Intellia Therapeutics, Inc. (NTLA) Q2 2022 Earnings Report, Transcript and Summary

Good morning. And welcome to the Intellia Therapeutics' Second Quarter 2022 Financial Results Conference Call. My name is Andrew and I will be your conference operator today. Following formal remarks, we will open the call up for a question-and-answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. As a reminder, all participants are currently in listen-only mode. [Operator Instructions]. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia.

Thank you, operator. And good morning, everyone. Welcome to Intellia Therapeutics second quarter 2022 earnings call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call. This release can be found on the Investors and Media section of Intellia's website at intelliatx.com. This call is being broadcast live, and a replay will be archived on the company's website. At this time, I would like to take a minute to remind listeners that, during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Joining me from Intellia 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 provide an update on our clinical programs with a focus on NTLA-2001 and NTLA-2002. Laura will then provide an update to our ex vivo strategy. Glenn will then review Intellia's financial results from the second quarter. And John will provide some final remarks before we open the call up for Q&A. And with that, I'll now turn the call over to John.

Thank you, Ian. And thank you all for joining us this morning. At Intellia, we're building the industry's leading genome editing company. We're deploying the 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 medicine. During the second quarter, and more recently, we've continued to advance our full spectrum pipeline and platform. Starting with NTLA-2001, we've made excellent progress in the ongoing Phase 1 study. In June, we presented additional clinical evidence that NTLA-2001 led to deep and durable TTR reductions following a one-time administration across all therapeutically relevant doses. David will provide a recap of the data presented an EASL and elaborate on the latest findings from the study. In addition, dosing is now completed in the dose escalation portion of the cardiomyopathy arm. With the more expensive data set, we're finalizing selection of a fixed dose corresponding to the 0.7 mg per kg dose to evaluate in the dose expansion portion of the cardiomyopathy arm. Our second in vivo knockout candidate NTLA-2002 has strong momentum, and we remain on track to share a first look at safety and activity data from the first-in-human study later this year. This will represent an opportunity to not only demonstrate the potential of NTLA-2002 as a treatment for people living with hereditary angioedema, but also the reproducibility of our modular platform. With our ex vivo efforts, we're advancing unique and proprietary allogeneic technology, which leverages our LNP-based cell engineering platform. Our novel approach is designed to overcome rejection by host T and NK cells, a key limitation to the durability of current allogeneic investigational therapies. Based on our compelling preclinical data, we're making a strategic shift to focus on exclusively developing allogeneic cell therapies. For our lead ex vivo program NTLA-5001, which you may recall is an autologous program, we are pivoting to an allogeneic version, which is now in preclinical development. Laura will share more on our decision and the advantages of our allogeneic platform for patients shortly. Finally, Intellia remains in a strong financial position. We ended the quarter with $907 million in cash, which gives us the capacity to continue to prosecute the strategic priorities we set forth at the beginning of this year. I'll now turn it over to David.

