Good afternoon. Thank you, everyone, for joining us. I'm Salveen Richter, a biotechnology analyst at Goldman Sachs, and we're really pleased to have Dr. Sam Kulkarni, CEO and Chairman of CRISPR, here. Sam, to start, could you give us a brief overview of the company at this point, your strategy, your pipeline, and really kind of the key focus areas headed into the second half of the year?
Yeah. Thank you for having us, and it's a real pleasure. We're about 11 years into the journey as a company for CRISPR Therapeutics. The platform itself was elucidated about 13 years ago, and it's been an incredible journey to take this platform and make medicine out of it. We now have CASGEVY, which is on the market globally for sickle cell disease and thalassemia. That was sort of the first phase of the company. Now, while we see how that ramps up and what the uptake is commercially, we've really diversified our portfolio beyond that. The two biggest pillars that we're building, one is in cardiovascular medicine, and we have targets that we're editing in the liver with a single shot of an LNP-encapsulated CRISPR-Cas9 system.
We had data recently for one such target, ANGPTL3 with CTX310, that showed remarkable data, nearly 80% reduction of both LDL and triglycerides from a single injection. It beat even our own expectations of what this might do on the LDL front. That is on the back of success with ANGPTL3, and we have other targets like Lp(a) and AGT that we're going after. We're going to build a big cardiovascular franchise with the notion that a one-and-done CRISPR-based editing therapy can lead to much better outcomes for these people or patients suffering from cardiovascular diseases or at risk from cardiovascular diseases. The second big pillar that we're building is in autoimmune disease. We recently, in the last year or so, brought on a new Chief Medical Officer, Naimish Patel, who came from Sanofi and was running Sanofi's autoimmune franchise.
This is a high priority for us because, in a world where we have autologous CAR-Ts, allogeneic CAR-Ts, and bispecifics all competing for the same indications, we have a strong belief that allogeneic CAR-Ts can win the race here and be a better solution for patients suffering from various autoimmune diseases. We'll have early data this year, but we're going to expand from not just lupus, but to several indications where a fundamental B-cell reset can bring patients into full remission and eliminate the disease. Those are two big pillars. Beyond that, we have our CAR-Ts in oncology, both with CD19 CAR-T and CD70 CAR-T. We have efforts in type 1 diabetes, both with ES and iPS-derived cells that are edited, whether they're in a device or not in a device. Most recently, we insourced an siRNA product.
One of the biggest questions we keep getting asked is, how is it going to play out in terms of siRNA or RNA silencing versus gene editing? The answer is, it may not be a zero-to-one answer. There will be some difference in market share based on the target and the indication we go after. One of the targets that kept coming up with all the advisors we are trying to bring on board in the cardiovascular space was Factor XI. This is a very interesting target where there is early proof of concept from antibodies and small molecules that you can get the holy grail of anticoagulation. What you do not want for a lot of patients is intrinsic coagulation, which could lead to strokes or other things that could be bad for the patients, but also prevent bleeding risk.
Factor XI is a target that can achieve a high level of anticoagulation without much bleeding risk. When we found this asset, it's an siRNA asset, we brought that in. I think what you see overall in terms of the portfolio, we have CASGEVY, which is commercial, and then a cardiovascular franchise, which has both gene editing and siRNA, and an autoimmune franchise with other efforts in oncology and type 1 diabetes.
Starting here with CASGEVY, can you update us on the ramp with regard to how many authorized treatment centers are currently online and the current cadence of cell collections? Can you potentially put that in the context of bigger picture, where the bottlenecks are at this point and what needs to be done to really make this be more of a widestream product?
Yeah. To provide an update on CASGEVY, it first got approved at the end of 2023 by the FDA in the U.S. Subsequently, in the middle of 2024, it was approved in Europe, and now it's approved in eight jurisdictions around the world, and we continue to expand the label into other jurisdictions. What you've seen so far is that we've activated, when I say we, it's our partner Vertex that's taken the lead in commercializing CASGEVY. We've activated over 65 authorized treatment centers around the world. The target goal was to get up to 75 in sort of the first phase of launch. We've made really good progress in getting these authorized treatment centers up and running.
The last disclosure, Vertex announced that over 90 patients' cell collections had been initiated for over 90 patients, and 2x that number of patients were initiated or referred into the system. These were comments from Vertex. What you are seeing is that funnel and pipeline building for CASGEVY. The one thing I will say from the outset is, when people compare launches or look at pharma launches, what we have at CASGEVY is a very different launch. It is more akin to medical devices. We are selling a procedure to the patient. A patient who comes into the system has to get their cells collected. We manufacture the cells, send it back to the patient, and ultimately get treated.
