CRISPR THERAPEUTICS - 2021 GROWTH STOCK AWARDS (transcript)



Below is a transcript from the 41st annual growth stock awards! This conversation is between top biotech research analyst Raju Prasad & the CEO of CRISPR Therapeutics Samarth Kulkarni... Enjoy!


Raju Prasad


All right, thanks everybody for dialing in. My name is Raju Prasad, I am the Research Analyst at William Blair, who covers CRISPR Therapeutics. I am required to inform you that for a complete list of research disclosures or potential conflicts of interest, see our website at williamblair.com. And with that, it's a pleasure to have Sam Kulkarni, the CEO of CRISPR Therapeutics with us for this fireside chats. Thanks, Sam, for joining us.


Samarth Kulkarni

Thank you for having me.


Raju Prasad

So, maybe just to set the stage for our discussion, you could maybe provide just a quick overview of the pipeline, as it stands today, and maybe just a few of the upcoming catalysts that investors can expect in '21.


Samarth Kulkarni

Yes, happy to do that. A decade after the CRISPR Cas9 platform was elucidated and developed by Dr. Emmanuelle Charpentier and Dr. Jennifer Doudna; we're very pleased to be at the forefront of leveraging this exciting platform for groundbreaking therapies in a very short amount of time as a company. In about six years we've gone from starting with a platform -- research platform to having multiple candidates in the clinic.


Our lead assets, CTX001 and hemoglobinopathies have shown remarkable data and could be potentially curative for patients suffering from sickle cell disease and beta thalassemia; we'll talk more about this program. But we continue to make progress in that program to get that program to patients in a widely accessible manner through -- by getting to filing an approval.


With our oncology programs, we have three different CAR-Ts. These are allogeneic CAR-Ts, that means that they are made from healthy donor cells -- healthy donor T-cells, and designed using the CRISPR platform to target the cancers and kill the cancers in patients suffering from diseases like lymphoma, and even solid tumors like renal cell carcinoma. Those programs are all in the clinic and we will have additional data for CTX110 this year, as well as initial data for CTX120 and CTX130; 110 being targeted towards CD19, 120 being targeted towards BCMA, and 130 being targeted towards CD70.


Beyond that, we have a very rich pipeline. Starting with our diabetes program, where we take artificial -- we've created artificial pancreas from iPS cells using CRISPR, and that -- that's going to the clinic by end of this year, and a number of in-vivo programs that are also moving towards the clinic rapidly. So very full pipeline; we're very excited with everything that's going on, we're over 450 people now as a company, and expect to keep marching on, especially as our own manufacturing facility comes online next year.


Raju Prasad


Thanks for that. You know, obviously with EHA coming up next week and the data update in sickle cell and beta thal; maybe provide just a little bit of context on what to expect in terms of data updates, obviously, you've provided updates in enrollment recently in trial. And then maybe after the ASH data, if you could provide any color on how physicians are looking at the data set to date? And how enrollment has proceeded since the data update at ASH last year?


Samarth Kulkarni

Yes, I think ASH last year was a very important milestone for the program. I think it was truly seen as a proof-of-concept or POC point for thalassemia and sickle cell. We presented data there for 10 patients; 7 thalassemia and 3 sickle cell patients, and all 10 patients were symptom-free. In the case of thalassemia, those patients didn't require transfusion anymore within a couple of months of being treated with CTX001. And all the sickle patients were free of hospitalizations or basic cause of crisis [ph]. And that's a remarkable difference for these patients that were been living with serious disease their entire lives.


So that was seen as big -- sort of proof-of-concept point. And subsequently what we've disclosed is that we've dosed more patients in our EHA abstract, there is a greater number of patients, we have 14 patients; 10 thalassemia, 4 sickle cell patients. And we also said that we dosed 30 patients now; so I think the program is getting more and more momentum. Both trials are designed to enroll upto 45 patients, but we don't -- we don't even think that we may need 45 patients worth of data if the -- if our approval of the data continue to bear out and hold out.