Thanks, John. And welcome, everyone. Beginning with NTLA-2001 for the treatment of transthyretin amyloidosis, or ATTR amyloidosis, we were thrilled to report continued positive interim data from the polyneuropathy arm of our ongoing Phase 1 study at EASL's International Liver Congress in June. These data provided early confirmation that deep reductions in a disease causing protein achieved by a one-time genome editing treatment are in fact durable over time. At all four dose levels tested in the dose escalation portion, editing the TTR gene with 2001 resulted in sustained reductions in protein levels over the follow up period ranging from six months to a year. At the 0.7 and 1.0 mg per kg doses, 2001 led to a greater than 85% mean TTR reduction at day 28, with maximum reductions of 97% and 98%, respectively. These results remain durable through the six months of ongoing follow up. We continue to believe the deep, durable and remarkably consistent levels of protein reduction support NTLA-2001's potential as a one-time treatment that could halt and possibly reverse the disease. In addition, we continue to make great progress in the cardiomyopathy arm of the study. Recall the primary objectives in both arms are to establish safety and an optimal dose to move forward in potential pivotal studies. There are now over 30 individuals who have been dosed with NTLA-2001 across both the polyneuropathy and cardiomyopathy arms, with the first ever systemically administered in vivo CRISPR candidate. For the cardiomyopathy arm, we announced today the completion of the dose escalation portion. While we look forward to presenting the first interim readout from the cardiomyopathy arm later this year, we're pleased to share that the initial findings have been consistent with the data previously ported from a polyneuropathy arm at EASL. Based on the recent data, the 0.7 and 1.0 mg per kg had very similar TTR reductions, have been generally well tolerated. We're now finalizing a fixed dose selection at or near a fixed dose equivalent of 0.7 mg per kg for evaluation in the dose expansion portion. We also announced today that we plan to evaluate the same fixed dose in a second cohort in the dose extension portion of the polyneuropathy arm. The decision to study a second dose was based on three main factors. First, the emerging data from the dose escalation portion of the cardiomyopathy arm. While still in a small number of patients dosed, initial TTR reduction data is indistinguishable after two doses tested. Second, the comparability of performance at 0.7 mg per kg and 1.0 per mg per kg doses in the dose escalation portion of the polyneuropathy arm. And third, while NTLA-2001 has been generally well tolerated, there was a recent adverse events in a patient dosed in the 80 milligram dose expansion cohort in the polyneuropathy arm that informed our decision. A significant elevation in liver enzymes in this patient at day 28 was observed in a routine laboratory assessment. The liver enzymes returned to normal levels without medical intervention. The patient was asymptomatic and had no increase in bilirubin. The event was considered non-serious by the investigator and deemed possibly related to study drug. As a result, we plan to evaluate a common fixed dose in both arms to better inform our future pivotal study design, in line with the goal of the Phase 1 study to identify a dose that delivers the maximum amount of benefit to patients at the lowest dose possible. Overall, this strategy reflects our strong conviction that NTLA-2001 can achieve the deep levels of TTR reduction expected to potentially halt and reverse the disease. We plan to submit a protocol amendment in the coming days. In addition, we expect to present the initial safety data from the 80 milligram dose extension cohort from the polyneuropathy arms at the upcoming NTLA-2001 data released later this year. We are incredibly proud of all the rapid progress in our ongoing Phase 1 study of NTLA-2001. And subject to regulatory feedback from the protocol amendments, we continue to expect to complete enrollment by the end of 2022. And turning now to NTLA-2002, our investigational therapy for the treatment of hereditary angioedema, or HAE. As a reminder, we are targeting the KLKB1 gene in the liver to permanently reduce plasma kallikrein and its activity. Other modalities have shown that a 60% reduction in kallikrein activity leads to a therapeutically relevant reduction in HAE attack. With NTLA-2002, we've shown compelling data in non-human primates where we have achieved and sustained greater than 90% reduction of both kallikrein protein and its activity after a single dose. If these results translate to humans, NTLA-2002 could be a transformative new treatment option for people living with HAE. We continue to make steady progress in the dose escalation portion of our Phase 1/2 study and look forward to sharing initial results from both the 25 and 75 milligram dose cohorts later this year. This interim data readout is expected to include safety, kallikrein reduction and HAE attack rate data. These results will offer an initial view of the safety and activity profile of NTLA-2002 and potentially demonstrate proof of concept for the modularity of our proprietary CRISPR-based LNT platform. I'll now turn over the call to Laura to provide updates on our ex vivo pipeline and R&D progress.

Thanks, David. I'll start with highlighting our recent decision to focus exclusively on developing allogeneic investigational ex vivo therapies and the impact this will have on our current autologous NTLA-5001 clinical program. As many of you are aware, some of the key challenges with autologous cell therapies for cancer treatments are well known. First, patients with cancer who have already been exposed to cytotoxic treatments do not provide an ideal starting point for collecting healthy cells for subsequent engineering. In addition, the complex manufacturing process required and associated high costs for these therapies present further hurdles to treatment. In response, many in the field have focused on developing off-the-shelf solutions. However, the development of an optimum allogeneic solution needs to meet the following criteria. First, cells should be sourced from healthy donors and be readily available for administration. Second, there needs to be an efficient manufacturing process able to produce the cell product with desired attributes at an accompanying lower cost. And finally, of critical importance, these engineered cells must persist for long periods of time, allowing for continued anti-tumor activity. This last key area, persistence, remains an unsolved hurdle. And recent clinical data has clearly demonstrated that lasting responses are not achieved with current approaches. At Intellia, we have developed a proprietary allogenic platform which leverages a novel combination of sequential gene edits. Our preclinical data strongly supports that our highly differentiated editing strategy should achieve both high anti-tumor activity and the persistence required for sustained responses in patients. Our allogeneic platform is a technology that already underpins the recent collaborations with AvenCell and Kyverna and our wholly owned NTLA-6001 candidate. Now for NTLA-5001. We have concluded it is in the best interest of patients to pivot as quickly as possible to an allogeneic version of this program using the same TCR. The decision to discontinue the current Phase 1 study is not due to any safety or efficacy data emerging from the trial. Instead, it is based on the potential to consistently deliver a high quality cell product by switching to an allogenic version. Most importantly, we believe an allogeneic version of NTLA-5001 will provide significant advantages to patients fighting an extremely aggressive type of cancer. In further support of this decision, we plan to present additional preclinical data on our allogeneic platform at the scientific conference later in 2022. Our platform innovations continue to support our robust research engine and a host of wholly owned and partnering investigation on CRISPR-based therapies. I'll now hand over the call to Glenn, our CFO, who will provide an overview of our second quarter financial results.

