CRISPR Therapeutics AG (CRSP) Jefferies 2024 Global Healthcare Conference (Transcript)

CRISPR Therapeutics AG (NASDAQ:CRSP) Jefferies 2024 Global Healthcare Conference June 5, 2024 10:00 AM ET

Company Participants

Samarth Kulkarni – Chief Executive Officer

Conference Call Participants

Maury Raycroft – Jefferies

Maury Raycroft

Good morning. My name is Maury Raycroft and I’m one of the biotech analysts at Jefferies. It’s with great pleasure that I’d like to welcome the CEO of CRISPR Therapeutics Sam Kulkarni. Thanks so much for joining us today, Sam. We’re going to do fireside chat format. So maybe to start off for those who are new to the story if you can give a one minute intro to the platform and programs.

Samarth Kulkarni

Well, thank you for having us here today, Maury. It’s been a great 10 years at CRISPR. In the decade that’s passed, we formed a company after elucidation of the technology by Emmanuelle Charpentier and Jennifer Doudna, and we’ve rapidly translated this technology into what’s today a commercially available product in the form of CASGEVY for treating severe sickle cell disease and severe beta thalassemia. And the data are quite remarkable and speaks to the power of the platform and the technology. But what’s also been — what we’re very proud of is that, we’ve parlayed this platform into a number of other disease areas. And where we stand today, we have five programs in the clinic across seven clinical trials and we have 10 preclinical programs that we’ve also announced and many more beyond that as we build a sustainable R&D engine that hopefully becomes a sustainable biotech company over the long run.

Question-and-Answer Session

Q – Maury Raycroft

Got it. Yes, it’s a great intro and we’ll definitely dive into the platform and how CRISPR/Cas9 is being leveraged at the company. Maybe to start off, you do have the commercial product with Vertex, where there’s a lot of interest in that. Maybe talk about just how launch metrics are looking there with 25 of 75 worldwide centers activated? And then it was also mentioned that there were FIVE patients where you’ve had cell collection there. Can you talk about what you’re hearing from the sites as well from the treating physicians?

Samarth Kulkarni

Yes, for those who are not familiar with CASGEVY, this is a product where it’s an ex vivo cell therapy product. We take patient cells, edit them using CRISPR/Cas9 to produce fetal hemoglobin and the elevated fetal hemoglobin makes up for the deficiency or defectiveness of the adult beta globin. And this was an approach that was pioneered over years of research. But ultimately I think we’ve shown remarkable data with our CRISPR/Cas9 editing with these ex vivo cells.

We’ve done this together with our partner Vertex. The relationship we have with Vertex is a 60-40 relationship. We have 40% of the asset, we own 40% of the asset and effectively get 40% of all the profits globally. And Vertex is responsible right now for the global commercialization of the product and we’re very proud to have Vertex as a partner to lead the charge with their tremendous expertise and experience they have with rare diseases.

So what are we seeing? I think, Vertex has been providing updates around center activation and patients cell — number of patients whose cells have been collected. Those are the two most important metrics for those who are looking to either model the launch or see what the trajectory looks like. Because I think what you have is a compounding effect. As you get more centers online and they all learn to have more patients go through the therapy, you’re going to see greater productivity in each ATC as well. So you will see greater number of patient cells collected as we go through the next few quarters here. And then it takes, there’s a bit of time lag between patient cells collected where we manufacture it and ultimately dose the patients. But that’s just more of a delay in revenue recognition because large — almost all patients whose cells get collected eventually in our clinical trials went on to get treated with the drug.

So, what am I hearing? Again, these are comments that Vertex have made as well, which is, from all the centers that are activated with the physicians, we’re hearing that an overwhelming majority of the patients want to get a CRISPR-based approach versus a different approach, if both options are available. Ex-US CRISPR approach is the only option available. And for these severe patients who have chronic pain, acute crises, they end up in the hospital all the time. A lot of them don’t want to wait. They do want to get on therapy as soon as they can. So we’re seeing a groundswell of interest across the US and outside the US for this transformative therapy.

Maury Raycroft

Got it. That’s helpful. And do you have a sense of what these patients look like, these early adopters? Are they similar to your Phase III? Or is it potentially a broader patient population, maybe even from less severe patients?

Samarth Kulkarni

Yes, it’s actually — this is a question we get a lot, which is what sub-segment of patients are more likely to get CASGEVY before others. And it’s actually very hard to put it in a bucket. There are patients — all have — it’s an (N01) (ph) when it comes to different patients. Each of them have a different comorbidity they’re dealing with in sickle cell. Some have lung complications, others have stroke risk, etc. So I think, it’s a function of which patients are very severe with different comorbidities and who’s going to raise their hands to say I want to get — I want to take a chance and I want to done therapy to be cured for life. And some who are more educated than others will come forth earlier, because they understand the therapy, they understand it’s safe, it’s FDA approved and it’s gone through all the rigorous testing.

