Newsfilter article unlocker

Hello, everyone. I'm Max Gore, a biotech analyst with Morgan Stanley. And before we get started, for important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com forward slash research disclosers. And with that, I'd like to welcome Sam Kulkarni, CEO of CRISPR Therapeutics. Thank you very much for joining us today. Thank you for having us. So maybe just to start off, Sam, you can kind of set the stage for us, walk us through CRISPR therapeutics key priorities milestones through year ends and where the portfolio stands overall yeah happy to and 26 has been a great year for us so far as we move to the next phase of the company but what we have are several layers of value one is caschevi which is our commercial product for sickle cell and thalassemia which we are partnered with vertex on and that's showing a very nice trajectory from a revenue standpoint, and we expect that to be a multi-billion dollar opportunity. The second is three assets that could potentially be ready for phase threes next year or pivotals next year, and these are namely CTX310, which targets ANGPTL3. This is for a one-shot reduction of cardiovascular risk by using CRISPR-Cas9 to reduce the ANCH-BTL-3. We have ZugoCell, which is an allogeneic CAR-T, which is off-the-shelf, very convenient, and it could do a one-time immune reset for various B-cell-driven autoimmune diseases. And the third being CTX611, which is our siRNA, which we're partnered with a company called Sirius on, for factor 11, which has the promise of anticoagulation without the risk of bleeding. And that can be applicable in many different settings and indications, such as stroke prevention. So those three assets represent the next layer of value for us. And then we have two early assets in the clinic now. One is for A1AT, which is our first advanced editor, which has leapfrogged Gen 2 editors to be, you know, something very efficient and potent and very precise. We call it synthase editing, and that's going to dose patients soon. And CTX340, which ist for refractory hypertension, where we actually target angiotensinogen, and that can result in a pretty meaningful reduction and blood pressure in patients very soon after being edited. And those two will have data in the not-too-distant future. So we have other programs beyond that. One of them is CTF321 for LPA, which, you know, hangs in balance based on horizon data, and also type 1 diabetes. And the last layer of value for us is our very prolific and productive research arm. And we have a best-in-class in vivo CAR T now, both in the form of a transient CAR T based on mRNA, but also permanent CAR Ts based on editing, where we insert the CAR into cells and it's permanent. We have in vivo HSC editing, whereby we directly edit hematopoietic stem cells, which can be durable, and many other things that we're working on. So all in all, a very rich portfolio, but we have this strong balance sheet to move all these programs forward ourselves and really change the face of medicine along many different dimensions. Great. So maybe we'll start with Casgevi, move on to some of the more mature assets, and then we can talk about the future from there, if that sounds good. So the FDA recently expanded the Casgemi label to children two years of age and older, adding approximately 5,500 potentially eligible patients with sickle cell or transfusion-dependent beta-foul. How should we think about the pace at which pediatric expansion could translate into patient referrals, treatment center readiness, initiations, and ultimately revenue? Yeah, it's a great tailwind for us on Caschevy. I mean, Vertex, in their last disclosure, announced revenues of about $76 million for the quarter. and also, more importantly, said that they're initiating over 100 patients per quarter. And that puts you, if you just do the math in terms of future revenues at around $2 million price tag, that you're already looking at future revenues well north of half a billion dollars and getting closer to a billion dollar mark, which makes it a blockbuster. and i think that tailwind of pediatric expansion is only going to add to the number of patients that are that are being initiated per quarter because with a lot of these with kids you know you have more children's hospitals at play and they're used to these kinds of procedures so they're going to be more productive as well as there's a more bigger addressable population and not to mention the fact that i think this with these diseases you want to treat these kids earlier and earlier. The sooner you treat them, the better, because you don't have any organ damage or any permanent damage that will be caused by these diseases. So all in all, I think a very favorable dynamic for CasGeV over the coming quarters. Okay. So more broadly, what are you seeing in regards to the movement of patients through the CasGev treatment journey? Where is the greatest remaining friction between referral, initiation, cell collection, conditioning, etc.? What are you seeing as potential bottlenecks, and what's the team working on to remediate that? Yeah, at this point, most of the bottlenecks have been worked out by our partner, Vertex. I think initially when we started the launch, there was a lot of work required to get the reimbursement set up to be well-oiled in terms of prior authorizations, getting all the approvals. And mind you, we had