Thank you, Laura. Good morning, everyone. Intellia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform amidst a challenging market environment. Our cash, cash equivalents and marketable securities were approximately $907 million as of June 30, 2022 compared to $1.1 billion as of December 31, 2021. The decrease was driven by cash used to fund operations of approximately $191.2 million as well as the acquisition of Rewrite for $45 million. The decrease was offset in part by $38.9 million in net equity proceeds raised from the company's at the market agreement and $14.3 million in proceeds from employee-based stock plans. Our collaboration revenue increased by $7.5 million to $14 million during the second quarter of 2022 compared to $6.6 million during the second quarter of 2021. The increase was mainly driven by our collaborations with AvenCell and Kyverna. Our R&D expenses increased by $31.3 million to $90.2 million during the second quarter of 2022 compared to $58.9 million during the second quarter of 2021. This increase was driven by the advancement of our lead programs and research and development personnel growth to support these programs. Our G&A expenses increased by $5.4 million to $22.1 million during the second quarter of 2022 compared to $16.7 million during the second quarter of 2021. This increase was mainly related to employee related expenses, including stock-based compensation of $4.5 million. Finally, we expect our cash balance to fund our operating plans beyond the next 24 months. With that, I will now turn the call back over to John for closing remarks.

Thank you, Glenn. It's been an incredibly active quarter at Intellia. We continue to make significant progress in our mission to bring forth a pipeline of CRISPR based medicines to patients in need. Having previously led the development for some of our industry's most groundbreaking medicines, I know from experience how important it is to follow the science and adapt quickly to information as it becomes available. I'm confident that the decisions our team has made across the pipeline are in the best interests of patients and our shareholders. Looking ahead to the remainder of the year, we will continue to advance the clinical development of NTLA-2001 and NTLA-2002 as well as execute against our strategic priorities. Of particular note, we plan to share interim data updates from NTLA-2001 and a first look at the safety and performance of NTLA-2002. With that, we'd be happy to answer any questions about our pipeline and platform. Operator?

[Operator Instructions]. The first question comes from Joon Lee with Truist.

What are your top one or two questions for APOLLO-B heading into ISA data presentation on August 8. I'm assuming you plan to attend at least virtually.

First of all, we're really excited about the outcome because we think it validates what we believed for a long time, which is the best way to deal with any form of amyloidosis, in particular TTR amyloidosis, is to reduce the offending protein to low levels. We, of course, have been targeting very, very deep reductions, and we think that we'll be able to take what we've already demonstrate and apply it to patients in cardiomyopathy and would expect to see profound clinical benefit as a result. But I think like all observers, we're interested in getting the full data set in terms of how the patient's performed. Obviously, a six minute walk test is a particular readout. But some of the harder endpoints I think are really important to understand, which will inform how we think about studying these patients. I don't know, David, if there's anything of particular interest to you that you might want expand on.

I think a couple of other things we'll be interested in, how patients did, who received tafamidis or didn't receive tafamidis that seem to be part of the story. And the biggest piece, we do think we can do better than what they did because of the deeper reductions we get in TTR. So, as we design our trial, that point will be important to show how we might show better efficacy than we've seen in that trial.

The next question comes from Maury Raycroft with Jefferies.

Hi. This is [indiscernible] on for Maury. Just a follow up on APOLLO-B as well. like, how does the data inform your next steps in the designs for the pivotal? Like, would you rely on the six minute walk test as like an endpoint or would you prefer like harder endpoints?

Well, as a first pass, I think the six minute walk test has some utility, but it's really not the most definitive endpoint in terms of how I think regulators, physicians, and even payers ultimately think about the effect of these drugs. So, for us, that's at the core of our program. But there's no doubt that six minute walk is a useful readout to some degree of improvement. And we think that what we've seen so far, again, is validation of the entire knockdown hypothesis for cardiomyopathy. David, any other thoughts?

As you say, we've been talking for a while that we do think the most important endpoints are cardiovascular events and mortality. And you don't see that yet in this trial. It's a smaller trial than some of the others. It's also fairly short term. It will be important to show that benefit by lowering TTR.

