Prepared remarks
Hello, and welcome to Intellia Therapeutics Second Quarter Conference Call. My name is Chloe, and I will be your conference operator today. Please be advised that today's call is being recorded. I would now like to turn the call over to Jason Fredette, Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.
Thank you, operator, and hello, everyone. Earlier this morning, we issued a press release outlining recent business updates in our second quarter financial results. This document 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 minute 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 now turn the call over to John to begin our business discussion.
Thank you, Jason, and good morning, everyone. We're excited to be speaking with you to recap the tremendous progress we made in our Phase III development programs of lonvo-z in hereditary angioedema or HAE, and nex-z in transthyretin amyloidosis or ATTR. The full results of our Phase III HAELO trial in HAE position us very well for a potential approval and launch of the world's first in vivo gene editing product in the first half of next year. We also have gained important new genomic insights that further our understanding of nex-z's profile and could help position us even more favorably within a large and dynamic ATTR market. Let's begin with lonvo-z. Simply put, the second quarter was a momentous period for this program. In April, we reported positive top line results from HAELO and got our rolling BLA submission underway with the FDA. This was followed by our late-breaking oral presentation at EAACI and a concurrent publication in the New England Journal of Medicine, Intellia's sixth manuscript in this prestigious journal.
HAELO was an unequivocal success as we achieved statistical significance for the primary and all key secondary endpoints. More specifically, during the 6-month primary observation period, we reported an 87% reduction in mean monthly attacks for lonvo-z versus placebo. Sixty-two percent of patients were entirely attack-free and therapy-free in the lonvo-z arm. A 23-point improvement was observed for the lonvo-z arm in the total angioedema quality of life score from baseline. For context, a change of just 6 points is considered to be clinically meaningful. The New England Journal manuscript also contained compelling figures and analyses underscoring the unique value proposition that could be afforded by this one-time therapy if it's approved. For instance, patient-level data demonstrated that all patients in the lonvo-z arm experienced attack rate reductions from baseline for weeks 5 to 28.
In other words, every single patient received a clinical benefit, including those who are not yet fully attack-free during that 6-month period. A subgroup analysis demonstrated meaningful attack rate reductions in the lonvo-z arm regardless of age, sex, race, weight, geography, baseline attack rate or prior therapy. The publication also included a figure depicting the mean number of HAE attacks over time. It traced patients from when they were on prior therapies before screening through the entire efficacy evaluation period and into crossover. And it showed that mean attack rates for the lonvo-z arm dropped well below the prescreening attack rates by week 4. Attacks continued to decline in the months that followed and approached zero in the crossover period after week 28. In the placebo arm, not surprisingly, mean attack rates didn't drop below prescreening levels until patients crossed over to lonvo-z. At that point, they dropped steeply and approached zero within a few months.
Also, notably, all patients who received lonvo-z at baseline or in crossover remained free from long-term prophylaxis therapy as of the data cutoff. And finally, favorable safety and tolerability data were observed. The most common treatment-emergent adverse events were infusion-related reactions, headache and fatigue. All treatment-emergent adverse events were Grade 1 or Grade 2, and there were no serious adverse events observed in the lonvo-z arm as of the data cutoff. These results are unsurpassed by chronic long-term prophylaxis therapies or LTPs. We believe it is clear moreover that they truly stand alone in the HAE space given that this is a one-time treatment. Most patients were attack-free and therapy-free for the entire 6-month efficacy observation period following a single lonvo-z dose. Based on our preclinical work and observations from our Phase I/II trial, our expectation is that this percentage will increase further over time as patients who have lived with HAE their entire lives adjust to their new normal.
So what's next for us? Well, we expect to be in a position to announce the FDA's acceptance of a BLA filing for lonvo-z by the end of this year. In the meantime, our pre-commercial readiness efforts are advancing well as we prepare for a potential U.S. launch in the first half of next year. Most of these efforts are well underway, including work streams across medical engagement, payer outreach, treatment center readiness, distribution planning and access strategy. We completed hiring for our field medical, reimbursement and strategic accounts teams, and they're now engaging with treatment centers around the country to ensure they are well prepared to address patient needs shortly after approval. We're also building awareness of the many burdens associated with HAE. During the second quarter, we launched haereframed.com, a disease awareness initiative designed to elevate understanding of the challenges patients face, including those related to lifelong chronic therapy.
