Good morning, and welcome to Intellia's First Quarter 2025 Financial Results Conference Call. My name is Drew, and I will be your conference operator today. Following formal remarks, we will open the call up for a question-and-answer session. This conference is being recorded at the Company's request and will be available on the Company's website following the end of the call. As a reminder, all participants are currently in a listen-only mode. I will now turn the conference over to Brittany Chaves, Senior Manager of Investor Relations at Intellia. Please proceed.

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics first quarter 2025 earnings call. Earlier this morning, Intellia issued a press release outlining the Company's progress this quarter, as well as topics for discussion on today's call. This release can be found on the Investors and Media section of Intellia's website. This call is being broadcast live and a replay will be archived on the Company's website. At this time, I'd like to remind listeners that, during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings for 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 from Intellia are John Leonard, Chief Executive Officer; David Lebwohl, Chief Medical Officer; Ed Dulac, Chief Financial Officer; and Birgit Schultes, our Chief Scientific Officer. John will begin with recent business highlights, David will then provide updates on our clinical pipeline progress, and Ed will review our financials before we open the call for questions. With that, I will now turn the call over to John, our Chief Executive Officer.

Thank you, Brittany. Good morning, everyone, and thank you all for joining us today. We entered the year with clear priorities and a plan for operational excellence, and we've already made tremendous progress in the first quarter. We're on a mission to offer life-changing benefits with one-time therapies for people living with severe diseases. Our progress is fueled by the core values of the company, one team exploring possibilities, delivering results and disrupting the status quo. We are committed to changing the treatment paradigm for patients suffering from hereditary angioedema and ATTR amyloidosis. Of the six milestones we outlined for 2025, we've accomplished two critical ones in the first three months of the year, dosing the first patient in our Phase 3 study for HAE and dosing the first patient in our Phase 3 study for hereditary ATTR with polyneuropathy. We continue to see significant interest from both investigators and patients across our programs. Enrollment in our global Phase 3 HAELO study for HAE is progressing rapidly and reinforces our market research that the unmet need remains high despite existing treatment options. Patients are eager to pursue more convenient and more effective therapies. The transformational potential from a single infusion of NTLA-2002 resonates strongly with patients and physicians. Our global Phase 3 MAGNITUDE study for ATTR with cardiomyopathy continues to be ahead of schedule. We now have over 90 sites actively enrolling, and we continue to benefit from interest in our emerging profile for Nexiguran Ziclumeran, which we also refer to as Nex-Z from our Phase 1 data. In the first quarter, the FDA granted Intellia the RMAT designation for Nex-Z for the treatment of ATTR with cardiomyopathy, which follows prior RMAT designations received for Nex-Z for ATTR with polyneuropathy and for NTLA-2002 in HAE. In parallel to the great execution of our Phase 3 studies, we've been building critical commercial foundations in order to bring our promising therapies to patients as quickly as possible. Through the past few months, our commercial team has broadened its leadership capabilities and includes extensive experience with one-time therapies and in disease areas of interest. We're increasingly confident in our ability to evolve into a strong commercially-ready company. We're excited to share multiple clinical updates throughout the year. We expect longer follow-up to further solidify the emerging and highly differentiated safety and efficacy profiles of our lead programs. In the case of HAE, we'll present new data from patients who have crossed over in our Phase 2 portion of our Phase 1/2 study later this year. This expansion of patients receiving the 50 milligram dose will provide a more robust perspective with more than 30 patients in total on the unique and valuable profile afforded by a one-time therapy like NTLA-2002. More immediately, in June, we'll have two-year follow-up data from our ongoing Phase 1 study of NTLA-2002 at the European Academy of Allergy and Clinical Immunology Congress. For ATTR with polyneuropathy, we'll extend the durability window out to at least three years, further extending our leadership position in in-vivo gene editing. We're confident in our plans, diligent in our execution, and excited by the value-creating opportunities that lie ahead. Before I hand the call over to David Lebwohl, our CMO, I want to address how we're thinking about the regulatory environment given leadership changes and developments at the FDA. Like everyone else, we will monitor the situation closely. At this point, we've experienced no tangible changes to our interactions with the agency or timelines associated with our programs. We remain on track to meet or exceed our stated regulatory timeline and objectives. We remain in close communication with our review teams and continue to move our programs toward approval as per our original plan. We have a strong active relationship with the FDA, as exemplified by the two prior RMAT designations and our most recent ATTR-CM. We remain on course to file our first BLA in 2026. Similarly, we continue to monitor potential implications of pending pharmaceutical tariffs. We have well-established manufacturing and distribution capabilities and are confident in our ability to manufacture and deliver supply for clinical trials and eventually commercial product upon approval. Beyond that, we're convinced our products will yield significant value for patients and the healthcare system. We're continuing to monitor the environment, but amidst all the changes, there's one thing that remains the same, and that's our dedication to bringing highly-differentiated therapies that have the ability to reset the treatment standards for patients with HAE and ATTR. I'll now hand the call over to David Lebwohl, who will provide an update on our clinical programs.