The next question comes from Dae Gon Ha with Stifel.

Congrats on all the progress. I wanted to pivot a little bit to a different set of questions because I'm sure you'll get a number of other APOLLO-B questions. On the HAE data expected in the second half, you outline in the press release safety, I guess, KLKB1 reduction and attack rates. But heading into it, what should we think about in terms of relevant comps? Is it lanadelumab? Is it berotralstat or something else? And as a follow up, for the 2003, I didn't see any specific guidance as to when the IND or the equivalent filing would be as opposed to the 3001 guidance. So, since 2000 program generally, I guess, has shared attributes between 2001, 2002 and now 2003, is there anything unique about the A1AT gene or the SERPINA1 gene that warrants a broader window for IND or equivalent filing?

We can do the 2003 question first. When we get to the appropriate point, we'll issue guidance as that program moves along, which is typically how we do it. The programs are related to each other, but they're distinct. And so, I think it's important to keep that in mind. Remember that 3001 is an insertion at a different gene, at a different locus, whereas 2003 targets the offending gene itself, SERPINA. So 3001 is a little bit ahead of 2003. They are independent programs. So, we've designed them in a way that, if we choose to, we can bring them together in the same patient. But at this point, they're separate from each other. With respect HAE, we look at the standard of care as point of departure, and we think that TAKHZYRO is a relevant benchmark here. We note that there are other agents that have met similar sorts of outcomes. And all of that is tied to the same sort of biological reasoning, which is inhibiting or reducing kallikrein levels. That's exactly the approach that we're taking. What we've seen is that the bigger the effect, the more of a pickup you get from a clinical endpoint point of view. So, with our approach, which extrapolating from the data that we've seen with TTR already, we believe that we should be well on our way to minimally meeting the levels that they've reported out and perhaps us surpassing them, which is, of course, our objective.

Next question comes from Gena Wang with Barclays.

I have one question regarding the one case of liver enzyme elevation at day 28. Can you give a little bit more color regarding how many [indiscernible] that reached and how long did it last? And since you also dosed 75 milligrams for HAE patients, do you expect similar safety profile there? And then second question regarding HAE update, you did say HAE attack rate data. Just wondering if you can give a little bit more color, would that be from each individual patient? And what was the comparison to the baseline and, say, one or two months follow up? If you can give a little bit more color regarding the attack rate?

With HAE, we'll show the data that we have, which starts with patients are at baseline and we'll give the follow up that we have, and the expectation is we'll give you as much information as we have at the time. So, the actual format of the presentation, we'll work on as we get to the point of actually doing it. But as I think you know, it's been our principle to try to be as transparent as possible. And I would expect that the general approach will be very, very similar to what you've seen with TTR because the programs are so related. With respect to the one patient in the 2001 program, we'll go through the information that we have when we do a data disclosure later this year. But I'd just emphasize that, as we've shared in our script, the patient did extremely well. It's entirely asymptomatic. It's a laboratory abnormality that was transient in nature. But because we believe we have so much room on the efficacy side that backing off the dose is a reasonable thing to do, particularly since – as our database has grown, we've seen that it's essentially indistinguishable TTR reduction levels between 0.7 and 1.0. milligram. Remember that when we did some of our first dose selections, it was based on essentially three people. And as we said all along, as we do our Phase 1 dose finding work, information will accumulate that will influence our thinking, and we've been very gratified with the outstanding safety profile and the continuing excellent TTR performance of the drug. I don't know, David, if there's anything else you want to provide.

I think a few other questions are in there. For the HAE patients, there have been no liver enzyme elevations and the safety has been outstanding there. In terms of the attack rate, just to give a little more detail there, we will be looking at individual patients in that analysis. And the main way this is done is by doing a running analysis, how many events are there before they get treated and then looking at how many events there are after that. And then there's usually over a period of two to four months, depending on the follow-up.

I guess just one other thought on the patient you asked about, Gena, is that, remember, it's at day 28. One of the things that it's important to think about with LNPs is as a class, we certainly look a lot like the class. LFT elevations, when they occur, tend to be right around the time of dosing, which is day one, two or three. We've seen very low elevations, which we've reported on. This is a transient finding out weeks later, which we have no idea if it's even related to the drug, although we've considered that it may be possibly so, and again, it was transient in nature. So, again, just thinking about the bigger picture here and choosing the right dose that balances what we're trying to achieve, we think we've got lots of room to go on the efficacy side.

The next question comes from Joseph Thome with Cowen and Company.