to do this not just in the U.S., but several jurisdictions around the world. But the good news is we're very strong payer coverage. Second thing was to get each of the hospitals contracted, and you have individual requirements per hospital potentially based on their own IT systems and what they needed to get these patients into the flow. So that's all been done. And then the last thing is manufacturing capacity, and we're steadily increasing the capacity as we see more and more demand coming to be able to serve the needs of all these patients. So I would say at this point, most of those elements of friction have been dealt with, and we're just now awaiting the patients to come into the funnel, move through the funnel and ultimately get treated. It still does take over six months, potentially nine months plus to get a patient from initiation to treatment, but at some point it's going to stop mattering because it's just a matter of getting into the tunnel and then getting through the funnel and getting treated. So all in all, I think that's looking very good and could be the basis for steady growth for a long period of time from here on out. Is there anything you would look at potentially to decrease that time, or will six months always kind of be the low end? Yeah, I mean, I don't know. I think we'll do everything we can, but it's not the manufacturing that's the major contributor to the time. I think the actual manufacturing itself happens pretty quickly, but a lot of patients opt to do exchange transfusions. For instance, you have two or three months where someone is doing an exchange transfusion before they're even collected. And then after the drug is manufactured, sometimes people wait because they have to get their life in order or they have take a break or they need vacation from work, et cetera. And so you do see some wait time there anyway. So it's never going to be one month. But at the same time, it doesn't matter at this point. I think we just want to get the, you know, what matters for the patients is the guarantee that they're going to get that drug product if they go through the journey, and that's what our main goal is, to have that assurance for the patient. The last thing also I'll say is the other tailwind that we should think about as we look at the next few years is gentler conditioning. I think Vertex will disclose more on gentler conditioning over the coming months, but I think that gentle conditioning agent that allows a patient to just do a three-day hospital stay or less instead of a two-week or three-week, that's going to be a big tailwind as well, and it's goingto expand the addressable market where some of the more moderate patients will also potentially opt for Caschevy. So I thinkthat's another factor that we're preparing for as we think about capacity expansion, not just, you know, in the U.S., but globally. Yes, I was going to ask that question on gentler conditioning, but also in vivo hemopoietic stem cell editing. Any updates around that? Yes, it's a major focus for us to do direct hematopoetic stem cell editing, and it requires a lot of different things to come together, whether it's the LMP platform, the targets, and the type of editing you're doing. we're making very good progress in our corporate presentation we showed durable editing of hematopoietic stem cells over a six month period and we didn't say which edit that was but you can see that being applicable to a number of different indications and diseases you could modulate several factors whether it's porphyrias, whether it is autoimmune conditions, etc. that you could do if you can actually establish a platform for HSC editing, not to mention the fact that sickle cell and thalassemia will be the huge beneficiary of that. And so, you know, the life cycle of the franchise for us and Vertex is that we have CasGevi in its current form. We have CasGevi with gentler conditioning agents. And then, you Know, in the 32, 33 timeframe, you're going to have in vivo HSC editing that's going to come to patients that will allow us to, like, you know, treat many more patients than what the current affordability indicates, right? You know, we go beyond Western Europe and U.S. and potentially even treat patients in Asia and Africa to get rid of this bad disease. Okay. That's helpful. Maybe we can pivot to CTX310. You recently presented data at ESC. Maybe just put the data update into context. I have a few follow-up questions, but maybe introduce the audience to what was presented. Yeah, this is a fascinating target that was elucidated about 15 years ago. It's called ANCHPTL3, angiobotanylactoceptor 3. And the basis is natural history data as well as some work that was done in the Boston area. But it starts, you know, there's a village called Campo di Mele in Italy where people have a naturally occurring mutation in their ANCHПTL2, which is a loss-of-function variant. and these people just have lower levels of NHB-TL3. And it turns out that the cardiovascular risk in this village is a lot lower, and while it's not statistically significant, they all tend to live longer. So a naturally occurring mutation in NHB TL3 resulting in a greater lifespan, lower cardiovascular risk. And we're just following the genetics, right, and following natural history data. and if we can recapitulate the same knockout, it doesn't have to be the same mutation, but we can knock