Good morning and thank you for joining Guggenheim's 2025 Healthcare Innovations Conference. I am Debjit, one of the therapeutic analysts and my privilege to welcome our next presenting company, CRISPR Therapeutics. Joining from CRISPR are Raju Prasad, CFO, and Naimish Patel, CMO. Thank you gentlemen for your time.
Thanks for having me.
Raju, if I may ask you to do a very quick intro given the very calm, broad portfolio that you're currently working with.
Absolutely, yeah. It's exciting times at CRISPR. Obviously the CASGEVY launch is going very well and Vertex has reported some exciting metrics as far as growth year- over- year, as well as some forward looking statements on over $100 million in revenues in 2025 and significant growth in 2026 with nearly 300 patients that have initiated the patient journey. Internally the pipeline is progressing very well. We had a great presentation by Dr. Steve Nichols for the CTX310 program targeting ANGPTL3, where we're seeing 55% reduction in triglycerides and 50% reduction in LDL in the overall cohort and very exciting KOL reaction which is making this a reality for doctors and eventually patients.
I'm sure Naimish will talk more about that, but we've got a cell therapy update coming by year end that is still on track for both oncology and autoimmune disease, where we're excited to show the initial results in autoimmune disease with CTX112, as well as additional data in oncology in some of the more aggressive lymphomas at higher dose level. On top of that we've got the Factor XI program, which was actually a big point at the American Heart Association conference with the Regeneron antibody data reading out. We're very excited about progressing that program forward in a TKA study with several readouts in the next 12 months that could significantly de-risk that target to make it one of the biggest targets in cardiovascular medicine next year. A lot going on, $1.94 billion on the balance sheet.
Remain well capitalized to execute across the board. But very excited about the year we've had at CRISPR in 2025 and 2026 is looking to be even better.
Awesome. Naimish, let's start on the Factor XI program because obviously help us understand how you guys are thinking about the initial target selection. This is a very competitive landscape. This is a big pharma landscape. How does CRISPR plan to position itself and compete there?
Yeah, great question. The promise of Factor XI, the differentiation factor, is one that you get fairly specific and potent inhibition of clot formation in vessels with limited bleeding risk. Across all the indications, there are patients who have a risk for clots that can either cause stroke or other very bad outcomes, but they're not taking any anticoagulation today because of the risk of bleeding. I think those populations across the board are places that we could really make an impact that are relatively low risk in terms of not having to go head to head against an established standard of care.
There are a number of areas within stroke prevention, within AF, and then some smaller indications within cancer-associated thrombosis, as well as other post-procedure prevention areas such as post peripheral intervention, where all of them, they do not have a very good standard of care, there is a risk of bleeding, and a Factor XI can make a significant impact and fairly low de-risk for us in terms of being able to develop something without having to go head to head with their established standard care.
Talk about the differentiated durability profile for your program versus some of the others which are being talked about at AHA, et cetera.
Yeah, exactly. I mentioned one of the limitations of currently available anticoagulant therapy is the risk of bleeding. Another one, a major limitation, is that a lot of them are daily tablets that suffer the same problems as many chronic medications, poor compliance. If we can establish something, some of these indications, such as cancer-associated thrombosis, there's actually a fixed window where the clots can happen. If you could just give a single-shot therapy in the office and you're actually covered for six months, after that, you don't have to worry about compliance at all. That's a potential big differentiator for an siRNA that has a prolonged duration of activity. The other interesting thing with an siRNA is, although it is very long duration activity, it's actually potentially safer than biologics and even oral medications.
Because say a patient has a fall on our molecule, because it's an siRNA, all it does is take away Factor XI protein. If the patient is bleeding and needs an acute reversal of their bleeding, you can actually give back Factor XI in various forms to reverse the action of the drug. If a patient is on a biologic that has a one month duration, whatever you give, that biologic is going to bind up and inhibit. You can't really reverse it very easily. Even with an oral, even though it's Q-D ay or BID dose, when someone's bleeding, you don't have 12 hours to wait for it to wear off. You want to reverse it right now. In that sense, although we have durability effect and infrequent dosing that could address the issue with compliance, there's also an added safety benefit of reversibility.
When do we get de risking data from the acquired program?
Yeah, so currently we're in phase two. The major de-risking study that everyone has gone through is a TKA study where you give the drug prophylactically against low molecular heparin to prevent clots. We're expecting a readout on that in the second half of 2026.
