CRISPR Therapeutics AG (CRSP) Earnings Call Transcript & Summary

Good morning, everyone. Our next company for a fireside chat is CRISPR Therapeutics. I'm joined today by Sam Kulkarni, the CEO of the company. Welcome, Sam. It's great to have you join us today. Since this is part of the oncology conference, we'll try to keep our conversation limited to -- mostly to your progress in the IO -- for the IO programs.

And maybe to kick things off, can you give us recent developments or any recent updates for your lead CAR-T assets? And what investors should primarily focus on over the next 6 to 12 months in terms of regulatory updates as well as clinical development?

Yes. Thank you, Kalpit, for having us at this conference. It's our pleasure. Oncology is one of the main pillars for CRISPR Therapeutics. If I just -- before I go into our CAR-T programs, just take a look back at the last 60 years or so of our fight against cancer. We've made progress, but still there's a lot work to do. We started with a bunch of small molecules, put them in different cocktails. A lot of them were very toxic. And oftentimes, cancer care is associated with significant side effects. We then had the era of targeted antibodies, and we've obviously had seen a lot of benefit from those targeted antibodies. We've seen the advent of personalized medicine. But still, I think it's hard to find cures in oncology. A lot of times, the medicines that we use have significant side effects leading to a very poor quality of life. And I think now that's where we're entering into this new era of cell therapies as targeted agents to fight the cancer and do it in a way where oftentimes it can be a single dose or a single course of treatment with very limited side effects compared to what we've seen traditionally in oncology. So we're looking for the next 15 years in the development of cell therapies for various oncology indications, and we hope to be at the vanguard of it. For us, this is a fundamental investment because I think cell therapies can only be successful if there's sophisticated engineering. And the best way to engineer them with the sophisticated tool is to use CRISPR. We've now seen cell therapies and our cell therapies going to the clinic now with 5, 6 edits, these are quite sophisticated constructs, and they're only going to get more sophisticated as we discover new ways of making these cell therapies more potent, more durable and even safer. So that's sort of the preamble for our investment and our continued efforts in oncology. Where we stand today is that we have efforts ongoing across 3 different targets. CD19, CD70 and BCMA. In CD19, where we disclosed where data for our CTX110 asset, this is an allogeneic CAR-T targeting patients with relapse and refractory lymphomas. And for those who are not familiar with allogeneic, we take a healthy donor blood sample. We extract the T cells from it and from those T cells, we make CAR-Ts. And these are immune cells targeted to kill the cancer in our manufacturing facility, but done in a way where it's done across patients, it's not individualized. And these cells can then be administered to patients right away within a couple of days of diagnosis. And some of them have shown remarkable effect in terms of complete responses. So what we showed for our CTX110 program is a relatively competitive profile. I can talk more about the data where patients with a single course of treatment, a single dose have been in complete response for over 2 years. And we showed that 1 in 5 patients or 19% of the patients treated with a single-dose regimen, in some cases, or optional redose had durable complete response. And that's quite significant for the first effort in allogeneic CAR-Ts that could move into registrational trials. We then have the next-gen CD19 CAR-T in CTX112, where we hope to dose patients this year, and we'll have data, but this is optimized for potency and the data could be even better. In the interim though, I'll talk about our registrational trial in CD19, which is the 2-dose regimen, which could also bridge us to a much better efficacy. CD70 is a very intriguing target. There are a number of pharma companies that have worked on it before. It's never been the right balance of benefit and safety in the ADC setting or antibody setting, but in the cell therapy setting what we saw were pretty encouraging data, both for T-cell lymphomas as well as solid tumors. We've probably demonstrated the world's first complete response in a solid tumor with an allogeneic CAR-T when we presented at the SITC conference last year, and we continue to do work to improve the potency of CTX130 in the form of CTX131 targeted towards CD70. In the meantime, we're trying to move forward as quickly as possible in -- with CTX130 in T-cell lymphomas, which hopefully gets to market as soon as possible because these patients have no other options. I know there was a long description of our portfolio, but we're encouraged by both the near-term assets, CTX110 and CTX130 in CD19 and CD70, respectively. And then the next-gen assets we're very excited about.

Okay. That's a helpful overview. And maybe I want to dive deeper into some of the things you just mentioned, starting with the 19% 6-month CR rate that you saw with CTX110. I think the pulse I'm getting is some investors might view this as sort of a half glass full and some might think of it as half glass empty situation. The 19% might not be enough to get investigator interest, but then some might say it's better than 0%, right? These patients have essentially no option at the late line setting. Curious to hear your thoughts on this. How competitive do you think the 19% would be if you receive approval?

