All right. Well, thanks everyone for joining us. I'm Terence Flynn, Morgan Stanley's U.S. Biopharma Analyst. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. I'm very pleased to be hosting Intellia today. Joining us from the company, we have John Leonard, the company's CEO, and Ed Dulac, who's the company's CFO. Thank you both for being here, really appreciate it. Looking forward to speaking with you. I thought we'd start maybe just high level, John, to talk about in vivo editing and just the potential for the platform. I think again, the technology's been in development for a long time now.
We're starting to see really impressive use cases here. As you think about the potential, maybe just talk to us about high level, where you think this can go over time, and then some of the outstanding hurdles to really effectively scale it, and then we'll get into your more specific pipeline for sure.
Sure, and thanks for the question, and happy to be here. We've pioneered the in vivo gene editing space. In the early days, as CRISPR was coming to be, I think a lot of people went off into ex vivo and started off in that space. We bit the bullet and went directly to the in vivo editing space, where that's where most of the actual targets reside in the body. The challenge there is solving for delivery, right? We benefited from people who'd gone before us in terms of delivering RNA, and set off with a Lipid Nanoparticle platform that we developed. We showed that you can open up the liver, which is, here we are, end of phase III for the BLA for our first indication, HAE, and then well into a phase III trial for TTR cardiomyopathy and polyneuropathy.
I think what the opportunities, still there are several that reside in the liver, but developing targeted LNPs to get outside of the liver to certain spaces, and then finding other therapeutic delivery modalities that take you into the brain and the lung, that lies ahead. I think as those insights come, there'll be many, many very valuable targets to pursue. At this point, we're really most interested in getting the first ones across the finish line and showing that we can successfully commercialize a CRISPR-based therapy.
Yep. Okay, great. Maybe just moving on to your late-stage pipeline here, lonvo-z, the BLA filing for HAE. Maybe just what are the gating steps here on the filing and then just overall confidence in approval?
Well, we heard from the FDA just a week ago that they've accepted the BLA, which is wonderful news. We had benefited along the way from our RMAT designation and other work that we had done with pilot programs and CMC. As you know, many of the RMAT-designated programs then benefit from a priority review, which we know that we'll have. We ultimately got a PDUFA date now of March 10th. One of the things we were obviously wondering about, given that we're the first example, was whether or not there'd be a need for an advisory committee, but the FDA has said that that's not something that they're currently planning on doing. We'd, at this point, I think, be surprised if that were to come. So from a confidence level, we think we've got a very, very strong package. The data are there for anyone to see.
The compound has just excellent efficacy and a very, very clean safety profile. So we look forward to the questions, and that's what lies between now and March 10th.
Yep. How do you think about the scope of the label, like age monitoring? Any tidbits yet at this point? Again, I think there's obviously some more to do here, but just what is our baseline?
Yeah. We tried to develop the program as essentially an all-comers program minus the pediatric patient population below age 16. There were no restrictions based on prior therapy, type of therapy, degree of disease, that kind of thing. In fact, the patient population that ultimately came into the phase III program largely represents what is the market in the United States, 70% LTP, 30% on-demand therapy, patients with varying degrees of control, and importantly, 20% of the patients in that phase III trial with complete control. We think that the product has broad appeal, and we would expect that the label will reflect that.
Okay. Maybe talk to us about just kind of some of the market access work you guys have done as you prepare for the launch. Any early insights from some of the payer conversations, and then just remind us as you kind of scale your commercial footprint, what is that going to look like?
I am going to turn to Ed to speak to the market piece. Yep.
Yeah, I will talk to that. Maybe we will start with the clinical data, since that is the basis of a lot of these conversations. We have all been trained to talk about attack rate reduction. We had 87%. That is sort of table stakes for today's LTP market, as we like to refer to it. But as importantly is the data that we have in terms of how many patients have an attack-free state at the 28-week primary observation period. In our case, that also is accompanied by no therapy, by definition. So we had 62% attack-free status. In both cases, that is as good or better than anything that has been reported. I would like to extend that, though, because I think there are two other bits of information as we think about the opportunity ahead that we are really excited about.
