Hello everyone. My name is Mitchell Kapoor. I'm a Senior Biotech Analyst at HC Wainwright. Today, I have the pleasure of welcoming CRISPR Therapeutics. From the company, Raj Prasad, CFO, is joining me today. Thank you so much, Raj.
Yeah, thanks, Mitchell. Thanks for having us.
Maybe just set the stage. You could just give us an overview of where we're at with CRISPR Therapeutics today. A lot has transpired over the past, you know, since the year started. Could you just level set for investors, and then we can jump into more specific questions across the pipeline?
Yeah, absolutely. Yeah, it's been an exciting time at CRISPR Therapeutics. You know, we're going through the launch of CASGEVY with our partner Vertex Pharmaceuticals, where things are going well on both cell collections and revenue from infusions of patients. You know, we're hearing the feedback of the patient community as well, which is fantastic. It's great to have a transformative medicine out there, especially the first one using CRISPR-Cas9 technology. You know, what we've done since then is we've been busy. We've been parlaying the technology into multiple therapeutic areas outside of our hemoglobinopathies franchise. We have wholly owned internal programs in autoimmune and oncology. We have programs in cardiovascular medicine, rare diseases, and type 1 diabetes.
If that wasn't enough, we expanded our technology basket with a deal with Sirius Therapeutics earlier this year to bring in some siRNA technologies with the thought that gene editing might not be the best approach for every indication. We think that RNA has certain areas where it can build upon and be synergistic with our platform gene editing technology. We did that with a lead asset where we're 50-50 on it for factor XI, which is in the anticoagulation space. We think it's an extremely valuable asset as well that will be one of the biggest targets going into next year with a competitor trial, abelacimab, that will be out sometime next year. A lot, tons to talk about. I'm sure we can have some follow-up questions, but we could not be more excited about where CRISPR Therapeutics is sitting at this point in time.
Yeah, with so much going on, so many different verticals in the pipeline, a key question that we spend time on is capital allocation trade-offs. You know, how big is this business? Where do you spend time? You have CASGEVY, you have in vivo cardiometabolic, allogeneic CAR-T, siRNA, diabetes. What, I guess, hurdle rates do you have to keep or partner assets?
Yeah, yeah, I mean, we think about this question like every day. The key point with our next suite of programs is we've invested a lot of time and effort over the last several years in creating next-generation medicines that are actually at a low cost of goods sold, or will be at a low cost of goods sold. With the allogeneic CAR-T program, we've made a significant effort with our manufacturing facility in Framingham, Massachusetts, to produce allogeneic CAR-Ts at a fraction of an autologous CAR-T therapy. Similarly, the in vivo program, it's a lipid-antiparticle plus mRNA, significantly low cost of goods so that we can be extremely competitive while also offering potentially a one-time durable cure to patients. When we think about the return on invested capital, the margin profile of these next-generation products are going to be extremely high at a reasonable cost point.
When we think about our portfolio more broadly and where to add the incremental dollar, there's obviously the return on investment. There's the market opportunity. We also have the experience of having an extremely successful partnership with Vertex Pharmaceuticals and CASGEVY, where we were able to bring this transformational medicine forward and continue to commercialize it successfully. We are being very thoughtful of that. We do have a good cash balance. We have $1.7 billion on the balance sheet. We don't want to do a hasty deal. We don't want to do a deal where we haven't fully fleshed out the target product profile, the competitive landscape, and what we can bring to the table versus maybe a strategic partner. We are continuing to sort of analyze that as now we are reaching human proof of concept across all these programs.
I think that's going to be an important question that we will hope to answer in the near term.
Okay, great. Yeah, in the space, after the Verve Lilly deal has kind of showed renewed interest in gene editing platforms and the ability to integrate those into like a broader play, how is CRISPR's in vivo gene editing engine with ANGPTL3, LPA, AGT positioned as a platform partner? What's underappreciated about kind of the ability to scale this platform?
Yeah, I mean, I mentioned the COGS point earlier. I think it was good to see, you know, that Lilly sees the landscape of genetic medicine similar to the way we do, I think, in that it's a continuum. I think that, you know, there is a subset of investors that I thought felt that, you know, it could be, it was one or the other between RNA medicines and gene editing. We don't see it that way. We do see it as a continuum. We obviously did an RNA deal ourselves. In cardiovascular medicine in particular, it also, I'm not surprised that this was the first large-scale investment from a pharma in gene editing or acquisition. We had always felt that cardiovascular medicine was going to be an area that would be transformed by genetic medicines because compliance is the biggest issue that we hear from cardiologists.