Together, these efforts reflect meaningful progress in building the infrastructure, awareness and access pathways needed to support our planned launch. So, let's turn to the progress we made with nex-z, our potential one-time treatment for patients with ATTR cardiomyopathy and polyneuropathy. We were pleased to have resolved the clinical holds in our Phase III trials quite rapidly earlier this year, and I'm excited to report today that we were able to resume enrollment and dosing in both trials in Q2. Investigator engagement and enthusiasm remain high and our screening rate is rapidly increasing globally once again. ATTR is a large, growing and highly underdiagnosed market with significant unmet needs. Today, patients are predominantly served by stabilizers, silencers or a combination of the two. About a month ago, disappointing top line results were shared from CARDIO-TTRansform, the pivotal trial of eplontersen, a TTR silencer for patients with ATTR cardiomyopathy.
Since then, there's been some debate about whether a silencer can work on top of a stabilizer. We and others believe the negative outcome is specific to eplontersen in this particular trial, and it does not speak to combination outcomes in general. We remain firm believers that combination therapy will work, but only with the right agent. This belief is based empirically on clinical evidence. First, we would point to the fact that another chronically dosed silencer, vutrisiran, has already shown a directional benefit on top of stabilizers in a well-controlled trial. But even more importantly, we would point to what was observed in the monotherapy data for each of the chronically dosed stabilizers and silencers. If you go back and look at the readouts for approved stabilizers like tafamidis and acoramidis and approved silencers like eplontersen and patisiran, you'll see that patients continue to progress while they're on those therapies.
Why is that? Well, we and others are convinced it's because they adequately reduce or control TTR protein. Focusing in on the approved silencers, you'll see that mean TTR reductions for each of them are about 80%. However, the details behind that number matter. For instance, it takes many months for those silencers to achieve their 80% reduction. There's significant variability in TTR from patient to patient with some achieving a 90% knockdown and many others receiving reductions of only 50% or 60%, and even within an individual patient, the knockdown fluctuates due to issues with pharmacokinetics and issues with dose interruptions and adherence, whether due to patient behavior or toxicity. Simply put, it appears today's silencers and stabilizers are leaving efficacy on the table and in a progressive disease with high mortality like ATTR-CM every day and every microgram per milliliter of TTR counts.
Nex-z has demonstrated its ability to deliver an unsurpassed knockdown of TTR protein for patients in both relative and absolute terms. Our Phase I data demonstrated a mean TTR reduction of 90%. While that percentage is impressive, we believe the absolute TTR reduction is even more clinically relevant. When nex-z is provided as monotherapy, mean serum TTR was less than 20 micrograms per milliliter, about one-third of the absolute level seen with leading chronic silencers. That knockdown was achieved rapidly within one month of the infusion, and it was extremely consistent across all patients. Best of all, patients began receiving therapeutic doses of nex-z in 2021. And as of our latest data cutoff, intra-patient TTR control was constant and was maintained across all patients following the one-time nex-z treatment. We look forward to presenting updated long-term durability data at future congresses.
We believe nex-z's distinct TTR knockdown is why disease stabilization or reversal is observed in most patients in our Phase I, while our would-be competitors have observed disease progression. Additionally, the response has been consistent across patients of all New York Heart Association classes, those with either variant or wild-type disease, and it also includes patients who have progressed on past silencers. And so we continue to have significant confidence in our ability to show a benefit on top of tafamidis and in MAGNITUDE. Additionally, unlike CARDIO-TTRansform, which was a time-bound study, MAGNITUDE's primary endpoint is strictly event-based. We've enrolled well over 650 patients in MAGNITUDE. We've been accruing events for quite some time, and those events continued unabated through the clinical hold. While still premature for us to guide to data timing, what I can say today is that the blinded event rate in the trial remains within the range we had projected internally.
