Intellia Therapeutics, Inc. Q1 FY2022 Earnings Call

Good morning. My name is Drew, and I will be your conference operator today. Welcome to the Intellia Therapeutics First Quarter 2022 earnings conference call. At this time, I would like to turn it over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

Thank you, operator. Good morning, everyone. Welcome to Intellia Therapeutics first-quarter 2022 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 at intelliatx.com. This call is being broadcast live, and a replay will be archived on the company's website. 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 and 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 from the Intellia side are Dr. John Leonard, Chief Executive Officer; Dr. David Lebwohl, Chief Medical Officer; Dr. Laura Sepp-Lorenzino, Chief Scientific Officer; and Glenn Goddard, Chief Financial Officer. John will begin with an overview of recent business highlights. David will recap the recent update from our first-in-human study of NTLA-2001 as well as progress across our clinical program. Laura will then recap the company's R&D progress, and Glenn will review Intellia's financial results for the first quarter. John will then offer some concluding remarks before we open the call up for Q&A. with that I'll turn the call over to our CEO, John?

Thank you, Ian, and thank you all for joining us this morning. At Intellia, we're building a full spectrum genome editing company. We're deploying the industry's broadest and deepest toolbox, including novel editing and delivery solutions to harness the immense power of CRISPR-based technologies for in vivo and ex vivo therapeutic applications, each with the potential to revolutionize the future of medicine. At the beginning of this year, we laid out three core priorities: accelerating the clinical validation of our in vivo pipeline, expanding our pipeline, and building on our scientific leadership by driving forward key platform innovations. We're making excellent progress against these objectives. During the first quarter, we shared updated interim data from our landmark study of NTLA-2001. These results demonstrated the treatment was generally well tolerated and delivered rapid, consistent, dose-dependent reductions in serum TTR in people with hereditary ATTR amyloidosis with polyneuropathy. Among the three patients in the 0.7 milligrams per kilogram dose group, treatment with NTLA-2001 led to a mean serum TTR reduction of 86% by day 28. And six patients treated with a single 1 mg per kg dose achieved a 93% mean and 98% maximum reduction by day 28. Further, the reduction of TTR levels has been sustained through the observation period, which provides the first evidence that a single dose CRISPR investigational therapy may provide a lifelong effect. David will review the data in greater detail, including selection of the fixed dose to be evaluated in the expansion portion of the polyneuropathy arm. We plan to present additional data from the polyneuropathy arm of the study at the upcoming EASL International Liver Congress being held in June. In addition, we hope to share the first interim data from the cardiomyopathy arm later this year. These updated data not only bolster our confidence in NTLA-2001 as a potential treatment for ATTR amyloidosis, but also reinforce our belief in the power of our platform for in vivo gene editing. Notably, we look forward to sharing the initial clinical data from our second in vivo program, NTLA-2002 for HAE later this year. Switching to our ex vivo pipeline. In March, we dosed the first patient in our clinical study of NTLA-5001 for the treatment of AML. Altogether, the modular nature of our platform is on full display as we've advanced and expanded our pipeline considerably in both the in vivo and ex vivo settings and initiated multiple strategic business development collaborations that extend the reach of our technology beyond our core focus. Finally, earlier this week, we were pleased to welcome Muna Banji to our Board of Directors. She brings over three decades of experience in commercial strategy and market access. Her history of successfully navigating global health care systems to improve patient access to innovative medicines will be invaluable to Intellia. In addition, her appointment is an important step forward as we believe that it is essential that our Board members represent diverse backgrounds and have experiences and skills in areas that are most relevant to the company's strategic plans. With that introduction, I'll hand the call over to our Chief Medical Officer, David Lebwohl, who will review the NTLA-2001 data in greater detail and detailed progress across our pipeline.

