Hello, and welcome to day one of the Bank of America Healthcare Conference. I'm Greg Harrison, one of the biotech analysts here at BofA. Today we have Intellia Therapeutics with us. Representing Intellia is Ian Karp, SVP of IR and Corporate Communications. Ian, would you like to start off with some opening remarks, then we'll jump into Q&A? Sure. Thanks so much for having us. Yeah, Intellia, for those that are a bit new to Intellia, we're one of the leading, full spectrum genome editing companies, which really means three things. We're focused in three core areas, which is building out a deep, gene editing capability and a toolbox that we can use for therapeutic purposes, and we then deploy those tools, both on the in vivo and ex vivo side of human therapeutics. On the in vivo side, we're actually delivering the CRISPR machinery to make those edits, typically to address disease-causing proteins or the genes for those proteins in the body. On the ex vivo side, we are using that technology to alter cells that can then be used for cell therapies. It's been an exciting year or few years for us, and I'm sure we'll get into, some of the recent developments. That's essentially, who Intellia is. Great. Yeah, thanks for that. Let's jump into the clinical programs. Maybe start with NTLA-2001, which is an in vivo therapy for ATTR, both cardiomyopathy and polyneuropathy. Could you discuss the overall therapeutic strategy of 2001 and how it could be differentiated from other attempts to treat ATTR? Sure. ATTR amyloidosis has primarily two forms of the disease. There's a form of the disease which primarily manifests within nerve cells and causes polyneuropathy or symptoms associated with that. There's another form of the disease where these deposits of protein occur in the heart and patients primarily manifest with cardiomyopathy and a cardiovascular disease. There are patients that unfortunately have a combination of these symptoms. What NTLA-2001 does, it's a gene editing program that in one of our in vivo programs that specifically targets the gene that makes the TTR protein. What we've seen across now, we've dosed and reported on 27 patients across both polyneuropathy and cardiomyopathy. We've seen very consistent knockdown of the offending protein, of the TTR protein, at the therapeutic doses that we're moving forward with. We're seeing, 90%+ knockdown of this protein. We think this obviously could have significant benefits for both aspects of this disease. That's the premise. We've now shared on a few occasions some of the early data from part 1 of this Phase 1 study. We're really excited by that. Also, we've shown the safety data so far, which has been quite encouraging. The next steps for the program, we have fully enrolled and dosed the patients in part 2 of this study. We haven't reported yet on those results, but that will be forthcoming. We've guided to, sort of in the midpoint of this year to file an IND associated with the cardiomyopathy future pivotal study that we hope to have up and running subject to regulatory feedback by the end of the year. A lot of great progress on this program on both the cardiomyopathy and polyneuropathy side of it. Great. You know, what conclusions can you draw from competitor data, you know, which has shown, you know, knockdown of TTR, you know, at lower levels than you've shown? You know, what does that imply for your expectations when it comes to clinical outcomes for these patients? Well, what we believe and the scientific hypothesis really for this program is that the deeper you can knock down this offending TTR protein, the better for the patient in terms of clinical outcomes. We've seen this with other forms of amyloidosis. We've seen this in some of the data that's already been presented for patients with polyneuropathy for other drugs using other technologies that also knock down TTR, but perhaps to a lesser extent than what we're seeing in our earlier studies. What our hope is that by knocking it down even more, again, 90% and beyond, and consistently for the patients that have received this therapy so far, is that we'll see really conclusive clinical improvements. That will really be the design and the desire for our future studies is how do we demonstrate this? There are other studies using other technologies that are looking at this as well, and there's a host of endpoints you can look at, typically in terms of on the cardiomyopathy side, you can look for, morbidity and mortality, cardiac events, hospitalizations and so forth. There are surrogate endpoints and markers that you can look for, and I think all of this data together is what, you know, the field is looking for to validate and to understand just how effective any of these drugs are. You know, that'll be our goal as well as we move into pivotal studies and, but the hypothesis remains that, you know, the deeper and more consistently you can knock down that protein, the more likely we'll be able to show a clinical benefit. Now you touched on some of the other technologies, you know, approved or in development. Where would you see a one-time, you know, curative intent strategy like NTLA-2001 fitting in a landscape that, you know, has a number of different approaches between small molecules, RNA, and then gene editing? Sure. Yeah. We We ultimately think that if the studies continue to be positive and we continue to build on that a therapy like this could be appropriate for, you know, a wide range of patients. I mean, if you could imagine, there's a couple of components. I mean, certainly, you know, efficacy is on the top of that list. I think if you're a patient with a, you know, debilitating and potentially fatal disease, you know, efficacy is always gonna be, if not the most important, one of the most important attributes that you look for in a therapy. Certainly, we wanna prove to ourselves and to clinicians and to regulators that