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spk17: Good morning. My name is Drew, and I will be your conference operator today. And welcome to the Intellia Therapeutics first quarter 2022 earnings conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call up for your questions. Please be advised that this call is being recorded at the company's request. If you require operator assistance, press star then zero. At this time, I would like to turn it over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intelia. Please proceed.
spk07: Thank you, Operator, and good morning, everyone. Welcome to Intelia Therapeutics' first quarter 2022 earnings call. Earlier this morning, Intelia 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 of Intelia's website at inteliatx.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, Intelia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for discussion of potential risks and uncertainties. All information presented on this call is current as of today. and Intelia undertakes no duty to update this information unless required by law. Joining me from the Intelia side are Dr. John Leonard, Chief Executive Officer, Dr. David Levwall, 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 Intelia'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.
spk03: Thank you, Ian, and thank you all for joining us this morning. At Intelia, 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 that 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. In six patients treated with a single one make per gig dose, a 93% mean and 98% maximum reduction was achieved 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 these 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 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 healthcare systems to improve patient access to innovative medicines will be invaluable to Intelia. In addition, her appointment is an important step forward as we believe that it's 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 Lebwall, who will review the NCLA 21 data in greater detail and detail progress across our pipeline. David?
spk06: Thanks, John, and welcome, everyone. I'll begin with review of 2001 and our recent data update. We are developing 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 one trial of 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 were 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 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 one milligram per kilogram of 2001 led to a 93 percent mean and a 98% maximum reduction in serum TTR by day 28. And finally, mean reductions were maintained through the observation period, ranging from two 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, 2001 has the potential to halt and perhaps even to reverse the course of this disease. I'm completing the dose escalation portion of the polyneuropathy arm Intelli is now evaluating a six dose of 80 milligrams in part two of the phase one study, which is expected to deliver a similar exposure to one 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 Easel International Liver Congress, which is taking place June 22nd to 26th. 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. 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 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 on patients remains significant. To that end, we're applying our modular LNP delivery system to 2002 to knock out the KLKB1 gene in the liver to permanently reduce plasma calocrine protein and activity. As a point of reference, a 60% reduction in pre-calocrine activity has been associated with a clinically relevant reduction in HAE attacks. To date, In non-human primates, Entelia has demonstrated our ability to achieve greater than 90% reduction of both pre-calocrine protein and activity after a single dose, which remains durable through a two-year observation period. These results, if achieved in humans, highlight the potential of 20.02 to provide continuous suppression of calocrine 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 1-2 study for 2002. We've completed dosing in the first cohort, evaluating 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 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 homogeneous robust cell products that epitomize the patient's natural immune system for the treatment of cancer and autoimmune diseases. For our first program, 50-01, we are employing 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 one two-way 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. I'll now hand over to Laura, our CSO, who will provide updates on our platform and R&D efforts.
spk12: 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 treatments relevant to the particular disease phenotype. This includes NTLA-3001, our gene insertion candidate for the lung disease, and NTLA-2003, a knockout candidate for the 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 Keystone 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 DCRT and CAR-T cell therapy. This data highlighted that NTLA-60-01, which incorporates our lead CD30 CAR construct, showed complete tumor regression and protection from tumor rechallenge in a T cell lymphoma model. We're now beginning IND enabling activities for NTLA-60-01. 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 Kiberna, which is focused on advancing an allo-CD19 CAR-T cell candidate for select autoimmune diseases. The second one with ONK Therapeutics, which is focused on developing CRISPR edited NK cell therapies for cancer. In total, across our business development 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 Walton, Massachusetts. This new facility will provide us with significant manufacturing capacity to support preclinical through commercial production of intelligence investigation therapies. And now hand over the call to Glenn, our CFO, who will provide an overview of our first quarter financial results.
spk03: Thank you, Lauren. Good morning, everyone. Intelia 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. 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 Avancel. 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 Freeride, 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 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 robust pipeline, including Bacoli-owned and partnered programs, now with multiple programs in the clinic. Next, we're expanding in the 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 and platform. Operator?
spk17: We will now begin the question and answer session. To ask a question, you may press star then 1 on your telephoned keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star and 2. At this time, we will pause momentarily to assemble our roster. The first question comes from Swetno Melikar of Piper Sandler. Please go ahead.