Just in terms of the flip for 5001 over to allo, maybe when will that be in a place to move into the clinic? Is that going to be a nearest term milestone? And maybe how would that relate to when 6001 could enter clinical development?

We haven't guided to a particular date yet. Remember what we've said which is the next incarnation of this will be with the same T cell receptor. So, we remain absolutely excited about looking at T cell receptor biology, the WT1 target, etc. And remember that behind all this is the logic that, well, CAR Ts are – certainly have their place and performed well and we have our own Car T programs, we believe the larger opportunity with cell based therapy for cancer is with other formats. And TCR we think is the most promising one of those. So with respect to moving forward, we've got many of the innards in place, if you will. And it's really adapting our allogeneic platform, which we're incredibly excited about to that. So as we finalize those steps, we'll share that with upcoming updates and look forward to telling you more about that at that time.

Maybe just a quick follow-up on 5001. Are you going to present any of the data from the auto program if you've dosed any patients there?

We’ll look at what we get. We're certainly following patients we've dosed. Remember that, we are not making the switch based on any efficacy or safety readout. This is really just based on the merits of what we think is an allo approach as Laura laid out, just you get better cells, faster, that we think are going to just be superior in performance to anything that an autologous format would be able to provide. But as we collect information and think about future updates, particularly in the context of the allo program, we'll think about that and share it as we see appropriate.

The next question comes from Swapnil Malekar with Piper Sandler.

I guess a couple of them. One on HAE program. So, given that there were some regulatory concerns during TAKHZYRO approval related to chronic suppression of the kallikrein pathway, like what has been the regulatory feedback on this program? And are there any additional safety monitoring requirements for the 2002 program? And then I have a follow-up.

HAE is moving very briskly. All of our regulatory interactions have been pretty straightforward. But, David, I don't know if there's any additional color you want to share?

No, I'd say in multiple nationalities, we've had good feedback on what we're doing. They're happy with the safety program that we've put in place. And as we've just alluded to, you'll see the data later this year, but are also pleased with the safety we're seeing.

For the fixed dosing regimen of 0.7 mg per kg equivalent, looks like safety and liver enzyme elevation was one of the key reasons to pursue that. So, the question that I have is, like, of the total 30 patients that are dosed to date, is there any other patients who had any ALT or liver enzyme elevations, even if not significant, like any minor or incremental elevations?

Well, you've seen some of the data that we've presented. Certainly, around the time of infusion, you'll get very low level increases . In all cases, we've presented that information. At the last EASL presentation, I think there was an example of one patient who had just an excursion just outside the limits of normal at day 28. So, yes, in that sense, there's other examples.

The next question comes from Salveen Richter with Goldman Sachs.

With regards to the decision to study a second dose in the TTR study, how much do you anticipate this will delay development timelines? And separately, on the switch to allogeneic for your AML program, could you just expand on the rationale here that's behind pursuing a better product and your understanding of construct here? I'm just trying to get a sense of the foundational work on the allogeneic side.

Maybe David can say a word about any impact, if any, to the timeline. And then I'll have Laura take you through the thinking on the allo and why we're so excited about it. But, David, how about you go first.

Let me take you back to really EASL where we showed 15 patients from a polyneuropathy program. And what we saw there was deep reductions really starting at 0.3 mg per kg is where we see it, durable and up through 1 milligram mg per kg. At that point, it looked like the 1 milligram mg per kg was slightly better than the 0.7 mg per kg and went forward with that. As we've said now, we have more than 30 patients. We have really multiples of the number of patients at 0.7 mg per kg. So that with this increased data, it's quite clear that the efficacy at 0.7 mg per kg and 1 mg per kg are really indistinguishable. So with that – and you see that the rate of enrollment at this point, investigators are really excited about the program. We're doing very well. So we have a lot of information on patient cardiomyopathy. And what we do going forward, we'll still be able to enroll all the patients by the end of the year as we've guided from everything we say. And that has to do with the – how much we've learned. And recall that, with the cardiomyopathy patients, we did study both 0.7 mg per kg and 11 mg per kg in order to pin down this question. In product development, you really want to go with the lowest dose that gives you that efficacy. What we're seeing in this program is a very flat dose response curve.

Laura, you want to talk about the allo platform a little bit and how we think about it and why we're pivoting.

