CRISPR Therapeutics AG (NASDAQ:CRSP) Citi 17th Annual BioPharma Conference September 7, 2022 8:50 AM ET
Company Participants
Sam Kulkarni – Chief Executive Officer
Conference Call Participants
Yigal Nochomovitz – Citi
Yigal Nochomovitz
All right, well, welcome everyone. I’m Yigal Nochomovitz, one of the biotech analysts here at Citi. It’s my great pleasure and privilege to have with me, the CEO of CRISPR Therapeutics, Sam Kulkarni. Welcome.
Sam Kulkarni
Thank you, Yigal for having us.
Yigal Nochomovitz
Great to have you. I have been following the story for a long time since even before the IPO, I believe. So, a lot’s happened in the last several years. I guess to start out a big picture question to level set so that people that are less familiar with the story can learn a little bit about your mission. What are the key aspects of the strategy? What are the key aspects of the story? And how do you differentiate yourself in the complex gene editing space from some of your notable peers in Boston and elsewhere?
Sam Kulkarni
Thank you. You’ve certainly followed the story from right from the beginning. It’s hard to believe that it’s over seven years now and we’re actually on the cusp of filing for one of the first therapies that used CRISPR gene editing. This would be in sickle cell disease and thalassemia. But that aside in terms of our mission, I think, the guiding principle always for us or the North Star was to build a great company. At first we said the next Genentech, and now we think that we can build a greatest biotech company ever.
And what does that mean? Obviously it means that we have to have medicines that transform patients’ lives on one axis, but the other axis is equally important, are we continuously innovative? Are we the Mecca of science? Are we the place everyone wants to work? Are we the place that generating value with the horizon that’s 10, 20 years out? And that’s the kind of company we’re trying to build at CRISPR. So what does that mean in terms of strategy and how we’re trying to achieve that vision? You have to take a stepwise approach. You can’t just get there right from the beginning, unless you get very lucky. And there are companies that have built that have been a $100 billion companies off of one drug, for instance, one or two drugs.
But for us, the idea was let’s start with sickle cell and thalassemia with ex vivo, de-risk the platform, get – focus on execution, get to a BLA filing and some sense of actually a marketable opportunity. But then the next step is diversify. And that’s what we’ve done is diversified into three other platforms right now with immuno-oncology. And we’ll talk about each of these regen med and in vivo, where we’re taking risk and continuously innovating. And if any of those hit, then how do you build upon those franchises?
And eventually the third step for us as a company will be starting in 2025 to 2030, will be to then capitalize on all these franchises and put 30, 40 different programs into clinic with this powerful platform.
So we’re in Phase 2 of our growth right now. And every time we change phase it is an easier story to tell in 2018, 2019 you are like a return [ph] get to sickle cell and thalassemia this is how we’re going to get to data, initial data is what everyone is thinking about and expecting. Now it’s a multi factorial story, we have a BLA filing coming up, we have six readouts next year, in terms of the clinic. So we’re relatively diversified across different platforms and all exciting programs and we not only are stopping there, we’re doing the next, next, next gen thing. We’re, putting new edits in place, new programs in place and our platform, our portfolios we’re expanding.
So, I think, all that said, we’re probably at the leading edge of what is the biggest wave in biotech, we’re putting substantial capital behind it over five hundred half a billion dollars a year or more. We have our own manufacturing facility and the ability to iterate fast. And we are continuously focused on innovating and growth, which should bode well for us in terms of building the next Genentech.
Yigal Nochomovitz
So you mentioned all the programs, so we’ll get to all of them, hopefully be efficient. But let’s start with the tip of the spear with exa-cel and hemoglobinopathies. So I guess the big picture question is, who is the ideal patient for exa-cel? And more specifically, are you focusing just on the Adakveo and Oxbryta failures or the highest risk patients, the ones at highest risk for stroke and ACS, or is it broader than that? And if so, can you elaborate on how you are going to penetrate the market?
Sam Kulkarni
Yes, I think, we’re starting on two ends of the spectrum in terms of the sickle cell population. In the U.S. there’s a hundred thousand odd sickle cell patients that have severe enough disease. I think for someone who is dealing with four, five, six VOCs per year, taking a medicine that you – one of the medicines that you mentioned and going from five to four VOCs per year, isn’t dramatically changing their life. I think they are still living a life of pain, they are still living with all the risks that they have, that any of these hospitalizations could turn into a fatal event. There is other risks that they are dealing with, organ damage, et cetera. So for them, they need a transform fundamental cure. And so we’re starting at one end of the spectrum.
I think what you are seeing with Oxbryta, crenezumab is somewhere in the middle of spectrum. People are off of reasonably compliant and they want to reduce their symptoms, but it’s not curative, right. So it’s a different patient population. It’s not really failures that we’re talking about. And then the other end of the spectrum is hydroxyurea, of course.