spk14: Great. Good morning. Thanks for taking my questions. So first one is with the fixed dosing regimen, are there any concerns in lighter patients who might get exposed to more than one mcper kick dose, especially related to safety? And then I will follow up.
spk03: David, do you want to give your views on how we think about the fixed dosing and safety?
spk06: Yeah. No, thank you. The fixed dosing was based on looking at all the data that we had as we were going forward to part one. So you recall in part one what we saw and reported in February were very deep reductions, 93% average reduction in six patients, and that at that point it was durable with variable follow-up from two to 12 months. We also then had 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 essentially are experiencing the same exposure of drug. And we think this is related to the fact that no matter how much what your weight is, depending on fat or not, that 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 two, of course, we want to confirm what we found from part one, is that we will see the same type of deep reductions, the good safety, and then be able to move forward to further studies.
spk14: Got it. And then one follow-up is, although like a little bit premature to discuss, but do you have any thoughts on the upsized and extended duration trial for IMS's CardioTransform trial and its implications to future Intelia strategy for a pivotal cardiomyopathy trial?
spk06: Yeah, 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, you know, 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 Bridge Bio and from Onylin will help inform our trial as we move forward.
spk14: Great. Thank you for taking my question.
spk17: The next question comes from Mari Raycroft with Jefferies. Please go ahead.
spk08: Hi. Good morning. Congrats on the progress, and thanks for taking my questions. I was going to ask one on HAE. I'm wondering if you can elaborate on what preliminary proof of concept data could look like 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?
spk03: 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?
spk06: Yeah, 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 2001 and bring it to 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 2001 trial. We will be bringing forth data. And the next dose level, as you said, was 75 milligrams, which would be similar to the highest dose that we treated in the 2001 trial. So we do expect this to be safe based on what we know from 2001. And what we expect to see in terms of what we report in the second half of the year in proof of concept is seeing a decrease in the biomarkers. And the particularly pre-calocrine levels and activity are both being looked at in this trial. And that, as we've seen in previous and other compounds, that is very likely to be associated with a decrease in attack rate, actually a very substantial decrease.
spk03: I think we may have lost David's audio there. I can just finish up. Maury, you know, for sure we'll be in a position where we can talk about the effect on the biomarker, and I think that we'll be in a position to assure that, and we'll apply the same principles that we've applied in the past in terms of making those judgments about, you know, significant, interpretable, and consistent. And if we're in a position to share attack rates from a clinical point of view, we can't, you know, guarantee that at this point because it ties down to having sufficient time to make those observations and the characteristics of the patients. We will certainly, if we're in a position to share that, we'll try to share that as well.
spk08: Got it. That's really helpful. 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?
spk03: 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 there's, we're not requiring a high attack rate to get in. But, you know, these are all attack rates that have, over the course of a, 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, you know, sufficient time to observe the patients thereafter. Got it.
spk08: Okay, thanks for taking my questions.
spk03: Sure, thank you.
spk17: The next question comes from Dagon Ha of Stifel. Please go ahead.
spk00: Great, good morning. Thanks for taking our questions. I'll add one more question on 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 MIG, if I'm not mistaken. So first part is, since your cohort will be, or at least looks like, N of three to six per cohort, are you able to comment on what 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. Thank you.
spk03: A three-part question. With respect to the dosing of 25 and 75 fixed doses that we just referred to, David spoke to how that relates to the TTR program. And, you know, that is all derived from looking at the preclinical results and drawing heavily from what is the highly, highly related dosing form that we're using in TTR. So, you know, a simple rule of thumb if you want to try to extrapolate to the animals, it's more complicated than this, but if you divide by approximately three, you'll get to a similar sort of effect. If there's more complications than that, you've got to take into consideration the activity of the guide, et cetera. But for the purposes of discussion, that's how I would do it if I were looking from animals to humans. With respect to how large the cohorts are, the rules are, you know, as we've done with the PTR program, one starts with an N of three if a dose limiting toxicity is reached. that drives an expansion to an additional three patients. And that would determine the final number of patients, the final capped number of patients within a dose cohort. And repeat your second question, Mike.