there's a clinical benefit. I think the one-time treatment is obviously also a very important and attractive attribute. If you can imagine living a life with a chronic, you know, debilitating, potentially fatal disease that requires, you know, either frequent injections, whether that's infusions or subcutaneous injections or oral medications, there's a clear advantage, I mean, both from a patient quality of life as well as potentially, you know, pharmacoeconomic benefits of a one-time treatment. I think that's really part of the premise of what, you know, gene editing has the potential to deliver is that, you know, one day this disease and other diseases could be treated, you know, one time with a lifetime of benefits. That's what we're seeking to prove with our clinical trials. I think if we can show that, there will be lots of different types of patients that would be interested in that kind of therapy. Okay. How does safety play into that? How do you get people comfortable, you know, with having a permanent change made to the genome? Yeah, that goes hand in hand, I think with the efficacy profile. You know, safety and demonstrating safety in clinical studies and then in, you know, real-world experience is of critical importance to these programs. It really starts with the preclinical work, and one of the things that Intellia spends a lot of time and resources on are doing preclinical work to demonstrate that when we're editing a target gene, that that editing machinery is only going to its intended location, to the, to the gene that you want to edit. We spend a lot of time and energy and resources on validating that and testing that, and then showing that data to regulators as well, so that we are as confident as we can be that the CRISPR machinery is going to the place that you want it to go to to impact the disease. We've done that. We've done that with the two programs, obviously, that are in the clinic today. We use that methodology and those tools to demonstrate that for our other programs. We obviously are looking at safety, you know, immediately after the infusion, as well as long as these patients are in our clinical trial. We report on that. So far, the safety profile has been very... The safety, Yeah, the profile of the drug so far has been very encouraging, for all. The FDA generally would like to sort of will require that companies with gene editing and gene therapy products will monitor these patients for 15 years as part of some registry or long-term follow-ups, but that's outside of these clinical trials. I think the longer that time goes on and as we report on this data, the safety profile becomes clearer and clearer that this can be done so far, fairly safely. Sure. Okay. Looking forward to the update from the program later this year, what should we look for as far as, you know, what you'll report, the amount of data, and then, you know, what in your mind constitutes, you know, a positive readout? As I mentioned earlier, There's basically two arms of this study that have been going on, one in patients with polyneuropathy and one in patients with cardiomyopathy. Later this year, we'll present longer term follow-ups. Going back to your question about, you know, safety, we'll see for a longer period of time we've been following these patients, so we'll report any findings we've seen on the safety front. We'll report again the knockdown of this offending protein, the TTR protein. We'll now have many more months that we're following all these patients. We'll have a clearer picture. I mean, our hypothesis and what we've seen so far and all the preclinical work we've done suggests that these edits are permanent and that this knockdown will remain durable. The longer that we've followed these patients, the longer amount of time we can see what these protein levels are. We should begin to get some early clinical data. We are capturing clinical endpoints in these studies. We'll begin to share as that data comes in for full cohorts of patients. We'll begin to be able to report on certainly when data is meaningful and interpretable, what early signs we're seeing from a clinical standpoint. Now, again, these are single-arm studies. There's no comparator arm in the trial. There can be some, I would say, early indicators that we're looking for and looking at to see if, you know, this knockdown of protein is having a clinical impact on patients. Okay. What does later-stage development look like for NTLA-2001? You know, how would it differ between the cardiomyopathy and polyneuropathy, and how do you design a study, you know, to make sure that you have the best chance to show, you know, separation if it's between, you know, placebo or whatever the comparator is? You know, we've seen some others trials in the space that have had difficulties. Do you do an event-driven or longer follow-up to make sure that you're able to capture that delta? Yeah. I mean, those are all the things that are being considered right now. As I mentioned earlier, we expect to file our IND in the mid-part of this year for a pivotal study. I think we're getting close to what we think that design could look like. Obviously, we're interacting with regulatory authorities, both the FDA and the U.S., also outside the U.S., as our preference would be to have a single global study. I think ultimately, you know, we're gonna be looking for, you know, clinical endpoints like cardiac morbidity and mortality, hospitalizations, events as key endpoints as part of this study. There are other secondary endpoints that we would look at, that other companies look at, that may look at more surrogate-type endpoints in terms of imaging studies of the heart or certain biomarkers that you can look at in the blood that would indicate, for example, you know, heart inflammation or heart injury. All of those things will be part of the study. You asked a good question about the