Intellia Therapeutics, Inc. (NTLA) Earnings Call Transcript & Summary

Good morning, everyone. My name is Gena Wang. I'm SMid-cap biotech analyst at Barclays. Welcome to our second Virtual Global Healthcare conference. First, I wish everyone is safe and healthy. And I would like to thank all the participants, investors, companies and especially our event team and corporate access team who made this virtual health care conference possible. With that, I would like to introduce our next presenting company, Intellia. With us, we have John Leonard, Chief Executive Officer; Laura Sepp-Lorenzino, Chief Scientific Officer; and Glenn Goddard, Chief Financial Officer. So with that, I will hand over to John for the introduction slides.

Thank you, Gena. So it's great to be here. Give us 1 second. We have a couple of slides that I think it will be helpful for the audience to get a sense while I just talk a little bit about Intellia. So maybe we can go to the next slide and show our forward-looking statement very quickly. And from there, Glenn, if we just go to the slide. This is a really, I think, a good way to think about Intellia and how we conceptualize ourselves. It's this idea of building, what we call, a full-spectrum genome editing company. What that means is that we take the underlying core technology, which is CRISPR/Cas9 based genome editing and apply it both in vivo and in ex vivo settings. And we do that in what we call a modular platform where various insights that we learn from a delivery or an editing from a -- delivery or editing point of view can find its way into subsequent versions of the product. So when we think about in vivo, that's very much a delivery question. The approach that we focus on, and we think the approach that distinguishes us, is a systemic approach that lies around the lipid nanoparticle. And this is a format that you may know has many advantages, and that being chemically based, it's inherently not immunogenic, so you don't have to deal with pre-existing immunity, doesn't have issues with respect to capacity. And importantly, one can not only have transient expression of the editing format, but you can redose if that were required. And so we deploy this in terms of what we call fixing broken genes. So as you can imagine, parts of the body that not -- can't be taken out of the body, you need to take the modality to it. LNPs are well suited for that. And we'll show you in a moment, our pipeline, how this is playing out. But it starts, as you might imagine, with targets that are very attractive in the liver, where we're making very, very good headway. On the other side is what we call the ex vivo basis. And here, we take cells outside the body and manipulate them using CRISPR, not as the drug, but as a tool. And the idea here is that we've built technology so that, in theory, the number of edits that we could apply to any given cell should be almost limitless. So that's how you transduce the cell. It's any of the various types of tools that one would want to make any number of different modifications, whether knock-in, knockout, silencing, et cetera, all of that is applicable with the technology tools that we build. And you'll see here in the pipeline where we're going with that for our first-generation of products, which is a TCR-based application for immuno-oncology. But the technology is robust and can be applied across any number of different cell types. So at the company, there's about a 50-50 effort on both these sides. It's not one to the exclusion of the other, and we tried to build a research organization that can produce development candidates from either side of this on an ongoing basis. Next slide, I mentioned the pipeline, as it currently exists, and here you see it exemplified, red being the in vivo side of it; and teal, the ex vivo side. And as you can see, we've made really excellent progress over the last couple of years. Our lead program in red, NTLA-2001 is the TTR amyloidosis program, which is a knockout. That's in the clinic, and let's say a word or 2 about that here in a moment. This is something we're very, very excited because it's the first example of any systemic CRISPR-based genome editing in the world, and we think that as we produce clinical data, it will be very important, not just for the field, but obviously important for our company and ultimately for patients suffering from amyloidosis. Behind it is 2002, a disease that also can benefit from knocking out a causative gene, and that is moving into the clinic later this year. And then in partnership with Regeneron, the insertion programs are focused around hemophilia A and B, where we've made really excellent headway. And behind that, there's any number of different programs on the in vivo side, either knockout or knock-in, maybe we'll talk about that in a little bit. Ex vivo, the lead program is primarily in the hands of Novartis, where there's ex vivo, hematopoietic stem cell editing for sickle cell disease. Our own approach, the Intellia wholly-owned approach, is one that we think will leapfrog the ex vivo, and we'll apply that on an in vivo basis. Nonetheless, we are working out the editing way to do that, and we're quite pleased with the success that we have. And as I referenced before, the first program that's wholly owned