spk00: I think that's actually all of it. So I can just go on into the follow-up question, which is, The LNPs, when we think about 2003 and 3001 going after either the liver or the lung, I guess just curious on the 3001, is it correct to assume that the LNP used here is going to be characteristically different from the ones used in 2001, 2002, and presumably 2003? And when, I guess in the prepared remarks, you alluded to another in vivo candidate selection before year end 22. I guess, does the 3001 progress imply that a lung program might be up next? Thank you very much.
spk03: 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, has an LMP 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 limpid shell and the cargo elements, which consists of mRNA and guide RNA, are all the same with the exception of the last 20 nucleotides or so of the guide RNA. So with respect to the LNP, across all of these programs, there is just very, very extensive similarity, and I would think about it that way. With 3001, we're bringing AAV into the equation as a way of delivering the transgene to be inserted. So that's the distinction. And, you know, 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. 20.03 targets the gene itself and eliminates the production of the defective protein. And 30.01 provides 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.
spk00: Excellent. Thank you so very much. Sure.
spk17: And in the interest of time, we kindly ask that you keep yourself to one question. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
spk01: Good morning, thanks for taking my question. Just on the HAU 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?
spk03: David, do you wanna, I think you're back. We lost David's audio for a minute there, but David, where do you think this treatment fits into the treatment of HAU patients?
spk06: Thank you, and I'm sorry for my technical difficulties this morning. So this treatment, of course, would be a prophylaxis. What we'd 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 fits 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 the... both 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 of levels that could occur with prophylaxis. This would become the preferred treatment for patients.
spk01: Thank you.
spk17: The next question comes from Joseph Thorne with Cohen and Company. Please go ahead.
spk13: Good morning, and thank you for taking my question. Just in terms of the easel 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 for? Thank you.
spk03: David, when are we going to see some clinical data, polyneuropathy or
spk06: Yeah, so in the polyneuropathy arm, those measures come at later points in treatment, so it does take a long time to get it and not yet available for evil. However, what we do know with the type of reductions we're seeing, and as mentioned, 93% reduction, this is better than what's been achieved with other agents. And with that is also expected to potentially achieve better results, clinical results for patients. If you look at data available from silencers, if you look at other types of amyloidosis, the lower the protein the patients have, the better their clinical outcome. So we won't have the clinical data to show, but we do depend on the results of other studies to predict what will be happening with this type of effect.
spk13: Great, thank you.
spk17: The next question comes from June Lee with Truist Securities. Please go ahead.
spk05: Hi, good morning and congrats on the progress. This is Mehdi on for June. So our question, the first question is related to HAE. IONIS has, Donnie Dollerson, a 95% reduction in pre-calcarin and a 97% attack rate reduction after basically month one, five to 17. So the question would be, what is your goal for this treatment and how confident you are in reaching at least these levels or surpassing them? Thank you.
spk03: Maybe I'll address that, thanks for the question. You know, the way we think about HAE and its treatment is that there's various elements that patients, doctors, and payers are going to want to address. Obviously, the first is the disease itself, and based on our preclinical data and extrapolating somewhat from the TTR data we've accumulated so far, we're pretty confident that we'll be in a position to certainly meet and we think ultimately perhaps surpass what's been achieved for virtually any treatment modality thus far, including, and I'm not sure those numbers are entirely representative of what you just described, but including some of the more recent data. So I think from an activity point of view, we're on the right track here. Obviously, that needs to be confirmed in ongoing clinical trials, and we're all very interested in seeing attack rates as we accumulate additional back-down data in the ongoing study. And as I said earlier, you know, as that data accumulates, we'll certainly share it. But we also think that there's a couple other elements that – bedevil the treatment of these patients. Number one is the treatment burden. If you go and ask patients, if you ask doctors, one of the troublesome elements is what it takes to get to those effects. These are otherwise pretty normal people from a disease point of view, and oftentimes they're young, including sometimes adolescents. And so the number one issue, once their attacks are somewhat within control. It's a treatment burden itself. And we believe that a one and done sort of potentially lifelong treatment will be a major advance for those patients. And that's certainly what the patients and the doctors tell us. But there's another element as well, which is the cost of these patients. And if you look certainly in the United States for the most effective therapies, many of these patients have, just for access to their medicine alone, costs of over a million dollars a year, which is an extraordinary number over the lifetime of these patients, particularly when you think of the age of onset and when they're diagnosed. And so also from an economic point of view, we believe that there's a massive opportunity to improve on the cost to these patients and to the healthcare system. So I think all things considered, You know, there will be attractive elements of this treatment for patients, payers, the doctors, the family members, caregivers, et cetera. And, you know, we expect that it will be well received. I mean, when you think about this, and I think Salvino asked a question about the treatment paradigm, I don't think gene editing is going to be the very first intervention that doctors do. I wouldn't recommend that as a physician. But certainly as information is accumulated and as we understand how this drug performs, I think it's going to be a very, very attractive offering for patients in the scheme of all the other elements that are available.
