Intellia Therapeutics Inc (NTLA) 2022 Q2 法說會逐字稿

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. (Operator Instructions)

I will now turn the conference 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 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 & 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 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 I study. In June, we presented additional clinical evidence that NTLA-2001 led to deep and durable TTR reductions, following a onetime administration across all therapeutically relevant doses.

David will provide a recap of the data presented at EASL and elaborate on the latest findings from the study. In addition, dosing is now completed in the dose escalation portion of a cardiomyopathy arm, with a more expansive 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 are making a strategic shift to focus on exclusively developing allogeneic cell therapies. For a lead ex vivo program, NTLA-5001, which you may recall as 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 patient 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 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 I study at EASL's International Liver Congress in June. These data provided early confirmation that deep reductions in the disease-causing protein achieved by a one-time genome metaling treatment are, in fact, durable over time. At all 4 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 6 months to a year.

At the 0.7 and 1.0 milligram per kilogram 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 6 months of ongoing follow-up. We continue to believe these deep, durable and remarkably consistent levels of protein reduction support 2001's potential as a onetime 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 study. There are now over 30 individuals who have been dosed with 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 are pleased to share that the initial findings have been consistent with the data previously reported from the polyneuropathy arm at EASL. Based on the recent data, the 0.7 and 1.0 milligram per kilogram have very similar TTR reduction have been generally well tolerated. We are now finalizing a 6 dose selection at or near a fixed dose equivalent of 0.7 milligrams per kilogram for evaluation in the dose expansion portion.

We also announced today that we plan to evaluate the same 6 dose in a second cohort in the dose expansion portion of the polyneuropathy arm. The decision to study a second dose based on 3 main factors. First, the emerging data from the dose escalation portion with cardiomyopathy arm, while still in a small number of patients dosed, initial TTR reduction data is indistinguishable at the 2 doses tested.

Second, the comparability of performance at the 0.7 milligram per kilogram and 1.0 per milligram per kilogram doses in the dose escalation portion of the polyneuropathy arm. And third, while 2001 has been generally well tolerated, there was a recent adverse event in a patient dosed in the 80-milligram dose expansion cohort in the polyneuropathy arm and 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 6 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 out of benefit to patients at the lowest dose possible. Overall, this strategy reflects our strong conviction at 2001 and 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 initial safety data from the 80-milligram dose expansion cohort from the polyneuropathy arm at the upcoming 2001 data readout later this year. We are incredibly proud of all the rapid progress in our ongoing Phase I study of 2001 and subject to regulatory feedback on the protocol amendment, we continue to expect to complete enrollment by the end of 2022.

Turning now to 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 effectivity. Other modalities have shown that a 60% reduction in calcarine activity leads to a therapeutically relevant reduction in HAE attack.

With 2002, we've shown compelling data in non-human primates where we have achieved and sustained greater than 90% reduction of both calcarine protein and its activity after a single dose. If these results translate to human, 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 cohort later this year. This interim data readout is expected to include safety, calcarine reduction and HAE attack rate data. These results will offer an initial view of the safety and activity profile of 2002 and potentially demonstrate proof-of-concept for the modularity of our proprietary CRISPR-based LNP 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 therapy 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 treatment do not provide an ideal studying point for collecting healthy cells for subsequent engineering.

In addition, the complex manufacturing process required and associated high cost for these therapies present further hurdles to treatment. In response, mainly 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, sales should be sourced from healthy donors and be readily available for administration.

Second, there needs to be an efficient manufacturing process, able to produce a full product with desired attributes at an accompanying lower cost. And finally, of critical importance, this engineer cell must persist for long periods of time, allowing for continued anti-tumor activity. This last key area persistence remains an untold hurdle and recent clinical data has clearly demonstrated that lasting responses are not achieved with current approaches.

At Intellia, we have developed a proprietary allogeneic platform, which leverages a novel combination of sequential gene edit. Our clinical 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 pave 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 allogeneic version.