So I think it’s hard to say if a certain type of patient is going to be the predominant, patient that’s going to be treated first. But again, we’re seeing a lot of interest across the board.

Maury Raycroft

Got it. Okay. And in the patient journey brochure, it says it could take five to six months to get the treatment. Is there a — what are the rate limiting steps there? And is there room to optimize and make the process more efficient?

Samarth Kulkarni

Absolutely, there’s always room to optimize the — how quickly we release the product, how quickly we get it back to the center. But typically the time lag is not always based on our operations, it’s based on — this is an elective procedure, so the patient typically decides that they want to get dosed during a certain window of time where they may have a break from their job or they may have family to support them, whatever else. So it’s similar to some of the medical procedures people go through. They want to pick a window of time where you may be away from your work, for instance, for three or four weeks or you may be in the hospital. So yes, there’s opportunities to improve, but it won’t matter in a way.

As you — it only matters in the early going. Once you start getting more patients into the funnel, that time lag will matter in terms of what we see as more patients getting treated and how often they get treated, how quickly you get more patients treated.

Maury Raycroft

Got it. Makes sense. And we’ve talked about the different regions where CASGEVY is approved. And it’s approved in a couple of countries in the Middle East, which could be underappreciated. Just wondering if you could talk about the market opportunity there and provide insights into pricing and clarify how medical tourism could work with this therapy?

Samarth Kulkarni

Yes, I mean this has been something we were keenly aware of, the opportunity. As CRISPR, we did trips to Saudi Arabia back in 2018 for instance, because there were — the number of patients that suffer from severe sickle cell diseases, it’s not well documented and well — it’s not a good data source for it, but it felt to us like there was probably even more patients in the US.

And recall that a lot of the reason why sickle cell is so prevalent is because it had a protective effect against malaria. So there are regions, both on the West Coast of Saudi Arabia, the South, where there was — malaria is still prevalent and malaria is still a big killer. And so you end up with very high prevalence of sickle cell trait, which leads to high prevalence of sickle cell disease. And so, you have markets where there are a number of patients. These systems have the ability to pay for these types of therapies. And it’s not just Saudi or Bahrain, there’s other markets there as well. And I would point to Asia as well. Now it’s different in Asia where it’s not like there’s going to be insurance coverage for every person in the population or every patient in the population, but you’re going to have a subset of patients where they’re going to have that ability to pay for it. So we’re looking at every way to get the medicine to these patients. But right now the US is a primary focus for us as well. We want to make sure the launch goes well in the US.

Maury Raycroft

Got it. Okay, makes sense. And I think let’s shift gears to your in vivo programs where you’re moving pretty quickly with those — with the two in vivo gene editing programs that you’re now in the clinic with. And so you’ve got 310 for (ANGPTL3) (ph) and then 320 for Lp(a). Is there potential to see initial clinical data this year from either of these programs and what could that entail in respect to number of patients and amount of follow-up?

Samarth Kulkarni

Yes, I think, for those who are not familiar with these programs, chronologically they fall later in our pipeline, but from a time-to-data perspective could go very quickly. These are validated cardiovascular risk factors. There is 11 million people with very high LPA in the U.S. Alone. 11 million. So It’s a huge market. And all of them have greater susceptibility to cardiac events at pretty young ages. There’s people in their 30s who get heart attacks if you have very high LPA. And what we’re talking about is a one-shot approach using an LNP to deliver the CRISPR/Cas9 with one injection in the vein that could knock down your LPA by 80% for the rest of your life.

And the outcomes correlation has to be established yet, but it could be that if the siRNA trials work out or the ASO trials have established the outcomes, what you could have is something that could be transformative for this population. ANGPTL3 3 is more of a rare disease. While the targets were validated and it could be applicable to a broader population for LDL reduction, we’re developing it in a way in these smaller segments of population where we don’t think we need outcomes trials and we can actually get it to approval quite rapidly just based on how the development has gone for drugs like Evkeeza which also target ANGPTL3 with an antibody.

So, we’re quite excited about moving these LNP-based programs forward. We haven’t guided to data. We surely will have data this year, but we just want to get to a certain threshold of data before we disclose it.

Maury Raycroft

Got it. Yes, it’s interesting. And I cover (Alnylum) (ph), they’ve got a big readout coming soon. And there’s a lot of discussion around the derivative readthrough from that Helios B readout to other companies in the space. When we see the first outcomes data from the Lp(a) program next year. How is that going to impact other companies in the space as far as CRISPR? I’m guessing that investors will probably be looking for other players. Will you potentially have data by that point, you think?