Got it. For cancer associated thrombosis, if that is the indication and you get it to the finish line, how are you thinking about pricing? This is going to be a very niche market versus the much broader cardiovascular market. If you launch there first, is there a differentiated pricing before you can go into the cardiovascular segment?
Yeah, I mean, one of the important parts when we did this deal was that we're going to be about a year to 18 months behind some of the other programs. We get the benefit of seeing both Milvexian and Abelacimab. Milvexian is a Bristol J&J drug and Abelacimab is the Anthos drug, now Novartis. We get to see both from a de-risking perspective on the indications as well as on pricing, and we can sort of benchmark against that. The great part is, again, as Naimish mentioned, that we do have a differentiated product in terms of durability and reversibility, where we can come in with. You have seen this now happen in other markets, right? TTR, for example, where the siRNA drugs have come in and taken big market share.
You know, we believe that not only will we have the best asset coming forward a little bit later, but we'll also have the ability to see how the strategy play out a little bit ahead of when we have to make our decisions.
Got it. Let's move from Factor XI, which is not core, to the name of the company, CRISPR. When you talk about gene editing, the sector is sort of clouded now by the unfortunate event that happened with the Intellia program. How are you guys thinking about differentiation or the challenges stemming from that?
Yeah, no, I mean, you know, we're limited to what's in the public domain as you are. You know, what Intellia said is they believe that this is an indication-specific occurrence. You know, obviously we've gone back and we've looked at our programs. The CTX310 profile looks very good, you know, and Naimish can comment on the safety data more. You know, we've just made sure that we've gone back and checked our data and that we're comfortable with our platform moving forward. Again, it's a different LNP, it's a different indication, different guide. The drug product is very different between our company and Intellia and even Verve for that matter, when they had their issues. We continue to focus on what CRISPR can do and we'll see what happens with the ongoing investigation with our competitor Intellia.
Yeah, maybe I could say, I mean, what they have shared is that the reactions that they've seen are fairly late in the sense that they're post 20 days. Typically there is.
a
We can call it toxicity, but a known effect of LNPs on the liver in terms of when they're initially taken up. They can cause a bit of an inflammatory reaction and cause a brief spike in liver enzymes. That usually is fairly concordant with the exposure to the LNP. When the exposure to the LNP is highest in the blood, that's where you see it. This is something quite different where they're seeing it late. We know from their PK data that they published previously, the exposure's almost gone by that time. They have commented, so they don't think it's LNP related and it's more likely target related, which sort of makes sense in the sense of when the gene disruption happens and the downstream consequences. They also shared that they had actually seen something similar in early phase 1/2 studies.
We've dosed similar number of patients early and we haven't seen anything like that. The one liver enzyme elevation we did share, that we've seen so far in the program, is a patient who had already elevated enzymes and it was that same pattern, very brief up and down, and it was resolved by day 14. We don't have any evidence. What Raju said around, it's a different compound, different LNP, different target. We haven't seen any that type of reaction. It gives us some level of confidence that we have something differentiated.
You had a pretty interesting presentation at AHA with the 310 program. What are the next steps there and how do you plan to sort of homogenize the baseline, because the data were variable, but also it was a very sort of varied baseline.
Yeah. So just very quickly it was a dose escalation study. The study is designed as a part A and a part B. Part A was dose escalation. Escalation part with the objective, one, establishing safety and, two, establishing the dose that we'd like to take forward in the part B. The emphasis, it was a mixed population, but the emphasis was looking at the safety of the drug and then the pharmacogenic output to help identify the right dose would be the ANGPTL3 knockdown. We know that there's much less heterogeneity in that across different patient populations versus looking at LDL and triglycerides when you have patients who had variable elevations of those at baseline. What we're able to establish is that the two top doses, 0.7 and 0.8, were getting very, very high levels of ANGPTL3 knockdown, essentially close to saturation.
That's going to translate into a dose for us. We're going to flat dose and we're going to study that flat dose within the individual populations in a part B of that trial. Severe hypertriglyceridemia, mixed hyperlipidemia and the others as and after we have enough data on that, we'll have regulatory interactions and plan next steps in the trial.
Got it. Now, a criticism for every gene editing company has been, well, you're going interrogating targets in the liver and unfortunately going after diseases which are relatively well served. Right. So your thoughts on what the next step should be beyond 310 if you can't get that baggage off your back for the.