We’re looking at are the patients there is 25,000 odd patients, and we have a very good sense of the patient population because they all – we’re trying to get into our trials, we all know what centers they are, what these patients are looking for. And a lot of them just want to take a chance. This is like surgery for many of them. Why do people take a chance on hip surgeries, or other major surgeries, because once you do that, it’s one and done, and then you feel better that. And that’s the patient population. And that demand, I think, will be – will surprise people. There will be more demand than most people anticipate.
Yigal Nochomovitz
And the other interesting thing that, I think, you unveiled during the Innovation Day back in June, if I’m remembering correctly, was the idea to expand to perhaps make a mild or gentler preconditioning regimen, given some of the historical concerns with busulfan. So that’s obviously an important strategy as I understand it to broaden the adoption curve. Tell us more about what that strategy looks like. And do you have some specific initiatives there to do that?
Sam Kulkarni
Yes. This is a top five piece of strategy for us as a company, which is the 25,000 odd patients can benefit from what we have right now, with busulfan conditioning and exa-cel in the combination that we’ve shown in the clinical trials.
To expand beyond that, I think, for patients that have let’s say one or two VOCs per year, or have some of the symptoms, but are not don’t want to jump into busulfan conditioning or a transplant if you can get a gentler conditioning agent that is very targeted, a CD117 or c-Kit antibody and we’re specifically going after an ADC attached to CD117 that hones to the bone marrow, takes out the long-term hematopoietic stem cells and it’s a very, much milder procedure. That will expand the population dramatically. And I think that’s going to come.
Now there is five or six different efforts out there in the industry around this antibody and around these types of molecules or conditioning agents, and any of them could benefit us, right. We don’t have to have our own but certainly we want to push the boundary ourselves because the PK curves, the profile that you’re looking for is different for sickle cell and thalassemia or rare diseases relative to the typical development ground for these agents, which is AML. And so we want to have something that disappears quickly from a PK standpoint, so that it doesn’t affect our drug product, has any impact on cells that go into the patient.
So this is something we’ll talk more about. I think we’re seeing that the ADC relative to the naked antibody does have greater depletion capabilities and we’ll present these data next year.
Yigal Nochomovitz
Well, can you talk at this point, or is it too early to talk about timelines for further clinical development of that agent?
Sam Kulkarni
We’ll provide an update next year on the timeline for that.
Yigal Nochomovitz
Okay. And then, there has been some discussion amongst the KOLs regarding busulfan and long-term risk associated with busulfan. Are you going to be measuring that in the commercial setting in terms of risk for busulfan, or not necessarily focused on that?
Sam Kulkarni
Well, we’ll certainly monitor that. But I think, there is large studies we can rely on, there is a 2,900 patient study in sickle cell with allo-transplants or haplo match transplants which we use busulfan.
Yigal Nochomovitz
Okay.
Sam Kulkarni
And those patients have been tracked for over ten years. And I think there hasn’t been anything that’s seen that’s been long-term safety issues. In Europe there have been studies as well with both busulfan and treosulfan and those have been tracked as well. So we don’t think there is any long-term safety risks here, but something that certainly we be looking carefully at.
Yigal Nochomovitz
Okay. And then just give us a quick update on the timelines what’s happening with the discussions with the FDA? How close are you to getting that submitted? And same sort of question for Europe.
Sam Kulkarni
Yes. Well, encouraging discussions. I think with Europe, I think, we’ve kind of wrapped up a lot of the discussions. I mean, when you say wrapped up, you say, here is all what we’re putting into a filing package, here is all the modules, here is all the components of it, here is all the information we’re providing. And general agreement around that.
In the U.S., I think, we’re continuing the discussions, very encouraging and positive discussions. It’s a different nature of discussions that the U.S. because of the RMAT designations. We have more frequent discussions and dialogue with the division. And I think we’ll provide an update in the next few weeks, but I think they are training in the right direction.
Yigal Nochomovitz
Are the discussions with – I mean, aside from the RMAT designation are the different agencies in Europe and the U.S. focused on different aspects of your clinical data or safety, or you sort of getting the same sort of questions?
Sam Kulkarni
Very similar. I think the threshold matter in all of these filings is CMC.
Yigal Nochomovitz
Yes.
Sam Kulkarni
I think you need to get comfort around CMC before you really then say what’s sufficient from a patient follow-up and duration – duration or follow-up standpoint or number of patients standpoint. But I think the advantage we’ve had at CMC all along is that we started with afresh process, clean process and said from a blank slate, what’s a commercial-ready process that we can start with in Phase 1. And that served us well, where many other companies have tripped on that. I think you’ve seen at least three or four companies that open to file BLAs, two, three years ago they haven’t been able to file because of CMC.