Samarth Kulkarni

Yes, it’ll be a less complex equation. I think if the data are good, it’ll help everybody. Because the Helios data readout is very complicated because you have the silencer versus stabilizer and the question of what’s better and how to combine. So it’s a very complex scenario analysis, if you will. But for Lp(a), I think if you see positive correlation shown by Intellia, I think it will read through positively to everyone who is doing Lp(a) knockdown.

Maury Raycroft

Yes, makes sense. And for the types of patients that are being enrolled into that, the Amgen Arrowhead study and the Novartis, Ionis, Lp(a) studies, are there specific questions you’re aiming to answer strategically in your initial readout besides Lp(a)?

Samarth Kulkarni

Yes, absolutely. I think that one of the big questions — one of the things we want to look at is, levels of Lp(a) and how the subsegments read out in terms of outcomes, because the cutoff –is the Novartis studies around 150 to 175, I think the Arrowhead cutoff — cut off is somewhere similar with Amgen and Arrowhead, but the subpopulation analysis for people with Lp(a) 200 or 225, I think those levels are going to be really important, because we want to start in a more severe population eventually to try to get approved. And I bet you’ll see a stronger correlation in the higher the Lp(a) is.

Maury Raycroft

Got it. Makes sense. And for — Intellia is a gene editing company in this space with in vivo gene editing. What have you learned from their approach when it comes to optimizing the mix or ratios of gene editing materials you want to deliver to a liver cell?

Samarth Kulkarni

Yes, I think there have been a few learnings in the last three years for gene editing based on what Intellia have done and some other data readouts. Firstly, I think typically with all other modalities, when you went from nonhuman primates to humans, you saw some benefit in terms of dosing based on allometric scaling. That was typically in the 2x to 3x regime, not a 5x to 10x regime. But with Intellia’s initial data readout in TTR, what it showed is that, for gene editing, because you’re using a human targeted guide against human genetics, you get an even greater benefit going from monkey dosing levels to humans. So we’ve shown very good pre-clinical data with our non-human primate studies, and we have to see how it translates to humans, but we expect if things play out the way it did for Intellia that we will have the same benefit, right?

The second is, I think everybody assumed that because LNP delivery to liver worked out for CRISPR/Cas9, it would work out for base editing and it would work out for any other form of advanced editing. It’s not always the case, because the payload is different. So you have a different charge balance, you have a larger mRNA, you may have a different ratio of guides. So, it may not work for every editing approach if it’s not standard CRISPR/Cas9. So we’re trying to do everything as similar as we can to Intellia, and it’s a different LNP of course, and we may have a more potent LNP. So let’s see where the data come out, but we don’t expect the therapeutic window to be different from what Intellia have seen.

Maury Raycroft

Got it. Okay. And let’s talk about competition as it relates to these two assets and also the appeal of having a one-time treatment and ultimately how you view positioning in the commercial landscape.

Samarth Kulkarni

Yes, I think, it’s hard to have a crystal ball to see how the world is going to evolve, but the paradigm of medicine is going to change. We’re going to have this mix between small molecules, antibodies, RNA therapies whether it’s ASOs or sRNA and gene editing. And we get questions all the time, why would anyone do gene editing if there is a once every three or every six month sRNA. And you could do a survey right now, but that survey is today. If you did a survey on sickle cell disease and said, do you want gene editing for sickle cell six years ago, you got a very small percentage response. But today, you’ll get a third of the patients you survey saying, I’ll try it. So the world changes as you have more data.

And so it makes a lot of sense to think that the world’s going to evolve to a place if the data are safe where it’s one and done. Now, what may happen is, you may get this polarizing effect where you have people who like taking the once a day pill and people who like the one and done at the cost of some of the biweekly antibodies or every three month sRNA. So open question, I don’t think it’s going to be winner-take-all. It’s going to be based on preferences. But I’m pretty excited about the role that gene editing can play across a host of common diseases and rare diseases.

Maury Raycroft

Got it. And you also have a couple other gene editing programs and capabilities as well. And you’ve recently shown preclinical data targeting the eye and additional programs including your 340 program targeting AGT in refractory hypertension and 450 targeting ALAS1 for acute porphyria. Both targets are validated by (indiscernible) RNAi. Maybe talk about the timelines for entering the clinic and then more broadly on your next gen editing capabilities?

Samarth Kulkarni

Yes, I mean we’re trying to move beyond liver with LNP delivery and showing the demonstrate — demonstrating that in the eye, the front of the eye with myosilin editing for glaucoma was a nice milestone and that could move very quickly, because you don’t have to deal with systemic talk studies for LNP. It’s very localized. It’s very accessible for an injection. It’s one time. And I think these patients really don’t have much options. You can do surgery for glaucoma, but just taking eye drops doesn’t work for these genetically defined glaucoma patients where you see deterioration over the course of years and many of them turn blind.