Yeah, I mean I think 310 itself gives us two-way flexibility.
Right.
There is a fairly rare market there that we could potentially serve with familial hypercholesterolemia as well as the genetically determined high triglyceride, familial chylomicronemia syndrome and others. There are much larger populations with mixed dyslipidemia and hypercholesterolemia and severe hypertriglyceridemia. One of the major, major issues in lipid management is that there are lots of modalities. Orals, biologics, siRNA injectables, and all of them suffer from the same problem, which is compliance. For statins, 50% of patients who initiate a statin stop taking it within a year. Even with a siRNA that does have better compliance than something that's daily, Q6 month inclisiran, Leqvio, even that, only 70% of patients persist beyond a year. In the subsequent years, it gets lower to around 50%. Even though there are all these modalities, patients aren't actually being controlled.
We think, and that's part of the excitement that we have from our KOLs, that finally they have a treatment where they can give it and they know exactly the response, again in terms of lipid knockdown. That is really potentially transformative for the whole sector. That is really the point of differentiation versus all the other modalities.
Yeah. I think one thing to add is the Verve acquisition by Lilly did prove that there are pharma companies that see the world sort of as we do, in that the RNA modality and the gene editing modality aren't antagonistic, they're synergistic. The fact that Lilly, with already an RNA platform as well as a small molecule approach for some cardiovascular diseases, brought on a genetic approach, it does show that the pharma look on here is evolving. That's jiving well with what we've seen from our pharma discussions. The other thing we learned at AHA was in severe hypertriglyceridemia, the ASO approach did show significant increases in hepatic fat fraction as well as in HbA1c. You know, we think that ANGPTL3 could actually be a target that mitigates hepatic fat fraction from the siRNA therapies that we've seen.
That could actually be a point of differentiation as we progress in that indication.
Got it. Let's switch to 320. Expectations for data are in middle of this year. We sort of delayed it for other reasons. How are you thinking about the program? Is it really gated by the outcome of the Horizon [audio distortion] study? Maybe your thoughts on Lp(a) as a target? How are you as a company thinking about the Horizon study and implication for 320 development?
Sure, absolutely. Lp(a) is a cholesterol-like particle that is largely genetically determined in terms of the level. Unlike LDL triglycerides, which has a heavy dietary and lifestyle component to it, Lp(a) levels are elevated generally by adulthood in the patients who are going to have an elevated level, and it stays stably elevated throughout life, just regardless of other factors. The other interesting thing is that risk over the lifetime is cumulative in terms of cardiovascular risk. The longer you have a high Lp(a), the higher the risk goes. In that sense, a gene editing intervention is very attractive because it's largely genetically determined. A gene editor to go in and fix that is the only true long-term solution to fix a problem.
The other solutions are looking at siRNAs or orals, but they suffer from the same problem in terms of long-term compliance. If you're 30 years old and you have a high Lp(a) level, what would you choose? Fifty years of an oral, fifty years of injectable, or a single dose treatment and you do not have to worry about the rest of your life. A lot of younger people would just choose the single dose. That is the value proposition and differentiation. There are, of course, lots of questions because there has not been an interventional trial to show that the increase in risk, if you address that level, will translate to improved outcomes. We have a couple of trials, the Horizon trial most notably, soon coming next year with a readout that will inform that.
There is a number of things we do not quite understand. The translation to population for intervention and outcomes, what is the best population to target? Even within the Horizon study, there are two. The overall population is 70 milligrams per deciliter or greater and then there is another population of 90 or greater. That is also an analysis population. Understanding what population with intervention needed to intervene and also what is the level, the treatment effect that we need and how will that correlate to interventions? How much do we have to drop Lp(a) to get a specific change in cardiovascular outcomes? They estimate that about 100 millimolar risk will reduce outcomes by 20% in terms of all combined ASCVD events. We do not really know that for a fact. It is based on genetics and epidemiology.
I think that will also be very different, important, I should say, for determining how we're going to dose and what our targets are in terms of the drug. Finally, the other question is how low should we go in terms of do we just need to treat patients to a certain cutoff and get them below that threshold, or is it like LDL where there's no safe level, you just get it as low as possible for. All these things would influence our target tpp, the dose we want to use, and also how we design the down phase trials, downstream trials. All that sort of makes us think, let's wait until we have the Horizon readout and then really go forward with the program because it'll help us understand how to go forward with the program.