Yigal Nochomovitz
I want to give you a chance to comment on the competitive landscape. I mean, obviously there is some competitors in the neighborhood that are marking up the same tree as you. So specifically, I mean, give us the pitch as to if you are a physician and you’re choosing between your therapy exa-cel and say a baby cell for beta thal or exa-cel versus lovo-cel for sickle. What is the pitch that you want physicians to hear? What is the argument to pick exa-cel?
Sam Kulkarni
Yes, I mean, first of all, I think, whenever I talk to physicians, I always say that this is a new category. We’re building a category and we’re glad that Bluebird is doing that with us. I think it is two different companies, two different efforts in generating what could be curative therapies for patients, right. In many regards, I think, this is a boon for patients to have these options. And I think what you are going to see, the dynamics are hard to predict. I think in thalassemia, it’s a very small patient population in the U.S.
Europe is a bigger patient population and that’s really the, I wouldn’t say battleground, but that’s where you’re going to see different countries, and different dynamics and different markets, whether it’s Italy, France, et cetera.
Sickle cell in the U.S. again, is a state by state thing. And it’s a very nuanced marketplace depending on which state you are in and the patient population there. So I think it’s early to say how the competitive dynamics may work out. But what we are consistently hearing is the patients whatever the narrative they are hearing, they want to go with CRISPR over a virus. Okay. It’s a very simplistic way of putting it, but in this choice of matter, there is a physician.
We’re going to look at the data and it’s, I would say at a very high level, 20,000 foot level, similar data in a way. I think large fraction of the thal patients are doing better. In our case, in sickle, every patient has done has had a transformative effect. We’ll see at the end where all the data land. But I think from a patient standpoint, we’re going to have a huge advantage in the narrative.
But again, I am less focused on the Bluebird versus CRISPR competition. This is about category building and making sure that the system has the ability to pay for these therapies, the ability for patients to access these therapies, the transplant centers build their capabilities in terms of nursing staff and qualified personnel. And those are all important. And I think eventually this could be a bigger category for both players.
Yigal Nochomovitz
So have you given guidance in terms of what your strategy will be in the United States, I assume it’s a go-it-alone strategy in the United States for launching? And is that correct?
Sam Kulkarni
Well, I think, the advantage we have is Vertex has taking the lead.
Yigal Nochomovitz
Okay.
Sam Kulkarni
In launching globally. I think one of the things that we had originally, if you recall, in 2019 timeframe was that CRISPR was responsible for the U.S. launch and Vertex was going to the ex-U.S. launch.
Yigal Nochomovitz
Right.
Sam Kulkarni
And as we started looking at all the launch factors and what we need to do, it’s highly overlapped. I think, what you want to do is one global launch. That’s very coordinated. And I think it’s only natural that Vertex will be the right party to do it. And they have so much experience. They have built a great team internationally, globally, not just in Boston here or in the U.S. And we’re putting all the efforts in to make sure we have a very smart, targeted, and effective launch, should we go there.
Yigal Nochomovitz
And I assume Vertex is taking the lead with respect to thoughts about pricing and outcomes-based pricing models. Are those under consideration as well?
Sam Kulkarni
Yes, correct. And we’ll be flexible. I think we’re generally both CRISPR and Vertex are flexible around the pricing model. I think what we’re hearing from the payers is many of them actually just prefer a single payment, whether it’s the U.S., or even in Europe, as opposed to measures where you would really have to monitor the patient and do outcome pricing. But we’re open to any of those ways of pricing this obviously given the Bluebird launch first with the certain price tag, I think, it anchors around a certain price point.
But again ICER’s document around the price effectiveness is a very important publication. I think it says that in thalassemia, even price, up to $5 million of pharmacoeconomic value generator for the system with this therapy. I think in sickle cell I expected even more on the number. And that means that we’re not only helping patients, we’re helping this system eventually.
Yigal Nochomovitz
Did you want to add anything else on exa-cel or do you want to move on?
Sam Kulkarni
Yes, we can move on. I think generally overall, on exa-cel, I think, we’re heads down executing at this point. And this can be a large filing package, there is a lot to do. And we’re focused on that. We have both Vertex and us have said, this is a high priority for us. We’ll provide further guidance on the U.S. filing in the coming weeks. But at this point, I think, it’s large fraction of what occupies us day-to-day, but we’re focused on getting what could be the first, not only the first CRISPR-based medicine to patients, but would also be a best-in-class and transformative therapy to patients.
Yigal Nochomovitz
And I think in your intro, you mentioned there is six data points next year. Are any of those exa-cel data points or that’s other things?
Sam Kulkarni
I just meant other things as well. So, if I just – there is continuing data for our CTX110 and CTX130, but then we have new data for CTX112, CTX131. Now, we haven’t disclosed the disclosure paradigm for all that we haven’t talked about.