The other two targets, angiotensinogen for refractory hypertension and ALAS1 for what we — It’s a type of acute hepatic porphyria. They’re very different profiles. So one question, what the logic is and going after one that’s a more common indication versus rare, but what we’re trying to do is to say, where is there very strong biological validation? Because we don’t want to stack biological risk on top of technical risk. And a very — where we’re first movers from a gene editing standpoint, from a competitive share perspective. And both of these fit really well. Angiotensinogen has been validated by siRNA. And we could do the same with gene editing. And at first glance, you say, why would you do gene editing for hypertension? What if you overshoot? But these patients that have refractory hypertension or treatment resistance hypertension, they’re on like five pills a day trying to control their blood pressure. So if you can give them baseline support with editing, then they may not have to take five pills. They may take one pill or two pills or maybe no pills, right? So there’s a lot of titration you can do beyond the gene editing, but this is the only way you can actually control their blood pressure.

And the second is in, with ALAS1, this is a condition that typically affects a lot of middle-aged women — early to middle-aged women who have severe GI pain, often underdiagnosed or other pain associated with a defectiveness in the heme biosynthesis pathway. And this edit, ALAS1 has been demonstrated by an approved siRNA product to be effective, yet the approved siRNA product is a once a month injection which comes with ALT/ASD elevation which younger people may not want for the rest of their lives. So I think, again, it provides a more elegant solution. So that’s why I said, we have this is just a start. Once you unlock these scalable modules of delivery with LNP to the liver, we have five or six programs behind it. Once we unlock correction of genes in the liver, we have five or six programs behind it. And so these modules are going to open up. Once we get LNP delivered to the eye, we can have multiple programs behind it. And I wouldn’t be surprised if we have 15 programs in the clinic by 2027 or 2028.

Maury Raycroft

Got it, Interesting. And maybe let’s shift gears in the last couple of minutes to your CAR-T I.O. Program. For your CD19 program 112, you’ve guided to interim data this year. And for the program, you have the Regnase 1 and the TGF-beta knockouts in it. So how are you setting expectations when it comes to clinical efficacy, such as responses and six months CR rate?

Samarth Kulkarni

Yeah, we’re developing CTX112, which is a CD19 directed allo CAR T, and –both in oncology and autoimmune indications. And I am very confident at this point that we probably have the most potent allogeneic CAR T or CAR NK cell, the class of effector immune cells in the entire industry. And so, we’re now developing it in oncology and in large B cell lymphomas, we expect to have data by the end of this year, which — you may not have all the durability data, but you at least have a comparison to the first generation program, CTX110. And then we also are starting trials in autoimmune, where we want to dose patients with SLE and the more severe lupus nephritis patients in particular. We may not have a lot of data this year, but we may accrue some data, but we’re probably going to disclose the data next year.

So very exciting on the CAR T front. We also manufacturing it ourselves with very low cost of goods, making antibody-like cost of goods, which is a major breakthrough for us, going from where we started to reduce our cost of capital or reduce the capital outlay that we need against these programs. So we can do large trials, and we have all the inventory needed to do 300, 400 patient trials.

Maury Raycroft

For autoimmune, is your strategy any different from some of the other autoimmune CAR T players?

Samarth Kulkarni

Yeah, we’re going to start with the standard lympho depletion as opposed to tinkering with that up front. We may eventually change that, but we want to start with what’s shown to be working in the CAR T space, and we want to show a few durable responses, and then from there we can go and optimize that condition.

Maury Raycroft

Got it. And you mentioned your CAR T is the most potent versus the others. Is it one factor that makes it that way, or is it kind of the multi-variable?

Samarth Kulkarni

It’s these edits. The Regnase-1 edit is a very interesting edit. It makes the cells more naive and central memory phenotype, at the same time making it more cytotoxic with the cytokine profile that it releases. So it’s a very interesting edit that we’re going to learn more about as we put this into the clinic, as we’ve completed our clinical trials, but others put it into the clinic as well, and the TGF beta R2 edit matters as well. So a lot of the fundamental innovation outside of process changes and manufacturing comes from the biology itself.

Maury Raycroft

Got it. And we’re pretty much almost out of time, but maybe if you want to comment on your RegenMed platform and just highlight key catalysts ahead that investors should be focused on over the next six to 12 months.

Samarth Kulkarni

Yeah, I’ll comment about the RegenMed platform and also our CRISPR-X platform. RegenMed, we’re doing pretty amazing things with our iPS cells where we can do 10 edits now on iPS cells. So we’re doing — we’re making that a big platform for ourselves on RegenMed and on CRISPR-X we’re doing all forms of next gen editing, including gene writing. We’ll disclose more about that either towards the end of this year or early next year in terms of timelines of the clinic. But the science — we have a wonderful balance of execution and innovation right now, which is hard to maintain. And I’m very pleased with the early stage progress as well as the late stage.

Maury Raycroft

Got it. Thanks so much for joining us today, Sam.