Good afternoon, everyone, and thanks for joining me at the first day of the Needham Healthcare Conference. My name is Gil Blum, and I'm a Senior Analyst here. I specifically cover immune oncology, and it is my pleasure to have Sam Kulkarni, the CEO of CRISPR Therapeutics, with me today. Sam, maybe you don't need much of an introduction, but maybe a good place to start, just 2025 really marked a transition for the company. Maybe just looking forward, how does the company think about the pipeline as we move past Casgevy? Maybe for those who are unaware, maybe a quick overview across therapeutic areas of where you guys are making progress.
Yeah. Thank you for having us, Gil, and we're very excited with where we are as a company. For those who are new to the story, CRISPR was founded about over 10 years ago now, and the phase I of the company was about getting this platform to patients, and that's what we did with Casgevy, which is the first approved CRISPR drug in the world. That's treating a number of patients with sickle cell and thalassemia today with our partner, Vertex Pharmaceuticals. The phase II was to then use the same platform, both ex vivo and in vivo, to advance a number of different programs forward. That's where we are today, where we have potentially six programs that would read out in the next six-twelve months.
There's obviously a phase III beyond that, which I won't talk about today, but it's really how do you create even more transformative therapeutics once we have this phase parlayed from one drug in Casgevy to multiple other clinical readouts. Where we're focused today, I think we're very committed to building two franchises. One is a cardiovascular franchise, and we have a number of programs there. The second is an autoimmune franchise, where we have a number of programs. We also play in oncology, and we'll talk about that a little bit with Zugo-cel that applies across both autoimmune and oncology. Obviously within the cardiometabolic realm, we have a type one diabetes program as well, and we're expanding into rare diseases, like alpha-one antitrypsin. All in all, in this period of time, we've been expanding the portfolio quite a bit.
We believe we have best-in-class programs across a number of areas, and I look forward to discussing those with you today.
Perfect. Lots to unpack, so we're going to start with Casgevy. It generated over $100 million in sales last year, a sizeable chunk in the Q4 . What should be expectations for 2026, and should we foresee the momentum carrying forward?
Yeah. I think Casgevy's had a nice uptick or trend in the last couple of quarters. I think what's important to realize is after we launched Casgevy, this is not a typical medicine where people get initiated right away and get a medicine, and you see revenues right off the bat. This requires an installed base build, if you will, where we have authorized treatment centers that can actually deliver this medicine to patients, and that's similar to some of the more complex medical devices. That also forms a competitive moat because once you build that, it's very hard for others to do the same. At this point, we have over 75 authorized treatment centers around the world, and Vertex has established those in all the jurisdictions in which we've been approved.
If you look at the trend line of patient cell initiations, collections, and infusions, the initiations is a leading indicator of where we may end up with on infusions. What you're seeing there is a significant number of patients were initiated in the last quarter, over 100 patients. I think at that rate, what you'd see is a clear path if those patients translate to get their cells collected and then ultimately to get infused. You're looking at a multibillion-dollar opportunity. That's what Vertex and us have been saying about Casgevy and why we're so excited about the prospects and why we continue to invest so much in making this a drug that can bring cures to many patients.
All right. When do we think that we're going to start seeing these revenues hit your P&L?
Yeah, we haven't commented on when the franchise will become profitable for Casgevy. The one thing as you look at our collaboration expense right now, it's hard to disaggregate what's true Casgevy profitability versus investments we're making towards gentler conditioning and also towards in vivo editing for sickle cell and thalassemia. We are with a long-term mindset. We continue to invest in the overall franchise, if you will, together with Vertex. We're confident that the franchise will turn profitable in the not-too-distant future, and I think it'll start buffeting, not just our overall R&D spend at CRISPR, but our entire enterprise-wide spend, in a meaningful way.
Maybe you should spend a second on mitigating transplant-related mortality. What do you think are the lead strategies, and where do you guys think you're going with this in order to expand the market access?
Well, I think, from an access standpoint for Casgevy, it's been very heartening to see very good coverage across regions and jurisdictions. I think in the U.S., we have the CMMI pilot, which all the states have signed on to, which has been terrific in terms of supporting these patients and giving access to these medicines to patients. Ex-U.S. as well, I think there's been good, broad coverage for Casgevy across both thalassemia and sickle cell. I think, as you compare what options these patients have, which is, whether to go for a haplo transplant, whether there's no matches, or to take medicines that don't really change the underlying disease, like hydroxyurea, I think this is the one option the patients have to return to normalcy.