We're looking forward to reviewing the detailed CARDIO-TTRansform data later this month at ESC. And of course, we have the opportunity to consider changes that further optimize MAGNITUDE's design based on what we learn. Now let's move on to one other encouraging update we're able to share today related to nex-z. As we reported late last year, Grade 4 liver transaminase elevations have been observed in less than 1% of patients enrolled in MAGNITUDE. These were transient and in most cases, they resolved without any intervention. Based in part on the fact that the observations consistently occurred 2 to 5 weeks after dosing, we hypothesized they were caused by an adaptive immune response. As a result, we implemented mitigation measures to enhance monitoring for transaminase elevations and intervene if they are observed. These measures are very straightforward and could easily be implemented in a real-world commercial setting if required.
We also went further, working with Regeneron and other external experts, we sequenced and analyzed data from over 600 patient samples across all nex-z clinical trials to date. Our goal was to understand if there were subpopulations that might be most susceptible to higher-grade transaminase elevations. This work focused on HLAs, which are proteins on the surface of cells that play a key role in regulating the immune system and helping to distinguish native and foreign peptides. This blinded analysis revealed one statistically significant finding. Patients carrying a specific HLA allele known as C*05:01 had a significantly higher rate of Grade 3 or greater transaminase elevations than the broader population. In fact, each of the five highest elevations observed following dosing occurred in patients carrying this allele. Now some important context on what this does and doesn't mean. Only 12% of the 600-plus samples we analyzed carry this allele and the strong majority of C*05:01-positive patients did not experience severe transaminase elevations.
So we continue to see the potential for a favorable benefit-risk profile even in the subgroup, particularly with the mitigation strategy that is now in place. What the finding gives us is valuable: a mechanistic explanation for a general signal we had already flagged and a way to identify patients who are more likely to be affected before it happens. In doing so, it further increases our confidence in nex-z's ability to deliver on its long-recognized potential. So here are our next steps. We're engaging with FDA to review the findings. In the meantime, we already have updated our protocols, investigators' brochures and informed consents to incorporate HLA typing for all patients in the Phase III trials. These documents are in the process of being rolled out to regulatory authorities, IRBs and sites globally. Following the reviews, investigators and patients will be informed about the HLA results during screening or prior to crossover so they can make more informed treatment decisions.
And so to close, I'm exceedingly proud of all the team continues to accomplish here at Intellia. We're marching towards the world's first potential launch of an in vivo gene editing therapy with lonvo-z. We're on track to complete enrollment in MAGNITUDE-2 later this year, and we're demonstrating precision medicine at its finest with our HLA work on nex-z. These achievements layer on top of all the other pioneering work we've undertaken as we seek to harness the power of gene editing to deliver optimal treatment outcomes for patients with just one dose. So with that, let's now turn the call over to Ed to share some financial color.
Thank you, John, and hello, everyone. In addition to the tremendous clinical, pre-commercial and scientific progress we made in the second quarter, we also kept the company on sound financial footing. In April, we completed an equity financing that yielded approximately $195 million in net proceeds for the company. Cash, cash equivalents and marketable securities were $628.4 million as of June 30, 2026, compared to $605.1 million on December 31, 2025. We believe this cash balance will be sufficient to get us at least into 2028. Importantly, while we expect to obtain approval and launch lonvo-z in the U.S. in the first half of 2027, our cash runway guidance is conservative in that it excludes all product revenues. Collaboration revenue was $7.7 million for the second quarter of 2026 compared to $14.2 million for the prior year quarter. This change is primarily due to a reduction in revenue from Regeneron.