It is sort of more similar to medical devices, like catheter devices for mitral valve replacement, for instance, or you have sequencing with Illumina in the early days of how you had centers qualified and start to do sequencing, and then they had greater sequencing over the years in each center. I think you may see the same dynamic here with CASGEVY. We have more treatment centers that can do more per month, and that is going to result in compounding growth for CASGEVY, but it takes a little bit of time early on because you have to get the system up and running in terms of getting the treatment center authorized, but then get the referral flow, do all the scheduling and prior authorization for the patient, get their cells collected, manufacture it, and ultimately dose them.
Over the coming quarters, I expect that you'll start seeing the uptake, and you already saw some inflection in the last quarter's update based on the cell collections. Overall, I think we feel very confident in how CASGEVY is going to shape up and what that means for the company.
Help us understand just with regard to gentler preconditioning regimens, where you stand there with those efforts. I believe there's also just some fundamental work you're doing around kind of increasing the ability for patients to have access.
Yeah. Gentle conditioning is going to be a very important advance in the field. For those who are less familiar with CASGEVY, what we do now is take cells from a patient, separate the long-term hematopoietic stem cells, edit them, and then we do a transplant process where they get agents like busulfan to clear out the bone marrow, and then we administer CASGEVY that takes up that space in the bone marrow. With gentler conditioning, what you're doing is sending these targeted commandos to go in and only take out those cells in the bone marrow that are the progenitor cells of long-term hematopoietic stem cells.
You do not lose all the neutrophils, you do not get neutropenia for patients, you do not lose all the other cell types that are essential from an immune system standpoint, and you only replace the hematopoietic stem cells that end up being your long-acting stem cells. That notion of gentler conditioning will shorten the hospital stay, will improve the experience for patients. I think you will go from just severe patients and expand the addressable market to even go to the moderately severe patients. That is almost a 3x-4x expansion of the addressable market if you can get gentle conditioning to work. I am starting to see a lot of positive developments with gentle conditioning where we have our own c-KIT-targeted ADC with less toxic toxin than what you see in oncology. You are starting to see very good depletion in mice and monkeys.
Vertex have their own efforts. They have two to three different agents that they're testing in different animal models. What you're seeing is very good depletion in these animal models of the HSCs. The question is, can you then transplant or transfer in edited cells and see what the chimerism is like? That data hasn't been disclosed, but you're seeing progress not just from Vertex and us, but also some of the smaller companies as well that have come up with novel agents for conditioning. It's hard to say exactly when, but it's not in the distant future that you see gentle conditioning coming into the mix in the commercial setting. When that comes into commercial setting, that's going to be a significant boost to CASGEVY and its potential peak revenues.
Just pivoting over to the cardiovascular program here. You have wholly owned in vivo gene editing cardiovascular assets, 310 and 320, and you recently disclosed initial data from 310 targeting ANGPTL3. Could you just walk us through, based on the data we saw, whether the numbers that we were seeing are in line with expectations and what level of clinical benefit you expect this to translate into within heart disease?
Yeah, absolutely. ANGPTL3 is a very important target that's been validated in the last 10 to 15 years. PCSK9 emerged as a very important target in cardiovascular medicine in the 2005, 2006 timeframe, and ANGPTL3 was the next one a few years later. It turns out that for patients that have very high triglycerides and have high LDL, there's very few options. In fact, you can look at the blood collected from these patients with very high triglycerides, and you see an entire milky layer on top. It is very fatty blood. If you have risk of cardiovascular disease, it gets compounded dramatically because those fatty substances in the blood will agglomerate onto the plaques and make the plaques bigger, lead to obstruction of the arteries, and ultimately all the sequelae associated with that. What are we doing?
We're taking an LNP particle that has a CRISPR-Cas9 system, doing one infusion of this drug over a two to three hour period, and then we have to observe the patient for a day or two to make sure there's nothing that goes wrong. That is all it is. After that, your liver cells get edited. ANGPTL3, the way it works is it actually acts on lipoprotein lipase. Lipoprotein lipase is an enzyme that chews up the fatty substances in your blood, like the triglycerides. If you downregulate ANGPTL3 or completely delete it, what happens is your lipoprotein lipase can go ahead and do all the work because ANGPTL3 is an inhibitor of lipoprotein lipase. You see a dramatic clearance of all the unwanted triglycerides. What the positive surprise is, you also reduce LDL quite a bit.