length of the trial. And that's part of what is going into the thinking now. Obviously, the greater the therapeutic impact of a drug in a study, typically the shorter amount of time you need to study that, though. But some diseases obviously evolve and take longer time to see benefit. Other diseases take shorter time. All of that is part of the process to design the study. I think there are some pretty good analogs out there that have set some precedent in terms of, you know, whether you're looking at a year or a year and a half. Certainly, it seems that you need to wait typically at least about a year before you'll start to see some of the benefits of lowering or stabilizing this offending protein. Again, the stronger or the greater the impact that any drug is providing, gives you the potential to see that impact sooner. That'll be part of the what goes into the design of the study. Okay. That's helpful. Let's switch gears and talk about NTLA-2002 a little bit, which you have in development for HAE. Could you maybe talk about the unmet need there and the overall therapeutic approach of NTLA-2002 here? Sure. This is a very different disease. 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, in your legs. It can occur in your abdominal area, in your throat. It can be fatal. 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. Most of these are injectable or infused drugs. Some have better efficacy than others. There are certainly treatments that are available. There are some oral treatments available as well. They all have some level of efficacy and some, I'd say, burden of treatment, whether they're frequent injections, or cumbersome injections, or, you know, oral pills, with different side effect profiles. The unmet need certainly is that, you know, patients, despite these available treatments, most patients will still continue to have some attacks. Again, what's often most challenging for patients is that the predictability of these attacks, is that they don't know when they're gonna occur, and they can occur at sometimes the worst, you know, times. Then there's the burden of that treatment. You know, how difficult is it to get infusions or injections or to do this frequently. Then maybe the third piece of this is just the pharmacoeconomic component. You know, how expensive is it to treat a disease like this? Most patients with this disease will begin to get symptoms in their adolescence, and be, you know, once you're diagnosed and treated, will be treated, you know, for life. From adolescence through the rest of their life. There's a fair amount of unsatisfied patients, and we think that with a one-time gene editing treatment, 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, NTLA-2002. All 10 patients have gone to an attack-free state, we're continuing to monitor that. We'll report more data later this year with additional follow-up. We're really encouraged by that. We think if this kind of data continues, that, you know, we could potentially have a really long-term, maybe even functional cure for these patients following a one-time treatment instead of chronic therapy for the rest of their lives. Okay. Yeah, that was gonna be my next question is, you know, 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 NTLA-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 for all these patients, plus 4 additional patients who have been treated since that data was released. I'm sorry. We presented data on the first 6 patients for attack rates, and we'll be adding 4 more, so there'll be a total of 10. It'll be a longer period of time. I'd say scientifically, we don't see a reason why patients would resume getting attacks. Mm-hmm. if their kallikrein levels have been knocked down sufficiently. Time and data will tell. Our expectation, or at least our hope is that we'll continue to see, you know, robust, either complete or near complete reductions in these attacks. We'll see, and we'll report more data later this year, and we'll see how things are going. Okay, great. kind of a similar question as with NTLA-2001, but, you know, what does a pivotal study look like in this indication? Yeah. 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. You know, the design of those studies is fairly similar across these drugs. Typically, you know, the primary endpoint tends to be a reduction in HAE attacks. You have some baseline level of attacks that these patients are having per month. You're given a therapeutic intervention, and you're measuring, you know, how many attacks are these patients still getting. There are other endpoints you could look at. If they're still getting attacks, are they more severe, less severe than the attacks they were getting? Maybe where are they getting them? There's other things you can measure, but the primary endpoint tends to be, you know, at around six months, what does the attack rate look like after six months? Again, we haven't given the full design of- Mm-hmm. -of our expected phase three, but I would imagine that it would be not too far off from the types of studies that we've seen. I think the obvious advantage of this program is it's a one-time treatment. 