R&D expenses were $82.6 million for the second quarter of 2026 compared to $97 million during the prior year quarter. The decrease was primarily driven by lower external costs related to lonvo-z and nex-z and reduced stock-based compensation, partially offset by higher employee-related expenses due to increased headcount. Stock-based compensation expense included in R&D was $9.4 million for the second quarter of 2026. G&A expenses were $37.8 million during the second quarter of 2026 compared to $27.2 million for the prior year quarter. This increase was primarily driven by costs associated with the ongoing build-out of our commercial infrastructure, higher legal expenses and stock-based compensation. Stock-based compensation expense included in G&A was $8.6 million for the second quarter of 2026. And finally, net loss for the second quarter of this year was $106.6 million, which compared with $101.3 million for the prior year quarter. With that, we are ready to begin our question-and-answer session. Operator, would you please open the line for questions?
Questions and answers
Operator provided instructions for the question-and-answer session.
Congrats on the progress. I'll ask one on the allele finding, which is interesting for that C*05:01 allele. Can you talk about the implications for the 12% of patients where there could be some added risk? Is there another parameter that you could use to help fine-tune patient selection? And lastly, is there more you can share on the biologic relationship for what exactly is triggering the immune response?
Thanks, Maurice, for your question. So we think that the finding confirms our initial thinking about an adaptive immune response. As many will know, HLAs are deeply implicated in cell-mediated immunity, and this is an important part of understanding what we saw with our early observations and the timing of the immune response. So it gives us significant confidence that the mitigation measures that we put in place are appropriate and are on target for what seems to be going on. With respect to the patients that carry C*05:01, as I said in my earlier comments, we're making that information available to all investigators and patients. There's a relationship that's significant, but many of the patients that carry C*05:01 do not have liver transaminase elevations. So the first order of business is to make sure that if patients have that, they're aware of it, and they can discuss the elevated risk with their physicians and make a determination of what's appropriate for them.
Our expectation, based on conferring with our steering committee members and experts we've been working with during the course of our findings, is that many patients may choose to self-exclude and that's appropriate for them. But for those who believe that the state of their disease and other opportunities available to them warrant continuing to receive the therapy and advancing the trial, we're making the drug available for them. As we continue to learn during the course of our trial, we discussed these findings with the FDA and any further implications. In the meanwhile, we think that this will give enhanced confidence to the physicians and patients who are entering so they can drive the best possible outcome, all things considered.
The next question comes from Joseph Thome with TD Cowen.
This is Jacob on for Joe. Just sticking with the HLA allele. I wanted to confirm that this is something specific to nex-z and not lonvo-z. And then also, you said that approximately 12% of the 600 samples carried the allele, but only a fraction of that 12% actually had elevations. Is that correct?
Yes. In my comments, I said that across the study there's about 12% of patients who carry the C*05:01 allele. That broadly reflects what's seen in a North American and Western European population. There will be some variance across different ethnic groups with numbers sometimes lower than that, but that's what we've observed in the study. With respect to specificity, almost certainly, this would be specific to nex-z and not have any implications for lonvo-z. There are a couple of reasons for that. When you think about what an HLA molecule is, it binds to a very specific short peptide, and we wouldn't expect those peptides to be implicated in any way with the lonvo-z treatment effect. That is further supported by the fact that, as shown in the New England Journal publication that was recently released, there's no signal in patients with lonvo-z. At this point, we think that this is a finding limited to nex-z.
I'll just add one thing. The vast majority of those patients who had C*05:01 did not experience severe transaminase elevations. So 12% of the samples represent those carrying the allele, but only a small subset have had these higher-grade elevations.
The next question comes from Luca Issi with RBC Capital Markets.
Congrats on all the progress. We have yet to see the full CARDIO-TTRansform trial. I was looking forward to that data at the European Society of Cardiology. You already mentioned potential to maybe optimize your trial to maximize the probability of success. Can you talk about the options you are contemplating at this point? Can you enroll more patients? Can you extend the minimum follow-up longer than 18 months? Could you limit the use of SGLT2? Walk us through, at a high level, how you're thinking about potentially tweaking your trial.