Even, you know, PCSK9 therapies that are available that, you know, have a once-in-a-six-month profile, we're seeing, you know, 30%, or we're seeing papers that say 30% of patients aren't compliant with therapy. If you're a cardiologist from that perspective, you're having issues with patients that are, you know, in the case of AGT, for example, or hypertension, patients with refractory hypertension are on five medications plus a diuretic. The ability to take those, you know, every day or multiple times a day in some cases, gets difficult for patients. Those are things where you want to be in a controlled range. You want to be in a normalized range.
If we have the ability with a one-course therapy to get patients into that range for, you know, potentially for a lifetime, I think that that value creation and that transformation to the patient profile is extremely enticing to doctors and cardiovascular specialists.
Great, okay. Moving along into that segment of the pipeline with CTX310, showed some interesting data so far. The phase one includes SHTG, HoFH, HeFH, and mixed dyslipidemia. With Olezarsen's win, we just had Ionis up here a couple of firesides ago. With their win in SHTG, is this now a lead registrational path potential still? How do you think about this with Olezarsen?
Yeah, no, I mean, kudos to the CORE-CO2 trial and Ionis Pharmaceuticals for that result. I think that highlighted to us that, you know, significant reductions in triglycerides lead to significant benefit in acute pancreatitis. I think, you know, from the data we've put out, we're seeing reductions in triglycerides in patients, you know, up to 86%. We think that, again, that SHTG could be a very enticing indication for that. We're also seeing reductions in LDL. With one target, we're seeing both, and we're seeing reductions in the LDL patient that we called out. I mean, we're seeing a reduction of up to 82%. If we have this dual benefit, then, you know, patients that have severe hypertriglyceridemia and an increased LDL, maybe not to that level, might see a benefit. We're getting to get it within the normal range for both.
We think that actually might be a differentiating factor. Obviously, the durability of effect and the no need for, you know, multiple doses is obviously a huge benefit to our therapy. That trial was, you know, groundbreaking. We look forward to sharing more data with our patients in SHTG in the second half of this year, as well as later to come.
Okay, great. You mentioned a key facet there, durability. I'm wondering if that ends up being the defining feature of what could be incremental versus what is in the space. If you have something that's similar, but a more durable response, is that something that a patient would be more apt to go on? Is that how you're thinking?
Yeah, I mean, we think so in the high-risk populations. I think doctors are going to be likely to put patients on it. I think you also think about patients that are in that, maybe the younger time, the younger age range where they're staring down 40 years of therapy. You know, does a one-course therapy just transform themselves? I mean, we have patients that we've treated with sickle cell that are climbing Mount Kilimanjaro now, right? If you gave them the option of having a lifetime treatment regimen or CASGEVY, I think a strong percentage of that population is going to choose CASGEVY. Yeah, we think the same thing for severe hypertriglyceridemias. With those patients, when you pull their blood, there's a thick, milky white layer on there. You're seeing that annually. We all know now that increased triglycerides is associated with acute pancreatitis.
There's going to be a meaningful patient population, in our opinion, that will opt for a one-course therapy.
Okay, as investors are thinking about modeling that type of a commercial adoption for a therapy like this in SHTG or mixed dyslipidemia, how do you model uptake for like a one-time therapy versus like a chronic siRNA? How do you think about like the pareconomics, the adherence, pricing, things like that?
Adherence is easy. That's the easy question. The COGS of this will give us a lot of latitude. This isn't going to be something where we're going to price significantly higher. When we get later in development, we'll have more to comment on pricing specifically. You can imagine that if we have COGS in a very low five-figure range, to get to 90% margins doesn't need a super high price point. We'll have to look at the pharmaco-economic data that we have, obviously the durability when we file a BLA or get approved at some point in the future. We do think that in these larger indications, there's going to be a strong subset of severe patients that will choose this therapy. I think over time, like any new technology, people will get more and more comfortable with it over time.
We do think that in these high TAM indications where even the high-risk SHTG populations are over a million patients, there's going to be room for multiple modalities and I think multiple blockbuster products.
Okay, great. Moving from 310 to 320 LPA, the readout delay that you all have aligns well with the Novartis Horizon trial with Pelacarsen with Ionis as well. If results are, you know, modest at the first initial update, how does CRISPR differentiate? What is the way that this would be positioned versus Pelacarsen or others in the LPA space?
