CRISPR Therapeutics AG (CRSP) Earnings Call Transcript & Summary

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 commitment to a price, but just help us think through what the value proposition looks like?

The value proposition is for everyone. For patients, today, we're saying, okay, if there's a once every 3-month sRNA, why would you do a onetime treatment. But that question is going to flip. If you have a onetime treatment that's safe, we would just not do that because people still have compliance issues. People leak into sometimes they miss a dose of 3 months, they may go into the fourth month or whatever. And you get the softing 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 primary argument for why you would do that. Second thing is, I think ANGPTL3 is probably a better target than [indiscernible] for these patients. And that's because you're also getting LDL reduction in addition to triglyceride reduction, you get better glycemic control with ANGPTL3. It seems like the some of the sRNA or ASO data. And you could actually potentially have better liver fat reduction with ANGPTL3 relative to [indiscernible]. So I think all of those point towards ANGPTL3 being a better target as well. And I think as we look at the data will tell us, but eventually we feel very good about the prospects because if you have that as a solution to patients and by the way, the pharmacoeconomic benefit, if we price something at about 5x SRNA pricing, that's a big value to the system essentially to employers, to the government because eventually, over a lifetime I'm going to spend a lot less on these patients.

Okay. That's helpful. Let's move on to CTX611 and zugo-cel. Maybe if you could just briefly introduce CTX611 and then we can move on to the Phase II, what looks like a successful readout and benchmark expectations?

Yes. Factor XI is going to be a very interesting target. Some people are saying now it's going to be a $20 billion category in the pharmaceutical space. And a lot of big pharma are very interested in Factor X1. And the reason for that is because there's always been this holy grail with anticoagulation. We had these [indiscernible] that came into the scene, several -- almost 2 decades ago now that had a major anticytolytic effect, but they cause a lot of bleeding risk. So many, many patients are not able to take DOX 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 XI represents because our bodies have 2 pathways One is an intrinsic pathway and one is an intrinsic pathway that's tissue factor pathway that both come together a Factor Xa. And Factor Xs is what were the [indiscernible] act. And so both pathways converge into the clotting cascade. And what we're only turning off one versus both. And because [indiscernible] 10a, they turn off both. And so the promise is for indications like stroke risk, you have stroke risk, A lot of patients who have strokes whether it's a transient ischemic stroke or if it's a major stroke, many of them go on baby aspirin or something like that because they can't take DOX. And some people will try low-dose tox, et cetera, but it's not very effective. You could have a once every 6-month injection of Factor XI that dramatically reduces your stroke risk. Same with AFib patients who have similar risks. And then there's a number of indications like the total neothroscopy, 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 thrombus formation. And that's where 6.11 comes into play. This is our first-in-class and potentially best-in-class sRNA that has deep durable reduction of Factor XI up to 95% in our Phase I studies. And now we're doing a Phase II study in a total nearthroscopy setting, and we'll read out the top line from the Phase II study at the end of the year. And if that's positive and some of the other Phase IIIs are turning out to be positive, then you have a big category here that where we're very well positioned versus small molecules and even biologics. And we're doing this together with -- this came through our BD efforts with the molecule was developed by a partner, Sirius Therapeutics, but we're developing it together, and we're actually responsible for all the Phase IIIs and ultimately commercialization of this asset.

Yes. So 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?

Yes, absolutely. I think to get to registration, I think we need to have information from this Phase II 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 XI knockdown, but also APTT levels, et cetera. And once we have that, we can put a package together to say, here's a Phase III. And the different indications where we could go, one -- 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 prevention, you had a positive trial for [indiscernible] in Phase III, you have a milvexian trial reading out soon and potentially some other indications like cancer associated thrombosis. There are drugs like cribrovan from J&J, where -- it's an ADC and you take the ADC, and you get 30% of patients get thrombus formation. They get VTEs, events, et cetera. So lots of cancer patients suffer through that. And you can do -- for any of these 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 will disclose as we get past our Phase II 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 and aPTT even through the course of a day. And it's been convenient from a compliance standpoint, whereas once every 6-month injection subcu 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 your now and have an emergency or something like that because the antibody still circulates, whereas with sRNA, you can simply replace the factor through plasma and you reversed it in case of an emergency. So several things, the nuance is why an sRNA is much better in this setting than an antibody or a small molecule.

