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

Sure. This is a very different disease. So hereditary angioedema is a genetic condition in which patients get unpredictable and often uncontrollable swelling events or angioedema attacks, and they can occur in the extremities in your hands and your legs, can occur in your abdominal area and your throat. It can be fatal. And it's, oftentimes, again, unpredictable, unclear, what triggers these events. There's a couple of ways that patients will get treated. There are prophylactic therapies that patients can take sort of by definition, in advance to prevent these attacks. There -- most of these are injectable or infused drugs. Some have better efficacy than others, but there are certainly treatments that are available. There are some oral treatments available as well. They all have some level of efficacy in some, I'd say, burden of treatment, whether they're frequent injections or cumbersome injections or oral pills with different side effect profiles. So the unmet need certainly is that patients -- despite these available treatments, most patients will still continue to have some attacks. And again, what's often most challenging for patients is that the predictability of these attacks is that they don't know when they're going to occur and they can occur at sometimes the worst times. And then there's the burden of that treatment. How difficult is it to get infusions or injections or to do this frequently. And then maybe the third piece of this is just the pharmacoeconomic component, how expensive is it to treat a disease like this. Most patients with this disease will begin to get symptoms in their adolescence. Once you're diagnosed and treated, will be treated for life from adolescents through the rest of their life. So there's a fair amount of unsatisfied patients. And we think that with a onetime gene-editing treatment, again, we've seen pretty, I would say, encouraging data so far. We've reported on the first 10 patients who have been dosed with our gene editing in vivo investigational drug, 2002. All 10 patients have gone to an attack-free state, and we're continuing to monitor that. We'll report more data later this year with additional follow-up. And so we're really encouraged by that. And we think if this kind of data continues, that we could potentially have a really long term, maybe even functional cure for these patients following a onetime treatment instead of chronic therapy for the rest of their lives.

Okay. Yes, that was going to be my next question is, is the expectation that patients would remain attack-free? Or would there ever be a situation where you would expect maybe not exactly combo use but continued use of some of these other therapies after 2002 treatment.

I mean we don't know yet. It's obviously still early. We've presented on the first 10 patients out for, I think, the longest patient had gone 10 or 11 months without an attack. We'll present later this year, many more months of -- for all these patients plus 4 additional patients who have been treated since that data was released. So we'll -- I'm sorry, we presented data on the first 6 patients for attack rates, and we'll be adding 4 more. So it will be a total of 10. And it will be a longer period of time. So I'd say, scientifically, we don't see a reason why patients would resume getting attacks, if their kallikrein levels have been knocked down sufficiently. But time and data will tell. But our expectation or at least our hope is that we'll continue to see robust either complete or near complete reductions in these attacks. And so we'll see and we'll report more data later this year and we'll see how things are going.

Okay. Great. And then kind of a similar question as with 2001, but what does a pivotal study look like in this indication?

Yes. I mean this is a disease that has some precedents. There are a number of drugs that have gone through the full regulatory and approval process. And the design of those studies is fairly similar across these drugs. So typically, the primary end point tends to be a reduction in HAE attacks. So you have some baseline level of attacks that these patients are having per month. You're giving a therapeutic intervention and you're measuring are these -- how many attacks are these patients still getting? And there are other end points you could look at the type -- if they're still getting attacks, are they more severe, less severe than the attacks they were getting? Maybe where are they getting them? So there's other things you can measure, but the primary end point tends to be at around 6 months, what does the attack rate look like after 6 months. So I would -- again, we haven't given the full design of our expected Phase III, but I would imagine that it would be not too far off from the types of studies that we've seen. I think the big -- the obvious advantage of this program is it's a onetime treatment. So you're infused once with this CRISPR-based therapy, and that's it. And then you're measuring how these patients are doing over time. And that obviously is different from if you're getting injections every couple of weeks or every month or you're taking a pill every day. So there's obviously a big difference there.

So this next one, I know it's a difficult one to forecast, but -- and we're about to see some real-world kind of evidence as far as what happens when a gene-editing therapy gets on the market with CRISPR. But what does it take in your mind if you are able to show an absence of attacks going forward and kind of a best-in-class profile? What does it take for a gene-editing therapy to become standard of care over time?

