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, 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 Intellia. Please proceed.
Thank you, operator, and 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 & 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 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 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 solution, 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 innovation.
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 mg/ kg d ose group, treatment with NTLA-2001 led to a mean serum TTR reduction of 86% by day 28.
In six patients treated with a single 1 mg/kg 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 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 Bhanji 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 Intellia. 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 Lebwohl, who will review the NTLA-2001 data in greater detail and detail progress across our pipeline. David?
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 I trial of 2001, d emonstrating 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 1 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 1 mg/ kg of 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 2-12 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.
On completing the dose escalation portion of the polyneuropathy arm, Intellia is now evaluating a fixed dose of 80 mg in part 2 of the phase I study, which is expected to deliver a similar exposure to 1 mg/kg. We are happy to share that we have recently dosed the first patient in this 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- 26. In the cardiomyopathy arm of the study, we continue to dose patients in separate dose escalation cohorts at 0.7 mg/kg and 1 mg/ kg.
Following results from this 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 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 on patients remains significant. To that end, we're applying our modular LNP delivery system to NTLA-2002 to knock out the KLKB1 gene in the liver to permanently reduce plasma kallikrein protein and activity. As a point of reference, a 60% reduction in prekallikrein activity has been associated with a clinically relevant reduction in HAE attacks.
To date, in non-human 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 two-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 mg, and have advanced to the second dose level at 75 mg. 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, NTLA-5001, 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 I/II- A 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.
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 Symposia'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 it's readily deployable for TCR-T and CAR- T cell therapy. This data highlighted that NTLA-6001, 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-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 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 Waltham, Massachusetts. This new facility will provide us with significant manufacturing capacity to support preclinical through commercial production of Intellia's investigational therapies. Now I'll 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 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 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 c ompared 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 both wholly owned and partnered programs, now with multiple programs 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 of programs outside our key areas of focus. 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?
We will now begin the question-and-answer session. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. The first question comes from Swapnil Malekar of Piper Sandler. Please go ahead.
Great. Good morning. Thanks for taking my questions. First one is, with the fixed dosing regimen, are there any concerns in lighter patients who might get exposed to what more than 1 mg/ kg dose, especially related to safety and then I have a follow-up.
David, do you wanna give your views on how we think about the fixed dosing and safety?
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. You recall in part one, what we saw and reported in February were very deep reductions, 93% average reduction in six patients. That at that point, it was durable with variable follow-up from 2 - 12 months. We also then had the PK from this work. What it showed is that the exposure of patients was not significantly affected by the weight of the patients. We will be showing you more details of that in our upcoming presentations at EASL. What that means though is that small patients and larger patients essentially are experiencing the same exposure of drug.
We think this is related to the fact that in, you know, 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's coming out. What we expect going forward, and this will be tested in part two, of course, we wanna 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.
Got it. 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 Ionis's CARDIO-TTRansform trial, and its implications to future Intellia strategy for a pivotal cardiomyopathy trial?
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 gonna learn from some of the ongoing trials. That one will come a little bit late for the trials we're gonna do, but certainly the trials from BridgeBio and from Alnylam will help inform our trial as we move forward.
Great. Thank you for taking my questions.
The next question comes from Maury Raycroft with Jefferies. Please go ahead.
Hi. Good morning. Congrats on the progress and thanks for taking my questions. I was gonna 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. Have you decided to dose higher than 75 mg fixed, or do you know at this point that that's not needed?
Maury, 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?
Yeah. For HAE, I think we've said a lot of times this is using our modular approach. 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. With that, we did start at a higher dose. We started at 25 mg, which is basically equivalent to the 0.3 m/ kg dose that was used in the 2001 trial. We will be bringing forth data in and then you know and the next dose level as you said was 75 mg, which would be similar to the higher dose that the highest dose that we treated in the 2001 trial.
We do expect this to be safe based on what we know from 2001. 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, and particularly the prekallikrein levels and activity are both being looked at in this trial. That, as we've seen previously in other compounds, is very likely to be associated with a decrease in attack rate, actually a very substantial
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 share that. 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. 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.
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, or?