Okay. That's helpful. And then maybe let's just touch on zugo-cel and then we could talk about the future. But how are you weighing the relative opportunities in autoimmune disease, oncology, plans going forward?

Yes. Our major focus with zugo-cel right now is autoimmune diseases. And the logic is as follows. I think what you're seeing in autoimmune disease is a real opportunity to cure these autoimmune diseases with a onetime reset of the immune system for B cell-driven diseases. And these are numerous. There's rheumatology indications like lupus, myositiscleroderma. There's heme indications like ITP. There's neuroimmune indications. And I -- everyone is 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 help the CAR-Ts traffic or the T cells traffic to this site of disease. Whereas CAR-Ts do traffic to the site of disease are very deep penetration. And the dynamic we have right now is that [indiscernible] can move very fast relative to autologous CAR-Ts, which take time from an enrollment perspective, there's safety overhang with autologous CAR-Ts, even if it's 150 patients, you have that issue. And so allo CAR T off-the-shelf is right available and I think could be very important. In vivo CAR T, it's 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 zugo-cel to be the leader or within the AlloCAR T space, especially because we have these edits that make them much more potent and autologous like relative to other allo CAR-Ts 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 end in terms of patients, but also a greater follow-up across some of the subsets. So we'll have systemic sclerosis, for instance, we'll have a reasonable number of patients, myositis, will have a reasonable for patients that would indicate in these indications can we get to a Phase III 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 that 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 Allo CAR T zugo-cel, that does go into the CNS system, and there's activity there. We've seen that with the oncology setting where people had CNS manifestations and the CAR Ts did go into the CNS and there was a response for met in the brain.

Okay. That's very helpful. And maybe briefly before we dive into maybe the broader questions in the last 6 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?

Yes. I think CASGEVY will be a steady cadence of updates every quarter. And obviously, next year, I'm sure we actually 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 3 assets that may move into Phase III for 310, I would point to our Phase Ib data that's for severe hypertriglyceridemia. And that's the data set you'll see by the end of the year. For zugo-cel, you'll see data from the basket trial, but I think we'll have more data for one of the subsets, one of the indications that kind of tell us how we're going to move forward into Phase III there. With durability, we'll have reasonable follow-up but not all the follow-up we need, but reasonable follow-up. And then for 611, we'll have the top line data just at a very high level in terms of the control arm enoxaparin versus the drug arm, which is 611 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 we'll get the top line data on these 3 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 ANA, we're already starting at a reasonable dose that's efficacious versus dose escalating from beginning because we have a platform designation for our LNP platform. So we'll have data from A1AT. And then for refractory 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, the blood pressure is going to likely drop. And so you're going to see what that looks like. So I think we'll have more catalysts early next year for those 2 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 or 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 of concerns or things that have popped up recently.

Yes. I think there's broadly -- the platform is advancing, right? The editing platform is improving and improving. And with our [indiscernible] platform, we can do precise editing with very high potency. The delivery solutions are improving. But for us broadly as a company, we look at 2 axes for improvement. One is delivery. So we want to get beyond liver into the matopoi system into the immune system into other organs like kidney, CNS, et cetera, muscle. And that's 1 axis for improvement is more and more expansion across the disease organ systems. And the other axis is the -- on editing is going beyond correction to full holding insertion as well. And I think at this point, even [indiscernible] 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 you're past the sort of the bottom on cell and gene therapies, and we're now into this phase where lycoGenentech, by the way, Genentech 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 1 or 2 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?

Yes. I think you'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 of IPs, 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?

Yes. I was sort of in AI skeptic not so long ago, but now complete convert because we're seeing productivity gains everywhere with AI. Take, for instance, our FDA filings, our medical writing, all those operational elements, AI is helping us move down much 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 Australia, 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 -- I don't think this is going to be as helpful, but as we do various things around editing or even looking at different mutations and to play out, there was a paper that 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 are knocking Gen x, y, z. You can do these massive simulations around mutations. We can do massive simulations around product design that we're not able to do before to come up with better answers, whether it's on optimization or whether it's picking the right locus to edit. So all in all, I think we're probably just at the beginning of AI making a difference to what we do, but we're heavy adopters in AI, and I think it's particularly useful with CRISPR-based gene editing.

Great. Well, thank you very much, Sam. Really appreciate you attending.

Thank you for having us.