Hello, and welcome to Intellia Therapeutics Third Quarter 2025 Financial Results Conference Call. My name is Rocco, and I will be your conference operator today. Please be advised that today's conference is being recorded. I will now turn the conference over to Jason Fredette, Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed, sir.

Thank you, Rocco, and hello, everyone. Earlier this afternoon, we issued a press release and filed our 10-Q outlining our recent business updates and our third quarter financial results. These documents can be found on the Investors and Media section of Intellia's website at intelliatx.com. At this time, I would like to take a moment to remind listeners that during this call, Intellia management may make certain forward-looking statements. We ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Joining me on the call are John Leonard, our Chief Executive Officer; and Ed Dulac, our Chief Financial Officer. With that, I'll turn the call over to John.

Thanks, Jason, and thanks to all of you who have tuned in for today's call. In terms of the agenda for today, we'll begin with the status of our nex-z program in ATTR amyloidosis since that is obviously top of mind for all of you. We then will provide an update on the significant progress we have made with lonvo-z, which is being developed as a potential onetime treatment for patients with hereditary angioedema or HAE, and we will close with Ed's financial review. First, for nex-z. Since the start of 2024, we've been enrolling patients in MAGNITUDE, our Phase III clinical trial for ATTR amyloidosis with cardiomyopathy. And we've been enrolling MAGNITUDE-2 for patients with hereditary ATTR amyloidosis with polyneuropathy since the start of 2025. Both trials have advanced rapidly, which we believe demonstrates patients' interest in a potential onetime treatment option. On October 24, a patient was admitted to the hospital after reporting abdominal pain to his principal investigator. This is a patient with ATTR cardiomyopathy in his early '80s who enrolled in MAGNITUDE and received a dose of nex-z on September 30. The patient's labs showed that his AST and ALT levels exceeded 3 times the upper limit of normal and that his bilirubin exceeded 2 times the upper limit of normal. These levels triggered a protocol-specified pause on patient dosing and screening for MAGNITUDE in the interest of patient safety. We decided to also pause patient dosing and screening in MAGNITUDE-2 as a precaution. On October 29, the FDA notified us verbally that it had placed a clinical hold on MAGNITUDE and MAGNITUDE-2. We are now awaiting the FDA's formal clinical hold letter. We were very saddened to learn that the patient passed away last night. We have been advised by the treating physician that this is a case with complicating comorbidities, and the case is being further evaluated. Since learning of this case, we've taken a number of actions in the interest of patient safety. For instance, we've mandated that clinical sites collect additional labs from patients in the initial weeks following dosing to detect potential liver elevation sooner. An internal team has been closely reviewing the blinded safety data, baseline characteristics, among other factors, to identify potential contributors to the liver-related events seen in MAGNITUDE. We've been working with the trial's independent data safety monitoring committees as we consider other potential monitoring and risk mitigation strategies. And of course, we are engaging with global regulatory authorities and other stakeholders to understand their perspectives, concerns and requirements so we can develop a plan that would allow us to resume enrollment as soon as appropriate. Not surprisingly, given the clinical hold, we are unable to maintain our milestone guidance for nex-z, and we expect to provide an update once we finalize the plan with regulators. Simply put, a lot has transpired over the past couple of weeks and in recent hours, and there is still much work ahead. There's a lot of focus on the safety profile of nex-z at this stage as there should be. That said, we continue to believe in this product candidate's potential to address important unmet needs for patients with ATTR amyloidosis. This is based on a few key factors. First, ATTR amyloidosis is a disease with high mortality. While undeniable progress has been made in this treatment, current therapies only slow its advance, and most patients continue to face progressive morbidity and mortality. Second, we've enrolled more than 650 patients in MAGNITUDE and 47 patients in MAGNITUDE-2. To date, Grade 4 liver transaminase elevations have been reported in less than 1% of all patients enrolled in MAGNITUDE. Each of these cases has been observed approximately 3 to 5 weeks following randomization and dosing. There have been no Grade 4 liver transaminase elevations in MAGNITUDE-2. And third, we are highly encouraged by the data from our ongoing Phase I clinical trial of nex-z. On Monday, in a late-breaker oral session at the 2025 AHA Scientific Sessions in New Orleans, we will have the opportunity to share longer-term data for nex-z that we believe demonstrates its potential to improve various disease measures and mortality. Let's move on to lonvo-z, which is being investigated in our ongoing HAELO Phase III clinical trial for HAE. Over the course of 2025, we've made considerable progress in this trial. Enrollment was completed in September, less than 9 months after we dosed our first patient. This puts us on track to share top line data by mid-2026, submit a BLA to the FDA in the second half of 2026, and prepare for an anticipated commercial launch in the U.S. in the first half of 2027. We believe lonvo-z could completely redefine the HAE treatment landscape. We aim to reset expectations and the standard of care for patients living with this debilitating disease by completely eliminating attacks and the need for other HAE medications for a majority of patients, all with one dose. This Saturday, at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting in Orlando, we will be presenting longer-term safety and efficacy data from all of the patients who received a 50-milligram dose of lonvo-z in our Phase I/II clinical trial. I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results for the third quarter 2025.