Yigal Nochomovitz
Okay.
Sam Kulkarni
But we’ll have new data for CTX112, CTX131. On diabetes, both CTX210 and CTX211. And then I think on in vivo we don’t have a timeline yet, but we’ll start seeing some data there as well. So pretty catalyst rich over the next 18 months.
Yigal Nochomovitz
Okay. So, let’s switch to IO and allogeneic. So obviously the CD19-CART space is quite crowded to say the least. So just high level, what’s the distinguishing feature or features of your, of your approach at CRISPR for this class?
Sam Kulkarni
It’s very crowded from an early data standpoint. But if you think about what’s the most important metric, which is durability and getting durable remissions. Right now, there is only two companies that have shown durable remissions that are Allogene and us, right. I think there is a lot of interesting early data from NK cells, there is data in from other gene editing companies, but it’s all early data. You haven’t parsed out what the contribution is from the conditioning or preconditioning with Flusi or any other agent that you have, you haven’t parsed out, dose levels and how far it can go.
And I think what we have is now a path to starting our Phase 3 registrational trial. I think we already said, we’re going to go into pivotal trials earlier this year. And I think we had a number of discussions. Again, the RMAT designation helps a lot to have those discussions to what’s required to get into a Phase 3 registrational trial. And we believe we can get approved off of a single-arm study, given the safety profile that we have for CTX110, for instance.
And I think if you can enroll in a group quickly, we are on the market. What you have is yes, it’s a very complex landscape. You have the bispecifics, you have autologous CARTs. This is all after RITUXAN, you have an ADC like POLIVY, then you have some other agents like XPOVIO, Zynlonta, Monjuvi, et cetera. But all in all, I think, if you look at it, you really have the CD20 paradigm and then a CD19 paradigm with some other targets like CD79.
But in the CD19 space, I think, what my belief is, bispecifics are going to move up in line of therapy and bispecifics and autologous therapies use the same mode of action, which is the endogenous T-cells from the patient. And a lot of these patients have exhausted immune systems.
And I think what are you going to see is if they fail bispecifics, unlikely that they succeed wild on autologous therapies. And I think you are going to move into allogeneic therapies beyond that. And what you are going to see is a squeeze on autologous eventually. This is a five-year view, five-, six-year view with bispecifics and then allogeneic. And allogeneic are going to improve over time. And even the first gen allogeneic right now if you simplify all the data, with the best autologous therapy has about 30%, six months CR rate on ITT basis intent-to-treat basis, right. And then Breyanzi somewhere in the 25% range.
So one in four or in some cases, one in three, one in four have durable remissions. Allogeneic is a one in five, right now with the first generation. And safety profile being much better, the ability to do in outpatient settings. And the ability to dose immediately thereafter, two days thereafter.
So there are advantages. Now I think that doesn’t mean we have to stop. We do need to get better in terms of efficacy, which is why CTX112 is something we’re excited about. We also have modifications we’ve made with CTX110 in terms of the manufacturing process ahead of starting this registrational trial. So that it’s gives us the best chance of success. But we don’t want to increase the conditioning agent to any point where you impact the safety. The key feature of this is safety. So you can do it in the – in the community settings for 80% of the patients that get treated in the community settings, in addition to the economic centers.
Yigal Nochomovitz
Is that your operating bar for Phase 3? Is the one in five statistics you cited or do you feel you can need to do a little better than that or not? And also remind everybody what exactly is different in CTX112 versus CTX110.
Sam Kulkarni
Yes. So, I think 20%, six-month CR rate, I think, is meaningful enough where that gets you approval of a single arm.
Yigal Nochomovitz
Okay.
Sam Kulkarni
Okay. Now there is a sensitivity in the market beyond that in terms of we’re 25%, this is a multi-billion dollar drug. If you’re a 20% you are trying to get to a $700 $800 million drug, and big revenues. So there is this commercial sensitivity given the competitive landscape in that range. But there is a threshold for a single-arm approval.
Now our single dose study with CTX110 got us to around that one in five, right. Now with two doses, the presumption is that data only gets better over time. So we’ll have to see how that all comes out, we’ll have data updates end of this year for our initial trial, with single dose with longer follow-up, as well as a commentary on how the two-dose regimen is going.
Yigal Nochomovitz
Okay.
Sam Kulkarni
Now what we did with CTX112 was very interesting. We did this large scale, robust screening to say, what makes these cells better. And without saying – without supposing that TGF made us better, or the X, Y, or Z is better, there were some hypotheses going into the mix. And we did not only our own screens, we partnered with a company called KSQ to do their screens as well, so that we have two different data sets going into this. And that’s where we identified Regnase and TGFβRII. And now TGFβRII is been identified by some other parties as well, but the synergy and combination of the two, Regnase is a transcriptional activator or some of the cytokines. So you’re not just backpacking one cytokine adding one cytokine to the mix, you are actually regulating multiple cytokines around that CART.