on the ex vivo side is for AML, NTLA-5001. And again, that's a TCR-based approach that will be moving into the clinic this year. That -- it can be applied to a variety of [ data ] from solid tumors. And then behind that, our scientists are working on any number of enhancing edits for that cell type to go after different malignancies and after different targets with different TCRs. And we have what we believe is an allogeneic approach that will leapfrog anything that we've seen that's been presented or is in the clinic currently today. So stay tuned for that. Next slide. Here are some of the key milestones for the company as we look forward to 2021. As I referenced at the beginning, this is a very important year, again, not only for us, but for the field. We're looking forward to continuing the enrollment of our Phase I study for TTR amyloidosis. Again, that's 2001. The key point here is that we expect to report interim Phase I data that will give us insight into the safety and activity profile of that product as we move forward. And again, just to put that into perspective, assuming we see favorable activity, that will be the first example of systemic editing done with CRISPR anywhere in the world, and we're very, very excited to be a part of that. Again, we're trying to move the pipeline forward broadly, and filing an IND for AML, middle of this year, as well as following up on the modular approaches for the knockout in vivo target of hereditary angioedema, we expect to be submitting an IND in the second half of this year as well. And behind that, the pipeline will continue to fill. We will move forward programs from our own research labs. We expect to nominate at least 1 new development candidate this year. And certainly, we have stretch goals to go beyond that. And then behind that, we have a very robust discovery effort where we're continuing to refine the tools we have and expand the tools in our tool chest, whether it's dealing with the nuclease, whether dealing with ACE editing, different approaches to access cells, insert them. I think that as we survey the field, we're quite confident that we have a state-of-the-art tool box and perhaps the best toolbox in the business, which we're excited to deploy. Next slide. I just want to call attention to what I focused on earlier, which is the flow of clinical data this year. Many of the listeners will know that last November, we began dosing our very first program, which was the LNP, called NTLA-2001 into patients with primarily polyneuropathy for hereditary ATTR. You see the outline of the study here. It's a 4 cohort, single ascending dose, standard 3 plus 3 design with the intention to expand at the optimal biological dose where we would accumulate some additional subjects, characterize better the profile of the product at that dose, and that would set us up for subsequent dosing into programs that follow emphasizing, moving into cardiomyopathy as quickly as we possibly can. The study is going to teach us a lot about the TTR reductions. That is, of course, with safety, the key readout of the study. And we know from prior work that what you see from a TTR knockdown point of view is going to predict pretty much what you should expect to see clinically thereafter. So this is a great way to start. Again, we look forward to sharing interim data at some point this year. We will do that at a medical meeting, and we will telegraph in advance which meeting that is expected to be. So we're very, very excited about this. The study is going very well. It began in the U.K. and New Zealand, and there's other sites that we're actively discussing adding to the program. Next slide. And then finally, just stepping back, when we think about the company and where we're going, we're very pleased with the platform we've built. Again, we emphasize modularity, this idea that once you figure something out, you can deploy it again very, very quickly for related targets or related applications. We believe on the in vivo side we've unlocked liver targets, both for knockouts and knock-ins. We think that we have the leading TCR platform in the industry right now, which applies itself to hematological and solid tumors. And thereafter, it's about deploying the technology more broadly. So you'll know that we've initiated a collaboration with the Gates Foundation, leapfrogging standard bone marrow transplantation techniques to go after sickle cell disease. Here, our LNPs would be deployed to a systemic administration for patients with sickle cell disease, where we think we can obviate the bone marrow transplant all by itself. And today, we will be presenting data on proof-of-concept and a keystone [ mean ] showing that we can do just that in a preclinical model. And then expanding a variety of ways into the hematological editing, especially applying multiple edits to bring additional modalities to various cell types with something to look forward later this year, what we think is a breakthrough approach to an allogeneic approach that solves not only the off-the-shelf problem, but also persistency. And that, we think, will reset the bar. So there we have it. A lot going on this year in -- at Intellia, and we look forward to the flow of information as the year progresses. So happy to take your questions, Gena.