What we've learned from our study, but importantly for others, is that the importance of an allogeneic platform is not only to have a consistent solid product with high quality, efficient manufacturing, resulting also in lower cost of goods as compared to an autologous therapy. But what is of critical importance is that these engineered allo cells must persist for long periods of time in the patients to allow for continued anti-tumor activity. So having complete responses that last month or two months don't really provide the benefit we want for patients. And as we have seen with several clinical programs from other sponsors, the current approaches for allogeneic cell therapies do not bring that persistence. And we are really excited about what we have been able to achieve, which is to ensure that not only we avoid graft versus host disease, like others, or rejection by host T cells, but importantly, we avoid rejection by natural killer cells. And we believe that that is very important for the long-term persistence. We are going to be sharing more data later this year, going into detail in the actual editing strategy and continue to share data on the performance of the cells. So, looking forward to having this conversation at that time.

Salveen, it's important to also think about the manufacturability of this. One of the things that sometimes gets lost with an autologous approach is you're literally manufacturing each patient one at a time, which brings tremendous cost, time lags, etc. And if you're able to manufacture for 50 to 100 people at the same time, that just brings tremendous opportunities in terms of the efficiency, cost of goods improvements that we think can ultimately expand the use of these products. And we think with this persistence in particular, one can achieve perhaps even better outcomes with them with the current autologous format. So that's why we're excited. And we think that a program can move along very, very quickly. So, from the standpoint of timelines, although we're not guiding yet, when we look at our plans and look down the road, I think that, well, the allo may start a little later. I think it can finish very, very quickly, assuming it performs to the levels that we expect.

The next question comes from Luca Issi with RBC.

Sorry to go back to this one. But I think you mentioned a couple of times that the 0.7 mg per kg or 1 mg per kg were indistinguishable in TTR cardiomyopathy. However, in TTR polyneuropathy, it does look to me that a 1 mg per kg drove a better knockdown, which is obviously important to beat the silencers. So wondering how you rationalize the difference between TTR polyneuropathy and cardiomyopathy? Again, understand, small numbers, but would love to kind of hear your thoughts on how you rationalize that difference. Maybe on HAE, I think IONIS' show 65% to 70% knockdown in PKK in the serum with their antisense oligonucleotide. Wondering if that's the right bogey for us to keep in mind as we see your PD data?

Well, with respect to the data on 21, remember, we get to see a lot more than you do. And so, that certainly informs how we think about this stuff. David, I don't know if you want to say a word or two about…

Let me give you a little more detail about it. And you could see it in our data, actually. If you recall, when we were looking at the patients with polyneuropathy, the patients at 0.7 mg per kg had a wide standard average – mean for their mean reduction. And this is actually driven by a single patient, an outlier, who's actually an outlier not only from 0.7 mg per kg and 1 mg per kg, but also from 0.3 mg per kg. So this patient is quite different. Now looking at the results for cardiomyopathy with a good sample, it looks like that is not – that outlier isn't something that probably would have to be not looked at in terms of what's really happening in these patients. So we will continue to collect data, but it does look both based on our modeling and also on what we're seeing with the patients with cardiomyopathy – we do think react biologically pretty much identical to patient polyneuropathy that the TTR reduction will be the same at 0.7 mg per kg and 1 mg per kg.

I guess the other question was, again, just what we use as benchmark for HAE.

Yeah, the benchmark we're looking at is what – TAKHZYRO gets about a 60% reduction. You recall in our preclinical models, we're able to get a 90% reduction. And what you've seen with TTR. So, we think that we will be able to get to a good target reduction with kallikrein.

We haven't seen anything that we don't think we can beat or surpass ultimately is I guess the way to think about it.

The next question comes from Rich Law with Credit Suisse.

For 2001, as you think about registrational studies, do you think you need to demonstrate what tafamidis showed in its label to be competitive in regards to benefits for the six minute walk test and the safety outcomes? And then a follow up question is that, for the elevated liver enzyme, are you looking to make changes to the steroid anti-histamine regimen as well?

David, with respect to tafamidis, how do you think about that? We think that that's a first point of entry that we believe we're ultimately going to surpass substantially so. It's a relevant competitor out there, obviously, because it's an approved agent. And as we've seen with others who are studying the different drugs in the space, you have to think about what's appropriate for our study design and what's appropriate for patients. But from the standpoint of improving upon any of the outcomes for tafamidis, we think that the knockdown approach should be in a good position to do that. David, any other thoughts on that? With respect to our pretreatment regimen, any thoughts?

Just to repeat again, we do think that the cardiovascular events and mortality are the most important endpoints there. And I think you've seen in the BridgeBio data, the way people were doing a six minute walk is really changing over time. The disease is better managed than it was in the days of tafamidis. So, we're looking in general what we're hearing from a cardiologist, are patients who are really healthier, able to walk more, and maybe that measure is going to become less useful in terms of thinking about benefit. The real benefit is can we keep the patients out of the hospital, can we keep them alive longer? The second part…

Pretreatment regimen for 2001, any change?