All the other trials, whether it's siRNA or antibodies in the space, have shown maybe 60% triglyceride reduction and much lower LDL reduction. While it's early numbers for us, the fact that we had one patient at the highest dose that had 80% triglyceride reduction, and it was all very dose-dependent, and then we had one patient in the dose prior to the highest dose that had nearly 80% LDL reduction, this is just best-in-class data. If you'd asked me five years ago and told me this would be possible, I'd say this is unbelievable. For millions of patients around the world, they have very high triglycerides, very high LDL, and it's the number one killer out there.
If we can have a single-shot solution that can reduce their triglycerides and LDL and take away that risk, that can lead to much longer life, hopefully, and better outcomes for these people.
What information should we look for in the full data set in the second half to further de-risk this approach?
Absolutely. I think we'll have additional data, most likely at a medical conference. At this point, I think it's more a question of, and we want to get more patients treated to make sure that this is not a one-off effect and patients are consistently seeing that knockdown of ANGPTL3 and subsequently reduction in triglycerides and LDL for a larger end. Right now, we're dosing patients based on dose per kilogram or weight-based dose or lean body mass-based dosing. Once we have more data, we want to see if we want to convert that into a fixed dose or is it two different fixed doses based on weight category. Some of those PK/PD dynamics we're going to analyze will present the data as well as we advance this program into the next phase where we can pick between different populations.
Our thought is that we can actually do a phase II, and subsequently a phase three study and get approval just based on biomarkers. You don't need outcomes trial because both triglycerides and LDL are established as validated biomarkers by the FDA and other regulatory agencies, and you can use those established biomarkers potentially for approval for this patient population.
We're also awaiting first data for your program looking at Lp(a). Could you frame expectations here and what the profile you're looking to see here is for proof of concept? Do you see any read-through here from the ANGPTL3?
Yeah. For those who are not familiar with Lp(a), when you go to your primary care physician, oftentimes you get a lipid panel, you measure LDL and triglycerides, but people did not really measure Lp(a) before. It turns out that Lp(a) is six times more atherogenic than LDL cholesterol even. The other big difference is you are born with high Lp(a) if you have it. For LDL and triglycerides, typically they are lower until you hit your 40s and 50s, and then based on lifestyle, diet, etc., you see an increase in LDL and triglycerides, and they become bigger and bigger risk factors. Lp(a), you can measure it when you are six months old or a year old, and you know if you have high Lp(a). Now, there is a very clear correlation between high Lp(a) and higher cardiovascular risk, right?
That's been established based on looking at large patient population studies. What hasn't been determined is whether you can take someone with high Lp(a) and pharmacologically reduce that Lp(a) level, does that translate to better outcomes? That's going to be a very important trial that's going to read out early next year from Novartis, where they have an ASO, an antisense oligo, where they knocked down Lp(a). The question is, is that going to lead to better outcomes? It's a study that's been going on for almost over four years now. That data is going to tell us how valuable it's going to be to knock down Lp(a) with gene editing.
Our sense is if you see positive outcomes with an ASO, it's very likely the outcomes are even better with gene editing because what you don't have is a sawtooth effect that you see with siRNAs and ASOs. At the peak reduction, you'll see well over 85%-90% reduction, for instance, of Lp(a), but towards the end of the dosing period, you see it pick back up. That sawtooth effect could have impact on outcomes. With gene editing, it's one and done. You reduce it, and then it's durably low for life. We think we have a significant advantage should the Horizon trial, which is the Novartis trial, turn out to be positive and show that reduction of Lp(a) leads to better outcomes. We have a very similar LNP that we're using for Lp(a) as we're using for 310.
There's some minor differences, but we're moving that forward. We started the Lp(a) trial about three months after we started the 310 ANGPTL3 trials. We are trying to see how far we can get through in our dose range finding study to put data out there. Of course, we want to disclose more data at medical conferences subsequently as well.
Can you put this modality in context for us with regard to a permanent gene editing therapy in cardiovascular disease versus what's currently available and how they think about that versus more traditional modalities, including, I guess, at this point, siRNA therapeutics?
Yeah. I mean, the PCSK9 space is going to be a very interesting case study, ultimately. You have two biologics, Repatha and Praluent, out there in the market. Together, they have about $2.5 billion sales per year, but it's taken a while to get to those sales levels. It's a very clear benefit for people or patients with high LDL. And then now you have the introduction of an siRNA and inclisiran, and that's ramping up reasonably fast. It's already getting close to $1 billion drug. And recently, I think just yesterday, you had data on a macrocyclic molecule from Merck, which is more like a small molecule oral in a way, even though it's a macrocyclic peptide, which could provide many different options to patients. And on top of that, you're going to have gene editing. So what is best for these patients?