Thanks, John, and welcome, everyone. I'll begin with a review of NTLA-2001 and our recent data update. We are developing NTLA-2001 as a potential best-in-class one-time treatment option for people living with ATTR amyloidosis. Last June, we published landmark data in the New England Journal of Medicine from our ongoing Phase I trial of NTLA-2001, demonstrating our ability to deliver our in vivo CRISPR candidate to the intended tissue and precisely edit the target gene. In February, we shared updated interim data, and we're highly encouraged by the results which have begun to answer fundamental questions for our investigational genomic medicine. The update included interim data from all 15 patients treated across the four dose escalation cohorts in the completed part one of the polyneuropathy arm. Key insights from the ongoing Phase I include that NTLA-2001 was generally well tolerated at all dose levels. There was a dose-response relationship, which showed that higher doses yielded deeper serum TTR reductions. Importantly, these reductions occurred rapidly, with maximal reductions achieved by day 28. Treatment with 1 milligram per kilogram of NTLA-2001 led to a 93% mean and a 98% maximum reduction in serum TTR by day 28. And finally, mean reductions were maintained through the observation period, ranging from 2 to 12 months following a single dose across all dose levels. This finding is consistent with our preclinical modeling and provides early validation that these reductions are durable. Based on previously published data, it has been demonstrated that there is a strong correlation between the degree of protein reduction and clinical outcomes in both ATTR and other forms of amyloidosis. With the deep and persistent levels of TTR reduction we have seen thus far, NTLA-2001 has the potential to halt and perhaps even reverse the course of this disease. Upon completing the dose escalation portion of the polyneuropathy arm, Intellia is now evaluating a fixed dose of 80 milligrams in Part II of the Phase I study, which is expected to deliver a similar exposure to 1 milligram per kilogram. We are happy to share that we have recently dosed the first patient in the single dose expansion cohort. We plan to present longer-term follow-up data from the dose escalation portion of the polyneuropathy arm as well as PK data supporting our fixed dose selection at the EASL International Liver Congress, which is taking place June 22 to 26. In the cardiomyopathy arm of the study, we continue to dose patients in separate dose escalation cohorts at 0.7 and 1 milligram per kilogram. Following results from the dose escalation portion, we then plan to move to the dose expansion stage. As John noted earlier, our goal is to share interim data from the cardiomyopathy arm in the second half of this year, and we expect to complete enrollment in both arms of the study by year-end. Based on the activity and safety data we have observed, we expect to advance clinical development towards future studies for both forms of ATTR amyloidosis. This will include ongoing and additional engagements with regulatory agencies, including the U.S. FDA. Turning now to NTLA-2002, our investigational therapy for the treatment of hereditary angioedema or HAE. People with HAE experience recurrent, unpredictable, and painful types of swelling across multiple tissues. While there are approved acute and prophylactic therapies for HAE, the treatment burden of patients remains significant. To that end, we're applying our modular LNP delivery system to NTLA-2002 to knockout the KLKB1 gene in the liver to permanently reduce plasma kallikrein protein and activity. As a point of reference, a 60% reduction in pre-kallikrein activity has been associated with a clinically relevant reduction in HAE attacks. To date, in nonhuman primates, Intellia has demonstrated our ability to achieve greater than 90% reduction of both prekallikrein protein and activity after a single dose, which remains durable through a 2-year observation period. These results, if achieved in humans, highlight the potential of NTLA-2002 to provide continuous suppression of kallikrein activity and address the significant treatment burden associated with currently available therapies for HAE patients. We continue to progress the dose escalation portion of our Phase I/II study for NTLA-2002. We've completed dosing in the first cohort, evaluating NTLA-2002 at a fixed dose of 25 milligrams and have advanced to the second dose level at 75 milligrams. We anticipate presenting initial interim data from this trial during the second half of the year. With these results expected to characterize the emerging safety and activity profile of NTLA-2002 and potentially demonstrate preliminary proof of concept for this program. Moving on to our ex vivo pipeline. Our ex vivo approach is designed to produce homogenous robust cell products that epitomize the patient's natural immune system for the treatment of cancer and autoimmune diseases. For our first program, NTLA-5001, we are deploying a TCR-based approach targeting the Wilms Tumor 1 intracellular antigen, which is overexpressed in more than 90% of patients with AML regardless of the mutation subtype. In March, we dosed our first patient in the Phase I/IIa study and also received orphan drug designation from the FDA for the treatment of AML. We continue to enroll patients in the ongoing study, and later this year, we expect to provide an update on the progress of the trial.