Most importantly, we believe an allogeneic version of NTLA-5001 will provide significant advantages to patients fighting an extremely aversive type of cancer. In further support of this decision, we plan to present additional clinical data on our allogeneic platform at the Scientific Conference later in 2022. Our platform innovations continue to support our robust research engine and the host of wholly owned and partner investigational CRISPR-based therapy.

I 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 aftermarket 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 in Intellia. We continue to make significant progress in our mission to bring forth the 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 interest 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. A 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 8th. I'm assuming you plan to attend at least virtually. Thank you.

Thanks, Joon. First of all, we're really excited about the outcome because we think it validates what we believe for a long time, which is the best way to deal with any form 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 demonstrated and apply it to patients in cardiomyopathy and would expect to see a 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 patients performed, obviously, a 6-minute walk test is a particular readout, but some of the harder end points I think are really important to understand, which we'll 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 to expand on?

Yes, I think couple of other things we'll be interested in how patients did receive 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.

This is [Faton] 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 6-minute walk as like endpoint or which prefer like harder end point?

Well, as first pass, I think the 6-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 6-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?

We've been talking for a while that we do think the most important endpoints are cardiovascular events and mortality. And we 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 come 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 outlined in the press release, safety, I guess, calcarine 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 is generally, I guess, shared -- has shared attributes between 2001, 2002 and now 2003, is there anything unique about the A1AD gene or the SERPINA1 gene that warrants a broader window for IND or equivalent filing?

So we can do the 2003 question first. When we get 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 and a different locus whereas 2003 targets see offending gene itself, SERPINA.

So 3,000 is a little bit ahead of 2003, they are independent programs. We 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 to HAE, we look at the standard of care as a point of departure and we think that attacks the 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 calcarine levels and that's exactly the approach that we're taking.

What we've seen is that figure 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 surpassing them, which is, of course, our objective.

The next question comes from Gena Wang with Barclays.

So I have one question regarding the one case of living enzyme elevation at day-28. Can you give a little bit more color regarding how many photos upper limit norm that reach and how long did it last? And since you also dosed 75 milligram 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 up, say, one or 2 months follow-up, if you can give a little bit more color regarding the attack rate.

I think that might be 4 questions, Gena, but I try to keep up with you. With HAE we'll show the data that we have, which is -- 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 we have when we do a data disclosure later this year. But I'd just emphasize that as we shared in our script, the data or the patient fit 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 it's -- our database has grown, we've seen that it's essentially indistinguishable TTR reduction levels between the 0.7 and 1.0 milligram.

Remember that when we did some of our first dose selections, it was based on essentially 3 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 in there.

I don't know, David, if is there 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 you 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 it is usually over a period of 2 to 4 months depending on the follow-up.

I guess just one other thought on the patient you asked about, Gena, we've said, remember, it's at day 28. Yes, one of the things that is important to think about with LNP is as a class certainly look a lot like the class. LNP elevation -- LFT elevations when they occur tend to be right around the time of dosing, which is day one, 2 or 3. We've seen very low elevations which we reported on. This is a transit funding 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 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 what 6001 could entry clinical development? Thank you.

Thanks for the question. 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, et cetera. And remember that behind all this is the logic that while 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 in TCR, we think is the most promising one of those.

So with respect to moving forward, we've got many of the inners 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.

Great. And maybe just a quick follow-up on 5001. Are you going to present any of the data from the auto program if you dose any patients there?

We'll look at what we get. I mean, 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 yellow program, we'll think about that and ensure as we see appropriate.

The next question comes from Swapnil Malekar with Piper Sandler.

Hey, thank you for taking my questions. So 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 calcarine 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?

Yes, 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 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.

Got it. And then for the fixed dosing regimen of 0.7 mg per kg equivalent like 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, like is there any other patients who had any ALT or liver enzyme elevations even if not significant like any minor or incremental elevations?

While you've seen some of the data that we presented, certainly around the time of infusion, you'll get very low level increases in LPs, we 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 time lines? And separately on the switch to allogeneic for your AML program, could you just expand on the rationale here, but 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.