It's hard to say how it's going to turn out because there's probably going to be some patients who prefer a small molecule. They're just used to that. They don't want to get injected. There are some who are going to say biologics may have better data. I don't mind getting a sub-Q injection every month. Others may say, "I prefer an infusion every six months and glycerin." I think there's going to be a large fraction of people who will say, "I don't want to keep getting medicine all my life. I just want to do a one and done." That one and done, it's going to take me four hours and another day of observation, but after that, I don't have to worry about medicines at all. If it's shown to be safe, I think that is going to ultimately be the superior modality.
The other part of all this is we have a lot of pricing flexibility. Take an Lp(a) patient, and let's say you start intervening at the age of 25. You may be giving somebody a once-every-six-month injection of siRNA for the next 50-60 years of their life, right? And the price point is not these siRNAs is probably in the $25,000-$30,000 per year range. That versus saying you're going to do a one-and-done gene editing therapy when they're 25 years old, and that may cost $150,000 a year, and you're done. I mean, that has a huge advantage from a compliance standpoint, huge advantage from an outcome, potentially a huge advantage from an outcome standpoint, but also a dramatic advantage from a pharmacoeconomic standpoint. I think payers are going to start recognizing this part of the equation as well.
Eventually, that's going to give us that advantage. I think this may take several years to play out, essentially. I think we have very strong belief that gene editing will have a very important place in cardiovascular medicine.
Do you believe outcome studies would be required?
At this point, we believe that for ANGPTL3, which is why we started that first, we do not think we need outcome studies because both LDL and triglycerides are validated biomarkers. There is precedent out there for approval with siRNA based on biomarker alone. I think we can move that forward ourselves. For Lp(a), I think the answer will depend on how the siRNA or ASO trials play out. If the ASO and siRNA trials all turn out to be positive, where a pharmacological reduction of Lp(a) leads to better outcomes, that may become a new validated biomarker with the FDA or with the regulatory agencies. It is hard to answer that now a priori while those trials have not read out yet.
With regard to the partnership that you announced with Sirius Therapeutics, could you speak to what stood out with regard to the profile here to warrant an investment, but also how you're thinking when you talked about CRNA? Are you going to move into a multi-modality approach in different verticals and not just be CRISPR gene editing focused on the forward?
Yeah, absolutely. I think as we—I am not saying this is a Google Alphabet kind of thing, but as we move forward in these franchises, as a company matures, what happens typically is you are technology forward at first, but then you build all the expertise and you become disease area or franchise back, essentially, as you develop new therapies. At this point, we have significantly invested in the cardiovascular medicine space and in autoimmune disease. We are building that team up. If we look back and say we are disease back, it naturally means that we look at modalities beyond gene editing. We will predominantly be a gene editing player, but I think where it makes sense, for instance, in the autoimmune space, it may make sense to do a cell therapy intervention followed by maintenance with biologics, which is much less lower-tox biologics.
You'd want to look at something that's biologic or bispecific in addition to cell therapies there. In the cardiovascular space, I think it may make sense in some cases to do gene editing, and then it would be complementary to siRNA approaches for some other targets. For instance, when we talked about Factor XI, you don't want to gene edit this permanently. I think you want long-acting, but you don't want to do it permanently because you want to have the ability for the body to have coagulation should there be injuries or you fall or whatever else. Only during the period of risk, perhaps after surgery or when you need it, do you take a Factor XI drug that would prevent serious complications from unwanted thrombosis.
In this instance, we're going to look at some targets, and we're also going to use the same siRNA platform. We have two other programs we licensed from Sirius. This was a company that was founded by the ex-CSO of Arrowhead, which is a leading siRNA company. With the view that there's a lot that can be done to optimize siRNAs, they took the entire siRNA backbone and tried different modifications to every base pair on this siRNA to create a huge combinatorial library and pick the best candidate that leads to very durable reductions. It's one of the few companies that have shown in humans a 95% or so reduction of the target protein over a six-month period. It's almost best in class in the siRNA space.
For us to get access to three targets with this platform was great for the kind of deal we had to strike. The other two targets that we're going to use with this siRNA platform, we'll unveil probably one at the end of this year and one early next year, but they kind of fit into the franchises we're developing around cardiovascular medicine and autoimmune disease. Again, having a once-every-six-month injection sub-Q really changes the game.
Can you frame the allogeneic CAR-T platform for us? On the cancer side, you've been optimizing, and we're going to see some data from 112 mid-year. Help us understand how we should compare this data set to what was presented prior. What will be that first proof of concept data that we will see on the autoimmune side?