Thanks, David. I'll start with our in vivo pipeline. We're now advancing two wholly owned development candidates for the treatment of alpha-1 antitrypsin deficiency or AATD. For AATD, our modular platform provides us the optionality for patient-tailored treatment relevant to the particular disease phenotype. This includes NTLA-3001, our gene insertion candidate for lung disease, and NTLA-2003, a local candidate for liver disease. We're now progressing IND-enabling activities for both candidates and expect to file an IND or equivalent application for NTLA-3001 next year. Stay tuned for more updates as we expect to nominate at least one new additional in vivo development candidate before the end of the year. Moving to our ex vivo pipeline. Earlier this year, we announced the nomination of NTLA-6001, an allogeneic CAR-T candidate designed for the treatment of CD30 expressing hematologic cancers. It is the first internally developed candidate using our proprietary allogeneic cell engineering platform. At Kista Symposium's Precision Genome Engineering Conference, we presented preclinical data that our allogeneic solution created immune evading T cells with high viability, potency, and persistence and is readily deployable for TCR-T and CAR-T cell therapy. These data highlighted that NTLA-6001, which incorporates our lead CD30 edit, showed complete tumor regression and protection from tumor rechallenge in a T-cell lymphoma model. We're now beginning IND-enabling activities for NTLA-6001. With the strength and breadth of our CRISPR-based platform, our strategy is to partner with others who possess complementary capabilities to maximize the value of our platform and gain future product rights to innovative therapies. This year, we've already completed two strategic collaborations. The first one with Kyverna, which is focused on advancing an allo CD19 CAR-T cell candidate for select immune diseases. The second one with O&A Therapeutics, which is focused on developing CRISPR edited NK cell therapies for cancer. In total, across our business economic transactions from the past 12 months, we have now gained options for commercial rights for up to seven additional therapeutic candidates. In addition, we have added new technologies to our leading toolbox, such as DNA writing that are complementary to our existing CRISPR/Cas9 and base editing capabilities. We continue to pursue additional capabilities that will allow us to employ the best and most appropriate tool for each therapeutic application. Finally, to support our growing pipeline, we have entered into a lease agreement to build a GMP manufacturing facility in Waltham, Massachusetts. This new facility will provide us with significant manufacturing capacity to support preclinical through commercial production of Intellia's investigational therapies. I now hand over the call to Glenn, our CFO, who will provide an overview of our first-quarter financial results.

Thank you, Laura, and good morning, everyone. Intellia continues to maintain a strong financial position to support our plans. And in particular, over the past few months, we've delivered on our strategy to expand our pipeline in a capital-efficient manner. Our cash, cash equivalents, and marketable securities were approximately $995 million as of March 31, 2022, compared to $1.1 billion as of December 31, 2021. The decrease was driven by cash used to fund operations of approximately $95.7 million and the acquisition of Rewrite Therapeutics for $45 million. The decrease was offset in part by $38.9 million in net proceeds raised from the company's ATM program and $8.4 million in proceeds from employee-based stock plans. Our collaboration revenue increased by $4.8 million to $11.3 million during the first quarter of 2022 compared to $6.4 million during the first quarter of 2021. The increase was mainly driven by our joint venture with AvenCell. Our R&D expenses increased by $93.8 million to $133.1 million during the first quarter of 2022, compared to $39.3 million during the first quarter of 2021. This increase was driven by $56 million of expense related to the acquisition of Rewrite, which includes a $45 million upfront payment and $10.5 million related to a potential stock-based earn-out payment. The remaining $37.8 million was driven by the advancement of our lead programs and the continued expansion of our development organization. Our G&A expenses increased by $8.8 million to $22.4 million during the first quarter of 2022, compared to $13.6 million during the first quarter of 2021. This increase was mainly related to the employee-related expenses, including stock-based compensation of $5.3 million. Finally, we expect our cash balance to fund our operating plans beyond the next 24 months. With that, I will turn the call back over to John for closing remarks.

Thank you, Glenn. We're already making significant progress against our 2022 strategic priorities. First, we're advancing a robust pipeline, including the wholly owned and partnered programs now with emerging products in the clinic. Next, we're expanding into new therapeutic areas with continued investment in platform innovation. Further, we're strategically licensing our technologies to accelerate development programs outside our key areas of focus. And importantly, we remain in a position of financial strength that enables us to realize our vision for Intellia. With that, we'd be happy to answer any questions about our pipeline platform.

The first question comes from Swapnil Malekar of Piper Sandler.