down ANCHP-TL3, it basically is a protein that acts on lipoprotein lipase and endothelial lipase and these lipases are enzymes that chew up the cholesterol, right? So you're unhinging those lipases of the enzymes to reduce your cholesterol levels and when you knock down anCHPTL-3, no surprise, your triglyceride levels, your LDL levels all come down. And in the phase 1a data that we presented, we presented some early data last year at AHA and then continuing data at ESC, which shows that we get dramatic reductions at the higher dose levels of ANCHP-TL3 up to 80%. It's not 100% because there's some ANCH-PTL2 produced outside the liver. So we're pretty much maxing out the liver editing with ANCHB-Tl3. and when we knock down ANCHP-TL3, you get near 50% reduction of LDL, cholesterol, near 50%, reduction of triglycerides. Now, it's a little variable because different patients in a Phase Ia, it is a mixed population. Some people have high LDL. Some people have high triglyserides. So, that's really encouraging. And then we presented data at ESC that shows that that edit is durable. If you knock it down 80%, it remains knocked down 80% a year later. And that is a very good sign because it means that is durable for life, essentially. So it lays the groundwork for a one-and-done gene edit that's going to reduce your bad cholesterol for life. We'll have more data coming soon in our Phase 1B where we've segmented the patients into severe hypertriglyceridemia, mixed dyslipidemias, refractory hypercholesterolemia, et cetera. But the first one that we're moving forward obviously severe hypertriglyceridemia, and we'll get a greater sense of the data for that population later this year in terms of what is the triglyceride reduction that you get there and what else are you seeing in terms for LDL reduction, hepatic fat traction, et cetera. And so from the ESC data, if I could just ask, what did these data teach you about dose selection, patient level variability, durability you've commented on, but just the therapeutic window as you advance into the Phase 1B. Yeah, it basically proves that at the highest dose levels that we did in the Phase IA, which is about as high as we need to go, it's very safe and it's durable, essentially, laying the groundwork for our Phase 1b, where we picked a fixed dose based on that highest level dose. There is some variability between patients because they're all different types of patients. Some have both high LDL and high triglycerides. Some have low LDL but high trigzycerides and vice versa. And that obviously leads to, you know, if you have normal LDL or triglycystides, you're not going to see much reduction because you're already normal. But essentially, it's a very clear indicator that ANCH-PTL3 was dose-responsive reduction. And if it's reduced to a certain level, it remains reduced for a long period of time and it's durable. And it gives us a good window into what the dose is that's safe. that we can go forward into Phase 1B and potentially pivotal. So I think, you know, the Phase 1D data we get later this year is the last piece of information we need before we can goes to the regulators and say, how do we start a pivotal trial for ANCHP-TL3 in Population A or Population B? So that's a great segue into the Phase 2B data. Could you just set expectations? What clinical and biomarker evidence would support advancing into this indication? How will you determine which population offers the most practical first registrational opportunity? Yeah, each of these populations will have different level of information or evidence, right? So you have in severe hypertriglyceridemia, I think what we're trying to get a handle on is what is the level of triglyceride reduction you see in patients with very elevated triglycereids? You know, if you look at the SRNA trials, they usually had a cutoff of about 500 milligrams per deciliter as their triglycerides, lowest triglycereids, so 500 and above. We're trying patients that are well above that, and we're trying to get a handle on how much triglycera reduction there is, and then all the other biomarkers, such as what happens with LDL, what happens with their A1C, what happened with hepatic fat fraction. So I think we'll get a hand on that, that'll allow us to say, are we getting the same reduction that you see with sRNA for triglycerides, and then what is the population we want to go after? What's the cutoff of triglycarides that we wantto go after in a Phase III trial? So that's for trigloceridemia. For refractory hypercholesterolemia, what's very interesting is ANGPTL3 is synergistic with PCSK9. We had patients in our Phase Ia that were on PCSk9 therapies, had reduced their LDL, but still high, uncontrolled LDL. even after PCSK9 therapies, and they had 50% reduction on top of PCS K9s, indicating that ANCHO-B-TL3 is very synergistic with PCS-K9 therapies. And so there's that population of refractory hypercholesterolemia, which we'll get to next. I think we want to do this in a phased approach, but our immediate focus right now is severe hypertriglyceridemia. Okay. And as you commented on, there are siRNA approaches out there. Could you just talk to the value of a one-off treatment? I'm not asking you for a price or committing to a price, but just help us think through what the value proposition looks like. The value proposition is for everyone. You know, for patients, you know, today