If you take a big step back and you look at all patients we've treated, phase I, phase II, phase III, that's in excess of 100 patients. All patients eventually get to an LTP-free state. I'll just say it again, every single patient has gotten to LTP free, and none have gone back to LTP. As you think about healthcare resource utilization, that's an important consideration. It is already a very expensive disease to treat. The reason being is, for the most part, that LTP therapy, which can be in excess of $700,000 annually. When we show up to a payer conversation, it's very interesting because their question is, "Well, what is the right multiple to think about?" Right? We will test things like 2, 3, 4, 5 times multiple. Not surprisingly, when you get to the upper end, you're going to face a lot of resistance.
Yeah.
We haven't decided a price. We're obviously not going to communicate any price today, but somewhere within that range is precedent for a one-time therapy that is highly effective. That's the other important part here, the durability of clinical benefit, where now have already shown 3+ years of data, those patients continue to mature. We're at 4+ years in the earliest phase I/II patients, and we're going to continue to follow the phase III patient population. We think in a relatively small market that relies on patient switches, we have an extremely differentiated profile. The one thing I would say is that this is somewhat of a unique market in that we all talk to physicians. Their perception is, my patients are pretty adequately served. There are lots of treatment options, and there are. The patient voice is the one to really focus on.
They are actually uniquely educated. There's an advocacy group that they all participate in. They know what studies have been run, they know the clinical data, and they're very much a part of that conversation. It's usually more joint decision making. When you talk to the patient's perspective, they see a high degree of unmet need. In fact, go to our phase III patient population and 70% were LTP users, 30% were on-demand, which we think is really important, so it's more of an all-comer patient population opportunity. 20% of the patients, though, Terence, had complete control of their disease. Think about that for a second. They are adequately controlled on their existing therapy, are willing to wash off that therapy, establish a baseline number of attacks, and run the risk of getting a placebo in the hopes that they can get a definitive treatment option.
We're really encouraged by the setup, and we've been working with payers for quite some time, doing it all again, in essence, now that we have the phase III data. We've had very constructive conversations.
Okay, that's great. Maybe just remind us of kind of the mix, like how much commercial, Medicare, Medicaid, what to expect here, and then again, sizing of the commercial footprint. Again, seems like this will likely be a very small targeted sales force.
It's the perfect starter indication for us doing this for the first time. To answer your first question, about 70% of all covered lives are commercially insured, about 20% Medicare and 10% Medicaid. That's pretty important as you think about covered lives and what the curve looks like post-approval. You can typically get to 60%+ in the first six months, and then continue to advance it from there. We've got a lot of folks in the field already. The medical team has been out there for quite some time educating on the unmet need, educating on CRISPR, of course. Now that we have our phase III data for lonvo-z, talking about that. We also have liaisons focused on authorized treatment centers. Do they have the right capabilities? Making sure that they're prepared. We've been looking at, obviously, the market access continuum, thinking about distribution.
How do different institutions prefer to get the product? Do they want to buy and build? Do they want a specialty pharmacy option? We're doing a ton of work. A lot of this stuff will have to come post-approval, which we can talk about. You're right, the footprint is relatively concentrated. 250 prescribers, the top 250 in the U.S. cover about half of all U.S. patients, so we can be very targeted, and we think that's a good place for us to start. There will be a referral component to this for folks in the community or institutions that are not willing to take it on directly, and we have more plans for that underway.
Okay. Have you started to build out I know you probably have your leadership in place, some of the MSLs, but have you started hiring yet for the regular field force, or is that kind of more early next year?
We have.
Okay.
We have not. We wanted to make sure we used the lead time we have. If you look at 2025, last year was really the foundational leadership, really experienced people that have both HAE and one-time therapy experience. This year in 2026 has been more the field build-out. Beyond medical, some of these liaisons to do the ATC assessments, for example, have been in place. We have also actually hired the field reps that will be promotional in the market post-approval, assuming that comes around that March 10th timeline. There is training required, but we are in a really good position, and should the agency surprise us to the upside with even earlier approval, we would be prepared to do that. Same to be said for manufacturing. We are in a really good spot there as well.
Okay. Okay, great. I guess as we think about the early launch analogs, should we look at the Ionis product as kind of the most relevant one just because it is a more recent launch? Again, I know it is a different technology platform, but is that the way we should think about kind of early ramp of patient numbers, or what is the right analog to think about here for the early part of the launch?