Great. So first one is with the fixed dosing regimen, are there any concerns in lighter patients who might get exposed to more than 1 mg per kg dose, especially related to safety? And then I have a follow-up.

David, do you want to give your views on how we think about the fixed dosing and safety?

Yes. Fixed dosing was based on looking at all the data that we had as we were going forward to Part 1. So you recall in part 1, what we saw and reported in February were deep reductions, 93% average reduction in 6 patients. And at that point, it was durable with variable follow-up from 2 to 12 months. We also then have the PK from this work. And what it showed is that the exposure of patients was not significantly affected by the weight of the patients. And we will be showing you more details of that in our upcoming presentations at EASL. So what that means, though, is that small patients and larger patients are essentially experiencing the same exposure of the drug. We think this is related to the fact that no matter what your weight is, depending on fat or not, your liver size is similar, and that's really the target of our drug, and that's where the exposure is coming out. So what we expect going forward, and this will be tested in part 2, of course, we want to confirm what we found from Part 1 is that we will see the same type of deep reductions, the good safety, and then be able to move forward to further studies.

Got it. And then one follow-up is although a little bit premature to discuss, but do you have any thoughts on the upsized and extended duration trial for IMS' cardio transform trial? And its implications to future Intellia strategy for a pivotal cardiomyopathy trial?

Yes. We did look at the announcement and some of the things they said about it. What they're saying is it's not based on any data they really know from their trial; they're really looking to have a more robust trial. What's important to us as it moves forward is we are going to learn from some of the ongoing trials. That one will come a little bit late for the trials we're going to do, but certainly, the trials from BridgeBio and from Alnylam will help inform our trial as we move forward.

I was going to ask for one on HAE. I'm wondering if you can elaborate on what preliminary proof-of-concept data could look like in the second half of this year? And have you decided to dose higher than 75 mg fixed? Or do you know at this point that that's not needed?

Maurice, there's a lot of questions in there. We can probably talk a little bit more about the dosing as the year goes on. But maybe David, what do you have in store for data releases and how are you thinking about the progress of that trial?

Yes. So for HAE, I think we've said a lot of times, this is using our modular approach. So what's important here is we could learn from what we did in NTLA-2001 and bring it to NTLA-2002. One of those important lessons is what's the safety of the product at the early doses? And with that, we did start at a higher dose. We started at 25 milligrams, which is basically equivalent to the 0.3 milligram per kilogram dose that was used in the NTLA-2001 trial. We will be bringing forth data at the next dose level, as you said, with 75 milligrams, which would be similar to the higher dose, the highest dose that we treated in the NTLA-2001 trial. So we do expect this to be safe based on what we know from NTLA-2001. And what we expect to see in terms of what we could report in the second half of the year in proof-of-concept, is seeing a decrease in the biomarkers, particularly pre-kallikrein levels and activity are both being looked at in this trial. And that, as we've seen in previous and other compounds, is very likely to be associated with a decrease in attack rate, actually very substantial.

I believe we may have lost David's audio. I can finish up, Maurice. We will definitely be able to discuss the impact on the biomarker. I think we will be able to share that information and we will use the same principles we have used previously to make judgments that are significant, interpretable, and consistent. While we cannot guarantee that we will share attack rates from a clinical perspective at this moment, it depends on having enough time to make those observations and understanding the patient characteristics. If we are able to share that information, we will certainly try to do so.

Got it. That's really helpful. And maybe a quick follow-up. If you can talk about the types of HAE patients that you're enrolling into the study as far as baseline attack rates at this point?

Well, the attack rates is not really the primary determinant. There's a threshold level. I mean we want to have everybody with obviously the disease diagnosed, and we're not requiring a high attack rate to get in. But these are all attack rates that have, over the course of, I think it's a four-month observation period, they should be expected to have had several instances of attacks within that time period. And so that's why you need to have a baseline and then a sufficient time to observe the patients thereafter.

I'll add one more question on NTLA-2002 if I can, and it's a two-part question. So I think this is actually the first time we're hearing about the 25 and 75 mg if I'm not mistaken. So first part is, since your cohort will be or at least looks like NF3 to 6 per cohort, are you able to comment on what the N was in the first cohort that just completed? And what determines the final N in each of these cohorts? And secondly, when we look at 25 and 75 mg fixed dosing, there was the NHP data that you presented at Quad AI last year, what dose level would this correspond to when we think about allometric scaling? And I've got a follow-up.