Thanks, John. I'll begin with NTLA-2002 in development for HAE. As John noted, we dosed the first patient with NTLA-2002 in our HAELO Phase 3 study in the first quarter. HAELO is a 60-patient global, randomized, double-blind, placebo-controlled study. Patients are randomized two to one to either a single fifty milligram infusion of NTLA-2002 or placebo after washing out their long-term prophylaxis therapy. They are then followed for a 28-week primary observation period and for a total of 104 weeks in the study. Enrollment is going very well and progressing ahead of our projections. We are motivated by the early progress and excited by this patient and investigator interest. The team is executing well, and we are in a position to go from the first patient to last patient dosed in less than nine months. This speed of enrollment confirms our market research and speaks to the high unmet need and demand in the HAE community, as well as the significant room for improvement. We expect to complete enrollment by the end of the third quarter of this year. We are pleased to share that new NTLA-2002 data were accepted for an oral presentation at the European Academy of Allergy and Clinical Immunology Congress on June 15th in Glasgow. This update will include at least two years of follow-up in patients in the Phase 1 portion of the Phase 1/2 study. Later this year, we plan to present longer-term data from patients in the Phase 2 portion of the study, including those who initially received a 25-milligram dose or placebo and were subsequently given the fifty milligram dose of NTLA-2002 selected for the Phase 3 study. As John mentioned, this Phase 2 update will more than double the total patients who have received the 50 milligram Phase 3 dose to more than 30 patients. Intellia is committed to ending the burden of HAE attacks and chronic treatment for HAE. The emerging profile of NTLA-2002 from our Phase 1/2 study suggests that many HAE patients can be free from attacks and free from the medications that are currently used to treat this disease. We believe and our market research shows that NTLA-2002 will bring significant value to patients, physicians, and payers. The value proposition for NTLA-2002 is comprehensive and compelling, offering patients freedom from HAE attacks and chronic treatment, physicians freedom from persistent administrative burdens in managing chronic HAE therapies, and material pharmacoeconomic benefits for payers. NTLA-2002 is poised to be the first-ever one-time treatment for people living with HAE and the first approved therapy using in-vivo CRISPR gene editing. Let's move on to Nex-Z in development for the treatment of ATTR amyloidosis. In March, the first patient was dosed in the global Phase 3 MAGNITUDE 2 study for the treatment of hereditary ATTR amyloidosis with polyneuropathy. This pivotal study is a placebo-controlled study with expected enrollment of 50 patients. Patients are randomized to either a single 55 milligram infusion of Nex-Z or placebo. We plan to measure key clinical endpoints at 18 months. Full study enrollment is expected to be completed in 2026 to enable our second BLA filing by early 2028. Also in March, we announced the FDA granted RMAT designation to Nex-Z for the treatment of ATTR amyloidosis with cardiomyopathy. As John mentioned, with the granting of a third RMAT designation, all of our lead programs and indications will benefit from earlier and more frequent engagement with the FDA. This is a testament to the potential of our therapies to reset the standard of care and the impact they can have on patients. We continue to be very pleased by the enrollment of the global Phase 3 MAGNITUDE study in ATTR amyloidosis with cardiomyopathy, which is ahead of our projections. We expect cumulative enrollment to exceed 550 patients by year-end. Later this year, we will present longer-term data from patients with either ATTR polyneuropathy or cardiomyopathy in the Phase 1 study, which will include updated measures of clinical efficacy and safety. We look forward to sharing these updates in the second half of 2025. I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of first quarter 2025.

