2023-05-15 13:48:03 ET
CRISPR Therapeutics AG (CRSP)
JMP Securities Life Sciences Conference
May 15, 2023 11:30 AM ET
Company Participants
Sam Kulkarni - CEO
Conference Call Participants
Silvan Türkcan - JMP Securities
Presentation
Silvan Türkcan
Thanks. Welcome back. My name is Silvan Türkcan, a senior analyst for JMP Securities. I cover precision medicines. It’s my pleasure to host Sam Kulkarni, CEO of CRISPR Therapeutics. Thanks for joining us today.
Sam Kulkarni
Thank you, Silvan, for having us.
Question-and-Answer Session
Q - Silvan Türkcan
So, first of all, congratulations on your filing of exa-cel in the U.S. and EU, and obviously lots of people are interested in what that entails and how the launch will be. And I think you’ve discussed that in the recent months in plenty of details. So, maybe I just want to have a big picture question. What do you think it means for the Company and the field of CRISPR gene-editing?
Sam Kulkarni
Yes. I think it’s a very exciting time in the field of CRISPR. If you think about the technology itself, it was elucidated in 2011 by Emmanuelle Charpentier and Jennifer Doudna. That was not too long ago. And in less than a dozen years, we’re the cusp of taking that technology and making a medicine that’s available commercially to patients. And that is a very rapid technology cycle. If you’ve looked at other biomedical innovations or revolutions in the past, whether it’s antibodies or proteins, they all took a lot longer to come to fruition. And so, it just speaks to the power of the CRISPR technology, the facile nature of it, the flexibility you have with the technology, but also the convergence of CRISPR technology with everything else to support it, whether it’s delivery technologies, whether it’s electroporation for instance, whether it’s the ability to handle cells, and all that’s coming together, which just speaks to the rapid pace of innovation that we live in today when it comes to cell and gene therapies. And we’re very-pleased with our partners Vertex to have been able to file in both, the U.S. and in Europe to bring exa-cel to patients.
Silvan Türkcan
Great. And maybe just in terms of news flows and gating, I guess events, what’s kind of the news flow in Europe and in the U.S. in terms of approval dates, ADCOMs and launches?
Sam Kulkarni
Well, the key -- I wouldn’t say news flow, but the process after we file, one of the important points in the process is obviously to get the letter from the FDA saying that the filings is accepted. That’s when you also find out whether you have -- where your PDUFA date might be, whether there’s an ADCOM or not. And all that will be coming forth in the next few weeks. We’ll update the market when we hear on that. But we expect -- this is a rolling submission and we’ve been working with the agency quite closely on account of the fact that we have RMAT designation, so we expect that things will flow smoothly. But I think, as we go along, we’ll update.
In Europe, I think, again, there’s -- obviously there’s questions back and forth that you get from regulators throughout the approval process or the review process. Nothing per se that I would point to and say, this is where you’re going to get an update. But generally I think, both in the U.S. and Europe on account of the fact that we start working with regulators very early, on account of the fact that we had all the designations that allow us to have that fluid dialogue, we don’t expect any surprises and we expect that things will move along. Although, it’s a very complicated filing package and everything else, and it’s a new modality, we expect that things move along quite rapidly.
Silvan Türkcan
And now, I’d like to switch gears maybe a little bit to your second, maybe business segment, immuno-oncology. Could you please explain how CRISPR approaches immuno-oncology with respect to maybe touching on allo versus auto and also one-off treatments versus re-dosing and maybe capacity to treat patients?
Sam Kulkarni
Yes. You’ve been covering us for a while, ever since we started the immuno-oncology vertical. I’m convinced that cell therapies are going to have a very important role in immuno-oncology. And I’ve talked to people who’ve been involved in oncology research for a number of years. And if you think about it, the modern war in cancer was declared in the sixties, and we’ve gone through -- cycled through a lot of toxic chemicals. We’ve cycled through the first generation of antibodies and now the next generation of antibodies and ADCs. But we’re really -- still when we think about cancer care, we still think about medicines that are highly toxic, patients that have to live through a lot of pain, a lot of nausea, a lot of other side effects, while they take the medicine and you still don’t get cures. And I think with cell therapies, you may have a completely new way of approaching cancer medicine, which is to have relatively safe medicines that could provide complete and deep responses that could potentially to cure.