So a three-part question. Regarding the dosing of 25 and 75 fixed doses, David discussed its relation to the TTR program, which is based on preclinical results and the similar dosing form we utilize in TTR. A general guideline for relating animal doses to human doses is to divide by approximately three, although it's more complex due to various factors, including the activity of the guide. For large cohorts, as we've done with the TTR program, if a dose-limiting toxicity is observed when starting with an NF3, we expand to an additional three patients, which helps determine the final number of patients in that dose cohort. Can you repeat your second question, Dae?

I think that's all I have for now. I can move on to the follow-up question regarding the LNPs related to NTLA-2003 and NTLA-3001, especially focusing on NTLA-3001. Is it safe to say that the LNPs for 3001 will differ from those used in 2001 and 2002, including 2003? Additionally, in the prepared remarks, you mentioned another in vivo candidate selection expected before the end of 2022. Does the progress of 3001 suggest that the lung program may be the next one to advance?

Well, one of the things to remember is that all of the work that we're doing that targets the liver, whether it's 2001, 2002, 2003 or the 3001 program, which remember is hybrid-based as an NP and an AAV component. All of this goes back to the modular approach that we've highlighted from the beginning, which starts with essentially the same lympho show in the cargo elements, which consists of mRNA and the guide RNA are all the same with the exception of the last 20 nucleotides or so of the guide RNA. So with respect to LNP across all these programs, there is just a very, very extensive similarity, and I would think about it that way. With 3001, we're bringing in AAV into the equation as a way of delivering the transgene to be inserted. So that's the distinction. And the way we're thinking about 2003 or 2003 and 3001 is that while they both target aspects of alpha-1 antitrypsin deficiency, they're really independent of each other. 2003 targets the gene itself and eliminates the production of the defective protein and 3001 a source of wild-type protein to forestall progression of lung disease. So for simplicity's sake, we treat them differently, but we would be in a position to merge them at the end within a single patient if we think that that's warranted.

Just on the HAE program as well, if you do see an optimal profile, where do you see it fitting into the treatment paradigm just given the current options here for these patients?

David, are you back? We lost your audio for a moment. What are your thoughts on how this treatment fits into the overall care for HAE patients?

Sorry for my technical disturbance this morning. So this treatment, of course, would be a prophylaxis. What we would expect to see getting reductions and what's been seen with other compounds in the 60% to 80% range is that you would have a greater than 90% reduction in attacks and perhaps even better as you get to those higher levels. So what we would have, we think, is a one-time treatment that would prevent attacks potentially for the lifetime of the patients. Where this sits in, right now, people are getting prophylaxis either by injection or by pills. The injections work better in general than the pills, but many patients want to avoid that because of the discomfort, the inconvenience, et cetera, of taking an injection. So we think that by getting excellent prophylaxis for patients and also being a one-time treatment that avoids any issues, it's really continuous reduction, any issues of recovery at levels that could occur with prophylaxis, this would become the preferred treatment for patients.

Just in terms of the EASL update, will we be able to see some polyneuropathy functional symptom data at this time? Or maybe when would you be in a position to provide this update? How long do you want to follow those patients out?

David, why are we going to see some clinical data from the polyneuropathy arm?

In the polyneuropathy arm, the measures are taken later in the treatment process, so it does take time to obtain them and they will not be available for EASL yet. However, we do know that the reductions we are observing, particularly a 93% reduction, outperform those achieved with other agents. This suggests a potential for better clinical outcomes for patients. Data from silencers and other forms of amyloidosis indicate that lower protein levels in patients correlate with improved clinical outcomes. Although we won't have specific clinical data to present, we rely on findings from other studies to anticipate the likely effects in this context.

Congratulations on the progress. This is Joon's representative. Our first question is about HAE. There has been a 95% reduction in prekallikrein and a 97% reduction in attack rates after the first month. What is your goal for this treatment, and how confident are you in achieving or exceeding these levels?