No, we don't think any changes are needed. With that patient, they came down very quickly without any type of treatment. So, we don't think we need to change the pretreatment.

The next question comes from Greg Harrison with Bank of America.

You've mentioned advancing new platform capabilities this year. How do you feel about your technology toolkit overall? And where could you add to it going forward?

My guess is that Laura was hoping you would ask a question like that. Laura, you want to give any insights into how you think about the toolkit?

Yeah. So, we really want to be unlimited by the gene editing modality as well as the delivery modality. So, we're investing in both fronts for in vivo, as well as ex vivo applications. So, yeah, we will be sharing more data when available. But we are really leveraging a very deep, experienced team, and working very collaboratively with our tech ops colleagues to ensure that tools we develop in research, they are robust and deployable. So, we can [indiscernible].

I would just reemphasize the idea of toolkit, the notion that you want to have more than one modality available to you. There's no single modality that's going to address all of the things that we pursue. And everything that anyone is working on begins with basic CRISPR/Cas biology, either from a homing point of view or for engineer proteins. And so you always want to start with a deep skill in that area, which we think that we certainly accumulated. But whether it's derivative forms of that that go on and have particular use cases or other approaches that can be combined, our goal here is to have access to all of those tools. So we think about the capabilities we want to have in terms of the particular genetic engineering problem that we want to solve and we want to be unlimited in that space. And we think we're well on our way to being able to make those claims.

The next question comes from Mani Foroohar with SVB Securities.

As we think about the pivot to focus more on allogeneic, are there specific technologies investments, some of the manufacturing infrastructure, the reason to think about potentially flowing through the CapEx in a meaningful way? Or is that infrastructure and tools that you've sufficiently built out that really is kind of baked into the underlying ongoing R&D spend, if you could comment a little bit on that?

Just at a high level, Mani, it's an interesting thought. But I don't think we're going to see a big effect from that. What the ultimate benefit, I think is going to be, downstream for the patients themselves, where the reagent that they receive, the actual engineered cell is a healthier cell that is there when you need it with a more efficient manufacturing approach. In other words, more material produced per run. And as Laura emphasized the critical missing element thus far in other approaches that the cells, when you put them in, should persist and be essentially equivalent to what an autologous source would be. But in terms of our R&D budget and the ongoing near term spent, I don't think there's going to be much of an effect. Glenn, do you want to add any color to that?

No, no. John, you've hit it. I think the one thing, just to remind people listening to is, we did establish a relationship with Cellex a year ago too that really had this in mind that we'd making this pivot in the future. So I think we're well established from an externalized relationship perspective on the upside.

I have one follow up. I feel like I was missing the party if I didn't ask something about TTR. Obviously, the scale of a clinical trial that's likely performed for a genome editing approach, it's unlikely to look like something on the scale of ATTRACT. But whatever your approach is, the statistics of showing an overall survival benefit don't really change. So, do you feel compelled in the past in pursuing a path of cardiomyopathy to do an outcome study? Is that even plausible for genome editing approach? Or should we expect that whatever pivotal paths in the TTR cardiomyopathy you pursue is going to be some kind of sort of clinical endpoint, six minute walk, etc.?

Well, I'll take a first pass at that. And David is closer to the statistics and the trial design that we're working through here. But I would just look to the models that are out there already for cardiomyopathy and expect that we will emulate a lot of that work that's been done. Obviously, inputs that are coming from the additional information will factor that in, which gives us more confidence about event rates and the like. But with respect to surrogate markers, that's a regulatory approach that comes from the Food and Drug Administration and other agencies around the world. And as yet, that has not formally recognized as would be, say, cholesterol or viral load in different disease conditions. So there's no doubt that that would certainly speed the process because TTR is so readily measured, but thus far, the stance of the regulators has been to look for those actual clinical outcomes, irrespective of the TTR effect. David, anything?

I think those are the main points. We're seeing the Alnylam study sort of as a wind to our back to figure all this out. We're going to see the results of that and help us really understand what we need to do to see an outcome study. And again, we have this advantage that by getting deeper reductions, we can anticipate a better result than what they'll see with that – with any of the agents because none of them achieved the type of TTR reduction that we can achieve.

The next question comes from Jay Olson with Oppenheimer.

I was curious about recent publications of novel targets, which have been revealed from human genetic studies showing that certain germline mutations provide protective effects against metabolic diseases. And they seem to be interesting targets for gene editing. Are there any comments or observations you could share on those publications? And as a related follow up, what is your interest level at Intellia you in pursuing a program that targets broader indications such as liver disease or cardiovascular disease related to protected mutations?