Be disingenuous if I said we are so unique and different, then say there is a natural analog for that. I do think it is an opportunity, though, to realize where we are different. In this case, I think it is important to know when you have a highly effective one-time therapy, we have no ability to take those patients on clinical supply-
Right. Yep.
...to commercial, right?
Yeah.
We don't have that same playbook. If you have a small molecule or-
Right
self at home injectable, that's a different paradigm.
Yeah.
We do not have that, right?
Yeah.
What you are hearing us saying is making sure we are going to great lengths to make sure we understand all the stakeholder needs, be in a really good position so it is at if and when we receive approval, we can quickly operationalize it. What that means, though, is we are not going to have that overnight flip to revenue.
Right.
You are going to have to start judging us early on things like ATC and our penetration there. Probably things like patient start forms. We are still working our way through all that.
Right.
The revenue will ultimately be captured downstream, but it is going to take a little bit of time out of the gate for that to mature. I would be looking for a couple quarters of revenue so you can get a better sense of what the real projections would look like for us in HAE.
Yeah. Okay. Makes sense. Any other considerations for the launch that we should keep in mind here as we look forward to March?
I think the way I look at it, and John can chime in, it is a small market, it's a switch market, and we look like we have a very different profile in that, to go back to some of my earlier comments that I don't want to repeat. We think this is going to be very transformational for the treatment of HAE. I don't think every patient shows up on day one. I also don't think there's a huge delay, and we see reasonably that there's a nice curve associated with it. As a company, though, doing this could be profoundly impactful for capital needs and our ability to reinvest in the business. I'm sure we'll talk about TTR next, but we also have active research.
We look at, even if we had a mediocre launch, quite frankly, we own the possibility of covering the operating cost of the company. As we think about how well we're funded today, what the future capital needs, the real question we ask ourselves and what investors need to come to terms with is what is the lonvo-z opportunity? It's going to be a premium priced product in an already premium priced market with very attractive margins, which gives us the possibility of really bending the curve in terms of the capital needs. There's many things going on, including for us as a company, and that would allow us then to allocate capital to the TTR program, but also the early research priorities that we've outlined.
Okay, great. Maybe we'll pivot to nex-z for TTR. A lot of focus, obviously, on the ongoing MAGNITUDE phase III program here. Maybe just any more details on timing, interims, how are events tracking? Help us think about when we'll be able to see data here from this trial.
Well, I'd start with the data that's come out recently and how we think about that with respect to ESC, eplontersen.
Okay
Even going back to vutrisiran, some of the things that we've learned about that, because that guides.
Yeah, absolutely.
In terms of how we think about endpoints and accrual, et cetera.
Okay.
I make the point that based on what we've seen, we think we're in a really good position. What we've learned from the recent disclosures is the relationship between degree of knockdown and stage of disease, and how that patient mix affects the ability to see an effect in an all-comers patient population, especially with the widespread use of stabilizers now. As we look at the study as it's currently designed, we think we've got the right set of endpoints. We've got the right patient mix. We will encourage investigators to think very carefully about the patients that they bring in, recognizing that there's more and more information that suggests that patients who are earlier in their stages of disease will benefit from therapy. We want to make sure that the physicians understand that.
We may tweak at the margins here somewhat as we go and look at all the numbers, et cetera. But generally speaking, as we look at coming back on after the clinical hold that we had, we feel really good about the ability to fully enroll the study and again, with the right set of patients. The more challenging point is that it's an endpoint-driven study. It really comes down to that patient mix and getting the right number of endpoints that will set the ultimate timeframe for this. I will say that as we've looked at the accumulating endpoints, because this has been going on for some time now, and even during the hold, we continued to accrue them. We're largely in line with the assumptions that we made at the beginning. That was gratifying, especially as we've gotten access to this additional data.
Again, I would just make the point that I think we're in a really good position, and because a few hundred patients remain to accrue, we can still benefit additionally from the insights.
Okay. Are you able to share anything about those tweaks at the margins that you might make any-
I think it really
change outcomes?