Well, the attack rates is not really the primary determinant. There's a threshold level. I mean, we wanna have everybody with obviously the disease diagnosed and 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. That's why you need to have a baseline and then, you know, sufficient time to observe the patients thereafter.
Got it. Okay. Thanks for taking my questions.
Sure. Thank you.
The next question comes from Dae Gon Ha of Stifel. Please go ahead.
Great. Good morning. Thanks for taking our questions. I'll add one more question on NTLA-2002, if I can, and it's a two-part question. I think this is actually the first time we're hearing about the 25 mg and 75 mg, if I'm not mistaken. First part is, since your cohort will be, or at least looks like N of 3 mg-6 mg 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? Secondly, when we look at 25 mg and 75 mg fixed dosing, there was the NHP data that you presented at ASGCT last year. What dose level would this correspond to when we think about allometric scaling? I've got a follow-up. Thank you.
A three-part question. With respect to the dosing of 25 mg and 75 mg fixed doses that we just referred to, David spoke to how that relates to the TTR program. You know, that is all derived from looking at the preclinical results, and drawing heavily from what is the highly related dosing form that we're using in TTR. You know, a simple rule of thumb, if you wanna try to extrapolate to the animals, it's more complicated than this, but if you divide by approximately 3 mg, you'll get to a similar sort of effect. If there's more complications than that, 'cause you gotta take into consideration the activity of the guide, et cetera.
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 TTR program, one starts with an N of 3 mg. 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. Repeat your second question for me.
I think that's actually all of it. I can just go on.
Okay.
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? In the prepared remarks, you alluded to another in- vivo candidate selection before year-end 2022, I guess does the 3001 progress imply that a lung program might be up next? Thank you very much.
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 LNP 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 lipid shell. The cargo elements, which consist of mRNA and the guide RNA, are all the same, with the exception of the last 20 nucleotides or so, of the guide RNA. With respect to the LNP across all of those programs, there is just 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. That's the distinction. 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. 2003 targets the gene itself and eliminates, you know, the production of the defective protein. 3001 provides a source of wild type protein to forestall progression of lung disease. For simplicity's sake, we treat them differently. We would be in a position to merge them at the end within a single patient if we think that that's warranted.
Excellent. Thank you so very much.
Sure.
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.
Good morning. Thanks for taking my question. 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, do you wanna? I think you're back. We lost David's audio for a minute there. David, where do you think this treatment fits into the treatment of HAE patients?
Yeah. Thank you, and I'm sorry for my technical difficulties this morning. 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%-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. 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. We think that 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.
Thank you.
The next question comes from Joseph Thome with Cowen & Company. Please go ahead.
Hey there. Good morning, and thank you for taking my question. Just in terms of the EASL update, will we be able to see some polyneuropathy functional symptom data at this time, o r maybe when would you be in a position to provide this update? How long do you wanna follow those patients out for? Thank you.
David, when are we gonna see some clinical data on the polyneuropathy arm?
In the polyneuropathy arm, those measures come at later points in treatment. It does take a long time to get it and not yet available for EASL. 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. 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. That's w e 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.
Great. Thank you.
The next question comes from Joon Lee with Truist Securities. Please go ahead.
Hi. Good morning and congrats on the progress. This is Maisie on for Joon . Our question, the first question, is related to HAE. Ionis has done it all since 95% reduction in prekallikrein and a 97% attack rate reduction after basically month one, 5-17. 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.
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 gonna 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, if 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 that you just described, but including, you know, some of the more recent data. 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 knockdown data in the ongoing study. As I said earlier, you know, as that knockdown data accumulates, we'll certainly share it. 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, you know, from a disease point of view that. Oftentimes they're young, including sometimes adolescents. The number one issue, once their attacks are somewhat within control, is the treatment burden itself.
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 to these patients. If you look, certainly in the United States, for the most effective therapies, many of these patients have just for access to the medicine alone, costs of over $1 million a year, which is an extraordinary number, over the lifetime of these patients, particularly when you think of the age of onset when they're diagnosed. Also from an economic point of view, we believe that there's a massive opportunity to improve, the cost to these patients and to the healthcare system.