I believe internally you probably have insights into the data. Is this program paused until, or are you still escalating? The second question to that would be, is this the ideal program where split dosing might be meaningful, especially if you want to go very deep with Lp(a) knockdown?
Yeah, it's a great question. The trial is ongoing and we're trying to answer some of these questions. Across all our programs, there's a potential for split dosing. One of actually the other posters that we had at AHA was one of our earlier programs in hypertension, where we also think titrating the dose, like everyone doesn't need maximal knockdown and maybe split dosing. We shared some preclinical data in primates where we were able to show that if we dose as an intermediate dose, we could get a certain level of knockdown. If we redose, it's an effect that it'll add onto the previous effect we saw. It's not completely 1+ 1, but maybe 1+ 1.5 or 1+ 0.5, I should say. Certainly split dosing is a way to titrate the treatment.
If maybe there are certain higher risk populations with underlying liver disease, we do not want to dose too high, we could give them a lower dose to start with to support benefit risk. That is another thing. If we are just going to a threshold level of Lp(a), say it is 50 millimoles is our threshold, or 50 milligrams per deciliter is the threshold, the patient is very high. Maybe they might need a split dose to get them all the way low, where the patient who starts at 200, maybe a single dose might be good enough. These are all sort of things that will work out in terms of development of the compound to figure out what our responses will be in different patient populations.
When we get the readout, we can say, well, this is how we're going to advance the drug in terms of dosing and patient populations.
That's helpful. And then Raju, on CASGEVY.
Do you.
Guys, are you guys still comfortable that 2028, the franchise would be completely profitable given the traction that you have so far?
Yeah, I mean, I think we're very excited about the growth trajectory. I think, you know, from CRISPR's perspective, this will be the max spend year for the program. With the revenues going up, there's also going to be, you know, costs will come to steady state as we complete the expansion in jurisdictions as well as, you know, additional label expansion to the pediatric population. You saw that we got the CNPV voucher for the 5-11 cohort in sickle and thalassemia. That's another sort of feather in the cap for CASGEVY, which has become a transformative therapy for many patients. We continue to anticipate a multi billion dollar opportunity. We continue to believe that revenues from that program will buffet the spend for the company in the long term.
In terms of Gen 1.5 and Gen 2 from a conditioning regimen perspective to really expand the scope of that opportunity, where are you and what are the next steps there?
Yeah, so we're actively working on the ADC approach as is Vertex. The way that structure works with ADC is we sort of will come together and choose a go forward candidate. At some point in the not so distant future, we'll hopefully have an update there. We're also very active on the in vivo HSC front. I think with some of the conjugated LNP data that we're seeing from the in vivo CAR-T space, you can imagine that there's been very active efforts for conjugated LNPs for in vivo HSC work. Recall that that is a 50/50 partnership between us and Vertex. We're very excited about moving that forward as well. Just the fact that we've built so much LNP capabilities in house, I think we have a unique vantage point now to advance those therapies.
You know, again, we're also working on, in addition to the AlloCAR-T, we're also working on an in vivo CAR-T approach as well.
Got it. To finish up, we'll have data in the fourth quarter on the autoimmune side. How you're setting expectations for that?
Yeah.
You know, the last data we shared on the CTX112 program was early in the year where we showed some preliminary data on the dose expansion part. We showed T cell expansion data where we're able to show that our CAR- T's, the expansion is on par with autologous CAR- T's. We showed some data around patients who are TCE experienced in oncology, T cell engager experienced. We showed a response in six of six patients who are TCE experienced. We have continued to dose patients on oncology and we'll have a readout. Also, the durability was a question because it was a very early look at the data. We'll have more durability data. On the autoimmune side, we have initiated a trial, started dosing autoimmune patients, and will have the first data on autoimmune patients.
That should show one, the pharmacodynamics of the drug, one, the CAR-T cell expansion, the B cell depletion, as well as some data around the phenotype of the B cells coming back where the data suggests. If you have mostly naive B cells coming back, that's correlated with that immune reset that you're looking for in autoimmunity to show that you'll get a long-term remission. Of course, we'll have some early efficacy data as well. In terms of the clinical outcomes, are the patients going into remission or close to remission after CAR-T cell therapy?
Unfortunately, we have run the clock. Appreciate the time. Thank you so much. Raju and Naimish, thank you.
Debjit, good luck.
Thank you.