Yes. I mean it's a great question. I think obviously, it starts with the safety and efficacy data. And I think it also -- there's a time component. And then when we go out and we talk to physicians, we talk to patients, and there tends to be kind of 3 segments. And this is not dissimilar from other innovative new technologies or even groundbreaking technologies. There's the rapid adopters of those that say this sounds amazing. I want this right now. There are those that say this sounds great, tell me more or maybe I want to see a little more data. Maybe I want to see a couple of years' worth of data or some more patients. And then you have the third group that says it's going to take more time and data to convince me. And I'd expect that, that's what we'll see. And I think that part of our job will be to educate the medical community and also the patient community about gene editing and what the potential advantages are and what the considerations are. And you're right that the first, I guess, CRISPR-based therapy is now -- our colleagues and another company have filed that with the FDA. So we'll wait to see what happens there, but we're optimistic for them, and we're rooting for them. Now remember that, that therapy is an ex vivo therapy. So a little bit different than what we've been talking about. That's a therapy where you're taking cells out of the body, you're using CRISPR to edit them and then you're putting them back in the body for a therapeutic purpose. And so we're working in some diseases in that area as well. But from an in vivo standpoint, where actually you're delivering the CRISPR machinery through a lipid nanoparticle, which is what we're doing, directly to the patient, I think, has some significant benefits. And so -- but we have a lot of work to do to, I think, educate the world about gene editing. And it's -- I think it's as rapid as the pace has been for innovation and how quickly companies like Intellia and like CRISPR Therapeutics, we're talking about, have taken these ideas to either clinical programs and potentially approved programs, has happened really rapidly relative to drug development terms. And then the next piece is going to be how do you educate the consumer in the world, patients. And that's what gets us really excited because we think there's a lot of benefits to this type of platform for health care in general.

Definitely, definitely. Wanted to move on to -- you have 2 programs for F1 antitrypsin deficiency 3001 and 2003. What's the status of each of those? One is focused on the liver manifestations of the disease, the other on lung. Where are those at? And how are you thinking about that overall strategy of having 2 different approaches for different stations of the disease?

Yes. So that's sort of the -- those are the next 2 in vivo programs that are currently in preclinical stage, and we hope to bring those to the clinic shortly. We have formally said that for 3001, the insertion program, and I'll explain that in a second, we expect to file an IND or an IND equivalent by the end of this year. But that's, really there's 2 approaches there. So alpha antitrypsin deficiency is a disease where -- there's, again, similar to what we're talking about with amyloidosis, there's 2 general forms of the disease. Some patients have a mutant protein. So they have a mutation in a gene that creates a protein that does not function properly, and it builds up in the liver and it causes liver damage. And unfortunately, these patients have a pretty poor prognosis and oftentimes move on to liver transplant. That's -- I don't know, that's probably 15%, 20% of the patients, something like that. And then the rest of the population that has this disease doesn't have enough functional protein that's needed in the lungs, and they wind up getting lung complications, pretty significant emphysema-type complications or COPD-type complications. And they're missing a protein that they need. And so we're approaching this disease in 2 ways using our technology. So for the first component where the protein is building up and causing liver damage, we're using the same machinery that we've been using for NTLA 2001 and 2002. But we're changing the guide of our -- of the guide RNA for the CRISPR machinery. So it goes to the protein for this disease and inactivates that gene and that protein. So that's a bit more straightforward because it works a lot like the 201 and 202 program. The other program, it will be our first insertion program. So this is sort of a 2-part technology where we're using our CRISPR machinery to actually now insert a healthy copy of a gene so that this healthy protein can be produced. And there's now 2 components. You have kind of the targeting component, which is similar in LNP and it finds the right gene. And then we have a separate component that we're using a promoter AAV technology to deliver a healthy gene. And you sort of put these 2 things together and you can actually insert this new healthy gene into cells and produce, at least in nonhuman primates, we've seen perfectly normal levels of this deficient protein. So we're really excited about that program. And like I said, that program we'll file -- we expect to file an IND or an IND equivalent in another region before the end of this year, and so that's moving along nicely as well. And I'd say, in concert with that, on the insertion technology, we're also working with our partner, Regeneron, who is leading a program in combination with us to take a similar approach with hemophilia where we'll be inserting the Factor IX gene and then produce that protein using this same technology in patients with hemophilia B. So that program is also progressing and uses a very similar technology.

Okay. Great. Would there be a case for doing both treatments in some alpha-1 patients, who maybe have both manifestations?

Yes. I mean so the idea would be, at some point, we could bring these 2 programs together. And so that's certainly part of the calculations that there are certainly patients who have really both forms of the disease or may have both forms of the disease at different times in their life. And so you could think about patients potentially at some point getting both of these therapies. And so that's absolutely something that we're considering and looking into. And one of the benefits of this LNP system that we're using allows us to do that. And so that's part of the calculus as well.

Okay. Just about 30 seconds left, but I wanted to ask about the earlier pipeline and where you apply your technology next.

Yes. So there's a few areas that we're working on. So we're working -- we didn't talk much at all about the ex vivo side of our platform, but we are working on therapies, where we're taking cells from healthy donors and manipulating them so that they can be used as therapies primarily for cancer indications and in one case with a partner in autoimmune diseases as well. So we're excited by that. That's a bit earlier on, but that's progressing. We're working on technology to move this treatment outside of the liver. So we're working on how do you deliver this CRISPR editing machinery to cells outside the liver. So we're excited by that. And those are probably the next 2 big areas that we'll be working on in addition to all that we spoke about.

Great. Well, with that, we're out of time, but thank you so much, Ian, for joining us. It's a great conversation, and thanks, everyone, out there for listening.

Great. Thanks so much.