CRISPR Therapeutics AG (CRSP) Earnings Call Transcript & Summary

Hi. 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 Sam Kulkarni, the CEO of CRISPR Therapeutics. This is going to be a fireside chat format. Thank you for joining us today, Sam.

It's a pleasure, Maury. Thanks for having us.

So maybe to start off, for those who may be new to the story, can you provide a 1-minute intro to CRISPR?

Yes, happy to. CRISPR is a company with a mission of creating transformative gene-based medicines, utilizing this powerful CRISPR platform that was elucidated about 10 years ago by Dr. Emmanuelle Charpentier and Dr. Jennifer Doudna. At the time, it was immediately seen as a breakthrough unlike any other in the biotech arena. And I would argue that the last such breakthrough that you saw in biotech was in the -- early 1980s with antibodies and recombinant proteins. We've moved very quickly as a company to take this powerful technology and make medicines from it and bring it to the clinic. Our lead asset is CTX001 in hemoglobinopathies, where we're partnered with Vertex to bring these to patients, and that's in late-stage clinical trials. And I'll talk more about that program and the absolute remarkable data we're seeing for patients suffering from sickle cell disease and beta thalassemia. And then we have a suite of CAR-Ts. These are chimeric antigen receptor T cells targeted and designed to go kill cancers of various types, whether they're heme malignancies or solid tumors. And we have 3 of those CAR-Ts in clinics now -- in the clinic now, and we have -- we will have data for all 3 of them later this year. And then we have some remarkably disruptive technologies. One program of note is the regenerative medicine program, where we hope to cure type 1 diabetes with artificial pancreas that are cells engineered using CRISPR to be able to be allogeneic and produce insulin response to glucose like our pancreas do. And that's just the start. I think beyond that, we have a number of in vivo programs in diseases like hemophilia, GSD Ia, DMD, DM1, et cetera, that are all making progress towards the clinic. And so there's remarkable hope for both patients suffering from rare diseases as well as more common diseases like cancer with the advent of CRISPR.

Got it. That's a great intro. And I guess maybe starting with 001. So you've maintained good progress, and that's -- this is with Vertex. You maintained good progress since ASH 2020, and disclosed greater than 30 patients have been treated across both sickle cell disease and beta thal. In the upcoming EHA conference, you're going to have 2 posters there on 001. The abstracts noted 2 months more worth of data with one more sickle cell disease patient and 3 more TDT patients compared to ASH. And so we're counting a total of 14 patients. How many more patients and how much follow-up should we expect to see at EHA?

Yes. Well, the trial is going really well. Since our presentation of data at ASH last year, where we showed data for 10 patients at the time, 7 thalassemia, 3 sickle cell patients, and the data were absolutely remarkable. All 10 patients were free of their symptoms. The 7 thalassemia patients were transfusion-independent. The 3 sickle cell patients were VOC-free. And that generated a lot of excitement not just among the PIs that are part of the trials, but also the general public and patient advocacy groups and everyone else. We've had a lot of interest in the program. There's patients lined up to be part of the clinical trials. And at the same time, we've actually ramped up our manufacturing scale. And with those 2 factors, we're able to enroll patients much more rapidly and get to our target of fully enrolling these studies this year. We haven't disclosed how many patients are in -- will be in the EHA posters or the nature of the data. But if you look at the abstracts, you have 10 thalassemia patients, 4 of whom were of the severe genotype, right? There was -- while the data at ASH were great, people say, okay, is this going to work across all the patients with all genotypes? And looks like this therapy CTX001 shows a very consistent fetal hemoglobin increase across all these patients regardless of genotype that are suffering from transfusion-dependent thalassemia. Then you go to sickle cell, and now you have 4 patients that are all, again, VOC-free to the time point at which they were followed. And again, you're seeing a very consistent increase in HbF. They're all around the 40%, 45% range of total hemoglobin, which is well above the range needed to prevent sickling of these cells. That's about 20%. So you're seeing very good data there in terms of HbF levels, the clinical correlates in terms of being VOC-free. And all the side effects are consistent with busulfan-related conditioning across these patients. So we're quite bullish about how the trial is moving forward. We obviously did a streamlining of our operating model with Vertex earlier this year, which allows for us to think about a coordinated global launch should we -- once we get there and also a coordinated global manufacturing scale-up to meet the needs of patients that are suffering from these terrible diseases.

Got it. That's really helpful. So it sounds like for EHA, you're not going to say how many more patients are going to have there. But is it fair to say that there will be some additional patients worth of data?

Well, I mean, the typical way we do this is we have a great deal of discipline around how we look at the data and how often we open the database. And I think we only want to do it if it's absolutely called for and necessary. I think we also, at the same time, operate with a sense of transparency. We want to show the data that we have in the interest -- not just in the interest of investors, but also -- but mainly because we want all the investigators to know what's happening, the patients to know what's happening. And that's how we're going to, one, gain momentum in the trials, but also establish our preeminence in the field.

Got it. Okay. And from the abstracts, it sounds like 1 of the takeaways is that you're seeing consistency across the different genotypes. And that shows the breadth of the approach.