Thanks for the question, Luca. The first order of business is really understanding the data that comes from the CARDIO-TTRansform study. As I said in the prepared comments, we believe, based on everything we know thus far, that the findings are likely specific to eplontersen and not generally applicable to how we think about treatment of patients with TTR disease or how combination therapy would perform broadly. What we think will be the most important information is the degree to which TTR is reduced, the variability or lack thereof as we see in our own patients, the speed with which treatment effect is achieved and the durability as patients go through many months of observation—factors where variability may be attributable to pharmacokinetics or interruptions for toxicity, for example. All of those elements will erode the overall treatment effect. It's important to really understand that before jumping to conclusions about combination therapy and how best to use it.
With that understanding in hand, we will of course work with experts who are deep in the data and consider if there are any changes we need to make. We remain open-minded and will adapt as necessary. The factors you mentioned are possible to change, but we won't start with a thesis until we have a strong understanding of the data. Like many on this call, we're anxious to see that information before making changes.
The next question comes from Salveen Richter with Goldman Sachs.
Can you remind us of the background stabilizer used in the study? And do you expect that to change given recent CARDIO-TTRansform results? Also on the HLA finding, do you see enrollment changes given screening for HLA?
Background stabilizer use is running around 80%, which is what we projected when we set out and what we've been confirming on various data releases along the way. That does not appear to be changing one way or the other. It reflects how stabilizers are broadly used around the world and at the sites where we're conducting the investigations. With respect to HLA, as we talk to investigators working in this trial, most of them view this as confidence-building in terms of how to think about patients and who to enter and potentially who to exclude should the patient or doctor think that's appropriate. Across the board, as we've gone through the data with practicing cardiologists and experts in the field, all of them have viewed this as a favorable finding that enhances overall confidence. Our job now is to make that information available to those doctors and patients in the trial as quickly as possible, and that's well underway.
The next question comes from Silvan Tuerkcan with Citizens.
Maybe you can talk a little bit about the patient gateway that you're building with HAE Reframe. Is that more to obtain data points for potential marketing, or is it to push your message around endpoints where the one-time treatment could be helpful? If so, what are those endpoints? And related to that, what symposium data can we expect coming up?
Let me speak first to the symposium. Across the entire HAE program, virtually every single patient at some point achieves something resembling no attacks and no therapy. It takes some patients longer to get there than others, but virtually everybody ceases to use long-term prophylaxis and almost all patients no longer require on-demand therapy. They may carry it, but overall utilization for these patients plummets, which we think is exciting for patients, doctors and payers. At the symposium, we'll present important information about how the drug behaves at a molecular level and how that can be traced with respect to high molecular weight kininogen. That will reference one particular patient who had significant benefit but did not reach an attack-free status; we will discuss the likely explanation that this patient had a second, unrelated process. That's exciting information that speaks to one patient who stood out from the vast majority who did very well.
With respect to the website, we're trying to make sure that people understand the burden of HAE. We typically talk about disease attacks and efficacy and safety of drugs, but what's often left out is what patients endure to get and stay on therapy, and how HAE continues to affect their lives despite therapy. By highlighting what patients must do to obtain therapy—sometimes requiring prior authorizations even twice a year—we want payers, patients and doctors to understand that burden. When they see the profile of lonvo-z, the contrast will be very apparent.
The next question comes from Leah Cann with Brookline Capital Markets.
My question has been answered.
The next question comes from Jonathan Miller with Evercore ISI.
This is Ginger on for John. I'd like to double-click on the allele analysis with two questions. First, how many patients with Grade 3 liver signals do not carry the allele? And are there any patients with lower grade signals that actually carry the allele? Second, are you considering additional prophylaxis for patients carrying the C*05:01 allele? What are the additional risks to consider for those carriers? And have any particular antigens on the cell surface caught your attention that may be relevant for the liver injuries?