And the data, I mean, this is like ten-fold better, if not a hundred-fold better in mouse models. And we think that’s going to translate into humans. Now, I think we have to obviously balance safety and efficacy, but we’re quite excited we’re manufacturing it at 30 minutes down the road here in our own manufacturing facility, which is also exciting. And we look forward to bringing that to the clinic.
Yigal Nochomovitz
Okay. Just a few more on IO. So you are going to have an update for the CARBON Trial, correct a little later this year. Just what is the – what do we need to watch further? What are we going to learn? Obviously not the details, but what are we going to learn conceptually from the product that [indiscernible]?
Sam Kulkarni
Yes. Well, I think – I think we had our company update on CARBON last year, and the question was if you kept going longer, where do we land on durability, and sort of long-term remissions, right? So that’s one question lead to answer. Are allogeneic therapies able to provide the same long-term remissions as auto CAR-Ts? And you have patients on auto CAR-Ts have gone three, four years now in remission.
Second question is, is the second – this is not the original study, but the next – next study was with two doses. Is that doing anything in terms of improving the efficacy? Now we won’t have the full data set because it’s still early, but we’ll have some early sort of color on the value of a second dose and that I think bodes – forebodes what may come for 110 going forward in a registrational study.
Yigal Nochomovitz
And just one more on that. So you’re, if I’m correct, you’re at 600 million cells currently. Is that the dose that you’re going to take into pivotal? Or are you still thinking about optimizing that?
Sam Kulkarni
Well, I think that’s the dose we came to because the dose matters and we’re not limited on dose as long as safety is – safety profile remains consistent. And actually not just that, but do it twice. So 600 million twice for the second dose with Flusi conditioning.
Yigal Nochomovitz
Okay. So CD70 obviously a very interesting program both in T-cell lymphoma and solid tumors with renal cell. So just tell us quickly where those programs stand? What are the key highlights from the data? And if you were to pick one of those, is one more promising than the other, are they just different?
Sam Kulkarni
No. I think – look, I think everybody in exa-cel will tell you solid tumor is the, I don’t want to call it Holy Grail or whatever, but if you crack solid tumors with cell therapies, it’s a whole new world, right? I think 80% of the cancers we deal with are solid tumors. I was having breakfast with a pharma exect three years ago at JPMorgan, right before COVID. And they were like; well it’s going to take three Nobel Prizes for you to have allogeneic CAR-T that will have a response in solid tumors. And here we are with CTX130; we have one complete response in RCC, which is a very difficult indication treat after they’ve had multiple other therapies.
Now that’s super encouraging. I think in the investor community, they’re like always focused on numbers of how many patients got CRS responses, et cetera, et cetera, but in the academic community, they’re very excited. And what we’ve seen is a lot of information. We’ll provide more data on 130 going forward, but across all the other patients what encouraging responses, but what we see on the PK/PD profile is very interesting. What’s happening at the side of the tumor? What’s happening to these cells as we take cells out of the side of the tumor or CAR-Ts what’s – what is their phenotype and what are we seeing those cells?
And a lot of thinking later, we do find that there’s exhaustion in solid tumors. That’s greater than what we see in he-malignancies. The solid tumors have a way of exhauste CAR-Ts. And so that’s why this Regnase and TGFβRII edits coming in a big way because they prevent exhaustion and the cells can keep going. They’re just literally go for 3X longer, 4X longer, mouse models. And so that’s where we’re going to go in solid tumors to go into CTX131, go to the next gen.
In T-cell lymphomas, I talked to these investigators all the time, they have no options. The only option they have for CD30 positive T-cell lymphoma is the brentuximab, which comes with a lot of talks. And again, patients come off it very quickly. So for those patients this CD70 drug and that’s why we got the EHA oral because there’s nothing else. And there’s a fast path to approval potentially for us. We haven’t fully established the dose and the regimen to say, we’re ready to go into registration. I think we still need some, some more data but we also need to continue some regulatory discussions, but early next year we’ll provide guidance on what that program’s going to look like going forward.
Yigal Nochomovitz
So since you’re seeing that CTX131 is looking so much better, you said then potentially even higher fold potency. Are you going to carry 130 through to the finish line? Or are you going to make a switch at some point and go with that for the late stage?
Sam Kulkarni
For T-cell lymphomas we’re going to carry to the finish line because I think we have a fast path. I think in T-cell lymphomas, the tumors are more accessible, right? So you don’t – they don’t – we don’t have – we don’t have the same evidence that they get exhausted in these tumor environment. And the patients need a drug. These patients literally have no options and things would make sense for us from a business standpoint as well to carry CTX130 all the way through.
Yigal Nochomovitz
Okay. Both as for RCC as well or?