Thank you, David. Good morning, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform. Our cash, cash equivalents, and marketable securities were approximately $707.1 million as of March 31, 2025, compared to $861.7 million as of December 31, 2024. Our balance sheet evolution reflects normal expenses from operations during the first quarter and nonrecurring costs associated with decisions we took to prioritize our portfolio and reduce our real estate footprint and workforce, all of which diminish the medium- and long-term capital needs for the company. These outcomes represent positive developments and allow our current balance sheet to bridge to our expected launch for NTLA-2002 in HAE during the first half of 2027. During this time, Intellia will achieve several important value-creating clinical development and regulatory milestones, which we expect will help us further capitalize the company and aggressively pursue our plans for Nex-Z in ATTR with polyneuropathy and cardiomyopathy. Our collaboration revenue was $16.6 million during the first quarter of 2025 compared to $28.9 million during the first quarter of 2024. The $12.3 million decrease was mainly driven by a decrease in collaboration revenue under the AvenCell License and Collaboration Agreement. Recall that during the first quarter of 2024, there was a transition to equity method accounting for AvenCell, which resulted in a one-time recognition of revenue of approximately $21 million. R&D expenses were $108.4 million during the first quarter of 2025 compared to $111.8 million during the first quarter of 2024. The $3.4 million decrease was primarily driven by employee-related expenses, stock-based compensation, research materials, and contract services, offset by an increase in the advancement of our lead programs. Stock-based compensation included in R&D expenses was $12.6 million for the first quarter. G&A expenses were $29 million during the first quarter of 2025 compared to $31.1 million during the first quarter of 2024. The $2.1 million decrease was primarily related to lower employee-related expenses due to a workforce reduction in January 2025 and lower stock-based compensation, partially offset by increases related to severance expenses recorded in the first quarter. Stock-based compensation included in G&A expense was $9.2 million for the first quarter. As guided previously, we continue to expect a year-over-year decline in GAAP operating expenses of between 5% and 10% this year and that our cash balance is sufficient to fund our operating plans into the first half of 2027.

Thanks, Ed. In conclusion, Intellia continues to meet and even exceed our goals in all programs, and we're excited to report on our progress in the months ahead. With that, we'll now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take one question per caller. Operator, you may now open the call for Q&A.

The first question comes from Gena Wang with Barclays.

Thank you. You have so many updates on different progress, but I will limit my questions to one, since that's the most pressing question. So we'll ask about the MAGNITUDE Phase 3 trial enrollment that seems to be ongoing very well. If you can give your updated metrics regarding the patient baseline characteristics, including the percentage of patients who are on baseline stabilizer and also the silencer dropping rate. What are these rates? And are these rates in line with your internal expectations?

David, do you want to speak to the evolving characteristics at baseline of patients?

Yes, and thank you for that, Gena. Yes, the exciting thing is the rate at which this is enrolling. In terms of the patients around the world, Tafamidis is becoming more commonly used, including in the UK recently. So as we've said from the beginning, we do expect more than 50% of the patients to be on Tafamidis in the study and we are monitoring that. We do think it's important to show a benefit over Tafamidis that hasn't been shown yet with the silencers and this is also valuable to have a large group of Tafamidis patients on the study. In terms of the silencers, of course, this has just been approved in the U.S. recently. We don't expect many patients to cross over, though at this point there are no patients. But over time, we do anticipate, in our statistics, that a percentage of the patients will be going over to the silencer and we are ready for that in terms of the results.

The next question comes from Mani Foroohar with Leerink Partners.

