actually gathering at this time.
A – Samarth Kulkarni
But generally, a very tolerable profile.
A – Phuong Khanh Morrow
Yes.
A – Samarth Kulkarni
So that opens up redosing maybe more than twice.
Q – Cheng Li
Cheng Li for J. Olsen Oppenheimer. I also have to go back to the previous section. So 2 for me. So for Axi-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? And for the allo CAR-T parts, 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 some other novel agents?
A – Samarth Kulkarni
Great, thank you. I’ll answer both questions briefly, just sensitive time here. I think on Axi-Cel, I think you’re right in that this sickle cell obviously affects a certain segment of the population which is distributors more incident in certain states within the U.S. and within — in certain countries in Europe. And 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 a view of having an effective commercial launch, right? So I think we have done that. I think you’d be surprise in Europe, there’s a lot more sickle cell incidents than people imagine. It’s not just thalassemia.
There’s quite a bit of a patient need for in sickle cell among the major European countries in addition to transfusion-dependent thalassemia and 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, P.K., do you want to address that?
A – Phuong Khanh Morrow
Yes, we’re actually looking at a variety, honestly, of sequences. I can’t actually tell you definitively which 1 we’re going to be choosing. We’ve met with opinion leaders and oncologists and investigators and discussed with them where do we actually — where can we have the greatest benefit? Obviously, some have suggested things like going after auto CAR-T. But I would say that right now, what we really need to do is further analyze our data and see where we combine sequence or — combined or even sequence. And honestly, combinations with other therapies is not out of the question either.
A – Samarth Kulkarni
Yes, I think — and it’s a difficult question to answer. I think there’s — you have bispecifics, you have auto CAR-T. And recently, you’ve seen interesting data. You saw data for a bispecific and frontline high risk, for instance, right? So the things are moving up in the different treatment lines. But again, bispecifics in Auto CAR-T are ultimately using the endogenous T cells from the patient. And not all patients have good immune system to work off. And 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 going to come into play at some point — and it’s going to be superior, I think, to bispecifics or auto CAR-Ts but only time will tell on that.
So maybe we’ll do 1 last question. Go ahead. Yes, Elizabeth.
Q – Elizabeth Webster
It’s Elizabeth Webster on for Salveen Richter at Goldman Sachs. And 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?
A – Samarth Kulkarni
Yes. Thank you Elizabeth I think that’s 1 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, frankly, success of Axi-Cel that allowed us to capitalize on that and build sort of for the future. And I think we’re going to leverage that. I think we are going to take risk and be aggressive across all these programs. Now ultimately, we don’t need to take all these programs to full approval ourselves. I think what we’ve seen is also a very prolific business development team at CRISPR Therapeutics, both on the buy side and the sell side. And I think for some indications like cardiovascular, I think there is a lot of interest from Big Pharma. I think that’s an area where big pharmacies that can be a huge value, not just in the U.S. but globally.
You’ve seen the interest in immuno-oncology go up and down in Big Pharma. I think that’s the nature of Big Pharma. Sometimes you have a lot of interest but then things change. But they’re — overall, there’s still — and 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. That’s one of the things if they don’t go into it or dive into feet first, they’re just going to be left out. And that’s not just the U.S. pharma companies, it’s Japanese pharma companies and other pharma companies as well. So I think you are going to see interest. And I think for us, obviously, we don’t want to get into a point where we’re burning so much cash that we created dilution spiral very sensitive around equity raises in the market and dilution. But 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 want to 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 on us but also in stimulating us to do the right things and be more aggressive and actually allocate capital efficiently. So I appreciate all the questions that you all had and look forward to further interactions.
At this time, I think we have — Susie, we have a small reception outside and Susie will direct us all there for those who want to 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 but most importantly, we’re excited about the ethos of innovation. And that, 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.
End of Q&A
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