Sam Kulkarni
RCC only, we’re going to 131.
Yigal Nochomovitz
Oh you are. Okay. Got it. That, yes, you made that clear, I think earlier in the summer. Okay. So let’s – let’s try to hit some of the other topics. So regen med obviously fascinating area. So just for everyone that’s less familiar, there are three programs, there’s the VCTX210, 211, 212. Can you quickly just summarize the evolution of the strategy there and how you’ve improved it over those three products?
Sam Kulkarni
Yes. Well, the big picture of this is for us, it’s the world of iPS cells meeting gene editing, and that just opens up the possibilities to. It’s like iPads and phone devices meeting high speed Wi-Fi everywhere, ubiquitous Wi-Fi. And you just have – you can have so many apps, so many different possibilities here. So I think it’s a fundamental core capability we’re building or on iPS cells. Now with diabetes, that’s the place we wanted to start because there’s evidence that you can take cadaveric islet cells, implant them into patients with immunosuppression, and they – even though they have very severe Type 1 diabetes they’re essentially insulin independent. And that I think, given that data that’s the aforementioned protocol. We said, can we do this with iPS derived cells or embryonic stem cell derived cells?
And this has been a 20-year saga; this thing don’t turn around very quickly. Back in the late-90s these efforts started with even companies like J&J jumping in. And over 20 years, the ability to differentiate these cells into islet cells or islet cell precursors has been perfected and developed. But you could never dream about immunosuppression free transplants until editing came along. And now with editing, we’re making edits to make it immune-evasive and the edits we started with were CTX210 or VCTX210 I should say with our partner ViaCyte, were around MHC Class 1. We saw good data from beta 2M in our IO programs. We insert a PD-L1 into these cells. We actually do HLA-E editing as well into them to make them immune-evasive.
And then we’ve actually have another edit called [indiscernible] that makes it – makes a cell more robust, and reduces stress related death. So that was VCTX210 right? So we started there. We made the master clone, seed bag, et cetera, put that in the clinic. That one was not fully tuned for efficacy. We want to understand the immune-evasiveness, but we didn’t crank-up the insulin production from these cells because we weren’t sure, we wanted to see where it comes out on dose et cetera, right?
211 is fully optimized for insulin production. So it produce a lot more insulin. Now because we’re producing more insulin in these cells you actually want to avoid ER stress. The endoplasmic reticulum is where a lot of the stress happens in these highly insulin producing cells. So we have two additional edits one’s called A20 and the other one’s called MANF, and those edits prevent stress related depth and actually make these cells much more robust. So in our mouse models, et cetera we see these cells going a lot longer, and more immune to cell death from other – from oxidative stress or anything else, right? So that’s 211.
So we’ve already advanced quite a bit with one jump. And now 212 is the next level of advance where you can actually get a lot more flexibility or device configuration, because one of the issues with device configuration is you get fibrosis and fibrotic cells going into the device or causing cell death. And these edits that we have with 212 actually prevent fibrotic depth. So there’s two additional edits that we’ve made with 212. So I think that’s the notion of this is we’re continuously innovating and it doesn’t cost us that much more for the next – in the next version of it. And as we bring it into patients, we don’t want to confound the experiment bringing all the edits in together. But as we learn from these edits and dosing patients, we can bring the next generation forward. And eventually we’re going to tackle immune evasion.
Yigal Nochomovitz
The long-term strategy, this is a device with implanted iPSC cells with the edits you’ve discussed, gets implanted. I’m not exactly sure where in the body you can tell us, but it’s the idea that this will have a lifetime of X years and then you’ll have to do another surgery and recharge essentially or is this a one-and-done well what’s the thinking?
Sam Kulkarni
Well eventually we want to get to the one-and-done. But initially the first generation process will probably have a lifetime of hopefully three, four, five years, right? I think this is a similar way the – the cardiac implant markets developed. Early on some of the stents et cetera only had like a two, three – three, four-year lifespan; you had to change them out. Now we have 10-plus years on these stents because you’ve made them much more unresponsive to foreign body reactions, et cetera, and I think that’s how it’s going to evolve eventually it should be a cure.
Yigal Nochomovitz
So if we could just get into a bit more specifics on the expected clinical data for 210, which is the one that’s going into the clinic first, what is the expectation there? Is the goal to reduce glucose levels by a certain amount or do you want to see normalization of blood glucose? What’s the idea?
Sam Kulkarni
Well in the patient the key event we’re looking at is reducing the volatility of their sugar control, right. If you – a lot of these patients suffer from sort of hypo glucose environments where there’s immediate secretion and then they’re low on blood sugars and that can cause a lot of different issues for the patients. So one is preventing sort of getting the range bound…
Yigal Nochomovitz
Excursions?