Yeah, again, I think, you know, we attended a conference last year with FDA and some industry folks where the question came up of, you know, you need Horizon to sort of say a reduction in LPA is a biomarker. I think the FDA, I mean, they're going to look at both Horizon and Ocean. I think that there's not a significant delta between the readout of those two. We'll have to look at both of those studies before truly understanding if there is a mixed result in that hypothesis. For us, we continue to look at patients with a high baseline. In the Horizon study, I think at 80 milligrams per deciliter, there's a high cohort.
We'll be looking at that data in particular, in addition to the primary endpoint, to see whether patients with a high LPA in that upper quartile do achieve an effect, because that would be the most relevant to us. For us, we wanted to make sure that we fully understood what happens when you therapeutically knock down LPA. We also wanted to determine from the KOL community as well, is there going to be a threshold thesis? Is there a normal range you want to see in between? Do you not want to go down close to zero like you do with LDL? I think these are questions that are still open that we'll get more answers from next year.
Okay, and Editas is now in this race with LDLR. How do you view LDLR as a gene editing target relative to ANGPTL3 or LPA?
Yeah, I mean, I think we were very happy with the targets we selected. I think, again, with ANGPTL3, it's a loss of function mutation that's out there. There's people, you know, that are genetically, that have genetically knocked out ANGPTL3 that have a reduction in cardiovascular events. You know, we felt very comfortable going after that thesis. Again, we've produced good clinical data. To be determined, I wish EDITAS the best of luck. Cardiovascular medicine, I think, is going to be changed by genetic medicine. We really like the target selection strategy that we have. We'll be taking angiotensinogen into the clinic in the near term as well. In the not too distant future, we're going to have three clinical programs in genetic medicine.
Great, okay.
Cardiovascular medicine.
For siRNA, briefly touched upon that, branching out in terms of modality from gene editing, you also have now RNA. Can you help us understand, is the siRNA play a tactical bolt-on or is it the start of a multimodality type of a model for CRISPR Therapeutics?
Yeah, it's a good question. I think for us, we wanted to supplement our current pipeline. When we talked to these CV docs, we were hearing about anticoagulation and factor XI from a lot of them as being an interesting target, as well as being an extreme unmet need, especially in terms of bleeding that happens with the factor Xs. The factor XI thesis was born out of not saying we need this technology and we need to bring something on. It was more of this is a very interesting target. It's complementary to some of our efforts. We think that we're still talking about the durability thesis. The small molecules and antibodies that are out there, we're still looking at potentially a once every six-month option. We're still focusing on this durability benefit over other players in the space.
The market opportunity for anticoagulants, especially patients that are ineligible for Xs because of bleeding risk, is significant. We looked at this as a deal with a great counterparty partner in Sirius Therapeutics. We think this could be another multi-billion dollar asset for us in the future. Also, we got EMA approval. Phase 2 trial will be initiated in the short term or it has been initiated. These trials don't take very long to read out either for the Phase 2s. Historically, the abelacimab trial took about a year from start to finish. We'll be moving forward potentially in the near term as well.
Okay, great. You're starting in surgical VTE. How do you think about sequencing into broader chronic cardiovascular indications? That could certainly be interesting.
Yeah, so we have, I mean, the benefit here is that we will see the abelacimab trials read out and the milvexian trials read out prior to making that decision. We'll have the phase two TKR data in hand. You know, we'll sit at a good strategic point sometime in the back half of next year, where we'll see all these competitor trials develop. We can sequence our phase three development based on that. You know, again, we thought that this was a very interesting asset with clear differentiation in a multi-billion dollar market. It sort of hit all of our metrics. You don't want to knock out, you know, factor XI for life. We also thought that that was a good target to go after with this technology, you know, synergism.
Great. Okay, finally, in three years, which franchise, cardiovascular, autoimmune, or diabetes, would investors view as CRISPR's anchor in your thoughts? What milestones by the end of, you know, next year would make that vision credible?
Yeah, I mean, I think right now it's too early to call what the lead candidate's going to be moving forward. I think we're seeing interesting data across all verticals at CRISPR Therapeutics right now, and that's a good problem to have. Again, we can, in the next, say, 12 to 18 months, I think we can determine, based on our balance sheet and our cash burn, we don't have any funding concerns in the near-term future. We can determine, based on our fundamentals, what do we need a strategic partner for, what.