Thank you, John, and good evening, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our clinical pipeline and build important capabilities required for future success. Our cash, cash equivalents and marketable securities were $669.9 million as of September 30, 2025, compared to $861.7 million as of December 31, 2024. During the third quarter, we raised approximately $115 million from our ATM facility. When combined with the benefits of the restructuring initiatives we implemented in early 2025, this enables us to extend our cash runway into mid-2027 and through lonvo-z's anticipated commercial launch in the U.S. for HAE. Collaboration revenue was $13.8 million during the third quarter of 2025 compared to $9.1 million during the prior year quarter. The $4.7 million increase was mainly driven by cost reimbursements related to our collaboration with Regeneron Pharmaceuticals. R&D expenses were $94.7 million during the third quarter of 2025 compared to $123.4 million during the prior year quarter. The $28.7 million decrease was primarily driven by employee-related expenses, stock-based compensation, research materials and contracted services, offset by an increase in the advancement of our lead programs. Stock-based compensation expense included within R&D was $12.2 million for the third quarter of 2025. G&A expenses were $30.5 million during the third quarter of 2025 compared to $30.5 million during the prior year quarter. Stock-based compensation expense included within G&A was $7.4 million for the third quarter of 2025. Finally, net loss for the third quarter of 2025 was $101.3 million, down from $135.7 million for the prior year quarter. We continue to expect a year-over-year decline in GAAP operating expenses of at least 10%. And as stated before, our cash runway is expected to fund operations into the middle of 2027. With that, we are ready to begin our question-and-answer session. Before we do, we would like to let you know in advance that we will be unable to answer some of your questions given a variety of factors, including the fact that we are still awaiting the FDA's clinical hold letter and a more thorough evaluation of the patient's case. We appreciate your patience and understanding. Operator, would you please open the line for questions?

Today's first question comes from Gena Wang with Barclays.

I'm really sorry to hear the unfortunate event. I know you are still collecting a lot of data, but just wondering if any initial hypothesis of the reason for liver enzyme elevation since this is one month after dosing. Is that because of lipid nanoparticle Cas9 or age-related or disease? Any initial thoughts that would be fantastic. And the related question is, you shared the color on Grade 4, less than 1% in ATTR cardiomyopathy. How is that rate for ATTR polyneuropathy and the HAE patient population?

So Gena, thank you for the question. At this point in time, we can only speculate, which we're not going to do in terms of what's the source of the liver function test abnormalities. As you pointed out in your question, we've seen across the entire study with over 650 patients enrolled an incidence of less than 1%. This particular case is distinct from what we've seen. It was a very complicated clinical course with other comorbidities that may have had some influence in the outcome of the patient. Of the other cases that have occurred, all of those cases have either resolved or are resolving, and no one is in the hospital.

And our next question today comes from Maury Raycroft with Jefferies.

Maybe one more on the patient. I know you can't say much, but you mentioned the other comorbidities. Can you say what those were and also potentially whether the patient was managed in the United States or ex U.S.? And then, yes, I guess, if you can't answer those, if you could talk about just potential risk mitigation strategies that you could implement going forward.