Hi. Thank you for taking our question. I just wanted to ask about cash burn and operating expenses. You mentioned an expected year-over-year decrease in operating expenses of 5% to 10%. Could you provide more detail on what we should anticipate regarding cash burn over the next 12 to 24 months, particularly as the restructuring continues? Are there any significant non-recurring costs or events we should consider?

Thanks for the question. Ed, do you want to walk through? There's a lot of details, but I think it's really important to understand what's going to be the baseline running rate going forward.

Yes. Thank you. Thanks for the question. This is an important focus for the company. The key point I want to make for investors is that we estimate our average cash use over 2025 and 2026 will be about $95 million per quarter. This is consistent with the guidance that we reiterated today, that our current cash will fund our operating plans into the first half of 2027. As I indicated during the fourth quarter call a few months ago, we expected the first quarter results today to be noisy, just given the broad restructuring decisions we made at the company earlier in the year. So I wanted to unpack a little bit about the cash and what drove our cash use during the quarter. The first key driver was our normal company operations. We spent $86 million to run the business, which is consistent with the cash used per quarter that I mentioned previously. So normal operations had a cash use of $86 million in the quarter. Employee bonuses were $18 million. We used that to pay bonuses to existing employees as well as to those who were impacted by the restructuring we announced in January. The last driver of cash use for the quarter was non-recurring costs, about $51 million in the quarter, which included severance and related costs, but mainly payments associated with real estate transactions that we disclosed in February as part of our 10-K filing. We're excited about the development and evolution of our real estate portfolio. We entered into a cash-neutral transaction to reduce our portfolio, simplify our operations, and identify significant savings. By the end of 2026, we'll have a new headquarters located in Cambridge, consolidating most of the company. We expect this will support our growth and collaboration and innovation. Overall, we will run a much smaller, simpler portfolio with about a 30% reduction in real estate capacity over the next couple of years, including releasing the long-term lease obligations in Waltham, Massachusetts of over 40,000 square feet. We estimate nearly $50 million in cash savings from operating our smaller footprint, with other synergies and potential sublease income, so we're confident we have the necessary runway.

Thanks for the question, Ed. It's important to clarify how we're thinking about our cash position and our cash burn rate moving forward.

The next question comes from Andy Chen with Wolfe Research.

This is Hannah calling. Thanks for taking our question. Following up on a previously asked question, we see that you guide to a cash flow way into the first half of 2027, but have you considered non-dilutive financing post-2027? If so, what options might be feasible to obtain?

Ed, do you want to keep on going from the prior question just talking about how we look further down the road and some of the options that we're actively thinking through?

Yes, I appreciate the question. In January, we made some difficult decisions on restructuring. We've seen early, encouraging signs in the first quarter. Our operating expenses were down 4% versus the year-ago quarter and down 7% already from the fourth quarter of last year. For things that are immediately in our control, we're focused on operating efficiently. Regarding capital raising, we believe there are opportunities for the company to click through several important milestones. We think these will be value-creating for shareholders, and we consider how to raise additional capital based on these catalysts over the next 12 to 24 months. Collaborations are an option. We currently have a collaboration with Regeneron on our TTR asset and potential partnerships with other wholly-owned assets, and pipeline assets. Another option that could be available as the company approaches commercialization includes royalty transactions. Further, term debt or venture debt could be feasible. We're optimistic about our balance sheet, where we're heading, and believe we have multiple levers to capitalize the company moving forward.

The next question comes from Kostas Biliouris with BMO Capital Markets.

Good morning, everyone. Congrats on the progress and thanks for taking our question. A question from us on NTLA-2002, given that you plan to file in 2026, and this will potentially be the first-ever commercial in vivo gene editing therapy. Can you help us understand how we should view the launch dynamics in terms of activating sites for patients, securing coverage, and the time required from patient decision to receive the therapy to infusion time? Should we expect similar timelines to in vivo gene therapies currently on the market?