Now, is it autologous therapies? Is it allogeneic? I think we’ve seen some great successes, autologous therapies, but it’s not scalable. It’s not -- doesn’t reach all the patients that deserve it. I think allogeneic therapies are the way to go. And I think while there have been some hiccups with the first generation of efforts with allogeneic, the key here is to pick a thesis and persist. And that’s what we’ve done. And now, we have not just the first generation programs, but the second generation programs.
And if I look back and say what have achieved over the last three or four years with CTX110, we’ve shown that patients can go out to two plus, three plus years in complete response with one shot of an allogeneic cell therapy. Not weekly injections for a year with toxicity, one shot of an allogeneic cell. That’s pretty remarkable for that patient and for science in general to say we’ve been able to achieve that.
What have we achieved in solid tumors? We achieved a complete response in a third line RCC which is -- which even PD-1s have not been able to achieve, right? And I think, if you look at first line PD-1 data, you’re at 9%, 10% complete response rate. And so, it just tells you what the potential is of cell therapies, and that’s why we’re moving forward 110 and 330 quite rapidly. And it’s further substantiated by the fact that regulators are very supportive, but with the RMAT designation we have, at various conferences like EBMT, we had the presidential symposium recently for 110. Investigators and regulators are highly, highly supportive of a therapy like this, because it can reach all the patients that deserve cell therapies in community settings. It’s relatively safe for the patients. We are going to get to a point where it’s a no brainer to try cell therapies first, and see what happens before you expose the patient to any toxic regimens beyond that.
Silvan Türkcan
Great. And maybe talking about 110, where -- what’s the latest and greatest update here and where -- how close are we to defining patient population for commercially relevant population and for pivotal development?
Sam Kulkarni
Yes. I think what we’ve said is, we are -- in a trial that could be potentially registrational and this is in DLBCL third line where patients have gone through therapies like R-CHOP, they’ve gone through other options, some of them have gone through transplants. And what we are seeing is reasonable durability of responses in these patients with single dose of CTX110, and now what we’re doing is developing two doses of CTX110. And the idea behind that is I think the second dose will consolidate any remaining cancer cells that are still present in the body. And the patients have shown -- it’s been shown that for patients, the safety profile is no different with two doses of LD chemo versus one.
So I think, at this point, we are trying to move that forward as quickly as we can to registration. We are moving forward 130, which is a targeting CD70 in T-cell lymphomas quite rapidly. But then for solid tumors, what we did is go to the next generation CAR-T which has these very unique edits in Regnase-1 and TGFBR2 that I think is going to improve the potency at least in order of magnitude, if not more than the first gens. And that’s really important in solid tumors.
Silvan Türkcan
Yes. And about that, I think it’s a crucial point to point out, because I think there is almost like different schools of thought around allo CAR-Ts and there is several of your competitors that are working on making more immuno -- transparent or how we are going to call them, CAR-Ts, right? So they are like either armored or they are invisible to the immune system. And for you, these edits are more on the potency side. So, it’s more about boosting the cell, the CAR-Ts per tumor cell ratio, but also to making them more potent.
Can you just comment on what we’ve seen at AACR, maybe in terms of the underlines that your strategy is valid here?
Sam Kulkarni
Well, take the -- at this point, we’ve dosed close to 200 patients with allogeneic cell therapy. That’s more than almost all the other allo companies combined. So, we have more experience in allogeneic cell therapies. And this includes data around what’s happening in the tumor microenvironment, how our cells doing. And one important observation we had is in solid tumors, the cells may be hanging around, the CAR-T may be hanging around the tumor, but they are not as active anymore because they’ve been exhausted. And that’s because the tumor microenvironment has a number of factors that exhaust these CAR-Ts and that’s the resistance mechanism for the tumors. So, what we want is to dial up the potency of these CAR-Ts. And even if the CAR-Ts survive about a month, but they are highly potent, they can actually eliminate the tumor. So, that’s the thesis, which is as you rightly pointed out, it’s a little different from some competitors who are going after more of the stealth edits. And our take was, sure, if you can make the cells last longer, but they are not potent, it may not mean much, in terms of potency or in terms of durability of responses.
Silvan Türkcan
So maybe talking about that, the CAR-T CTX112, which is the next-gen has moved into the clinic, when do you think we’d be ready for some data and what do you think would be a meaningful improvement from these extra edits?