Yes. At this point, Maury, we can't go into the comorbidities. I can only say that the patient had a very complicated medical course, and these other comorbidities may have influenced the ultimate outcome along with the hepatic abnormalities. We're not commenting on geography. I can only assure you that the patient received what we believe to be excellent medical care, and we have no reason to believe that there was any shortfall in taking care of the patient. With respect to risk mitigation strategies, that's ongoing work. As you might imagine, we're doing as comprehensive analysis as we're able to do, looking at all of the data we've collected, coming up with any potential hypothesis. The ultimate goal would be to find a way to exclude patients who may be at risk should we identify it or impose interventions that could deal with the liver function test abnormalities if they do occur.

And our next question today comes from Alec Stranahan with Bank of America.

I guess, how many ATTR patients are currently within that 3- to 5-week post-dose window on the study right now?

I can't provide specific numbers, but most patients have completed the process. Each day, there are fewer patients who still need to go through it.

And our next question today comes from Mani Foroohar with Leerink Partners.

My condolences, a tough outcome for the patient for sure. So let me dive in a little bit on a hypothetical that I've received from a number of clients, which is if this hold were to remain for an extended period of time, what does that mean for the ongoing OpEx spend of the company? i.e., I know it extends the duration to whenever we get a potential pivotal outcome for the study. But does it change the total amount of spend over the course of the study? Is your spend at a normal level during this hold or at least some activities interrupted? How should we think from a financial modeling perspective, recognizing that, that, of course, is a secondary concern to the moral obligations for the patient?

Thanks for the question. It was a little garbled, Mani, but I think you were asking how does the hold play into the financial runway of the company and how do we manage through it. I think there's going to be a two-part answer. Ed can speak to the runway and how we currently view it. As you can imagine, our priority is going through the data and coming up with the best possible path forward. And that is job one at this point, and it's something that we're working very, very hard to do. The goal is to be up and running as soon as appropriate so that we can regain what was a very substantial momentum, as we said. We had enrolled over 650 patients, and that's I think just a really stellar record. But maybe, Ed, you can say a few words about the runway and how we're thinking about this may impact that.

Of course. Thanks, John. Yes, I would say it's too early to provide precise guidance. However, based on what we know today, the timelines and plans for lonvo-z remain unchanged. We are continuing to move forward with the study as planned. Although we are currently on clinical hold and unable to enroll or screen new patients, we have over 650 patients in MAGNITUDE, and 47 patients on MAGNITUDE-2 are still being managed according to the protocol. We will ensure appropriate follow-up as we navigate the clinical hold. To your point, the only change is the additional cost of dosing per patient. Thus, in the near term during this clinical hold period, we could be spending a bit less money. We will still incur program management fees related to CRO costs and our internal efforts, but the incremental cost per patient will not take place during this time. We will reassess the timelines once we have a clearer plan for getting off clinical hold. Moreover, we do have ongoing research priorities within the organization. So, at this moment, we do not see a significant change in the company’s operational or cash needs, and we will continue to evaluate this collaboratively with regulatory authorities in the coming weeks and months.

And our next question comes from Yanan Zhu with Wells Fargo Securities.

I'm sorry to hear the update about the patient. I was wondering, when you mention comorbidities, are there any liver-related comorbidities? Additionally, you mentioned that less than 1% of the enrolled patients have Grade 4 enzyme elevation. Can you disclose how many cases of Grade 4 liver enzyme situations have occurred and how many are still resolving?

Thanks, Yanan. The 1% applies to the more than 650 patients. I remind you, this is an ongoing placebo-controlled double-blinded study. And what's attributed to what in precise numbers by case, et cetera, is not possible for us to get into. But you should think of this as less than 1% across that number. With respect to the comorbidities, it's not something we can get into at this point. I can assure you that there's an ongoing evaluation where we'll get more information that I think will be very helpful to understand the clinical course that this patient experienced. And we'll present that information at the appropriate time once we have it. But until that information is in our hand, I think it's premature to discuss.

And our next question today comes from Troy Langford with TD Cowen.