I think all things considered, you know, these will be attractive elements of this treatment for patients, payers, the doctors, the family members, caregivers, et cetera. You know, we expect that it'll be well received. I mean, you know, when you think about this, I think Salveen asked the question about the treatment paradigm. I don't think gene editing is gonna be the very first intervention that doctors do. I wouldn't recommend that as a physician. Certainly as information is accumulated and as we understand how this drug performs, I think it's gonna be a very, very attractive offering for patients in the scheme of all the other elements that are available.
That's very helpful. Thank you.
Sure.
The next question comes from Debjit Chattopadhyay with Guggenheim. Please go ahead.
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? 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 precedent for this and/or has Intellia observed this phenomenon in preclinical studies?
Well, I'm gonna 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 the 2001 data is certainly setting our expectations in terms of the range of knockdowns. You know, all of these programs do have some differences, different patients, and how they perform, et cetera. The guide itself is gonna have some of its own idiosyncrasies. We would expect to see knockdown levels that approximate where we've been in the TTR program. The most important readout is gonna be attack rates. I mean, that's the final indicator of relating whatever editing one gets to what matters to the patient.
That's gonna be a story that lags where we are on a knockdown story. 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 wanna speak to thirty oh one and how you think about the introduction of the transgene in the patients with the underlying mutation?
Yes, you know, briefly, right? Yes, there is the possibility that if you do have good expression of the, you know, the wild type allele, you may be able to restore the heterozygous phenotype in those livers, right? That's, you know, one of the hypotheses we are pursuing with NTLA-3001. The data will, you know, be shared when, you know, we're ready to share it. Stay tuned.
Thanks for that.
The next question comes from Gena Wang with Barclays. Please go ahead.
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 a 0.3 mg/kg to 0.9mk/kg, giving your ATTR program of a 0.7 mg/kg. Is that because you would like to achieve higher level of knockdown? I remember, John, you previously mentioned that 70% reduction will be sufficient to translate to clinical benefit. Was that the maximum knockdown level you wanted to achieve, or you wanted to even do beyond 70% reduction?
Thanks for the question, Gena. I mean, it's a couple of things. Remember, first of all, while these are modular systems where the, you know, 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. 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 knockdown numbers to what we believe will be the expected clinical attack rate.
That comes from the work of others who have been establishing those relationships in advance of our work. It relates to the questions that were asked before. You know, what's meaningful for patients and what's really gonna drive a profile of the drug that advances the ball for them. We believe that this, you know, HAE may ultimately be a curable illness here, and that's certainly what we're striving for. The expectation would be that deeper knockdowns are likely to drive those sorts of outcomes.
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. I wouldn't start by having a particular number from a dosing perspective in mind. It's really gonna 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, like, will 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?
We clearly wanna have levels that go beyond 60%. We've said that pretty much from the beginning, and that relates to what we see with Takhzyro and the good outcomes that they've had. 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 data, though, Gena, is gonna be the clinical readout. You know, we will be testing levels of reduction that you know go well beyond 60%, because that's where we believe you're gonna get those really good clinical outcomes.
Thank you.
Sure.
The next question comes from Luca Issi with RBC. Please go ahead.
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 bigger picture, how you're thinking about implications for filing your first IND. I have a follow-up.
As we read the guidance, it really conforms with how we think about how we run the programs. 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, s o 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 guide.
There really wasn't that much that added to the work that we're doing or changed how we think about it. You know, we're well into discussions with different regulatory agencies, including the FDA, that you know 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. One of the things that we you know feel very strongly about is the adequacy of off target characterization, which we think the additional guidance from the FDA is welcome there. As you have seen in the publication we had back in New England Journal, we think we've at least addressed any standards that have been laid out.
Got it. Got it. Super helpful. 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 Institute should the decision be ultimately upheld? Thanks so much, guys.
Sure. The process will play out. The findings thus far, you know, 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 progress 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 with respect to work outside of, you know, very, very limited area that this particular patent refers to if they wanna 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.
Got it. Thanks so much, guys.
The next question comes from Steven Seedhouse of Raymond James. Please go ahead.
Hi, this is Timur Ivannikov on for Steve. Just a quick question for us in terms of the EASL presentation. 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?