Sam Kulkarni
Excursions, yes. Giving them range bound, that’s sort of number one. We’re not going to make them insulin independent with this first product because we haven’t cranked up the insulin – the insulin production. I think we haven’t even – there’s some optimization also between the glucagon producing cells and the insulin producing cells, right. So I think that’s what we’re looking for from an efficacy standpoint. But the key thing we’re really looking for is immune-evasive. Do the cell – devices get integrated? Are they being – are the cells around six months later? I think that is the sort of a threshold level of immune-evasive that we want to see. And if you can see that, then it gives us the information for 211 to be able to get to that insulin independence potentially. So I think the 210 data is focused on immune-evasive. 211 data will be around; can we get to complete insulin independence? And I think that’ll come in quick succession.
Yigal Nochomovitz
Okay. About 10 minutes. So let’s switch to In Vivo another really interesting program. So tell us a little bit more about the high level strategy there. You’re starting with cardiovascular, which based on targets in the liver that impact cardiovascular biomarkers. But there are a lot of other options for example primary hyperoxaluria for example, HTA, hereditary transthyretin amyloidosis potentially even ocular. So what was the thinking in terms of starting with cardiovascular?
Sam Kulkarni
Yes. I think the field has come a long way. I think if people said in vivo gene editing, it was going to take 10 years, even three years ago, right. And I think kudos to Intellia for de-risking gene editing in the liver with TTR. Now for us the calculus has been we want to go pedal to the metal with in vivo. We want to have LMP that work. We want to have several programs, maybe double-digit programs at some point around liver editing. The ocular editing, I think is still not fully de-risked. I think using viruses for ocular editing as a delivery vehicle has its own challenges, and LMPs haven’t completely been de-risked in ocular settings, so it’s the liver.
So in the liver, you have a whole spectrum. You have something like PH-1 primary hyperoxaluria, which is a tiny indication all the way to something like PCSK9, which I think heart disease kills 25% of the people in the world; it causes 25% mortality in the world. So where do you want to fit? TTR or somewhere in between, right? And I think for us, the key criteria that tells us which sequence we should go in, and we may go to all these indications is developability to an approval.
We’re not interested in just getting the early data and then getting the enterprise value jump and then just take years after that to develop it. I think we want to get to approval because that’s [indiscernible] is to get these medicine to patients. And so cardiovascular makes a lot of sense. I know there’s a lot of questions about the business case and the commercial viability of cardiovascular, but the attitudes are changing. There’s going to be a point where there’s going to be half people in this room sitting and saying, maybe I’ll take – I’ll do a PCSK9 edit to prevent heart disease, if I have any history of family heart indications.
And so then – so we’re going after PCSK9 and BTL3 LPA. Now ANGPTL3 is a very interesting area to go into first. We want to go there first because from a competitive standpoint in terms of getting patients on study, there’s a set of patients with very high triglycerides that we think we can enroll very quickly in our study. And there’s even a potential path to early accelerated approval in some, in these indications. These are patients that that have other measures like pancreatitis et cetera they can look at in terms of events to get to developability and to get to a secondary marker besides just cardiovascular events, right, which takes many more patients and a much longer trial. So there’s a developability aspect of it.
LPA is emerging as a very interesting target. The studies from Novartis and Ionis and then Amgen, the early data emerges [indiscernible] that’s getting re-risk very quickly. And of course we wanted PCSK9. This is a little more competitive from a patient enrollment standpoint, given all the different modalities in PCSK9 right now. So we are all in on cardiovascular. I think the issue with indications like TTR, I think is, the developability is getting harder because a large majority of the patients are right now are on Tafamidis or are on – will are on Patisiran for instance. So then you have to show differential impact and it gets a little harder, but eventually I think the advantage is there of gene editing, a one and done over any of these chronic therapies is going to win out. It’s just a matter of what is the ROIC for us?
That’s a very important metric as we look at every program that we start investing in? What is the path to actually approval? It’s not just the path to first POC. A lot of the biotech specialist funds are all focused on what’s the data that de-risks, and then they’re off doing something else. For us we have to take that longer view. What’s the path to approval and a reasonable market potential? And if you think that way, and then pick indications, we’ll have a number of these going in and we have a strong balance sheet to support it. But we want to sequence it such that we have – we’ll probably have 10 plus programs but in a measured fashion so that we’re not getting – we’re not increasing our burn rate too much.
Yigal Nochomovitz
I mean, obviously everyone’s sort of, PCSK9 and most people I think LPA, LPa, but ANGPTL3 a little – maybe a little bit off the map. Is that a target that’s been being pursued by the big pharma players too or is it?