Thank you, John. This is super helpful. And I believe like a lot of investors also very excited, looking forward to see the ATTR program data later this year. So maybe I will just start this question on ATTR. Regarding the enrollment waiting period, I was notified that 4 to 6 weeks that we heard from multiple other programs, that was too long applied to your program since [ the safety ] mainly occur within first week. So is it fair to say you could enroll patients pretty quickly, like 3 to 4 patients per month? And you could collect a very meaningful number of patients by the time you want to share the data?

It's correct to say that standard gene therapy approaches do not have to be applied in this protocol. So if you think of some of the more traditional approaches where patients dribble in one by one with extended waiting periods, that's not how this particular protocol is run. In the first group, there was a limited waiting period for the first patient. But thereafter, we're able to collect patients far more quickly with limited waiting. So I'm not going to commit to how many patients per month. But the thesis of can things move along quickly? Absolutely. And with respect to presenting the data, the approach that we're taking is we want to have data that's substantive, that's meaningful, that's interpretable, but it will be interim. And so as you think about moving up through those different dosing cohorts, it's unlikely that we'll present all of the data at -- all at once, but we would do it in a way that show that we're convinced that we're well on our way to establishing this as a platform and that we're well on our way to demonstrating that you can have significant activity in amyloidosis that should give some line of sight to where we think we'll wind up with NTLA-2001 for its ultimate clinical use. So very important.

Okay. So regarding when to share the data, so would that be based on like the expectation that -- or if TTR knockdown could reach your 80% goal or even higher?

Yes. It's a really important question. We haven't said internally if it's not 80%, we won't share it because I think that's the basis of your question. But we would want to have substantial degrees of knockout so that we're well beyond variability against that when people look at it, they'll say the product is clearly working. And I'd just step back and say that as we design the protocol, it was our expectation based on preclinical modeling that we would have activity and some significant activity at each of the doses. So if it's 79% or 81% or 99%, we haven't set that threshold, but the intention is to have people look at it and say, "We see."

Okay. And then any safety concern if knockingdown is over 80% or 90%?

No, it's a question that on occasion has come up. But I think as others collect additional data, who have patients who have had substantial reductions in TTR, and we're talking about coming from the science or companies, the same questions have been presented to them. And thus far, as we look at their data and as they present their data, there's really no indication that, that's an issue. With respect to what the protein carries, vitamin A, you can supplement that, and that's done, so we think the risks are de minimis.

Also want to mention the edited efficiency will not -- you always have the cells that will not be edited. So when the [indiscernible] permanent knockout, you always have some cells has the protein -- has the....

Yes. I think what you're saying is correct. It's -- as one gets to higher and higher doses, there's an asymptote, I suppose, where some cells will not be edited in the liver. I would point out that TTR is also made in the brain, which is not an area that we access, and that's where the carrier protein is particularly important. So your point of there always being some levels of TTR present regardless is absolutely true.

Okay. And then can we walk through all the components that could lead to the safety concerns? If we look at the lipid nanoparticle, CRISPR/Cas9 being bacteria origin off targets, can we quickly walk through what could be the safety concern there?

Sure. As you've said, this is a lipid nanoparticle. It contains mRNA [ in the form of ] messenger RNA and a guide RNA. And it gets into a cell and it edits. So if you think about it along those lines, the LNP itself has the toxicity, safety profile that comes with the class of lipid nanoparticle. So LNPs from virtually any source, if you give enough of them in high doses, you can get some elevations of hepatic enzymes, you can get some activation of complement, et cetera. As with any drug, the idea preclinically is to establish a wide therapeutic index and have safety define the upper limits of that and have lots of room to demonstrate efficacy within that. And that's exactly what we did, and that's exactly how the study is designed. And frankly, we don't anticipate surprises just based on what we know from others in the field and from our own work. Your point that CRISPR or Cas9 is actually a bacterial protein is correct. That's why we chose a transient expression system. The LNP has the protein produced and gone in a matter of a few hours or a couple of days. You can fly under the radar screen with initiating immune response. And like other LNPs, we administer steroids and other agents at the time of the injection. Thus far, in the preclinical work, immunogenicity hasn't been an issue. We don't expect it to be as we go forward, which contrast with repeated applications. So we don't think of that as really being limiting in any way. And then the final question, I think, is off-target. Well, we put a lot of effort into identifying any possible place where the guide RNA can lead that Cas9 enzyme. And this is done at extremely high levels of scrutiny. And we are confident that we find essentially a very, very clean profile that probably exceeds the level of scrutiny just about any other drug that's been given to people. People don't typically look at genomic levels. And whatever double strand breaks that take place in cells normally, even as we sit here today, the level of those double strand breaks is indistinguishable from the time of administration to what would be an unedited person. So we're quite confident that this is not only safe, but likely to be highly effective. And the objective here is to surpass the standards that have been presented by those who have gone before us. That's what we think the field needs.

Okay. Great. And regarding the timing of the data presentation, we actually compile a list of all the medical conferences and then EAN, that's the European Academy of Neurology, and the other one is the Peripheral Nerve Society. These 2 conferences [ stood up. ] But would the timing be too soon since both will be in June?