spk05: That's very helpful. Thank you.
spk03: Sure.
spk17: The next question comes from Devjit Terapadhyay with Guggenheim. Please go ahead.
spk02: Hi, this is Ryan for DebJIT. Just curious for 2002, what do you see as a good or great outcome for the interim data readout? And the second question for 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 precedence for this and or has Intelia observed this phenomenon in preclinical studies?
spk03: Well, I'm going to turn to Laura with respect to 3001. But first, let me address 2002 and what do we think is a good data readout. You know, I think that 2002, I'm sorry, the 2001 data is certainly setting our expectations in terms of the range of knockdowns. And, you know, 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 that 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 legs where we are on the knockdown story. So I would say, you know, let's see how the data accumulates. As we've said, we'll share it later this year. And I would expect to see an interesting story develop that as, you know, we would want to advance as efficiently as possible. Laura, do you want to speak to 30.01 and how you think about the introduction of the transgene in patients with the underlying mutation?
spk12: Yes. And, you know, briefly, right, so, yes, there is the possibility that if you do have good expression of the, you know, the wild cat allele, you may be able to restore the heterozygous phenotype in those livers, right? So that's, you know, one of the hypotheses we are pursuing with 30.01. And the data will, you know, be shared when, you know, we're ready to share it. So stay tuned.
spk02: Thanks for that.
spk17: The next question comes from Gina Wang with Barclays. Please go ahead.
spk11: Thank you for taking my question. Just one regarding the 2002 HAE program. So when we look at the dose, you know, you do jump from 0.3 milligram per kit to 0.9, giving your ATTR program of 0.7 milligram per kit. Is that because you would like to achieve 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 you wanted to even wanted to do a beyond 70% reduction?
spk03: Well, thanks for the question, Gina. 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 PTR 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 calicrate, which is the biomarker readout that we're using. We extrapolate from those numbers, those knockdown 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. You know, 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, you know, 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 one 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.
spk11: John, like would be the knockdown also be 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?
spk03: 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 TAC0 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 of that biomarker to the clinical data. The ultimate beta, though, Gina, is going to be the clinical readout. And, you know, we will be testing levels of reduction that, you know, go well beyond 60%, because that's where we believe you're going to get those really, really good clinical outcomes.
spk11: Thank you.
spk03: Sure.
spk17: The next question comes from Luca Isi with RBC. Please go ahead.
spk15: Oh, great. Thanks so much for taking my question. 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 a bigger picture, how are you thinking about implications for filing your first IND? And I have a follow up.
spk03: As we read the guidance, it really conforms with how we think about how we run the programs. We, you know, there's various elements in there. It's the preclinical work. It's the characterization of the on and off target effects of the drug. And there's some, I'd say, very limited guidance that speaks to, you know, initial clinical programs because they tend to be, you know, each program is its own thing with its own particular considerations. You know, the fundamental point, I think, that the FDA made with respect to the clinical was, you know, just think about benefit-risk, which is exactly where we start with all these programs. So that was no real surprise to us. Our view is that we've pretty much addressed most of the considerations that we saw in the guidance. So there really wasn't that much that added to the work that we're doing or changed how we think about it. And we're well into discussions with different regulatory agencies, including the FDA, that certainly address and surpass with respect to the specificity of the requirements of what's laid out in those guidance documents. By the way, I think the guidance is appropriate. I think it's a good starting point for people coming into the space. And it's our interest as a company active in the space to have high standards. And one of the things that we feel very strongly about is the adequacy of off-target characterization, which we think the additional guidance from the FDA is welcome there. But as you have seen in the publication we had back in the New England Journal, we think we've at least addressed any standards that have been laid out.