Sam Kulkarni
Yes. We’re really excited to have started enrolling patients with CTX112 that we just announced. And we haven’t said when we’re going to disclose the data, but we’ll start accruing data. We want to get to past dose level one, because I think at dose level two and three, that’s where you’re going to start seeing a lot of activity. But even before we disclose clinical data on patients, what we’re looking for internally is what does the expansion profile look like of these CAR-Ts, what are the PK/PD dynamics relative to the CTX110? If it turns out these cells are expanding a lot more, if these cells are active beyond day 14, day 15, they retain more of the naïve phenotype, they’re more central memory phenotype. That’s going to give us a lot of confidence that this is going to be better than the first generation.
And those are all data we’re going to be seeing in the next four to five months, so before the end of this year. Now, we haven’t decided whether we’re going to disclose it or not. But we’re going to have that data. In fact, that’s one of the things that’s happening is, I think pharma knows that we’re going to have those data and that for them, they’d rather not wait until we disclose all the clinical data. And so, there’s a lot of inbound interest around these preclinical data.
Now, particularly more since there’s a publication by Carl June, last month in PNAS with the same edit that we’re doing, which is Regnase-1. And that’s ignited a lot of interests around this particular target, which I do think is going to be one of the most important targets in immuno-oncology, similar to a PD1 in the coming years.
Silvan Türkcan
Yes. That’s interesting. And I guess, similar for CTX130, you’re already in the clinic with 131. Here again, the solid tumor is probably more challenging. Again, you already started dosing patients, I believe. What’s the bar here for you internally? I think we had one out of five patients on their predecessor CAR-T. Is response rate something that we want to look for, or again, is this some of these other more earlier measures that you’re looking for?
Sam Kulkarni
Well, ultimately, we want to see what response rates are, and we want to see how many patients get -- either have a partial response or a complete response. And mind you, this is for patients that have no options left, they’ve exhausted the PD1 therapies, they’ve exhausted all the TKIs, and they’re at this point where they -- a lot of them go into salvage kind of care or going to palliative therapy. So, if you see any responses, that’s pretty meaningful. We had a patient visit us recently, who had a long stable disease in our 130 trial, right? And so, most investors say, okay, stable disease, that doesn’t encounter the response. But this patient thought they’re not going to have any time to get their affairs in order, and instead they had close to a year to do -- to plan for their family. And in fact, one of them wanted to attend -- be there for his daughter’s wedding. And all this matters for patients. And I think, people always take sort of this numerical view of patient care. And having a safe therapy that gives you that extension of life, a quality of life towards the end, I think really matters. But what we’re aiming for is, even more to get the responses and get a reasonable amount of responses that allow us to move -- not just establish our position in third line, but move forward to earlier lines of therapy in indications like renal cell carcinoma.
Silvan Türkcan
And the CTX130 obviously, it was not only in solid tumors, but also in a liquid tumor and maybe a smaller setting, but a difficult to treat with a CAR-T setting because of fratricide. So, could you tell us what’s kind of like the path forward there and, and how fast could we get to Pivotal?
Sam Kulkarni
No, I think we’ve solved the fratricide issue. I think we knock out CD-70 in these CAR-Ts, so that we can actually manufacture without fratricide. And that was one of the keys to be able to manufacture sufficient amount of doses to not just supply these clinical trials, but to make it economically feasible, where you still have a pretty attractive gross margin. And so, we’ve done all that. In fact, we’re very proud of, getting our own manufacturing facility on line now where we can produce these CAR-Ts very efficiently, very flexibly. We won the FOIA award for the best manufacturing facility, it is called the Facility of the Year Award. And last year we won the best manufacturing facility in biopharma. Normally, it’s big pharma that win these awards, but we have such a state-of-the-art facility that’s designed in a bespoke fashion for cell therapies, for mRNA, for AAVs and everything else in a 65,000 square foot facility, which is quite remarkable. So having -- being able to do that solves the issues like fratricide you’re mentioning, but also be able to supply, not just for patients in the U.S. and maybe Europe, but across the world.
Silvan Türkcan
And maybe thinking big picture, you have a lot of cash, you have a lot of capabilities, but you also have a lot of different segments, right? You have hemoglobinopathies, obviously partners with Vertex, but then you are going into in vivo, you have diabetes. How much CAR-T can you move forward into late stage development? And you mentioned partnering a little bit earlier. What are some of the strategic thinking around how to manage that?