My question to you is, do you know where I'll be on Tuesday, May 23, at noon? You've got my year marked out, Gena. I like the way you do it. It's very, very clever. And we're not in a position to guide today, but this is what we'll do, and it's a promise that we will absolutely keep to not only you, but to all of the audience out there. We will telegraph where we're going to present it. And the idea, we go back to the beginning, which is how fast are we enrolling the study -- again, I can't guide today, but the study is going very, very well. And you can imagine we and the investigators and people who want to have access to this therapy are presenting themselves in a very, very efficient fashion. So keep watching the calendar and make sure you've got some free time middle of this year sometime.

Okay. Okay. Point taken. And then when you say telegraph, means like once the abstract is accepted, you will share with us?

We will tell you where we're going to present and when. Yes.

Okay. Okay. And then the first time we will see the actual data will be the abstract release, right, from these -- whatever conferences...

I don't want to go that far because we will, as usual, and you know this. We'll work with the meeting in terms of making sure that we follow the rules and decide what is appropriate for that meeting and how best to present the data. So let's just leave it there.

Okay. That's fair. And I'll switch into HAE program, leveraging your experience with ATTR program. You start at a higher dose. So what gives you the confidence that HAE program will have a similar safety profile versus ATTR? And what learning you can have from ATTR program?

Right. And this stems from this basic foundational approach of saying, build a modular system. So what do I mean by that? The LNP, meaning the physical structure of the LNP, its surface, is identical. The mRNA cargo within it is identical to the TTR program. The only difference is the guide RNA, where 20 of the 100 nucleotides that compose it or comprised it, I should say, vary. So you're talking about something that, at least from the outside, looks the same to the body. And as we've dealt with regulators, they understand that. So not only does it accelerate our research effort, we can have some of the pieces already existing. The preclinical assessment can be accelerated as a result of that. And we're trying very hard to take information from the ongoing TTR study and apply that to our first-in-human for the HAE program so that we can refine where we start in that ascending cohort and hopefully, get to an answer with a very small number of moves.

So what would be the initial knockdown you will be aiming for, for this program?

For HAE? Yes, we -- as was the case with TTR, we benchmark with what we know, and we try to take what we think is the best out there and set that as a standard to surpass. So as we look at kallikrein activity reduction, about a 60% decline from baseline translates into a pretty meaningful clinical benefit. And preclinical data that we've shared elsewhere, it's not part of today's presentation, shows that we can handily surpass that with any number of different doses, several of which are even less than what we've used in the TTR program. So we're quite excited about what we think we can do, which is, again, improve on the efficacy, deal with the very, very substantial treatment burden these patients have. That's the thing they hate. And as you may know, some of these patients and their insurance companies have to pay over $1 million per year of a disease diagnosed in young people. So it's a lifelong thing. We think that there's all kinds of ways we can offer an improvement to patients and payers.

So what additional prep you need for [ IND timing? ]

Very advanced in the program. We've obviously dealt with our regulators. We know exactly what they want. We've been interacting with these people for a while. We're making material -- it's really assembling the final documentation. So we've now got one of these under our belts with TTR, and I think we've learned a lot, so we feel pretty good about making headway quickly.

Okay. So one last question regarding the insertion program, which I think is also very exciting, and you guys showed maybe so far the best insertion systemic delivery, in vivo insertion data. So will we see any additional preclinical data in 2021? And what is the -- any update from Regeneron part when -- in terms of future development path for the program?

Yes. Thank you. We will share information as we go along that we think sets the bar and addresses really important questions. There's a lot of, I think, really, very, very granular type work that's being done in terms of what happens in the liver, where does the transgene go, how is it expressed. And we may be in a position to share some of that, which I think will answer some really fundamental and important questions and give not only the scientific and medical community, but other people a good sense to show what we can do with our technology and how well we can understand what's going on. With respect to the Regeneron program, they are the leaders of that. They are the ones who ring the bell, if you will, in terms of development candidates. We're working very, very closely with them. We are very, very advanced in the work that we've done. And it will be in their hands to announce this, which we'll do together, but they'll be leading that. So you'll see progress on the insertion side, and I appreciate your comment about best-in-class. We believe that as well. We're not trying to just get over a therapeutic bar and jack it up with mutant forms of proteins. We want to reconstitute the normal state because we think that, that's what's going to make the best outcomes for patients.

Okay. Great. We are running out of time, but that was a super productive discussion. And we keep our fingers crossed and then looking forward a very exciting year for Intellia.

Thank you, Gena. Good to see you.

Okay. Thank you. Okay. Bye-bye.