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. That obviously is different from if you're getting injections every couple weeks or every month or you're taking a pill every day. You know, there's obviously a big difference there. This next one, I know it's a difficult one to forecast. We're about to see some real-world kinda evidence as far as what happens when a gene editing therapy gets on the market with CRISPR. You know, what does it take in your mind if, you know, you are able to show, you know, 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? Yeah, I mean, it's a great question. I think obviously it starts with the safety and efficacy data. I think it also. You know, there's a time component. I mean, when we go out, and we talk to physicians, we talk to patients, and, you know, there tends to be kind of three segments, and this is not dissimilar from other innovative new technologies or even, you know, groundbreaking technologies. There's, you know, there's the rapid adopters, those that say, you know, "This sounds amazing. I want this right now." There are those that say, you know, "This sounds great. Tell me more," or, "Maybe I wanna see a little more data. Maybe I want to see a couple years worth of data or of, you know, some more patients. Then you have, you know, the third group that says, you know, "It's gonna take more time and data to convince me." I'd expect that that's you know, what we'll see. I think that, you know, part of our job will be to educate, you know, the medical community and also the patient community about gene editing and what the potential advantages are and what the considerations are. You're right that the first, I guess, CRISPR-based therapy is now, you know, our colleagues at another company have filed that with the FDA. We'll wait to see what happens there, but we're optimistic for them, and we're rooting for them. Now, remember that therapy is an ex vivo therapy. Mm-hmm. 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. We're working in some diseases in that area as well. 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, you know, some significant benefits. We have a lot of work to do to, I think, educate the world about gene editing, and, you know, 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, who we're talking about, you know, have taken these ideas to either clinical programs and potentially approved programs, has happened really rapidly relative to drug development terms. The next piece is gonna be how do you educate, you know, the consumer, the world, you know, patients. That's, you know, that's what gets us really excited. Mm-hmm. Because we think there's a lot of benefits to this type of platform for healthcare in general. Definitely. Definitely. Wanted to move on to, you have two programs for alpha-1 antitrypsin deficiency, 3001 and 2003. What's the status of each of those? One is, you know, focused on the liver manifestations of the disease, the other on lung. Where are those at, and, you know, how are you thinking about that overall strategy of having two different approaches for? Sure. manifestations of the disease? Yeah. That's sort of the next Those are the next two 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. You know, we expect to file an IND or an IND equivalent by the end of this year. That's really there's two approaches there. Alpha-1 Antitrypsin Deficiency is a disease where, again, similar to what we're talking about with amyloidosis, there's two 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. Unfortunately, these patients have pretty poor prognosis and oftentimes, you know, move on to liver transplant. I don't know. That's probably 15%, 20% of the patients, something like that. 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. They're missing a protein that they need. We're approaching this disease in two ways using our technology. 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 the guide RNA for the CRISPR machinery. It goes to it, the protein for this disease and inactivates that gene and that protein. That's a bit more straightforward because it works a lot like the 2001 and 2002 program. The other program, it will be our first insertion program. 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. There's now 2 components. You have kind of the targeting component, which is similar in an LNP, and it finds the right gene. Then we have a separate component that we're using a promoterless AAV technology to deliver a healthy gene. You sort of put these two things together, and you can actually insert this new healthy gene into cells and produce, at least in non-human primates, we've seen perfectly normal levels of this deficient protein. We're really excited by that program. Like I said, that program will file or we expect to file an IND or IND equivalent in another region before the end of this year, that's moving along nicely as well. I'd say in concert with that, on the insertion technology, we're also working with our partner, Regeneron, who's leading a program in combination with us to take a similar approach with hemophilia, where we'll be inserting the Factor 9 gene, and then produce that protein using this same technology in patients with hemophilia B. 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? Yeah, I mean, so the idea would be at some point, we could bring these two programs together. 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. You could think about patients potentially at some point getting both of these therapies. That's absolutely something that we're considering and looking into. One of the benefits of this LNP system that we're using, allows us to do that. That's part of the calculus as well. Okay. just about 30 seconds left, but wanted to ask about the earlier pipeline and where you apply your technology next. There's a few areas that we're working on. We didn't talk much or at all about the ex vivo side of our platform, we are working on therapies where we're taking cells from healthy donors and manipulating them so they can be used as therapies, primarily for cancer indications and in one case with a partner in autoimmune diseases as well. We're excited by that. That's a bit earlier on, that's progressing. We're working on technology to move this treatment outside of the liver, we're working on how do you deliver this CRISPR editing machinery to cells outside the liver. We're excited by that. Those are probably the next two 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. Thank you so much, Ian, for joining us. It's a great conversation. Thanks everyone out there for listening. Great. Thanks so much.