I think when you look at comparisons and the payers recognize that, which is why you have such good access to this medicine or this therapy across all these regions.
I do want to spend a pretty significant portion of our time on in vivo program. One point of contention that we hear a lot is this idea that gene editing should be preserved for your dangerous, fatal indications and that non-fatal and chronic conditions, physicians and patients probably prefer chronic therapy over an expensive long-term gene therapy, with the reasoning centering on the reversibility of chronic dosing. How do you guys counter this line of thinking, and where do you hear feedback that contradicts this?
Yeah, absolutely. I think there's a big delta between what physicians are saying to us and what the investor community's asking, right? This question the investor community's asking is very different from what we're hearing from not just KOLs, but even regular physicians. There's always going to be this disconnect because, even in 2007, people were saying there's no way iPhone's going to be better than BlackBerry, right? It just takes time for investors to catch on to certain things that are inevitable in terms of a trend, and the question's going to flip to why not gene editing. Take the example of some of these patients. NBC just published a story about this father-son duo. The father had his first quadruple bypass at the age of 29, and has had several cardiac events, very high triglycerides and LDL.
The son was diagnosed with hypercholesterolemia at the age of 14. For these patients or people at the very young age, you're saying you're going to give them siRNA or medicines all through their life, and it's just not the best option for these patients. In fact, even those medicines don't provide full control, and the two patients we're talking about here were on anti-PCSK9 antibodies and couldn't control their LDL. After one shot of gene editing, their LDL, triglycerides, and all the lipids are looking much better than anything they've seen before. The reason for that is, with gene editing, it's permanent. There's no issue of compliance once you've done it. You don't get this sort of sawtooth effect that you might see with siRNA towards the end of the dosing period.
This question at some point will flip to why not gene edit? Why would you do chronic therapy if you can just gene edit once? You don't even have the question of it being a very expensive therapy. In many ways, gene editing is going to save the system money because if you think about where this is going to be priced, it's going to be priced around potentially four or five years' worth of siRNA therapy, and you're looking at people who potentially might take 25 years of siRNA therapy, which is a very high cost to the system. All in all, I think the arguments are very clear about why you would do gene editing. The bigger question is, how is this going to unfold?
Is it going to go from more serious patients to moderate patients to everybody, or what is the rate of acceptance of gene editing? It's eventually an inevitability that a large majority of patients are going to be gene edited.
A big portion of the ability to conduct this technology well is selective in vivo delivery. Can you tell us at least a little bit about how CRISPR's strategy is different maybe than some others? I don't know if you've disclosed a lot regarding your LNP delivery system, but being able to target specific tissues is key to some of these indications.
Absolutely. I think this is a major vector for us. If you ask us, in a world where you had this typical hype phase, hype cycle, right? There was a lot of hype around gene editing, and then there was a bit of a bottoming out, and we may be past that phase. But in that period of time when a lot of others have reduced their investment in platform, we're actually increasing our investment in the platform. And the two vectors that we're most focused on right now, one is extrahepatic delivery. So we already have shown some promising animal data for bone marrow editing with LNPs, and we're going to use LNPs for other organs, including CNS delivery, that we're working on. These are all conjugated LNPs. And the other vector is gene correction or gene insertion.
We've gone from just disrupting genes to potentially correcting a few genes with single base pair anomalies to now being able to correct or even insert entire genes into various tissues or various cell types. As those vectors develop, you're talking about a number of, you know, large, rare diseases. It's an oxymoron, but some of the more prevalent, I guess, rare diseases that can all be targeted, whether it's muscle or CNS or other organs. I see the platform unfolding the way we expected it to and the power of the platform being unleashed across different diseases.
Speaking of which, we're going to walk a little bit indication by indication here. Starting with 310 and ANGPTL3 targeting, really encouraging early signal for LDL-C reduction and triglycerides. How are you thinking about the total addressable market here? Who do you think is the patients that are best amenable for something like this?
Yeah, as we spoke about before, I think all the markets will unfold as there's more and more data, especially around safety. If you look at the homozygous FH population, that's only about 1,000-2,000 patients in the U.S., so it's a small population. That's probably the most straightforward path to doing a phase III and getting approval, especially because ANGPTL3 seems to be synergistic with PCSK9. You have the sHTG population, and that's about three million patients or people in the U.S. alone, of which nearly a third of them have acute pancreatitis. If you look at those one million patients and the fact that you don't need a full outcome study here, the endpoint could be reduction in pancreatitis, gives you a path for approval in about one million people in the U.S.