So I think -- we look forward to providing continued updates as we go along at this conference and next.


Raju Prasad

Great. And then there is obviously, a lot of development in the ex-vivo HSC space with sickle cell. You know, maybe just provide a little bit of color on how you're viewing CTX001 in the context of the clinical development landscape, obviously, a bunch of different modalities looking at HbH 87Q [ph], HbF and HbG [ph], for example. So did you -- interesting to think about as a -- as the leader in your particular modality, maybe thinking about your program, as well as potential competitor programs that might get advanced in the clinical trials in the future?


Samarth Kulkarni

Yes. There are a number of programs in this space but I think the advantage we have at this point in the position as a key -- as a clear leader in the space, is the fact that the data with CTX001 was quite remarkable. I think every patient so far has been free of symptoms as you compare that to lentiviral approaches, you know, the data look better, and when you combine that with the fact that CRISPR is a notionally safer approach relative to random integration of lentivirus, I think you'll have a huge advantage in the marketplace. So I think you have two players now, neck-and-neck, at the front; but we believe that CTX001, especially with the capabilities that Vertex brings to the table in terms of commercialization, globally, we would have a significant advantage.


I think there are a number of players that are following in our footsteps. But I think, you know, in this market, time is an important component; I think it's going to be difficult for -- for players to get a commercial foothold, if there has been a player existing already for four or five years with very good data, right. I think this is like the medical device space, and shares are sticky because there are certain centers learned and trained themselves on a certain product, and it's not very easy to switch. So I think while it's -- you know, won't be difficult for people to enroll patients because there is a lot of demand for gene editing in sickle cell and thalassemia, I think commercially, we are well positioned to take on that leadership mantle and maintain it overtime.


Raju Prasad

Great. And you mentioned Vertex, and I want to kind of drill into that a little more. I think it's a very innovative partnership, and obviously, the recent deal that you guys did to amend the partnership provided the company with significant upright capital for fairly minimal economic terms. So maybe can you just talk about how the Vertex collaboration started? And then, with the most recent deal with the negotiations over the 10%, and the control of the launch, how you were thinking about it from CRISPR's perspective?


Samarth Kulkarni

Yes, it all started with ASH Conference last year. We presented data and we said, "Oh, my God, you know, look at the response from physicians, from the patient community, the patients themselves". While we had exciting data with one patient in thalassemia -- two patient in thalassemia, one in sickle earlier; having 10 patients worth data made a big difference. I think everyone was looking at the program very differently and saying, gosh, this can be a huge advance in the field of medicine. And I do think that 20 years from now we're going to look back and say that was the moment, ASH 2020, when these data were presented, that marked the arrival of a new class of medicines that may change the face of -- change both, delivery of care with curative therapies and change the way we think about diseases and amelioration.


So, I think as we looked at both, Vertex, and I said, you know, how do we make sure we execute very quickly and get to a global launch. And if -- you know, in the original construct, we had CRISPR as the commercializing party for the U.S. with Vertex for ex-U.S. But in this context, as you look at the data, the trials are global; we're looking at the market in a way that there is a lot of shared responsibilities from a central global marketing, I would say, versus regional. It made sense to have a coordinated launch, you know, to have one company lead it, whether it's CRISPR or Vertex. And I think, you know, just looking at it from a capability standpoint, it made sense to align the capabilities in a way where you can leverage all of what Vertex have to this globally coordinated launch, and bring their best practices to bear from cystic fibrosis in other markets to ensure that we can reach as many patients as we can.


In the meantime, I think, CRISPR's capabilities are best harnessed thinking about what's sort of the next horizon; which is, how do we come up with gentle [ph] conditioning agents or expand the market? How do we come up with improvements in process and analytical capabilities to that so that we can further streamline that patient experience and improve outcomes for patients? So, I think it aligns capabilities well, the capital does make a difference for us as we further expand the rest of our pipeline. And most of all, I think it makes sense for patients suffering from sickle cell disease and thalassemia because this is the best chance of making sure that this program gets wide access to all these patients that need and deserve the therapy.