spk15: Got it.
spk03: Got it.
spk15: Super helpful. And then maybe quickly, what's the latest thinking on IP? I know CVC is obviously appealing, but how are you thinking about potential sub-licensing agreement from the broad should the decision be ultimately upheld? Thanks so much, guys.
spk03: Sure. The process will play out. The findings thus far, the process is incomplete. The findings thus far have no bearing on how we decide or to do what we do or what we choose to do. You know, it's full speed ahead with all the programs that we do. We've said since 2015, I think now, that, you know, none of these findings affect how we progress our programs, and it's in everybody's interest, including the Broad's, with respect to work outside of, you know, a very, very limited area that this particular patent refers to if they want to progress their own work as well. I think at some point there'll be, you know, if the legal process doesn't play it out, I'm sure there's other ways to get to an agreement here.
spk15: Got it. Thanks so much, guys.
spk17: The next question comes from Steve Seathouse of Raymond James. Please go ahead.
spk16: Hi, this is Timur Ivanovic of On4Steve. So just a quick question for us in terms of the easel presentation. So you've mentioned presenting exposure details. And we didn't see any mention of a biopsy. Will you present liver biopsy data to maybe see percent of edited cells to measure editing efficiency over time?
spk03: No, because there's no biopsies to present. We and investigators and regulators, for that matter, all agree that that's not a particularly informative analysis. and probably subjects patients to more risk than any kind of benefit that one might get. I think just about anybody who's looked at the space now believes that it's far more informative to do this on a preclinical basis where you can take healthy donor cells, these are primary hepatocytes, and subject them to many fold higher levels of concentration, which we think is what defines an adequate probing of the off-target profile of these editing agents and look with that provocative testing for any aspects of off-targets. And we've done that, and that's the work that was published in the New England Journal. A biopsy would provide far less information than that.
spk16: Okay. Thank you very much.
spk03: Sure.
spk17: The next question comes from Mani Fuhar with SVP Securities. Please go ahead.
spk04: Hey, thanks for taking the question. Something a little more, I guess, atmospheric and broad than some of the specific questions around individual programs that have been most of this call. Obviously, there's, you know, we're going to start seeing with Alpha 1 Antitrypsin a little data from you guys talking along. We have some partnerships looking at, diseases of bone marrow, sickle cell specifically. Can you comment on what the timeline is that would be reasonable for us to start seeing data in some human with an illness outside of the liver? And how should we think about delivering modalities as part of the modularity of your platform?
spk03: So do you consider lung disease? of alpha-1 antitrypsin as disease outside the liver, or are you considering that a liver-related disease? How do you think about that, Manu?
spk04: I would primarily consider a liver-related disease since you're delivering your editing constructs to hepatocytes. Yeah, okay.
spk03: So I can't give guidance in terms of some of these other programs, but You know, there's a lot of interest and work going on within the company of moving beyond the liver. We've talked about some of the work that we've done in bone marrow-related diseases, specifically sickle cell. There, as that data matures and we have more to present at a preclinical level, we would share that, and then we can start thinking about what that means for disease, you know, for development candidates and timelines, et cetera. But for the, you know, immediate future here, I think we're going to be related to the programs that we have in the clinic. And those are the ones that we've been talking about today. All right.
spk04: Thanks.
spk03: Sure.
spk17: The next question comes from Yanan Zhu with Wells Fargo. Please go ahead.
spk09: Hi, thanks for taking my questions. So first on the easel presentation, in terms of durability, could we expect incremental three-month additional durability for all the patients compared with your March presentation?
spk03: David, do you want to say a word about just what to expect at the easel presentation?
spk06: Yeah, so as you mentioned, we had, and mentioned before, about two or 12 months follow-up. And we will start to fill in cohorts here with more additional follow-ups. We think that'll be very valuable that with the additional follow-up, we'll be able to talk about a number of patients who've reached important markers in their time. And we do think when we get there, that data will speak for itself. So we really look forward to showing that soon.