My condolences on the unfortunate update today. Following up on some of the previous questions, is there anything you can do preclinically to try and disprove any potential causation between nex-z treatment and the safety event? Also, while I understand you can't provide too much detail, could you share any information regarding potential timelines or next steps with the FDA about reinitiating the study? I believe that would be very helpful.

Yes. I can't speak for the FDA, and we're certainly waiting for the letter that we expect to receive from them regarding the clinical hold. That letter will significantly influence our approach to resuming the protocol. As for preclinical evaluations, it's challenging to determine at this moment. However, we're examining all available information to identify any patients who may be at increased risk. Once we gather that information, we will share it in a meaningful way, but only when we're confident in our understanding.

And our next question comes from Brian Cheng of JPMorgan.

Ed, earlier this year in January, I remember that you said that the ATM would be used at an opportunistic time. And looking at your 10-Q, $128 million this quarter was executed through the ATM. What changed your mind here in executing the ATM? And is the ATM your path going forward in raising additional cash?

Brian, thanks for the question. And Ed, do you want to talk about how we think about the various tools for raising funds?

Yes. So we've often talked about ATM as not a primary strategy, but a tool within the toolkit to raise capital for the company. We're not going to comment on specifics going forward, but we do believe in having options. And so whether it's traditional equity that's often done in biotech, including the use of the ATM, you should expect us to continue to have that available to us and potentially circumstances dependent to utilize that strategy. But there are others for a company like ours that is approaching Phase III data and has a BLA filing. And so whether it's collaborations that we could consider, debt structures or more creative financing opportunities, I do believe we have the balance sheet to get to those milestones and multiple options to consider to improve the balance sheet in the future.

And our next question today comes from Jay Olson at Oppenheimer.

We're sorry to hear this news. Since you mentioned there are no Grade 4 liver transaminase elevations in MAGNITUDE-2, can you just talk about any notable differences in the baseline characteristics for MAGNITUDE versus MAGNITUDE-2? And any particular changes you may be considering to the enrollment criteria?

The primary difference is the indication itself. Patients in MAGNITUDE-2, as I'm sure you know, have polyneuropathy, which is a manifestation of TTR amyloidosis. And in MAGNITUDE, it's cardiomyopathy as the primary manifestation. Other than that, the differences tend to be really minimal, and I would think of it as on a continuum with respect to the drug as a whole.

And our next question today comes from Salveen Richter with Goldman Sachs.

I was just wondering if we step back, whether you could just help us understand the steps from here apart from the FDA letter.

Central to our path forward is the FDA letter and understanding their requirements. We are actively analyzing all the information we've gathered, including clinical and preclinical data, as well as manufacturing details. This is part of a thorough examination to identify any factors that might pose risks to patients. While we await the FDA's letter and their requested information, we will consider our next steps. Once we receive the letter, we will determine our actions, and we believe we will be equipped to address any concerns they highlight. We intend to collaborate closely with the FDA to develop an effective plan to mitigate risk.

And our next question comes from Jack Allen of Baird.

I also wanted to pass along my condolences, a tough update here. Stepping back, I was hoping you could help remind us of the differences in the construct as it relates to the ATTR candidate as compared to HAE. I believe they're using different LNPs, but could you help me understand that, and then also obviously targeting different genetic diseases as well?

Yes. Thanks for the question. As we've shared elsewhere, the LNP is the same. That is the lipid constituents, the mRNA is the same. It's the guide RNA that differs between the two. but that leads to a totally different sort of outcome in patients. So ultimately, the patients themselves are different. The disease that they have is different and the gene that is targeted is different. So we view lonvo-z and nex-z as absolutely distinct from each other and the patient experience thus far aligns with that.

And our next question comes from Silvan Tuerkcan with Citizens.

My condolences as well to the clinical team. My question is do you add any additional liver monitoring in the lonvo-z trial in HAE? And I'm asking because if the percentage is less than 1% on 650 patients, if you do the math, less than a patient in the HAE trial, right? So any chances you can pick up slight liver increases there before there's a potential launch?