Sam Kulkarni
Absolutely. I think there is lot of interest from companies big – two or three big pharma companies that are doing ANGPTL3 trials right now on srRNA and the data look very intriguing. You get dramatic triglyceride reduction and you’re getting LDL reduction together with that. And I think obviously in some of these trials, what’s become important is the baseline LDL matters in what reduction you see in these patients, but they present differently. These patients present differently. They have different set of risks, and I think that’s why ANGPTL3 for us is very intriguing target. Now, obviously other companies are doing as well in gene editing, but again, it’s not a one player takes all. I think this is a market development for a new segment that we’re trying to create.
Yigal Nochomovitz
And you had a comment at your innovation day regarding some emerging technologies for HDR independent or AAV3 applications or technologies for in vivo. Can you say more about that at this point or that’s just?
Sam Kulkarni
No. That’s actually – no, it’s emerging very quickly. So what we’ve done is create a company within a company, we call it CRISPR-X internally. And the idea was let’s unshackle this group from thinking about programs, but just go technology first and then we’ll find the disease later. Whereas everywhere else we’re saying here’s the disease we want to go after, here’s the best technology and we’ll develop it this way, right? So let’s create a separate company that’s like unshackled from all the, I wouldn’t say bureaucracy, but everything else I need to do or thousand zoom meetings and just focus on technology.
And the idea here is, anything that’s gene correction is 3 times the market opportunity as gene deletion, right? Whether it’s whole gene correction or tracks of genes, and there’s tens of disease you can go after, if you crack that. Right now the best way of doing gene correction is to have a donor template with the virus and AAV with the LNP mediated Cas9 delivery or guide delivery. The problem with using viruses and you’ve seen that for the AAV based therapies, the agency has a bar that’s pretty high on viruses because of the inherent variability, not just in manufacturing but also what you’re seeing in patients. So it’s not the most elegant way of doing gene correction using a donor template plus LMPs.
What we want to do is if it’s an all RNA based gene correction then it’s a much easier modality and from a manufacturing standpoint, but also hopefully less variability in patients. And I think that’s something that’s of high importance to us and not only for correcting or putting hold, inserting hold genes in, but take an indication like A1AT for instance, or something else like, you’re correcting one base pair, but you’re correcting not just disrupting, and that has tremendous potential. So that’s something that’s of great focus for us, and we’re not, what we don’t want happening is what’s happened to other companies in the past that were sort of the stars in biotech, you get disrupted by the next thing that comes along, because you’re so invested in your own platform that you’re not open to new platforms.
We’re going to be smart consumers. We’re going to be open to what’s the best technology out there. And similar to how Genentech navigated the antibody fields with humanization of antibodies, humanized antibodies and everything else to develop the best therapies we want to stay on top and bring best-in-class therapies against the diseases we’re going after. And that means that we have to evolve on technology access. We have to evolve in our manufacturing capabilities, and ultimately we have to be open to putting a significant portion of our capital into new technologies, which is always uncomfortable and we’re doing that.
Yigal Nochomovitz
And just one more on the topic of new technologies; you have some new base editors I understand which of the potential for seven or even more edits. And I’ve seen with some of your competitors up to five, but seven or more seems quite interesting. So can you say anything more about that initiative?
Sam Kulkarni
Well, this is for our Gen3 immuno-oncology, this is ex vivo. So in vivo is very hard to do that many. Ex vivo, what we can do off the seven there’s two that are knock-ins. So we make it – we do still make cuts to knock in genes and in the process of inserting those, we already have two disruptions, right? So we have four edits with the classical CRISPR/Cas9. So we can attack on three more edits if you want to with base editor.
Yigal Nochomovitz
Okay. It’s not as easy as elegant that everybody makes it seem, oh, here’s a pencil and eraser, and here’s a base you can change. There’s way more complexities to every platform, whether its space editing or whatever else, there’s random deamination, there’s everything else that happens with it. So there’s more controls necessary from a regulatory standpoint to bring these therapies ultimately to the clinic. But that’s – we’re going to – we’re going to espouse any know the new developments and bring it into our therapies.
The key test for us though before we invest a lot in our third-gen IO is, do the additional edits in second gen IO are they contributing more? If it doesn’t, it doesn’t make sense to keep going for more edits. We do have to establish contribution of additional edits. So there’s no dirt of interesting and challenges, our interesting things to think about on a day-to-day basis for us at the company. We appreciate your critical coverage and you’ve always pushed us in our thinking. I think I always appreciate that. And I think it’s on us to sort of stay ahead of it, I think and stay ahead of all this private capital that’s coming in. All the private companies are being formed and demonstrate that at scale investment in the cutting edge platform that we have with CRISPR is what’s going to generate tremendous value, not just for patients but for shareholders as well.
Yigal Nochomovitz
Well, you get the last word. So thank you very much, Sam, pleasure.
Sam Kulkarni
Thank you, Yigal.
Yigal Nochomovitz
Thanks. Appreciate it.
Question-and-Answer Session
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