Yeah. It is a study that looks at standard of care. Increasingly, stabilizers are that-
Yeah
...around the world. This is a study that is superimposed on top of that. So the proportion of patients that are on stabilizers, some people are probably not going to affect that much. But stage of disease, the degree of advancement and the progression of disease as measured by NT-proBNP is something that we can think about doing. There may be things that we do to ultimately cap the distribution in different subsets of NT-proBNP. That remains to be seen. We are working through those numbers now.
Okay. When do you expect to have that finalized?
Soon. Timeliness is really important to influence patients coming in. The other point I would make is that we've learned a lot about the endpoints themselves and those that are more discerning for the benefit than others, and that's something that we take into consideration on how to measure, which can, I think, increase the power of the study.
Yep. Anything you can share in terms of that powering at this point?
Well, we've powered the study with a high degree of power, we think, to have success in, again for all comers, which is the primary endpoint or objective of the study. When you think about the proportion of patients that are on stabilizers coming in, it's almost effectively an on top of tafamidis study, if you want to think about it in those terms. But yeah, we think we have the right statistics.
Okay. Great. How should we think about potential companion diagnostics, just given the HLA data? Is that something that is on the table?
Yeah, just for the audience, we learned after we went back on track after the clinical hold with additional analyses that there is an association between the liver findings that we had in an HLA allele that is strongly statistically significant. That is important information. We have made that available to physicians and patients, and we are putting in place the ability to actually know an HLA type as patients come in. My anticipation at this time is that probably will wind up from a commercial point of view. Although, we are not there yet, and that is obviously conversations that will take place when we get to labeling and that sort of thing. We are using a CLIA-approved laboratory, and the ability to go directly to a commercial sort of setting is something that I think we will be in a really good position to do.
Okay. Do you think that would have to be for pretty much everyone done across the board, and it is pretty straightforward to do that test?
It is very straightforward.
Okay.
It is something that, now in the study, is part of the screening procedures. Again, it is not to screen patients out.
Right.
It is to have an informed discussion that patients choose to self-exclude or based on their own priorities-
Yes
participate as a study. My expectation is it will look like that later on as well.
Just remind us what percentage of people would have that HLA subtype that would be impacted.
It really depends on ethnicity. If you look back in this trial population, it's about 12% of patients that have the allele. That's reflective of a European sort of Caucasian makeup, which is the predominant patient type in the patient population. As you move increasingly into an Asian ethnicity or into African Americans, the prevalence really falls to as low as 1%-2% in African Americans. It really depends on the patient type.
Okay. Understood. I guess as you think about the competitive landscape, again, a similar question to the HAE discussion we're having is just where do you envision this fitting in the paradigm? Again, I'd say not as crowded as HAE. Again, it is not the prophylaxis versus on-demand dynamic different here.
Right.
You have cardio versus PN, but again, where do you envision this fitting in that new paradigm?
Well, we know that ATTR amyloidosis, whether it's polyneuropathy or cardiomyopathy, is a progressive disease. We know that at least of the currently approved agents, the patient populations progress on those agents. I don't think experts in the field, certainly the ones that we talk to who know all the drugs and participate in all the trials and write all the papers, basically, that any of them believes that we're at the endpoint here with the pharmacopeia as it exists in approved therapies today. What we learned from our study and the Alnylam study, which I think has many similarities, is really, I think, going to set the stage for how these drugs are used. Cardiologists don't want to have a succession of drugs where you're chasing failures because as you fail, it becomes increasingly difficult to get the benefit.
The cardiologists that we work with want to stop the disease in its tracks, and it is best to do that with the most effective therapy as early as possible. I think that that is the patient population that we are trying to make sure we have plenty of examples of to show that, in fact, that it will work that way.
Yeah. As we think about the pricing dynamic, is it the same framework that we should think about here? Multiples of existing therapies given your same idea, your one and done here? Or is there a different framework here for some-
It is certainly a consideration.
Yeah.
I think the current science-- Well, it is a very extremely highly priced market right now, at least from a cardiology point of view. We think that this patient population, which is elderly and very much a Medicare patient population in the United States and outside the United States, these are mainly central payer type populations, that plays to our strong suit from a pharmacoeconomic point of view. So presuming an efficacy that is not surpassed by other agents, and I think that that is the likely outcome here, we think we are going to have a very competitive economic offering that will be very attractive to that group of payers that service those patients.