Thank you for the question. With respect to the full data set and the analysis, we'll release that information at the appropriate time and go through the molecular findings and the supporting statistics. That's not something we're in a position to do today. You asked whether we are doing something different for patients who choose to participate in the study if they are C*05:01 positive. At this point, the answer is no. We believe the mitigation measures we've put in place are appropriate for a cell-mediated adaptive immune response, and we now have increased confidence that's what's occurring in these patients with high LFT elevations. What we have found is that we can identify patients before the event occurs and give them the opportunity not to participate, recognizing that their likelihood of these increases is higher than the broader population. If you flip it around, for the approximately 90% of people who do not carry C*05:01, the likelihood of a high LFT elevation is extremely low, which is confidence-building. Even for C*05:01 carriers, most patients will not have elevations, but when they do occur, these tend to be the most severe.
The next question comes from Terence Flynn with Morgan Stanley.
This is Chris on for Terence. A quick follow-up on the HLA genotyping finding: looking ahead, do you expect that to potentially appear on the label if approved? And in the commercial setting, do you expect every patient to get genotyped?
I think it's too early to say. Often labels reflect aspects of how clinical trials were conducted and the data they accumulate. That's a bridge we'll cross when we get to that point. In the meanwhile, what we're excited about and what investigators are excited about is that this gives useful information on how to focus the benefit-risk for patients who can most benefit. We will collect this information during screening in the study, and we don't think it will slow down screening. This is a relatively straightforward process, and many investigators believe this will actually accelerate screening, which is already rapidly increasing. We are very excited about this finding and the positive things it can do for us.
The next question comes from Myles Minter with William Blair.
I've been getting a few inbound questions since you published in the New England Journal on lonvo-z and in the supplement. You showed the ALT and ASTs over time. I think around weeks 30 to 32 in patients that got lonvo-z first at randomization, it looks benign to me, but there are three patients with excursions outside the reference range. Is that just variability, or is there something else going on there at the later stages?
Thanks for the question, Myles. The data is laid out in the New England Journal for anyone who wants to see it. Across the entire program, there's never been an LFT elevation greater than Grade 2. Of the low-grade elevations, there are confounding reasons to consider. In one case you reference, many months after receiving the drug, this is almost certainly related to another issue occurring for the patient, which the investigator believed. The elevation was benign; nothing was done and it was low grade. For other patients we've reported, elevations were compounded by alcohol use; one patient had a Grade 2 that resolved rapidly. In another case reported in Phase III, a patient had LFT elevations during screening with a concomitant viral infection. Across the board, we see no concerning signal. There is variability in patients' lives and conditions, and we're very excited about the efficacy and safety profile of the drug as we move toward what we hope will be BLA approval.
The next question comes from Yanan Zhu with Wells Fargo.
This is Jeff on for Yanan. For the lonvo-z BLA, can you mention if the final BLA has been submitted to the FDA? If not, which remaining modules need to be completed? Based on your conversations with clinical sites for lonvo-z, are you expecting a bolus of patients at launch if approved?
We are far into the BLA filing, and I would anticipate that the next time you'll hear from us will be announcing what we hope will be FDA acceptance of the BLA. With that, we'll all gain more information with respect to PDUFA dates, priority review and related items. We've been pleased with the team's preparation and the rapid and efficient way they've been able to work with the FDA, and we're excited about the progress we've made.
Operator provided further instructions. The next question comes from Andy Chen with Wolfe Research.
This is Jason on for Andy. I wanted to ask about the HLA genotyping: is this specific to ATTR-CM, or do you see this in other indications like polyneuropathy? And do you see genotyping coming into other trials?
We're not currently doing genotyping on a standard basis for any program at the start. We don't think that would be necessary or feasible without a clear signal. We believe what we found here is a very specific finding. To answer your question directly, the genotyping is being done across the entire nex-z program irrespective of indication. We're treating it as a relevant finding for both polyneuropathy and cardiomyopathy and are applying the same rules and providing the same information for both studies.
This concludes our question-and-answer session. I would like to turn the conference back over to Jason Fredette for any closing remarks.
Thanks, operator, and thanks, everyone, for joining us. We hope you have a great end to the summer, and we look forward to seeing many of you at the upcoming conferences in September. That concludes the call.
The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.