Raju Prasad

Yes. And obviously, you touched on this a little bit, but the global manufacturing cohesion that you have, can you maybe just describe a little bit about how that -- how to view that in the context of the rest of the pivotal -- the rest of the current clinical trial, as well, as approaching the agency, just given some things that we've seen in the space recently with regards to regulatory filings with the lentivirus procedure? It'd be interesting to kind of hear how you're going to be approaching it, you know, learning from some of the things -- some of the aspects of the first mover has had to go through?


Samarth Kulkarni

Yes. I think one of the advantages we have is, right from the get go we said we're going to do one global trial, you know, we're not going to separate our trial for U.S. and Europe. We also said from the get go, we're going to have one manufacturing process that's -- that can be scaled into commercial versus starting with something that's more of an experiment, right. So, I think -- I think that combined with the fact that the regulators are quite closely in touch across the U.S. and Europe, it gives us that ability to sort of advance this as one global trial, ultimately, with the notion that the filing package would be similar or same across U.S. and Europe.


Now, I think the rest of the world and Asia is a different story. But at least at this point, that plan seems to hold true. We have the RMAT designation in the U.S. which gives us the ability to have frequent dialogue with regulators in the U.S. and PRIME designation in Europe which also gives the same ability to speak with the EMEA folks quite regularly. And I should say -- I would say that everyone's been very supportive. Now, ultimately when it comes to commercial and reimbursement, I think that'll be different by region, right. I think you'll have a different way of looking at reimbursement for maybe, you know, Germany versus Italy versus the U.S. And there we have to have a more nuanced and bespoke strategy, but otherwise, I think this notion of global trials makes a lot of sense, it gives us -- it allows us to move faster, and allows us to make sure that we have a very coordinated package.


Raju Prasad

Yes, that's helpful. If we could switch gears a little bit into the oncology pipeline; obviously, you know, going to be three separate readouts for 2021 from this pipeline. With regards to CTX110, you've presented some initial data there, seeing a 50% CRA, pretty impressive proof-of-concept in T-cells now, building on the H&C [ph] platform. What should we expect in terms of updates on the 110 program? Obviously, it's going to be a focus on more on durability now from those initial patients, but maybe set the stage on what to expect from CTX110 in the update? And then, maybe we can touch a little bit on contacts with some of the other players in the space.


Samarth Kulkarni

Yes, I think data from different allogeneic players is good, it just basically signals that allogeneic therapies are here to stay. You know, you're seeing response rates and CR rates that are similar to autologous therapies, right. I think you're -- that's something that's important. And, in fact, you're seeing some motional durability, it's -- we have to the trial this still early, but we can't really compare apples-to-apples, but there is a notion that patients can be in CR for a long time based on allogeneic therapies.


And the big switch, I think people are starting to understand allogeneic therapy is different from autologous therapy. You know, I think we used to get a lot of questions of CRS and ICANs; I think that's [indiscernible] understand that that may be more of an autologous phenomenon than allogeneic because you just don't have the same kind of expansion. I think you saw something yesterday in the news around ICANS with autologous therapies, but you may not necessarily see that with allogeneic therapies, even if you have the same potency of killing, right. I think you have cell expansion relate as the allo CAR-Ts go in there and kill the cancer cells, but it may not be the same profile as an autologous therapy, right. And in fact, even as you look at autologous therapies, you know, there is a correlation, there is some correlation expansion to CRs but it's not, you know, it's not a perfect correlation.


And so we're learning more about CAR-Ts in general, and we're also learning more about allogeneic versus autologous therapies, and the same sort of metrics and lenses that you apply to autologous may not apply to allogeneic. And what we've learned is that, as a year ago, there were probably two schools of thought; there is like this notion that you're going to re-dose every time you progress, and that's how you're going to ensure durability. And now there is this notion like in re-dose, preemptively, as a consolidation dose, and that's the way to get durability because you've completely eliminated the cancer.