Well, one of the things we've noticed is the excitement around enrollment in our trial remains very high, and that's always an indicator of how much physicians believe in this therapy. I think they've seen the data but there's a number of sites that want a dose basis tomorrow with CTX110. The reason being, while there's data from autologous and, again, you have to look at apples-to-apples, ITT basis, autologous therapies are probably at about 30% durable CR rate. But that's for Yescarta, and that comes with a significant proportion of the patients getting CRS and some patients getting ICANS in the real world. And what we've shown is you can dose patients 2 days later. That was the mean time to -- from diagnosis or enrollment to actual dosing. And we can -- you can see durable responses in patients with the healthy donor-derived allogeneic CAR-Ts. And 80% of the patients in the U.S. are cared for in community settings. A lot of these patients have no access to autologous therapies. Many of them don't want to come in for bispecifics over 9 courses of treatment because they have to travel to their site of care. And if you have a benign relatively safe allogeneic option, which whether the patients -- the practices don't have to deal with CRS and ICANS and they can administer an outpatient setting. There is a huge market for this. And right now, we're at 1 in 5, patients used to mention the 19% getting durable CRs with our consolidation dosing regimen where we have 2 doses instead of 1. I think the number is going to be even higher. And so we're very much in autologous territory already with CTX110. And so -- and we have the agreement with the regulators now about what the design and requirements are for the registrational trial and so -- where all systems go on, on getting CTX110 to approval, and we believe this can be a very competitive trial.

Okay. And you recently had discussions with the regulatory agency and opted in to do a pivotal study with consolidation dosing at dose level [ 4 ] and combining that with standard lymphodepletion. I guess what went into the decision-making for consolidation dosing versus a single dosing regimen?

Yes, a few things, which is we saw in our Part A trial that repeat dosing helps. There are patients that where the tumor start growing, whether you have a repeat dosing, and you see tumor shrinkage or tumor illumination. This is because you have a ratio that's really important of effector cells, which are the CAR-Ts to the tumor cells. So the more effector cells you have, the more likely you are of getting rid of the cancer cells, all right? What we saw is that we can do a repeat dosing with a relatively safe -- even if we have to do LD chemo again and patients are able to tolerate a second dose without any change in the safety profile of the drug. And this is -- these are data we haven't shown yet for our Part B of the trial that had consolidation dosing. We saw conversion of patients that had a PR after the first dose to a CR after the second dose. We saw instances where they had a CR in the first dose that led to a deepening of the CR in the second dose. In other words, patients getting to MRD negative essentially. And in fact, even stable disease turning into a CR. So there is definitely a benefit with the second dose because -- again, if you -- let's say you had 1,000 tumor cells, you brought it down to 100 after the first dose. The second time around, the ratio of effector cells or the CAR-Ts to the number of tumor cells is significantly higher and your chance of getting to complete response are that much greater. And so we feel confident that the consolidation dosing will have an improvement in the efficacy while maintaining the safety profile. And that all of a sudden makes it an even more competitive profile from a market standpoint.

Okay. And can you remind us what that pivotal study is, lymphodepleting patients again before the second dose?

Yes. We do. But mind you, our lymphodepletion regimen is -- the standard lymphodepletion used in autologous therapy is not very high or enhanced lymphodepletion that some other companies are using. We believe that the whole thesis is this is a product that's going to take off in the community settings, several cancer care networks that want to use it. What you don't want to do is create a safety profile for the drug that they can manage. And I think enhanced LD, whether it's the form of higher doses of Flu/Cy or addition of other agents like Campath, I think, will make it a less competitive profile in community settings.

Okay. And I guess when you do give that second round of lymphodepletion, do you think that sort of limits the total pool of patients that would be eligible for CTX110. And I think I get a pulse from investigators that they're sometimes scared to lymphodeplete these patients again, right? Or there's a group of experts that don't want to do this the second time. Curious to hear your thoughts on that.

Yes. I think -- so far, I think some of these reactions come early on before people are seeing the data, right? They -- most people assume that the second LD chemo -- second LD regimen would cause more infections or prolong cytopenia or anything else that we might see. But what we've seen is that we don't see any of that in the patients that we've dosed LD chemo again, 30 days later or 35 days later. There are patients who are -- who progress very rapidly and are very thrilled and they won't get the second LD chemo, right? I think this is anybody who shows response and benefit, I think, will be eligible to get the LD chemo and a lot of patients will have to take it. I think compare this to other approved therapies. R-CHOP is not a walk in the park. People when they take the first course of R-CHOP, they have significant talks associated with that, any approved therapies, it's not easy. But then if they see benefit, they continue on because that's what patients want to see is that open an opportunity to get a complete response. So that's something that we're not -- we don't think it's going to significantly impair or handicap the therapy. In fact, it's only going to make it more attractive.

Okay. Talk to us about CTX112. I guess what are you hoping to achieve by introducing this next-generation product of allogeneic CAR-T.

Yes. We've taken a strategy that we don't need to improve the persistence of these CAR-Ts for very long. I think the CAR-Ts do their work within the time frame of 10 days or so that they're in the patient. What we want is the CAR-Ts to not get exhausted in the tumor or in the tumor microenvironment. So we did a massive large-scale screening of T cell to see what's going to improve their potency. And these were pairwise screening. So it wasn't just 1 edit, it was multiple edits to see what combination works best. And we came upon this combination of Regnase on -- and TGFBR2. TGFBR2 is slightly better known in the field as others have also gone down that path of knocking out TGFBR2 because TGF-beta suppression is a major way that CAR-Ts get exhausted. But then Regnase-1 is a novel target. And we see in -- both in preclinical data and in manufacturing that these cells are much more potent. So you're going to get the same window of around 14 days, let's say, these CAR-Ts are able to do their work. What you're going to see is a much better potency, in my mind, in patients because the cells are engineered that way. Now we have to do the trial and make sure it's safe and you don't get CRS or any of the other things. But we're quite excited to start dosing patients with CTX112 and CTX131.