Kostas, thank you for the question. As you pointed out, HAE will be our first in-vivo gene editing launch, and something we're paying great attention to. In our Phase 3 program, things are progressing extremely well. We're ahead of our timeline and learning much about how to make the drug available, etc. We've been building our commercial organization staffed with people with deep insights into prior one-time therapies. Many of those, however, are not good analogs for what we're doing. Ours is a very straightforward outpatient infusion. How to provide that differs greatly from previous examples. With respect to switching from therapies that patients may already be taking, we are learning a lot. It's a simple matter of looking at the pharmacokinetics of the drugs that patients are currently taking, and compensating for how those will wash out over time while the effect of the gene edit takes place. We're in a good position from a drug profile point of view; we think we've got a well-prepared launch strategy.

The next question comes from Luca Issi with RBC.

Thanks so much for taking my question and congrats on all the progress. Maybe a quick one on pricing. What was your reaction when you saw Alnylam actually not lower their price, and they got their label expanded? Were you surprised by it? How are you thinking about pricing for your molecules more broadly, given the one-and-done nature?

Thank you. We are, of course, paying attention to the TTR market broadly. We see an increasingly large and rapidly growing marketplace. This translates into opportunities for all entrants. What we see as a significant opportunity for us is the profile we've seen thus far from our drug. As we get down the road, we'll hone our strategy further. We will not be setting any new records for high-priced drugs here at Intellia; we will address all of our stakeholders in the best possible way.

The next question comes from Maury Raycroft with Jefferies.

Going back to enrollment for the HAELO Phase 3, in late March you changed the minimum age from 18 years old to 16 years old on ct.gov. Just wondering if that's driven by patient interest or demand, or was it to accelerate enrollment or for other reasons? Based on cardiomyopathy enrollment continuing to track rather than expected, can you say more about where you expect it to land by the end of the year?

I guarantee you it will be more than 100 patients by the end of the year. Thank you for the question. Our interest is in having the broadest possible label, whether it's from age or disease severity. Patients in the Phase 3 study resemble those that came into the Phase 2 and Phase 1 studies and we see a range of disease severity. We've been gratified by interest across the board, both in the United States and outside the United States, where we've had patients essentially lined up. We will have the opportunity to further refine what that looks like, but we’re well ahead of what we projected.

The next question comes from Alec Stranahan with Bank of America.

Hi, guys. This is Matthew on for Alec. Thanks for taking our question. Maybe just one looking forward from us. I know that you said you're still developing other in-vivo and ex-vivo candidates. Maybe just some color on the timeline for these, whether they're likely to come after the potential approval in HAE/ATTR.

Yes, we've talked about some things in the past. Our focus since the end of last year and throughout this year is very much on the clinical programs, and that's what we're currently discussing. We do have significant efforts underway for additional in-vivo candidates. As time goes on, we’ll be talking more about the progression here.

The next question comes from Mitchell Kapoor with H. C. Wainwright.

Can you talk about the payer perception of potentially having to cover both Tafamidis and Nex-Z and how that changes the way we should interpret data from ATTR studies?

We are building a database with respect to payers where we have increasing insight. At the time of launch for Nex-Z, Tafamidis is likely to be a generic drug. Most estimates suggest that. If this is the case, I would expect that from a payer point of view, it won't be a significant point of discussion. We anticipate an expected benefit when the two drugs are used together, so we want to ensure this is reflected in our label.

The next question comes from Jay Olson with Oppenheimer.

Maybe just a follow-up on the previous question about the patient baseline characteristics of enrolling in MAGNITUDE. Can you talk about how these characteristics will impact your estimate for the time to reach the acquired number of events for the primary endpoint, and whether that would happen before or after the first half of 2027?

David, do you want to talk about baseline characteristics and our study progression?

Yes, the patients in this study are looking similar to the other Phase 3 studies, with a range of disease severity. The proportion of patients with variant disease remains in the 10% to 15% range, consistent with other studies. We do think the events will evolve similarly to recent studies based on patient enrollment from other early studies. But we’ll be closely watching the data, and as we get closer, we can provide more timelines.

The next question comes from Rick Bienkowski with Cantor Fitzgerald.