we're saying, okay, if there's a once every three-month siRNA, why would you do a one-time treatment? But that question is going to flip. You have a one time treatment that's safe. Why would you just not do that? Because, you know, people still have compliance issues. People leak into, you Know, sometimes they, you Know, miss a dose at three months. They may go into the fourth month or whatever. And you get this saw-toothing effect with SRNA. And so not every patient is compliant. So why would you not just not reduce the bad Actors that lead to cardiovascular risk once And for all, right? So that's sort of the primary argument for why You would do that. Second thing is, you know, I think ANCHP-TL3 is probably a better target than APOC-3 for these patients. And that's because you're also getting LDL reduction in addition to triglyceride reduction. You get better glycemic control with ANCH-PTL-3, it seems like, than some of the SRNA or ASO data. And you could actually potentially have better liver fat reduction with ANChP-PL-T3 relative to APOC3. So I think all those point towards ANCHP-TL3 being a better target as well. And I think, you know, as we look at the data, data will tell us, but eventually feel very good about the prospects because if you have that as a solution to patients, and by the way, the pharmacoeconomic benefit, you now, if we price something at about 5X SRNA pricing, that's a big value to the system, essentially, to employers, to the government, because you're eventually over a lifetime going to spend a lot less on these patients. Okay, that's helpful. Let's move on to CTX-611 and ZugaCell. Maybe if you could just briefly introduce CTX611, and then we can move on to the phase two, what looks like a successful readout and benchmark expectations. Yeah, Factor 11 is going to be a very interesting target. Some people are saying now it could be a $20 billion category in the pharmaceutical space, and a lot of big pharma are very interested in Factor XI. And the reason for that is because there's always been this holy grail with anticoagulation. You know, you had these DOACs that came into the scene, you know, several, you know, almost two decades ago now, that had, you know, a major anticoagnitive effect, but they caused a lot of bleeding risk. So many, many patients are not able to take DOAC because of the bleeding risk, what if there was this holy grail that says you get anticoagulation but you don't get the bleeding risk and that's what factor 11 represents because our bodies have two pathways one is an intrinsic pathway and one's an extrinsic pathway that's tissue factor pathway that both come together at factor 10a and factor 10 is what where the doax act and so that both pathways converge surge into the clotting cascade. But we're only turning off one versus both. And because DOACs act on 10A, they turn off both. The promise is for indications like stroke risk. If you have stroke risk, a lot of patients who have strokes, whether it's a transient ischemic stroke or if it's major stroke, many of them go on baby aspirin or something like that because they can't take DOEX. And some people try low, you know, low dose DOEX, et cetera, but it's not very effective. You could have a once every six month injection of factor 11 that dramatically reduces your stroke risk. You know, same with AFib patients who have similar risks. And then there's a number of indications like the total knee arthroscopy. You get the knee surgery and then you have major risk of DVTs or even pulmonary embolisms. You can take all that away because you don't have traumas formation. And that's where 6-11 comes into play. This is our first-in-class and potentially best-in class siRNA that has deep durable reduction of factor 11 up to 95% in our phase one studies. And now we're doing a phase two study in a total knee arthroscopy setting. And we'll read out the top line from the phase two steady at the end of the year. and if that's positive and some of the other phase 3s are turning out to be positive then you have a big category here that we're very well positioned versus small molecules and even biologics and we're doing this together this came through our BD efforts the molecule was developed by a partner of Sirius Therapeutics but we're developing it together and we are actually responsible for all the phase 3's and ultimately commercialization of this asset Yes, if you could just briefly kind of walk us through the potential registrational path and also just thinking about the competitive landscape where you sit amongst your peers. Yeah, absolutely. I think to get to registration I think we need to have information from this phase 2 study that shows that it has a therapeutic effect in patients. Also some more information on our MAD dosing to understand how multiple doses work in terms of both factor 11 knockdown but also APTT levels, etc. And once we have that, we can put a package together to say here's a phase 3. And the different indications where we could go, the obvious one is secondary stroke prevention. There's also the DOAC ineligible AFib patients where there's a major trial called LILAC that's being conducted right now for secondary stroke intervention. You had a positive trial for S-indexion in phase 3, you have a milvexion trial reading out soon, and potentially some other indications like cancer-associated thrombosis. You know, there are