Yeah. Happy to talk about that. For those who are new to the space, over the last 15 years, there's been a lot of development around CD19 CAR-Ts. It started with autologous therapies. We're now nearly 15 years since the first administration of the first CD19 autologous therapies. They've actually done really well in the market in a way where thousands of patients have benefited from these CAR-Ts, but they've not been able to create a profitable franchise, essentially, because the cost of goods for each patient is very high, and it's cumbersome to manage all the supply chain logistics to get this autologous CAR-T to patients. In the meantime, what's happened is a lot of the bispecifics around CD19 or even BCMA have moved up in lines of therapy.
While the data were not as good as autologous CAR-Ts, they've moved earlier and earlier lines of therapy, where in a lower disease burden setting, data may be good enough. Allogeneic CAR-Ts, meanwhile, the first set of allogeneic CAR-Ts that went into the clinic in the 2018, 2019 timeframe, it turned out that they showed some pretty interesting data. We have now patients with our CTX110, our first-generation allogeneic CAR-T, where they're disease-free five years out. You did get durable responses with the first-generation allogeneic CAR-T, but it turned out these cells did not expand as much as the autologous CAR-Ts. The max expansion you saw was about 5,000 copies per microgram with allogeneic CAR-T, where you saw 50,000 copies per microgram with autologous cells.
In a way, you didn't see the same impact with allogeneic CAR-Ts, but our next-generation allogeneic CAR-T, CTX112, has edits that make it more autologous-like. What we showed at ASH last year were data where we had expansion to the 50,000 microgram copies per microgram level that only autologous therapies have been able to show. There is no other allogeneic platform that has shown that kind of expansion. We did, not surprisingly, have very good response rates. The questions that were asked to us by investors and others were, "Okay, you've shown really good response rates in indolent lymphomas like follicular lymphoma. What does it hold for DLBCL or more aggressive forms of NHL?" The second question is, "What does the durability look like?
Are you seeing durable responses like autologous CAR-T? We are going to have an update on both fronts mid-year on the oncology front, and then we will also update very early still on the autoimmune side, but with patient data that shows at least some pharmacokinetics, some pharmacodynamics, and patient responses to CTX112. One of the key questions everyone's asking is, and we are curious, is how does the PK/PD profile translate from oncology to autoimmune? Do you see the same expansion profile? Do you see the same B-cell depletion? If you do see that same level of depletion, that implies that this notion of a one-and-done reset of the system can come into play, just like George Church's data, and that can be recapitulated with allogeneic CAR-T.
You also have the regenerative medicine program here. Are you still working on that program in conjunction with Vertex, or has that kind of been deprioritized?
We have partitioned it into two parts. There is a part on the diabetes side that the whole notion is, obviously, this is in the pre-GLP-1 world. We will see how that all impacts. For type 1 diabetes, GLP-1s do not work, right? I mean, basically, your pancreas is not producing insulin anymore in response to glucose, and that is a fundamental issue in terms of your metabolic system. Can you replace your faulty pancreas with exogenous cells that have been differentiated into pancreatic islet cells that will produce insulin in response to glucose? We had a partnership with ViaCyte that we were working on, and ViaCyte got acquired by Vertex, who had their independent efforts. We had to partition the system, where we licensed RIP to Vertex for editing as well as for cell differentiation, etc., that we had acquired from ViaCyte.
We're using RIP to develop products both in a device and unencapsulated that are derived either from embryonic stem cells or iPS cells that can be differentiated into these islet cells that effectively produce insulin and replace your bad pancreas, if you will. The trials with the device are ongoing, and we're going to provide an update at the end of this year from that trial. We're also in parallel pushing forward iPS-derived efforts that will hopefully go into the clinic at some point, not too distant future.
Given all these verticals that you're balancing, I recognize you have a good amount of cash on your balance sheet. Are you thinking about strategic partnerships on some of these verticals, such as cardiovascular disease?
Absolutely. I think one of the things that I've been saying is the pharma interest is ramped up again in cell and gene therapy. You had this initial wave of excitement in 2018, 2019 from pharma and investors alike, and then there was a bit of a lull in pharma interest and deal-making activity. We're now seeing a lot of interest as we moved into common diseases. I think that was the big switch. With rare diseases, not every pharma company was interested, but as this moved into common diseases like cardiovascular diseases, there's a tremendous amount of interest and excitement. Where we are is we don't want to do a deal right now that was premature. We want to see where the data play out, both on the cardiovascular front and the autoimmune front.
When we have a reasonable set of data, we're going to be faced with a choice. I don't think we can take both of those forward all the way to commercial and do oncology and diabetes. I think at some point, we have to pick and choose what we would partner versus what we would keep in-house.
Great. With that, Sam, thank you so much.
Thank you for having me. Appreciate it.