Yep. What does the commercial footprint look like here relative to HAE?
We haven't scoped it out-
Yeah
...to the same extent as you might imagine that we've done with HAE. There's more cardiologists, for sure, than physicians who treat HAE. So it's a bigger footprint, and here's where we have other options, and we certainly have our colleagues at Regeneron who are part of the mix here. As we get a little further into that, I'm sure we'll be talking more about it, but it'll be a bigger undertaking for sure.
Okay.
I'll just add in between HAE and ATTR-CM is this ATTR- PN indication that-
Right
...gets lost in the mix. It's a little bit smaller, but it should unfold that ATTR-PN will be first.
Right.
We will have the benefit of learning things from HAE in a population that's older but not quite as significantly older as the ATTR-CM population. I think there's some synergies there on the near term. But ultimately, there's a bigger build-out. Again, we have that collaboration with Regeneron that could help as well.
Okay. Just remind us how the split works there in terms of the economics, and are there any opt-ins, or that decision was already made?
Yeah. From the onset, it's been 75%/25% sort of in our favor. In terms of just decision-making, it's Intellia's ultimate decision, and we support 75% of the economics. That will hold true. From commercialization, there'll be essentially a 75%/25% profit split. There is an opt-in decision. It's sort of non-consequential from an economic perspective. We don't get an opt-in payment, for example. But they do have a right to co-promote in a minority fashion in the U.S. for the TTR asset.
Okay.
The way to simply think about that is if for every 100 reps, they will have some proportion that is actually Regeneron employees instead of Intellia employees.
Okay.
Net- net, it is still the same cost, it is still the same split.
Yeah
That comes roughly about 2 years before anticipated approval. That is on the horizon, but again, not all that consequential from the overall collaboration perspective.
Okay. They have to make that 2 years before approval.
Roughly, yes.
Okay, got it. I guess you mentioned this, Ed, before, just as you think about the HAE launch and what that means from a capital perspective for the company and having maybe more flexibility to invest in the broader pipeline. Maybe just talk through what that would look like, and do you guys already have opportunities that you are thinking about rolling out, or is that going to be staged? How do you think about capital deployment in the event that you do have a successful HAE launch?
Yeah. We have a pretty clear five-year plan. The good thing about running these studies in the case of ATTR-CM, which really drives a lot of our operating expense, is you have good visibility over the next few years. So we have been planning on that for quite some time. If we take a step back into the second quarter, we had about $630 million in cash, and we have been very conservative with our guidance, where if we just exclude lonvo-z revenue altogether, we still have cash to run the company into 2028. That is intentional, right? We want to make sure we not just get approval, but the key question investors have is, are you going to sell it? Can a one-time therapy be successful? We think the answer is yes. We need time for that to play out for the reasons we talked about.
Just last week as well, we announced now a debt facility with OrbiMed, which gives us $300 million in committed capital. We took down the initial $75 million of that, and we have given disclosures, but in a nutshell, we get another $75 million available to us at lonvo-z approval. There are three distinct $40 million payments that we can get linked to sales performance of lonvo-z, but that gives us even more optionality and flexibility. We have also preserved the opportunity to do converts or synthetic royalties, so we want to make sure we have a lot of options just given everything that is going on at the company. But the thing that is most fun for us to think about, which really transforms if we need capital, how much and when, will be the performance of lonvo-z. So we have given ourselves enough runway to see that through.
But in many ways, there's been a lot of stuff that's happened in the TTR landscape, as we just talked about in particular. The goal was always do really well with lonvo-z, but that gives us capital to then redeploy against much larger opportunities, particularly in ATTR-CM. And so despite some of the noise and the challenges and opportunities that come with the recent datasets, there's now a really big and growing market and probably one less competitor. Just think about the possibilities there. That's what we're really playing for. The other part we'll eventually talk about, not today, will be the pipeline. We do have active research going on. It is a competitive world out there. Given everything else the company has, we're not going to get credit, so we don't talk about that. But we do have very active, viable programs that we will in due course.
We thought about all that on a 5+ year view. We feel really good about where we are, but we really want to execute and deliver on the lonvo-z opportunity for good reason.
Okay. Well, thank you so much, both, for being here. Really appreciate it, and best of luck.
Thank you. Appreciate it.