drugs like Ribrovan from J&J where, you know, it's an ADC. And you take the ADC and you get 30% of patients get thrombus formation. You know? They get VTEs, events, et cetera. So lots of cancer patients suffer through that. And, you Know, you can do for any of those cancer patients before they take their chemo or their ADCs, you could prevent any of that happening by dosing them with the factor XI beforehand. So there's multiple places you can take this, but that's something we'll unveil, we'll disclose as we get past our phase two study as to where we want to take it forward. But I think we're very well positioned relative to small molecules and antibodies because small molecules right now are twice a day dosing essentially because you get these peaks and valleys in APTT even through a course of a day. and it's inconvenient from a compliance standpoint whereas once every six month injection sub-Q is much easier for patients and with antibodies you may get these again very high peak reductions but it's every month and by the way it's not very reversible in case you hit your nose and have an emergency or something like that because the antibody still circulates whereas with SRNA you can simply replace the factor to plasma and you reverse it in case of an emergency So several things, nuances why an sRNA is much better in this setting than an antibody or a small molecule. Okay. That's helpful. Thank you. And then maybe let's just touch on Zucasel, and then we can talk about the future. But how are you weighing the relative opportunities in autoimmune disease, oncology, plans going forward? Yeah, our major focus with Zucosel right now is autoimmune diseases. And the logic is as follows. I think what you're seeing in autoimmune diseases is a real opportunity to cure these autoimmune diseases with a one-time reset of the immune system for B-cell-driven diseases. And these are, you know, numerous. There's rheumatology indications like lupus, myositis, scleroderma. There's heme indications like ITP. There's neuroimmune indications. And, you know, everyone's excited about TCEs, but T cell engagers may not always be durable because the issue is they don't have deep penetration into the tissues, nor do they, you Know, help the CAR-T's traffic or the T cell's traffic to the site of disease. Whereas CAR-Ts do traffic tothe site of diseasere a very deep penetration. And the dynamic we have right now is that allocarti can move very fast relative to autologous CAR-Ts, which take time from an enrollment perspective. There's safety overhang with autologious CAR-T. Even if it's one in 50 patients, you have that issue. And so allocard T off the shelf is available and I think could be very important. In vivo CAR-Tea is still early phases. I think we have a lot more to see in terms of data before it becomes something real. So at this point, we see a major opportunity for ZugoCell to be the leader within the allocart T space, especially because we have these edits that make them much more potent and autologous-like relative to other allocartes or allo-NK cells. And so we're advancing this in a basket trial across indications, but by the end of this year, we will certainly have a greater N in terms of patients, but also a greater follow-up across some of the subsets. So we'll have systemic sclerosis, for instance. will have a reasonable number of patients. Myositis will have a reasonable amount of patients that would indicate in these indications can we get to a phase three and pivotal start soon. Meanwhile, we'll continue the basket expansion with neuroimmune trials. And the other fact of this thing is in neuroimmune indications, I don't think a TCE is really going to make a big dent because TCEs don't penetrate the blood-brain barrier and go into the CNS system. Whereas we know with our allocartes, zygocel, that it does go into the CNS system and there's activity there. We've seen that with an oncology setting where people had CNS manifestations and the CAR-Ts did go into the CNs and there was a response for METs in the brain. Okay, that's very helpful. And maybe briefly before we dive into maybe the broader questions in the last six minutes, could you just lay out kind of the clinical catalyst path ahead, things we should really be focused on maybe through year end and then early 27? Yeah, I think, you know, Caschevy will be a steady cadence of updates every quarter. And, you Know, obviously next year, I'm sure Vertex will guide to what the year will look like because we have a lot of forward visibility. Among our clinical assets, I think you'll look for key data on each of these three assets that may move into phase three. For 310, I would point to our phase 1B data that's for severe hypertriglyceridemia. and that's the data set you'll see by the end of the year. For ZugoCell, you'll see data from the basket trial, but I think we'll have more data for one of the subsets, one ofthe indications that kind of tells how we're going to move forward into Phase 3 there. With durability, we'll have reasonable follow-up, but not all the follow-ups we need, but reasonable follow-upp. And then for 6.11, we'l have the top-line data, just at a very high level in terms of the control arm inoxaparin, versus the drug arm, which is CTX611 and what the differences look like in terms of VTE rates. And we'll have more information on bleeding risk, et cetera, at a later time