ANGPTL3, I think, could be a better target than APOC3 in these patients, especially because APOC3 has been shown to increase LDL. Finally, I think you're looking at various forms of mixed dyslipidemia, starting with there's heterozygous familial hypercholesterolemia, where there's about 1 million patients. They have different types of mutations, especially there's several mutations being described now with LDL receptor genes. They have various dyslipidemias of either triglycerides or LDL. You have just refractory hypercholesterolemia, those that don't respond to PCSK9, et cetera. You have several million more people that could actually be eligible for a therapy like this.
Not to mention someone who's saying, I have family history of heart disease, and I just want to control my LDL now. I think you're going to see eventually millions of people being treated with therapies like ANGPTL3, or through CTX-310, which targets ANGPTL3. It's a built-in bispecific in a way because it addresses both LDL and triglycerides.
Well, what should we expect for disclosures from this program in the H2 of the year?
Last year at American Heart Association, we disclosed data for 15 patients in our dose escalation part of the study. Obviously, there's durability data from that initial set of patients dose, but also now what we're doing is a phase I-B where we're showing the specific effect in each of these subpopulations. We'll show data from as it applies to the subpopulations at the right dose level to figure out what the go-forward dose is going to be in a phase III. I think that this is also data that we would take to the regulators, and hopefully that's the basis for some of these designations like RMAT that allows us to have a seamless dialogue with the agency about how to develop this for the broader population.
That's something that we intend to do in the later part of this year and should be part of the broader update on this program.
I want to spend a minute also on the Lp(a) programs. Where do you guys stand on these, given we haven't seen any of the pelacarsen data yet? We're all highly anticipating this now.
The data for pelacarsen from the HORIZON study is one of the most anticipated readouts for the entire pharma industry. This is a trial for those who are new to the Lp(a) field. It's very clear from population studies that high Lp(a) equals high risk of cardiac events or high MACE risk. It's better to have low Lp(a), but is pharmacologic reduction of Lp(a) sufficient, and will that actually reduce your risk on a go-forward basis? It's something that has not been shown before, and the HORIZON study attempts to do that. I think we'll see what the level of benefit is that we'll see from HORIZON that'll inform our go-forward path for CTX-321 or 320. We have two assets that both reduce Lp(a) levels, and we want to get the most potent asset, which could be CTX-321.
Based on what we see from the various subgroup analyses of HORIZON as well, we'll decide what the cut-off should be for our phase II studies for Lp(a) going forward.
To be defined.
To be defined based on HORIZON, which makes sense. I think that's what happened is we had CTX-320, where we completed dose escalation. We had a pocket of time here before HORIZON trial read out, in terms of deciding what the go-forward path is. That's why we're parallel processing a second asset, CTX-321, and we'll make the decision based on HORIZON data.
Great. I did want to also talk about treatment-resistant hypertension. Just to remind people what this program is, what the target is, what kind of patients are we thinking about here?
Yes. CTX-340, which we said we committed to starting a clinical trial in the H1 of this year, and we're on track. CTX-340 targets angiotensinogen. Angiotensinogen is a substrate for the entire RAS pathway that regulates your blood pressure. It has been shown through siRNA trials that are being conducted by Roche and Alnylam that reducing the level of circulating angiotensinogen, which is mainly produced in the liver, can have a profound effect on your blood pressure. In fact, they showed across three trials systolic blood pressure reduction anywhere from 9%-19% in various subpopulations. What are we trying to solve here? We're trying to say is, there are patients with refractory hypertension that are on four or five different medications.
They have some combination of ACE inhibitors, ARBs that block the angiotensinogen, angiotensin receptors, you have renin inhibitors, and you have aldosterone pathway drugs as well. People are on different drugs to try to manage their blood pressure. If you can just reduce the angiotensinogen in circulation, and get a baseline reduction that's meaningful for these patients, not every patient may come back to normal blood pressure, but you've basically brought these patients back from four or five different agents a day to potentially one agent a day, even if they're not fully normalized. That's a pretty meaningful improvement for these patients because one, not everybody's compliant. Second is all these drugs have side effects that compound as you take on many different medicines.
This would be another paradigm shift where you could potentially completely alter the blood pressure profile and reduce the systolic blood pressure while keeping it safe, by the way. There have been no hypotensive events in the cardio trials reported of date with the siRNA. People say, "Why not just take a once every six-month injection or once every three-month injection if you can?" I think gene editing, again, gives you that baseline that doesn't have a sawtooth effect. God forbid, you take patients off their regular medications because they're on siRNA, and towards the end of their dosing period, they have elevation of their blood pressure, and something bad could happen. It's better to sort of have a nominal but have a consistent control that's predictable in these patients so you can titrate everything else.