And I think, you know, the -- I'm glad the field is pursuing both of those options to see what's better. But, you know, in all eventuality, you're going to get allo-therapies approved in the late-line settings. And once you're getting to approval, it's going to move -- it's going to leapfrog autologous therapies, because it's going to move much faster, it's easier to enroll patients in allogeneic therapies versus autologous therapies; imagine trying to expand your autologous cell therapy trials to community settings, just very slow, you're not going to get there.


Now, all that said, I think, you know, as we look at the data from our -- for ourselves versus other companies, there are many different ways to look at our data; you know, eventually when we disclose the data, you'll have a basis for comparison. But I think the beta-2-M strategy gives us that persistence, that's -- that's important for killing the cancer cells. And, you know, I think ultimately, maybe a safer approach with [indiscernible] conditioning relative to adding CD52 antibody.


I think those are all things that will be important to compare contrast as we go along, but it's less about us versus another company in allogeneic, it's more about allogeneic versus other modalities. And I do think, the sheen is [ph] worn off some of the bispecifics; if you think about ASH last year or where we were last year, at this point, there was a lot of excitement by bispecifics. Bispecifics have the same toxicity issues that autologous therapies have; and I do think allogeneic therapies are well poised now to becoming a very important part of the treatment landscape in lymphoma and other diseases.


Raju Prasad

Yes. One quick question on 110. I mean, you mentioned the consolidation regimen, is that something that you might look at with 110? Or is that something that you need to add increasing grafting [ph] window to do something like that?


Samarth Kulkarni

No. I think, you know, our hope is still that a one-time dose gives you a durable response, right. And that's -- that would be ideal if you can do that because then there is no argument really for doing autologous therapies. But I think if we do need to go there, we will; we will probe the consolidation dose regimen if we do need to do that, and we're obviously watching carefully for data from other players to see what the consolidation doses do.


And what are the relative kinetics of it, what are the relative dynamics of it in terms of tumor volume reduction and amount of doses you need, etcetera. So we're learning a lot, and we'll go there if we need to, but at this point we're -- we want to start that experiment to see what does a one-time dose do in terms of durability? And is that competitive versus autologous? And is that competitive enough to get single-arm approval? If you can expand to a pivotal trial?


Raju Prasad

Right. Yes, I mean I think the initial data clearly derisked the B2M knockout approach which was the big question going into your first data set. So this one will be interesting to see the durability and the persistence of the cells and get an answer to those questions. With 120, the BCMA targeted product; I mean, obviously, you know, the response rates are numerically higher with the autologous programs. Is that something that you think is a differentiator with 120 versus 110? I mean, how are you looking at your 120 update in the context of autologous? And maybe compare and contrast that with CD19, which is a little different?


Samarth Kulkarni

Yes. And I think the 120 CR rates are -- seem to be higher, right; I think or BCMA, in general. And especially, with the data that came out from legend yesterday, I think you're looking at a 2-in-3 types CR rate. And I talked with autologous BCMA programs which is better than some of the other programs out there today. So that does set a bar that's relatively high. The durability in BCMA has been -- has not been that great compared to CD19 in some cases, for the trials where we know the data; I think it'd be -- it'll be interesting to see what the median duration of response is for the CRs or for the legend J&J program, that would set the bar. So I think, you know, do you have to exactly meet the bar to be viable as an allogeneic therapy? Unclear.


You have some wiggle room; we got some latitude. So let's say, you have a program with 55% CR rate, relative to 65% CR rate; there is 10% delta. These are all small numbers, that -- you know, maybe sufficient to get a foothold in the market because you have a more convenient approach with allogeneic therapy, a lot of patients that don't have access to autologous therapies. And I think, you know, the allogeneic therapies can always improve it overtime.