Sam Kulkarni
Well, I think what we’re doing as we build the company is bit modular in a way. We’re building franchise by franchise. So, we have our hemoglobinopathies franchise, which now in a way is profitable on its own, right? We don’t have to expend a lot of money on that franchise. Everything goes well. And that becomes a profitable franchise that’s going to be profitable for years to come and grow. We then have our immuno-oncology franchise, which I think we want to get to that same point. Once we get the first one or two products to filing or to approval, that’ll pay -- that’ll continue paying for itself in terms of the research and we can do more. We now have the diabetes franchise where we’re partnered with Vertex and we’re continuing to enroll patients there. And then, we have the in vivo franchise, where we’re going to be in the clinic relatively soon.
And beyond all this, the base of all this is our platform improvements and our fundamental research, and that’s -- we’re calling that CRISPR-X, so we kind of built a company within a company. I think what happens when you -- company start maturing is that some of the same people who innovate in the smaller company setting, you kind of lose that in a bigger company setting. So, we created a company within a company called CRISPR-X, that are incented slightly differently from everyone else. And those people are working on new generation editing technologies. They’re working on LNP delivery for different tissues, and all that feeds into the different franchises. So, yes, we have a lot on our plate, but we have a strong balance sheet and we don’t have to make any immediate decisions on partnering or not partnering at this point.
I think for -- in vivo programs, for instance, once we have data for 5 to 10 patients, that’s where we would consider partnering. We don’t need to rush into it now where we give away value. Diabetes, we’ll have data from our program, but also Vertex have data from their programs and we actually, by giving them a technology license, have some interest and stake in what they’re doing as well and with their additive programs.
So I think all in all what we want to do is make sure each of the franchises have created sufficient enterprise value. There’s step change, enterprise value at every -- with a clear view of what the growth is for that franchise. And that model of operating has worked well for us as a company.
Silvan Türkcan
Thank you. Maybe talking about the diabetes franchise. You already moved on to dosing the next generation that may actually have some efficacy. What will be your first data disclosure look like, and what are kind of like the gating values that you see to move this forward?
Sam Kulkarni
Yes. Well, I mean, that’s the other thing -- I think if I put this all in perspective of biomedical history, it’s quite amazing that we have not just one but two generations of stem cell derived products with edits that are going into patients, right? If you -- when -- in 20 -- in the late -- in the first decade of the century, there were a lot of discussion about embryonic stem cells, people moved to IPS cells and there were a lot of research. And it gave rise to a whole new generation of cell types that you could produce or differentiate from IPS or from stem cells. That led to the Nobel Prize for Dr. Yamanaka in 2012. But it was kind of a cottage industry in a way with regen med. People were doing efforts, there were efforts in Japan, there were in California, supported by SERM. [Ph] And what we’ve done is harness all that, the development of regen med with CRISPR to be the first in the world to dose patients with edited stem-cell derived products. That’s a first in the world.
I think it kind of gets lost with all -- when we talk to investors, we often talk by exa-cel, we don’t talk about some of the other things we’re doing. But this is well ahead of anyone else in terms of having edited cells going into patients. And so, we’ll see data from that. And that could be transformative, which is diabetes is a huge market, needless to say. But it just opens up the notion that we can take edited cells to produce any factors in the body. So, we don’t -- we may not need to dose patients with antibodies in the future. We could just implant them with cells that are producing TNF alpha antibodies or producing other antibodies. You could have people with autoimmune diseases where they are -- they don’t have to dose themselves all the time. And that just -- that notion of cellular bio factories within the patient is pretty powerful concept.
And I think there is -- people are talking about all sorts of concepts now. They are talking about GLP- 1s being produced by cells inside patients in a regulated fashion. It’s one thing to take these drugs like Ozempic, or Wegovy with regular schedule. But what you really want is the GLP-1s or GLP-1s to be producing in response to meals or response to glucose. So, you just are entering a new horizon for cell and gene therapies.
If I look at some of the early research we are doing, it’s mind blowing. I think we can do organ-specific expression of peptides or proteins in response to metabolic circuits. We can do epigenetic editing to tune down expression or tune down production versus shutting it off. We can do correction, both long and short. And I think we are just going to see a next huge wave of applications come up, whether it’s autoimmune, whether it’s in the form of metabolic circuits, what have you. And all that’s going to come through in the next two, three years, I think.
Silvan Türkcan
Right. That’s very exciting. Unfortunately, we are running out of time here. But with that, I’ll thank you very much for joining us today.
Sam Kulkarni
Yes. Thank you for having us.
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CRISPR Therapeutics AG (CRSP) Presents at JMP Securities Life Sciences Conference (Transcript)