Okay, just given that the data is out there, where do you think the bar is for an early clinical study?
For the reduction in systolic blood pressure? Well, I think even high single digits or low double-digit reduction of systolic blood pressure is a pretty meaningful win for these patients. I think some of these patients are severely higher than what normal is in terms of blood pressure, but if you can reduce it in double-digit levels, you brought them much closer to normal. That's a very major improvement for these patients.
Okay. We'll spend a second also on your own foray for siRNA, that's CTX-611.
How does this vertical fit in with all the other things you're doing? Is there cross-program synergies or learnings here?
Yeah. That's how this program started, in a way, or the idea started for us, which is we're committed to building a cardiovascular franchise. One of the other areas that's very exciting in cardiovascular medicine is the anticoagulation space, which hasn't seen much innovation for a long period of time. It's very synergistic with what we're doing with all the other cardiovascular trials. Factor XI is not a target that you want to permanently edit. An siRNA makes a lot more sense, and we're talking about potentially a once every six-month siRNA because you're only using this sort of for a certain period of time. You're not lifelong going to use this drug against factor XI. You're going to use it when you need anticoagulation after surgeries, but you don't want to have bleeding risk.
You may need it if you have certain conditions where you may take it for a long period of time, such as secondary stroke prevention. You could do it if you have certain conditions like AFib. I think this is something that you want to use when needed. An siRNA actually could be far more beneficial than an antibody, which some companies are developing, or small molecules. The reason for that is by effectively eliminating factor XI at the root source, you never give it a chance to form factor XIa, which then ultimately forms factor Xa, which is the central node in both the intrinsic and the extrinsic pathways of coagulation. What we're doing here with factor XI is effectively shutting down one of these pathways, which is important for thrombus formation.
At the same time, preventing bleeding by allowing the tissue factor pathway to continue to remain active, that's sort of the logic behind this program. It fits in with the rest of what we're doing, cardiovascular medicines. The siRNA vertical is still genetic medicine. It's still nucleic acid medicines that fits from a capability standpoint as well, whether it's manufacturing, analytical, et cetera.
You have guided for some data in the H2 2026 from this program. Just maybe a brief recap of the trial design and what should we be looking for?
Yeah. The important trial in the space for factor XI therapies is the TKA study. It's a total knee arthroplasty surgery. When people have their knee replacements, for instance, they're not very mobile. During their recovery, there's a very high chance of DVTs, and some of these could even be fatal. Most patients get some sort of agent to prevent DVTs from forming, like enoxaparin. At the same time, you can't use DOACs in this setting because you get a lot of bleeding if you use DOACs after you're recovering from a surgery. That's not possible either. Even with agents like enoxaparin, you get a one in five chance of forming a DVT, some more severe than others. Can you prevent that from happening with the factor XI agent?
That's what we're trying to test here with our trial and see if we can reduce that percentage. That's what some of the other factor XI agents have shown. It's a good trial where you have a control arm, and you can actually see where you stand in the kind of pecking order of different therapies for factor XI and informs, to a large extent, where you're going to invest in trials going forward. Some trials are obviously very large, like the asundexion secondary stroke prevention trial was thousands of patients. Others will be smaller, like cancer-associated VTE reduction, for instance. We'll determine our path forward for phase III based on this TKA study, and also forms the basis for going to the regulators, because we'll have a much better sense of the PK/PD and how the drug is acting in patients.
Great. I don't want to skip Zugo-cel. I know you guys have a lot of subjects. I'm going to ask something that is out of order for me, just because it's from fresh off the presses this morning. Any thoughts on kind of the non-futility data from Allogene this morning? Very interesting study looking at frontline DLBCL as it relates to MRD positivity.
Yeah, absolutely. Congrats to Allogene for thinking of this paradigm of consolidation, post-standard frontline treatment. The data tell you that we always think of some of these frontline therapies as curative, like R-CHOP, et cetera. They're not. There's still some cancer cells left, and you want to consolidate those. I think it shows that cell therapies can get to places that the biologics may not. That same paradigm carries over into autoimmune disease, which is why I'm so excited about it for cell therapies in autoimmune diseases. Whether it's this paradigm or the paradigm we're doing where we use cells to deplete all the cancer cells and then consolidate with something like pirtobrutinib continuous dosing, I think both these paradigms can be very meaningful.