Thanks for the question. When we consider the treatment of HAE, there are several factors that patients, doctors, and payers want to address. The primary focus is the disease itself. Based on our preclinical data and the TTR data we've collected, we're confident that we can meet, and possibly exceed, the accomplishments of virtually any current treatment method, including the recent data you've mentioned. From an activity standpoint, we believe we're making good progress, although this needs to be validated in ongoing clinical trials. We are all eager to observe attack rates as we gather more background data from the study. As more data becomes available, we will share our findings. Additionally, we recognize other important factors that impact the treatment of these patients. One major concern is the treatment burden itself. When you talk to patients and doctors, they often highlight the challenges associated with achieving the desired effects. These individuals are typically quite normal from a health perspective, often including younger patients and sometimes adolescents. Therefore, once their attacks are somewhat managed, the main concern shifts to the treatment burden. We believe that a single, potentially lifelong treatment would be a significant advancement for these patients, which is what we hear from both patients and doctors. Another critical aspect is the cost associated with these patients. In the United States, the most effective therapies can cost over $1 million a year just for access to the medication, which is an extraordinary expense, especially considering the age at which these patients are diagnosed. We see a significant opportunity to reduce the costs for these patients and for the healthcare system overall. In summary, we believe there will be appealing aspects of this treatment for patients, payers, healthcare providers, family members, and caregivers, and we anticipate that it will be positively received. Regarding the treatment approach, while gene editing may not be the first choice for doctors, we believe that as more information becomes available and we better understand how this therapy performs, it will present a compelling option for patients compared to other existing treatments.

That's very helpful.

This is Ryan on for Debjit. Just curious for NTLA-2002, what do you see as a good or great outcome for the interim data readout? And the second question for NTLA-3001. In some of our KOL discussions, the hypothesis was offered that insertion of wild-type AAT expression may result in suppression of PiZ through a negative feedback loop. Is there any precedent for this? And/or has Intellia observed this phenomenon in preclinical studies?

Well, I'm going to turn to Laura with respect to NTLA-3001. But first, let me address NTLA-2002 and what do we think is a good data readout? I think the NTLA-2001 data is certainly setting our expectations in terms of the range of knockdowns. And all of these programs do have some differences, different patients and how they perform, et cetera. And the guide itself is going to have some of its own idiosyncrasies. But we would expect to see knockdown levels approximate where we've been in the TTR program. But the most important readout is going to be attack rates. I mean, that's the final indicator of relating whatever editing one gets to what matters to the patient. And so that's going to be a story that lags where we are on a knockdown story. So I would say, let's see how the data accumulates. I said, we'll share it later this year and I would expect to see an interesting story develop as we would want to advance as efficiently as possible. Laura, do you want to speak to NTLA-3001 and how you think about the introduction of the transgene in patients with the underlying mutation?

Yes. And you're basically right, so yes, there is the possibility that if you do have good expression of the PiZ, you may be able to restore the heterozygous phenotype in those livers, right? So that's one of the type of themes we are pursuing with NTLA-3001. And the data we'll share when we're ready to share it.

Just one regarding the NTLA-2002 HAE program. So when we look at the dose, you do jump from 0.3 milligram per kg to 0.9 mg given your ATTR program of 0.7 milligram per kg, is that because you would like to achieve a higher level of knocking down? And I remember, John, you previously mentioned that 70% reduction would be sufficient to translate to clinical benefit. Was that the maximum knockdown level you wanted to achieve? Or do you want to even want to go beyond that 70% reduction?

Well, thanks for the question, Gena. I mean, it's a couple of things. Remember, first of all, while these are modular systems where the elements are essentially the same, going from TTR to HAE to alpha 1, et cetera, each individual guide will have its own characteristics with respect to potency. So we do need to establish, we can't just assume. We do need to establish a dose-response curve. And that's exactly what we're doing so that we can see how these individual doses relate to the knockdown of kallikrein, which is the biomarker readout that we're using. We extrapolate from those numbers, those stock down numbers to what we believe will be the expected clinical attack rate, and that comes from the work of others who have been establishing those relationships in advance of our work. But it relates to the questions that were asked before, what's meaningful for patients and what's really going to drive a profile of the drug that advances the ball for them. And we believe that this HAE may ultimately be a curable illness here, and that's certainly what we're striving for. And the expectation would be that deeper knockdowns are likely to drive those sorts of outcomes. So we'll play out our Phase I study and look for that information so that we can make the best judgment for the doses that we carry forward into what would be a registrational study. But I wouldn't start by having a particular number from a dosing perspective in mind. It's really going to be what's the readout, and then we'll make the judgment as we go, which I think are the fundamentals of good drug development.