So, I think there is that notion. I think -- but with that said, I think you do need to be close to the bar, you can't be too far off the bar, otherwise you're going to create an ethical dilemma for people doing the clinical trials, in terms of using the available autologous therapy versus going on trials with new agents.


Raju Prasad

Yes, absolutely. And then, obviously, a few of the other companies looking at GSI inhibitors, gamma secretase inhibitors; is that an approach that you might think about looking at in the future or is that something that you're just going to wait and see how well B2M knockout works before making decisions on anything like that?


Samarth Kulkarni

Yes. I think, we -- it's certainly squarely within our sights. We haven't activated that because we want to see how it plays. Again, we want to do a controlled experiment. If we need to, we'll go that route of the GSIs but at this point, we're trying to work with the original hypothesis which is that beta-2-M gives us that persistence; it won't be overwhelmed by the soluble BCMA, and -- but we still see responses. And I think it may, you know, we'll see if we need to get tinker and tailor. But again, I think we need to be -- have a sense of activity that's close to what the benchmark is, for us to Tinker and Taylor, right. I think -- I do think that eventually, there is other constructs coming out where you're turbocharging with cytokines or making other edits. Eventually, I think allogeneic therapies will get it better than autologous therapies, even with the high bar that's set. But I think in the interim, you need to be competitive and get a foothold.


Raju Prasad

Yes, absolutely. On CTX130, obviously, is the solid tumor programming in your oncology pipeline. A question we get a lot is, what's the bar for success here? How are you viewing it in terms of being -- generating on the first data sets in solid tumors with allogeneic? And how are you viewing it internally?


Samarth Kulkarni

Yes, I think this would be huge. I think we all know that 80% of the cancer market is solid tumors, and the unmet need is tremendous in solid tumors. So any hint of a response from allogeneic CAR-Ts in solid tumors is a pretty meaningful step for mankind, I would say. I think it's an area that, you know, people have been trying to get responses for a long time. As you saw with some of the news, recently there is stalwarts in the field who've been trying to use auto-CAR-Ts to get any sort of response, whether it's visa-TLN [ph] or other targets, and it's been difficult.


And I think, for us with our allo-therapies, especially with the CD70 target, we think it's very attractive target given the expression and renal cell carcinoma in a highly immunologic cancer, I think it gives us that opportunity. I think CD70 program, the CTX130 program for us could be a very important program in the long run. And so far we're continuing the trial, there is a lot of interest in the program, we're dose escalating as we go along; and we look forward to providing updates.


Raju Prasad

Yes. And as far as, you know, how -- the medium to expect the data from those programs; you've had some where you've done, obviously, in concert with a medical meeting, some you've done with a webcast event, press release. I mean, are you thinking -- how are you thinking about the medium of disclosure?


Samarth Kulkarni

Yes. I think generally our philosophy has been the first, the initial disclosure on programs has been as a company press release or a company release or presentation. I think subsequent data releases have been as part of medical conferences, we did that with OO1 [ph]. So, I think for 120, 130, they are still early, I think these are all things that we determine as we go along, and see what the most optimal venue is, and the most optimal timing is. But we'll provide guidance as we go along throughout the year, as to when to expect the data.


Raju Prasad

Yes. You know, this is a question on the oncology platform and the company commercialization strategy as a whole. But, obviously, the CTX001 program, you're partnered with Vertex and update that program. How are you thinking about the oncology program? Right now you have three wholly-owned assets. Is CRISPR becoming more of a CAR-T company, then? If you're going to look to build out kind of commercial infrastructure to support global launches for that or do you partner one or more of those programs? How are you thinking about it now? I mean, obviously, a little early, but an important question on the direction of the company.


Samarth Kulkarni

Yes, and part of it depends on the data. But ultimately, I think our goal is to be half oncology, half rare diseases. At this point, given our programs, I think we have hemoglobinopathies, and we have type 1 diabetes, we have a number of other indications like hemophilia and GSD1A [ph] which we're working on as well. Not to mention, DMD/DM1 with two at Vertex. So, I think it's sort of 50-50 overall, in terms of oncology versus non-oncology. If the data look good from 110, 120, 130, then we have a Regeneron type platform that we can really expand and -- you know, will tilt us more in the direction of oncology.