I think, hope it brings back investment for cell therapy in oncology, which has largely been out of favour to a certain extent at this point. For us, we're fully committed on the autoimmune front with Zugo-cel, and we're progressing multiple indications in parallel, but we also have this pirtobrutinib combination, which I think could be very interesting in the oncology setting.
Spending a second on the value proposition for autoimmunity, you guys did see about 70% grade three CRS in your studies. Again, this is in oncology. Is this an issue, or there's a different tolerance for CRS in autoimmune disease?
In autoimmune, you probably will not see the same level of CRS, and the reason for that is because the B-cell burden's a lot lower. In a cancer setting, the B-cell burden's probably almost 10x that of what you're seeing in autoimmune disease. You don't have an overabundance of B-cells, you just have pathogenic B-cells. Unlikely that you're going to get the same level of CRS. Also, the doses we're exploring in autoimmune disease are lower than what we're doing in oncology settings.
Let's talk a little bit about the autoimmune direction. You've mentioned this multiple times in recent presentations. Just trying to understand the investment and where do you think you're going as it relates to an indication? I know there's a pretty large basket study that's ongoing, but if you can give us some broad strokes here.
Absolutely. We're expanding indications as we speak. We're going from the rheum basket. Initially, we were going after SLE, myositis, and scleroderma. We've now expanded it to ITP and AIHA, and we're looking to further expand into other indications, particularly in the CNS realm. We're quite encouraged by what cell therapies are doing in general in the autoimmune arena. This is where we don't think that typical biologics or even TCEs can have this one-shot cure that we could get with cell therapies. That's why we're so bullish on the whole opportunity across all these indications.
As it relates to data disclosures in 2026.
We'll have an update on Zugo-cel H2 of this year. We'll tell you where we are on both autoimmune or oncology, and hopefully by then, we also have a path forward from the regulators in terms of what a pivotal trial might look like in some of these indications.
Yeah, maybe on a personal note, but hopefully not another SLE study. I feel like we've seen too many of those.
Yeah. That is a conventional thing people saying, is that there are too many studies for SLE and it's hard to enroll patients. We continue to see a lot of unmet need, even in SLE, and particularly because some of the biologics and even some of the TCE trials may not be doing the trick of immune reset. We'll provide more information on how we're taking this forward.
Okay. A little bit of other category, just what updates can we expect this year from CRISPR's regenerative medicine portfolio?
Yeah. On regen med, I think we're bringing forward CTX-213, which is our iPSC-derived multiple edited cells. We haven't said exactly when we're going to get into the clinic with that. It's more likely to be next year. At the same time, I think the edits we have on there may be best in class. You have three or four companies that are pursuing this sort of approach, but the market's huge. It's really going to come down to whose data are better. The edits we've picked for immune evasion as well as making the cells more robust, we're very confident in and I think is going to work the best.
Great. Maybe we'll use the last few minutes just to discuss. What do you think people are missing about CRISPR? What would you highlight as something that people should be paying attention to but maybe are not?
Well, I think we have a very huge pipeline. In fact, we didn't even talk about A1AT and that program, CTX-460's going into the clinic soon. We have seven assets outside of Casgevy that we're advancing, and we'll have data for at least six in the next 12 months. Yet, I think a lot of the attention is on Casgevy. That's typical human nature is to focus on the lead asset. We're confident that Casgevy is going to turn the corner, inflect here, and be a meaningful contributor not just to us, but also to Vertex, even though they're a much bigger company. As that happens, I think the focus will shift towards our other programs, and we'll be in position with data across a lot of other programs to say, what's the next leg of the company?
I think we're doing all this from a sum of the parts perspective. If there are other companies in each of these spaces, and if we're doing all of this in a relatively lean fashion, that all these other companies are doing with singular focus, we can potentially be best in class across all these. As cell and gene therapy comes back in favour, we're poised to lead it from the front, in fact, sort of consolidate various pieces of the space to become the leader in the space by far. I think that's sort of the goal. Phase III of the company will tell. Now we're going from becoming a $5 billion-dollar company to a $15 billion-dollar company in the next three years.
phase III of the company will be how do you go from 15- 50 billion-dollar company or more? I think that's also something we're working on now, which we won't talk about, but obviously there's transformative medicines out there that we can create that could completely change how we think about therapies, even for common diseases.
It doesn't hurt to have a strong balance sheet either.
Absolutely. I think that's the advantage we have is we have a strong balance sheet, yet we're efficient, and that allows us to invest in multiple areas, especially when others are retrenching.
Right, Sam. As always, I appreciate your time.
Thank you.