Well, first of all, the lonvo-z HAELO trial is completely enrolled. And as we said at a prior update, that patient population is fully enrolled, and they've all passed through this initial window for the patients randomized in the primary evaluation part of the study. The monitoring that we have is not as intense as what we have in the nex-z trial. But again, our experience to date has been quite distinct. And if there were an issue, we would expect to be able to see it with the monitoring that we do have. I would say that an additional aspect to point out is that on Saturday, as we said in our comments, we'll be presenting at the AACI meeting, the combined pooled experience that we have of all patients who have received a 50-milligram dose for lonvo-z, and you'll be able to see the same not only clinical performance but safety performance that we're seeing ourselves.

And our next question today comes from Jonathan Miller at Evercore ISI.

My condolences as well to the family of the patient and to you guys, tough update. I guess I would love to dig further into the comprehensive analysis that you said you were doing. Obviously, you're going back over the individual patient. But how deep are you going across both the nex-z and the lonvo-z patient populations thus far? And can you maybe put some guidelines around what sorts of cases you would consider to be possibly fitting the pattern versus the sorts of cases you would be excluding? I'm thinking of patients who have subclinical liver enzyme elevations that might fit a timing pattern. How do you adjudicate whether you think those are part of this signal or not?

The first point I would make is that the lonvo-z experience is distinct from what we see with nex-z. But with respect to nex-z, you're correct in that we'll have more information coming from this particular patient, which I think can be potentially very illuminating in terms of understanding the patient's clinical course. But other than that, when I say comprehensive analysis, I mean comprehensive. And we're looking broadly. We're looking deeply, and the sorts of things that you're raising are all on the list of things for us to consider.

And our next question comes from Whitney Ijem with Canaccord.

This is Angela Qian on for Whitney. I also want to express our condolences. So we understand you'll be increasing the monitoring of lab values after dosing. But can you give us a little bit more color on how often the lab values are being monitored previously? In this one patient, the levels were discovered when he had abdominal pain. But in the other patients who did have elevations, how was that discovered?

We've always monitored in the window, and that's how we are aware of what we've seen thus far. We've not only picked this up as a result of more intense monitoring. But what we've done, as more information has become available to us, is move to at least weekly monitoring for the first few weeks after a patient has been exposed to the drug to see if we're able to actually characterize the full course of what happens when it happens. Again, it's occurring in less than 1% of all of the patients that have been enrolled in the trial. And the notion there is that if there's information that can be acted on, that's in the hands of the physicians who are caring for these patients.

And our next question today comes from Luca Issi with RBC Capital Markets.

This is Shelby on for Luca. Maybe a quick one on HAE. We appreciate that you don't see a lot of read-through here, but do you think the patient death in TTR could hurt the potential commercial opportunity for this indication? Any color there, much appreciated.

I can only speculate at this time. I think between where we are today and completing the readout of our Phase III trial for HAELO, there's a lot of time and information to be accumulated that will characterize the benefit risk profile for lonvo-z. Again, I would point you to a presentation that will be given on Saturday, just a couple of days from now, where the combined experience of all of the patients, 32 that have received 50 milligrams and the efficacy profile, along with the safety profile is there for everyone to see. And we think that, that is largely going to be representative of what we think we'll see in our Phase III or clinical use of the product more broadly. So until we get all of that information, I don't think we're going to be in a position to talk about the commercial opportunity. But thus far, we very much like what we see.

And our final question today comes from Myles Minter with William Blair.

Sorry to hear about the update. It's a straightforward one. Do you have a cause of death? This is a cardiomyopathy trial. You will have deaths in the trial, unfortunately. Just wondering whether this was a CV-related event or as it seems maybe something beyond that?

If I heard you right, I'm sorry, it was a little garbled. We'll give the information once we have all of the final material in hand. There are some things that are being done after the death to give us additional insights. And at the appropriate time, we'll share all of that.

Thank you. And that concludes our question-and-answer session. I'd like to turn the conference back over to CEO, John Leonard, for closing remarks.

So thank you all for joining us. We will look forward to speaking with you again when we have meaningful updates to share.

Thank you. This concludes today's conference call. We thank you all for attending today's presentation. You may now disconnect your lines, and have a wonderful day.