But the question for you to make sure I understand your question, are you asking me a germline question? Or are you asking me about somatic mutations that can have some physiological benefit?

Well, the specific publication I was referring to was a germline mutation. But you can answer the question from either perspective, I suppose.

First of all, from a germline point of view, that's not something we work on. And that was addressed some years ago as we were thinking about what was appropriate for us to work on where we could make the biggest benefit for patients, and do it in a way that just really with respect to where the technology is today and where we see it going. But germline mutations manifest themselves as somatic mutations, and you certainly get the readout from the fact that someone carries any genetic change. And so, to the extent that there's kindreds that have some clinical benefit, which stands behind all of the genetic reasoning that's been done with some of these particular risk reduction mutations, etc., we certainly look to that space as informative for relevant targets to go after. But what we would ask ours, is that addressable at the somatic level as opposed to going after the germline level? So, that's where we draw the line.

The next question comes from Debjit Chattopadhyay with Guggenheim.

This is Ry Forseth on for Debjit. Assuming an siRNA approval in ATTR CM, do you foresee challenges in enrollment? And how do you think about the need or requirement of authorities around comparator?

David, do you want to address?

What we see, all the studies that are being done currently, of course, don't have an active comparator. And if a silencer is approved, our study will likely be running before any approval comes certainly. Certainly in Europe, as well as the US. So we do feel – we obviously haven't talked yet exactly about what our study design is. But we don't know that we would need an active comparator at this point. In terms of enrollment, as mentioned, there's this enormous interest in what we're doing. I think that has to do with the depth of reduction that we're going with the fact that it's a one-time treatment for patients as well. And those things I think will drive a lot of interest in our trial.

And one follow-up. The bodyweight of the PN subject that showed the day 28 enzyme elevation, anything not typical or to note for that individual?

No.

We don't even know that the study drug is related. It's sort of a an open question at this point. And we don't think it's related to the direct LNP infusion. Remember, we said this of the patient who did extremely well with the infusion, as almost all the patients have done, and it's just finding at day 28 that was transient. But we're just being very, very thoughtful with respect to the information as we accumulate it. And again, that starts with the substantial efficacy that we have, which, again, as David has pointed out, when you look at it, 0.7 mg per kg, 1 million, as we've accumulated additional patients, we just really don't see a difference between them from an efficacy point of view. So it makes the decision pretty easy.

The next question comes from Kostas Biliouris with BMO Capital.

I had a couple of them, but I will limit myself to one. So, on the liver enzyme elevation, you mentioned that these occurred at day 28. And this is exactly when the maximum inhibition of TTR is reached. So I'm wondering if, in your view, this has anything to do with very high TTR inhibition at month one or the two are probably unrelated?

David, any thoughts?

Yeah, we believe these are unrelated. We can't think of any connection between the TTR going down and liver function changing – the enzymes changing.

And of course, we have all these other patients who are equally inhibited for which there's no…

Yeah.

So, the inhibition of this patient wasn't really higher than the others?

Yeah. No, not distinguishable.

And I believe the last question then will come from Yanan Zhu with Wells Fargo.

I have a very, very quick two-part question. You mentioned TTR reduction at the 0.7 mg per kg is skewed by outlier. Could you let us know the percent reduction if that outlier is taken out? Right now, I think they average 86. If you can inform us on that percentage without outlier, that would be great. And then for the ALT elevation at around day 28, have you ruled out immune response, i.e. specifically a T cell response to Cas9? I know this is unlikely because you have a transient expression, but just wanted to know if you ruled that out that.

The percentage without the outlier would be greater than 90%. Yeah. So, it will be more detailed than that. Yeah, we don't rule out a T cell. There's a lot of causes. Again, we mentioned it's just possibly related. We are looking, we haven't found any of the routine testing that discovered what's causing this. So we don't have an answer.

How much they had, at this point, we don't know. Again, the patient, asymptomatic. It was a laboratory finding that disappeared quickly. And just bear that in mind as we go. And as we learn more, we'll report on any insights that we have, if we get any, as the study progresses. Remember that we have a lot of patients that we've seen. And the question is, is this just an outlier or not? But, obviously, we're vigilant as we proceed and carry out our work.

This concludes our question-and-answer session. I would like to turn the conference back over to Ian Karp for any closing remarks.

Great. And thanks so much for all of your great questions and for joining us today, and your continued interest and support of Intellia. Look forward to updating everyone as we continue to progress. Have a great day.

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