For NTLA-2002, could you expand on the value proposition in HAE and thoughts on the flexibility you'll have for pricing?

It's a very important question. The clinical profile we've seen, and a majority of patients reach a state of no attacks off therapy is a strong differentiator. If they can behave in a way to not have to think about their disease, that's what they want. The value proposition is substantial and very significant based on the annual costs for current existing therapies. We will price the drug in a competitive manner and are refining our strategy as we go.

The next question comes from Yanan Zhu with Wells Fargo.

Hi, thanks for taking our question. This question is about Nex-Z in ATTR CM. We know overall the Phase 3 study enrollment is progressing well. Can you specifically talk about the enrollment in the U.S. and any impact from the approvals of Vutrisiran?

David, do you want to speak on the new drugs and enrollment in the U.S.?

Just first speaking to the enrollment; it’s brisk and consistent across regions. The recent drugs like Vutrisiran have not significantly affected our ongoing enrollment, which has remained strong despite their market presence. We expect physicians will have suitable options for patients and that will not impede our study progress.

The next question comes from Troy Langford with TD Cowen.

Congrats on all the progress this quarter and thanks for taking questions. I want to follow up on the recent Phase 1 data from the study. Can you share what one data point resonates most with healthcare providers since you've presented it?

David, what feedback from physicians have you received about NTLA-2002?

Physicians are impressed with the profiles we've shown for TTR reduction. Our nadir of about 90% reduction at one month is compelling compared to the competition that shows slower reductions. This is driving interest and enrollment and will be crucial for our trial results.

The next question comes from Myles Minter with William Blair.

This is Jake on for Myles. Thank you for taking our question. Can you please discuss the effects of recent changes at CBER on your plans for timing of your BLA submission and potentially hiring on a sales force related to NTLA-2002?

Our experience thus far suggests that recent changes at the FDA have not affected our plans. We have strong working relationships with our review teams. We are engaged and in good shape to move forward. The recent changes at CBER, in our view, focus on actual clinical data rather than surrogate markers. We remain confident in our clinical endpoints that are well standardized. We look forward to sharing our data on time.

The next question comes from Brian Cheng with JPMorgan.

Hi, guys. Thanks for taking our question. Can you elaborate on your latest thoughts on the timeline for ATTR cardiomyopathy? You indicated that enrollment is progressing better than projection. What should we consider for the timeline to the first interim look for the Phase 3?

Enrollment is progressing extremely well, and we're very pleased with the global progression of the study. David, do you want to discuss the interim analysis timeline?

The enrollment is expected to be complete by the beginning of 2027. We anticipate that the first interim analysis would occur after enrollment is complete. There is a possibility we could stop the trial early based on efficacy. As we get closer, we’ll have more information.

Yes, we believe it's more likely to be early than later based on what we're seeing so far.

The next question comes from William Pickering with Bernstein.

For the MAGNITUDE 2 study, could you talk about your expectations for the enrollment rate? You mentioned completion is expected in 2026. How should this be compared to the enrollment seen in prior studies?

This study is different due to the wider use of Vutrisiran. We’ll be enrolling in countries without those newer options available. There's a tremendous interest from investigators in the modern therapies. We are confident we will complete enrollment and there could be potential for accelerated approval routes given the high efficacy we see. Look for our data in June.

And the last question today will come from David Lebowitz with Citi.

Thank you very much for taking my question. In terms of the primary endpoint of the MAGNITUDE trial, given the range of events expected, if they were to come in slower, would that change your thoughts on cash needs? Additionally, looking at Alnylam's prior shifting of their primary endpoint, how do you think the FDA would view yours?

We've taken a conservative view that considers your scenario and even added patients if needed. Our runway remains solid, and we believe we are in good shape in terms of funding. The design of our study with clearly defined clinical endpoints is distinct. We don’t foresee an issue adjusting as we are following a preset structure. We are well-positioned for an accelerated path to commercialization.

This concludes the question-and-answer session and Intellia Therapeutics' first quarter 2025 financial results conference call. Thank you for attending today's conference. You may now disconnect your line.