spk03: I think it's important to add maybe that as the study progresses, the data is accumulated, I think, David, in three monthly intervals. And so while we have a lot of individual data points to present early in the observation phase, as these patients are followed for a longer period of time, it comes essentially in quarterly intervals. And so going forward, that's the way I think about this.
spk06: And actually, it goes from 12 to 18 months. So there is a big gap from the 12 to 18 month point, just so people, for expectations. But we'll make that very clear in the presentation, what the time point is.
spk09: Got it. That's very helpful. And then my other question is on 601. Thanks for your disclosure. at the Keystone meeting just this or last week, actually over the weekend. So with regard to your approach of knocking out receptor X to address both CD8 and NK cell rejection from the host CD8 or NK cells, I think the This knocking out this receptor knocks down HLA1 but does not eliminate HLA1. In order to prevent NK rejection, that's probably why you did not completely, you know, aim for complete elimination of HLA1. But because you didn't eliminate HLA1, there is still some host CD8 activation. According to the preclinical data presented at Keystone, how should we think about how effective this approach will be compared with the more conventional HLA-1 knockout approach? Thank you.
spk03: Laura, do you want to contrast the approach we're taking with what we see others doing? You know, I just hasten to add, while Laura comes on here, that we've not disclosed yet the precise edits that we make. But at that presentation, we showed, generally speaking, what were, you know, the characteristics that we're attempting to achieve. So, Laura, do you just want to describe, you know, exactly what, you know, what it is that we want in the attributes of these cells and why we're excited about 6001?
spk12: Yeah, and I'm sorry, but we're not yet describing exactly how we're doing it, but, you know, there are three immunological problems that, you know, you need to work on for allogeneic therapies that, you know, we believe we have addressed with our technology, right? So it's prevent graft-versus-host disease, then prevent rejection by CD4 and CD8 T cells, and, you know, others are doing that to some degree the concern with, you know, other allogeneic therapies in development is that they do not prevent rejection by NK cells. And there is clinical data that now it's, you know, it's supporting that with, you know, short duration of effect, right? So what we've been able to do was to ensure that, you know, our cells overcome all these three limitations and they are not rejected by host NK cells. And at the same time, retain all the on-target activity that results in, you know, these, you know, very efficient antitumor activity. The other thing to highlight here is that, you know, these cells are generated using our Intelia engineering process, where we do an LNB-based analysis. engineering, sequential editing, and that allows us to have very high quality cells that are not exhausted and that they can be manufactured with high quality attributes.
spk03: One thing to add to the work that Laura and her team have brought forward there is that we view this Allo approach as essentially a platform for the company. And 60.01 is the first example of our own wholly owned product moving forward. But it relates to the work we've done with Kiverna and Avancel, where as partners understand more about the shortcomings of what is the standard ALO approach out there. I think people are increasingly excited about this very differentiated approach. and what it can bring for patients, which is essentially off the shelf, the true ability to have something there immediately, but that's also going to persist beyond the, in our judgment, fairly poor performance of standard approaches where grafts tend to be vastly reduced in cell number within three to four weeks or completely eliminated. This, we think, solves that approach. or that deficiency, I should say.
spk09: Got it. Thanks for the cover.
spk17: The last question will come from Jay Olson of Oppenheimer. Please go ahead.
spk18: Oh, hey, congrats on the progress and thank you for the update. 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? Thank you.
spk03: Yeah, 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. And 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 PTR program, we think, broadly speak across the NVivo pipeline, and that's something that we're very, very enthusiastic about, and 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, get what to us is a convincing answer, and then step forward. uh as those programs play out and 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 space that gets outside the very narrow and extremely crowded uh largely b-cell driven car t-space so that's one important question for us and the other one is just showing that the aloe platform performs at the high level and then you see from the collaborations that we're doing that we look to extend our reach by taking technology aspects of 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 forward. But we will, as with any pipeline, prune and make decisions as appropriate as we accumulate data and move forward in what we think is the you know, the best possible way to identify the most favorable attributes of any of the elements that we're working on.
spk17: This concludes our question and answer session. I would like to turn the conference back over to Ian Karp for any closing remarks.
spk07: Great. Thanks so much. And thanks, everyone, for joining us today and your continued interest and support in Intelia. and we certainly look forward to updating you on our progress in the future. Have a great day.
spk17: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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