John, would the knockdown also be the specific number you'll be looking for like 70% that you mentioned in the past? Will you be looking for like targeting that knockdown level?

We clearly want to have levels that go beyond 60%. And we've said that pretty much from the beginning, and that relates to what we see with tech zero and the good outcomes that they've had. So for us, 60% would absolutely be a threshold in terms of how we think about the drug and the relationship with that biomarker to the clinical data. The ultimate data, though, Gena, is going to be the clinical readout. And we will be testing levels of reduction that go well beyond 60% because that's where we believe you're going to get those really, really good clinical outcomes.

Congrats on the progress. Maybe a quick one. The FDA obviously recently issued the guidance on gene editing. So wondering if you can comment on what was your take on that document, and maybe bigger picture, how you're thinking about implications for filing your first IND? And I have a follow-up.

As we interpret the guidance, it aligns well with our approach to running the programs. There are several components involved, such as the preclinical work and the assessment of both on-target and off-target effects of the drug. Additionally, there is limited guidance related to initial clinical programs, as each program has unique considerations. The key point from the FDA regarding the clinical aspect is to focus on the benefit-risk evaluation, which is also our starting point for all these programs. Thus, we were not surprised by the guidance. We believe we have largely addressed the considerations outlined in the guidance, meaning there wasn't much that changed or added to our existing work. We are deeply engaged in discussions with various regulatory agencies, including the FDA, which certainly meet and exceed the specifics set forth in the guidance documents. I find the guidance to be suitable and a good initial reference for newcomers in the field. As a company involved in this area, we are committed to maintaining high standards, particularly concerning the thoroughness of off-target characterization, which we appreciate as a welcome addition to the FDA's guidance. Moreover, as highlighted in our publication in the New England Journal, we believe we have met the standards that have been established.

Got it. Got it. Super helpful. And then maybe quickly, what's the latest thinking on IP? I know CVC is obviously appealing, but how do you think about potential sublicensing agreement from the Broad should the decision be ultimately upheld?

Sure. The process will continue. The findings so far are not final. The current findings do not influence our decisions or actions. We are moving forward with all our progress. Since 2015, we've maintained that these findings do not impact our program advancement. It benefits everyone, including the Broad, to work outside the very limited scope of this specific patent if they wish to further their own work. At some point, the legal process will unfold, and I believe there are other avenues to reach an agreement.

The last question will come from Jay Olson of Oppenheimer.

Congrats on the progress. Since you have a large number of early-stage clinical programs in your pipeline and preclinical programs, can you talk about how you're prioritizing all of those programs and also how you're optimizing your overall capital allocation?

Yes. It's a really important question, and I appreciate that you asked it. We start by pursuing targets with modalities that we think are going to be highly differentiated and bring really important medical advances if they perform to the level that reaches our expectations. From the outset, we've wanted to generate a lot of optionality within the company and within our pipeline because we've known that there's lots to learn. I mean it's just a new platform, there's new approaches, et cetera, et cetera. You'll see somewhat of a bias to the in vivo work. The results that we saw with the TTR program, we think broadly speak across the in vivo pipeline, and that's something that we're very, very enthusiastic about. The modular approach allows us to move that forward. On the ex vivo side, we're doing it in a very stepwise fashion. What we try to do is isolate an important question, what to us is a convincing answer, and then step forward as those programs play out. Right now, I mean, we're very, very interested in understanding how our approach to a T-cell receptor performs because we think once we understand that with the platform we've created, we will open up a space that gets outside the very narrow and extremely crowded, largely B-cell-driven CAR-T space. So that's one important us. And the other one is just showing that the allo platform performs at the high level. And then you'll see from the collaborations that we're doing, we look to extend our reach by taking technology aspects of the work we've done, perhaps even individual products, and work as appropriate to complement our reach. And together, we think that that's the best way for it. But we will, as with any pipeline, prune and make decisions as appropriate as we accumulate and move forward in what we think is the best possible way to identify the most favorable attributes of any of the elements that we're working on.

Great. Thanks so much, and thanks, everyone, for joining us today and your continued interest and support in Intellia, and we certainly look forward to updating you on our progress in the future. Have a great day.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.