Yes. I think several consistency across genotypes, the consistency at which the fetal hemoglobin goes up. It's not a one-off. You don't see the variability that you see with gene therapies. And that's one thing that -- if you think about what the FDA and other regulators care about, one of the biggest concerns they have is variability patient to patient. And you've seen that with both AAV-mediated therapies, gene therapies, as well as lentiviral-based gene therapies. And here, what you're seeing is the patient-to-patient variability is kind of limited. You're seeing similar consistency in the elevation of fetal hemoglobin, similar kinetics. And that similar pattern is leading to similar clinical outcomes. And I think those are all very good facts to support the notion that CTX001 is applicable across all transfusion-dependent thalassemia patients that are severe and across all sickle cell patients that have severe disease.

Got it. Okay. And will you say if you're going to be providing additional details on editing efficiency, bone marrow engraftment, et cetera, at EHA?

Yes. Again, we don't comment on the nature of data that maybe you may see. I think we always balance the notion of being very transparent about our data with having the right forum for doing it. I think you want to have -- these are various things that we're looking at the trials, right? We measure all sorts of correlates. We measure all clinical and nonclinical aspects including bone marrow editing, the peripheral editing, the percentage F cells, et cetera. And we want to package the data appropriately so we can interpret the data correctly. And that's the balancing factor between being completely disclosing this data but making sure they're robust. And we will show data that makes sense in this context as we get to a greater number of patients overall in the study.

Got it. I thought you're going to disclose the data at the Jefferies conference. Well, so let's see. So based on the initial data you've shared with regulators, I guess, what's been the feedback? And are there any specific points of negotiation?

I think the discussions with regulators is going really well. I think, again, these are not one-off meetings. This is a continuous set of meetings we have with the regulators on account of the fact that we have RMAT designation in the U.S. and PRIME designation in Europe. And both of those designations came on account of the fact that the regulators think this is highly promising therapy. And the discussions are going really well. I think the 2 aspects typically of discussions around how you get to a filing package or around clinical and nonclinical. And the nonclinical mainly being around CMC aspects. So I think on the clinical aspects, there is -- as the data matures, the question becomes what is the bar in terms of how many patients you need and what is the amount of follow-up you need on each of these patients or the last patient. That's what counts, right? Last patient in plus the follow-up time to get to a data set that could be filing ready. And then on the CMC aspects, the question is, as you scale up and mature and diversify and globalize your supply chain and your supply -- manufacturing supply, are they all comparable? Are they all sufficiently characterized and qualified to meet the needs of patients in a commercial setting? I think that's the discussion. I think those are the 2 aspects. One could be rate-limiting versus the other. But at this point, I think we're trying to bring all these to converge at the same time point as we continue to mature our data and discuss these aspects with the regulators.

Got it. Okay. And you've mentioned potential for 15 to 20 patients per trial. So maybe 30 to 40 patients total in duration of follow-up of 12 to 18 months to be sufficient. Can you talk about how you're getting to those projections? And do you have some alignment with regulators on this already?

We haven't provided any guidance saying this is officially aligned with regulators or anything like that. I think this is -- this was our ingoing hypothesis as CRISPR Therapeutics saying, this is what you may need from a regulatory standpoint, given the data we're seeing in the early patients and the data set hold across all the patients, right? And I think you've seen conditional approval for Bluebird in Europe based on a similar number of patients. And you're seeing now others attempting to file with small number of patients given curative type of data. And so it's -- well, it's very reasonable to think that 15 to 20 patients, if all of them are -- or almost all of them end up being transfusion-independent or VOC-free that, that could give us a lot of confidence that this is ready for a wider access in society. Now the specifics of these will have to be discussed with the regulators because it's different for a safety database versus the efficacy population. It's not the same type of statistics you're doing because here, you're seeing a majority of the patients have the effect or everyone -- almost everyone having the effect is the expectation. In which case, how do you really think about statistics in the classical sense where typically, if you've had drugs that only respond -- give you a response for a certain part of the population and the effect size is not as clear. Here, it's black and white in terms of effect size. So again, it's a bit of a discussion with regulators, judgment call, and ultimately, we'll get to alignment around that.

Have they provided any specifics on what the safety database should look like?

Again, so we don't discuss these regulatory discussions, any specific regulatory -- we'll combine all of it and give you an update at some point this year, regulatory discussions. But what I'll say is the regulators have been very supportive, both in the U.S. and globally because of the tremendous potential of this therapy.

Right. And when do you think is the earliest that 001 could be on the market for sickle cell disease?

Yes. Again, we haven't provided that update, right? I think if you look at the range of all the analysts on Wall Street, there's a range out there. And you yourself have put a specific time line -- potential time line on it. I think these discussions will be much easier and provide greater clarity once we've got to that clarity with the regulators. I think once we feel like we have enough confidence that we're all aligned on what that filing package is and what that might take, I think we'll provide that update ourselves and say this is what we expect. I think before that, it's a bit premature to speculate on what the time line might be for launch, et cetera.