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 manyfold 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. 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.
Okay. Thank you very much.
Sure.
The next question comes from Mani Foroohar with SVB Securities. Please go ahead.
Thanks for taking my question. Something a little more, I guess, atmospheric and broad than some of the specific questions that have been on individual programs that have been most of this call. Obviously, there's, you know, we're going to see with alpha-1 antitrypsin a little data from you guys we've been talking all along. You 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 delivery modalities as part of the modularity of your platform?
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, Mani?
I would primarily consider liver-related disease since you're delivering your editing construct to hepatocytes.
Yeah. Okay. 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. As that data matures and we have more to present at preclinical level, we would share that. We can start thinking about what that means for disease, you know, for development candidates and timelines, et cetera. For the, you know, immediate future here, I think we're gonna be related to the programs we have in the clinic and those are the ones that we've been talking about today.
All right. Thanks.
Sure.
The next question comes from Yanan Zhu with Wells Fargo. Please go ahead.
Hi. Thanks for taking my questions. First on the EASL presentation, in terms of durability, could we expect incremental three-month additional durability for all the patients compared with your March presentation?
David, do you wanna say a word about just, you know, what to expect at the EASL presentation?
Yeah. As you mentioned, we had mentioned before, we had about two- or 12-month follow-up, and we will start to fill in cohorts here with more additional follow-up. We think that'll be very valuable that with the additional follow-up, we'll be able to talk about the number of patients who've reached important markers in their time. We do think, when we get there, that data will speak for itself. We really look forward to showing that soon.
I think it's important to add maybe that as the study progresses, the data is accumulated, I think, David, in three monthly intervals. 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 increments. Going forward, that's the way I think about this.
Actually, it goes from 12-18 months. There is a big gap from the 12-18-month point, just so people
Yeah.
For expectations. We'll make that very clear in the presentation when what the time points are.
Right.
Got it. That's very helpful. My other question is on 601. Thanks for your, you know, disclosure at the Keystone meeting, just this or last week, actually over the weekend. 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 this knocking out this receptor knocks down HLA-1 but does not eliminate HLA-1. In order to prevent NK rejection, that's probably why you did not completely, you know, aim for complete elimination of HLA-1. Because you didn't eliminate HLA-1, there is still some host CD8 activation according to the preclinical data presented at Keystone. How should we think about, compared with, you know, the more conventional HLA-1 knockout approach? Thank you.
Laura, do you wanna 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. At that presentation, we showed, generally speaking, what were you know the characteristics that we're attempting to achieve. Laura, do you just wanna 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 601?
Yeah. I'm sorry, but we're not yet describing exactly how we're doing it. 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? It's prevent graft-versus-host disease, then prevent rejection by CD4 and CD8 T cells. 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. There is clinical data that now it's you know, it's supporting that with you know, short duration of effect, right?
What we've been able to do was to ensure that 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 we saw in, you know, these, very efficient antitumor activity. The other thing to highlight here is that, you know, these cells are generated using our Intellia engineering process, where we do an LNP-based engineering, sequential editing, and that allows us to have very high-quality cells that are not exhausted and that, you know, they can be manufactured with high-quality attributes.
Now, 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. NTLA-6001 is the first example of our own wholly owned product moving forward. It relates to the work we've done with Kyverna and AvenCell, whereas partners understand more about the shortcomings of what is the standard allo approach out there.
I think people are increasingly excited about this very differentiated approach and what it can bring for patients, which is essentially, you know, 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.
Got it. Thanks for the color.
The last question will come from Jay Olson of Oppenheimer. Please go ahead.
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 p reclinical 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.
Yeah, it's a really important question, and I appreciate that you asked it. You know, we start by pursuing targets and with modalities that we think are gonna be highly differentiated and bring real, 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 a new platform, there's new approaches, 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 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, get 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, 'cause 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, largely B-cell driven CAR-T space. That's one important question for us. The other one is just showing that the Allo platform performs at the high level.
You'll 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. Together, we think that that's the best way forward. 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.
This concludes our question- and- answer session. I would like to turn the conference back over to Ian Karp for any closing remarks.
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.