I think -- but we always want to be looking at other diseases as well, we don't want to become a purely oncology player. Because I think -- why is that? I think ultimately, it's because that's how we can exploit the platform to the fullest extent, to bring transformative medicines for patients. It allows us to play across different business models; the business models would be different for other diseases versus oncology but I think as one single entity, we do get synergies by playing across both. So, I think -- I think if we project two to three years down the line, I think we'll be talking about oncology data but also talking quite a bit about -- potentially about diabetes, talking about some of the rare diseases like hemophilia, etcetera.


With oncology, how we play in the long run is isn't -- it's a question that we evaluate every so often. I think that our general goal is to take it all the way and commercialize ourselves. But that said, you know, I think pharma interest comes in waves, there is -- I suspect, as we show data and other show data, that pharma started to get more interested; for a while, I think people started moving towards the bispecifics but now I think everyone is coming back around to say, maybe allogeneic is the way to go, especially as iPS cells companies are bound and IPS technologies are maturing.


And so, if there is a lot of interest from pharma, and it may make sense for us to do something different, right, as a structure. But that's always things that we keep in our back pocket, I think, you know, we have very healthy cash balance but we don't want to be over reliant on equity financing. We -- and we're very sensitive about dilution in general, especially because there is so many other alternative mechanisms of financing that have different costs of capital but maybe more advantageous in the long run.


Raju Prasad

Great. I know we're running short on time, but I did want to just touch briefly on the ViaCyte collaboration because I think the type 1 diabetes is becoming more of a focus for the company and going into next year as given the TAM is so big. Can you maybe just give us a quick overview of that program, how you're viewing it? And, obviously ViaCyte has the autologous version data coming out this year; I mean is there any read-through or how you're going to look at that data in the context of the program for the allogeneic version you have with them?


Samarth Kulkarni

Yes, I think -- you know, ViaCyte have an allogeneic version; I mean with embryonic stem cells, except it's not edited, right. The original version is not edited, they rely on immunosuppressive agents, given together with the medicine to make sure that the artificial pancreas that are inserted into the patient are not eliminated by the immune system, right. So they're constantly immune-suppressing the patient, which is important as a proof-of-concept because under the immunosuppression, are we seeing these cells sense glucose and produce insulin; that's sort of the big question mark from biological standpoint.


And if you can see that -- if you can see that these cells indeed are capable of sensing glucose and producing insulin, that is a -- that takes meaningful risk off the table. Because then that would mean that, the allogeneic version that we're working on, which is edited, is also like those same efficacy in terms of production of insulin but we have the added advantage that can be stealth, and the patients don't need to be immunosuppressed, right.


At the end of the day, I think, you know, we're delving into an area where instead of fixing things mutation by mutation, we're just going to create a new organ, and put it into the body. I think we -- our pancreas are banana shaped organ that we're -- but only a small portion of that is actually catering towards glucose homeostasis. And what we're doing is creating an artificial -- a small device that serves the artificial pancreas and inserting it into the body.


You can imagine we do that with the liver cells, and these liver cells are small device that are inserted into your -- under your flanks, into your flanks or in your stomach, which can serve to be a biofactory for the body, they can produce any drugs you want, they can produce any factors or proteins you want. So I think there is tremendous potential in regenerative medicine, which I don't think everybody is catching on to at this point; we essentially get very little value I think ascribed to us right now in pre-gen med. But if you look at all the venture capital activity, all the places where money is going into, it's regenerative medicine, for a good reason.


Raju Prasad

Sam, thank you for the time. And again, I think the company has done an amazing job with bringing very -- relatively recent scientific breakthrough into real clinical results; I think that's kudos to you and the team at CRISPR. And thanks, again, for participating.


Samarth Kulkarni

Thank you for having me.



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