point, but at least you'll get the top line data on these three assets. So that's key. And then the data for A1AT and refractory hypertension will most likely be next year, but not too far into the future because with A1at, we're already starting at a reasonable dose that's efficacious versus dose escalating from the beginning because we have a platform designation for our LMP platform so we'll have data from A1AT and then for factory hypertension as well, you don't have to wait a long time to see what happens to the patients. Within days of getting gene edited their blood pressure is going to likely drop. You can see what that looks like. I think we'll have more catalysts early next year for those two assets as well. Okay, that's very helpful. I guess one other question that just interests me, I mean, gene editing was in its infancy. We're coming to a new age almost. It's expanding. You're even moving beyond the liver. There's competitors in the space that are advancing, moving to the clinic and closer to commercialization. As you look out across the landscape, what kind of excites you? What frontiers are you really focused on? And maybe a couple concerns or things that have popped up recently. Yeah, I think there's, you know, broadly, the platform is advancing, right? The editing platform is improving and improving. And with our Synthase platform, we can do precise editing with very high potency. You know, the delivery solutions are improving. But for us, broadly as a company, we look at two axes for improvement. One is delivery. So we want to get beyond liver into the hematopoietic system, into the immune system, into other organs like kidneys cns etc muscle and that's one axis for improvement is more and more expansion across disease organ systems and the other axis is the on editing you know is going beyond correction to full whole gene insertion as well and i think at this point even whole gene insertion into the liver is probably solved we have to get it there in terms of clinical candidates but that's a whole set of rare diseases that we can tackle that way. And so I feel pretty excited about this next phase of gene editing. And I think you're seeing that. I mean, if you saw what happened with Moderna and the excitement around these advanced therapies, I think we're past sort of the bottom on cell and gene therapies and we're now into this phase where, you know, like a Genentech, by the way, Genentec was in a bottom in 1988 or something like that, right? and then there was a big second wave of growth. I think you're going to see a similar second wave of growth, and hopefully we're at the vanguard of that growth as we take cell and gene therapy into the future and change the face of medicine. Okay, and then maybe one or two more questions if we have time, but in regards to the rise of China innovation, how is it changing your, I guess, competitive positioning, your thoughts on R&D and BD strategy? Yeah, I think we're seeing tremendous innovation coming out of China but largely in sort of the antibody space and ADCs, now SRNAs and fortunately they haven't done as much in gene editing and I think that still gives us an opportunity to be ahead of a lot of the Chinese companies in gene-editing. What that means for us in a lot IP is that we're going to keep it know-how, we're not going to file all the IP right away because we want to take it longer and also I think from a BD standpoint we are looking at assets in China continuously and we did one deal with Sirius, we may do more but I think we definitely have a very close look at what's happening out there it is a threat for the entire American biotech ecosystem but it could also be an opportunity and then one last question AI implementation How is AI being leveraged within CRISPR therapeutics? Your thoughts on it? Any takeaways? Yeah, you know, I was sort of an AI skeptic not too long ago, but now I'm a complete convert because we're seeing productivity gains everywhere with AI. You know, take, for instance, our FDA filings, our medical writing, all those operational elements. You know AI is helping us move damage faster. So that's just allowing us to, with the platform designations we're getting from the FDA, plus AI improvements. We're able to move very quickly in terms of execution of assets into the clinic. And we leverage the Australian and New Zealand phenomenon and do trials out there and also China. The second part of it is product design. I think this was, I expected, you know, I didn't think this is going to be as helpful, but as we do various things around editing or even looking at different mutations, and I'm going to play out, There was a paper that just came out last week that took 6,000 mutations that have been observed in humans and said, what is the likely outcome of those mutations or knocking gene X, Y, or Z? You can do these massive simulations around mutations. We can do massive simulations on product design that we're not able to do before to come up with better answers, whether it's, you know, code optimization or whether it is picking the right locus to edit. So all in all, I think we are probably just at the beginning of AI making a difference in what we do, but we are heavy adopters in AI and I think it is particularly useful with CRISPR-based gene editing. Great. Well, thank you very much, Sam. Really appreciate you attending. Thank you very very much.