So maybe David can say a word about any impact, if any to the time line. 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 your first.

So let me take you back to really EASL where we showed 15 patients from the polyneuropathy program. And what we saw there was deep reductions start really starting at 0.3 is where we see it durable and up through 1 milligram. At that point, it looks like the 1 milligram was slightly better than the 0.7 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. So that with this increased data, it's quite clear that the efficacy at 0.7 and 1 are really indistinguishable.

So with that, the -- we are -- now that we've -- and you see with the rate of enrollment at this point, the investigators are really excited about the program, doing very well. So we have lot of information on patients with 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 see. And that has to do with the -- how much we've learned. And recall it with the cardiomyopathy patients, we did study both 0.7 and 1 in order to pin down this question.

In the drug 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?

Sure. Yes, no, no happy to do that. So what we've learned from our study, but importantly for allos is that the importance of an allogeneic platform is not only to have a consistent cell product with high-quality, (inaudible) manufacturing resulting also in lower cost of goods as compared to an autonomous therapy. But what is of critical importance is that these engineer allo fills must persist for long periods of time in the patients to allowed for continued anti-tumor activity.

So having complete responses that last month or 2 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 persistent. 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 T 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 these long, long persistence. We are going to be sharing more data later this year, going into detail in the actual editing strategy and continue to share based on the performance of the cells. So looking forward to having that conversation at that time.

You know, it's -- 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 by one at a time, which brings tremendous cost, time lags, et cetera. And if you're able to manufacture for 50 to 100 people at the same time, that just brings tremendous opportunities in terms of 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 than 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 an standpoint of time lines, although we're not guiding yet when we look at our plans and look down the road, I think that well, allo may start a little later, I think it can finish very, very quickly, assuming it performs to the levels that we expect.

Thank you.

The next question comes from Luca Issi with RBC.

Great. Sorry to go back to this one, but I think you mentioned a couple of times that the 0.7 milligram per kilogram and 1 milligram per kilogram were indistinguishable in TTR cardiomyopathy. However, in TTR polyneuropathy does look to me that a 1 milligram per kilogram drove a better knockdown, which is obviously important to be the silencers. So wondering how you rationalize the difference between TTR polyneuropathy and cardiomyopathy, again, I understand small numbers, but would love to kind of hear your thoughts on how you rationalize that difference. And then maybe on HAE, I think Ionis has shown 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 in '21, remember, we get to see a lot more than you do. And so that certainly informs how we think about this stuff. And Dave, I don't know if you want to say a word or 2 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 had a wide standard ever means for their mean reduction. And this is actually driven by a single patient, an outlier with actually an outlier not only from 0.7 and 1, but also from 0.3. 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 is 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 we act biologically pretty much identical to patient polyneuropathy that the TTR reduction will be the same at 0.7 and 1.

I guess the other question was, again, just what we're -- what we use as a benchmark for HAE?

Yes, the benchmark we're looking at is what TAKHZYRO gets about a 60% reduction. You recall when our preclinical models were able to get 90% reduction, so -- and what you've seen with TTR. So we think that we will be able to get to a good target reduction with calcarine in that study.

I mean we haven't seen anything that we don't think we can meet or surpass (inaudible) I guess is the way to think about it.

Got it. Super helpful. Also the commentary on the outlier really, really helpful.

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 this label to be competitive in regards to the magnitude of benefits for the 6-minute walk test in the CV outcomes? And then the final question is that for the elevator liver enzyme, are you looking to make changes to the ceroid antihistamine measurement as well?

David, with respect to tafamidis, how do you think about that? I mean we think that, that's a first point of entry that we believe we're ultimately going to surpass substantially so. And so I mean, it's a relevant comparator out there, obviously, because it's an unapproved agent. And as we've seen with others who are studying 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 a 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 pretreatment, Rich, any thoughts?

Right. Yes, 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 that the way people are doing on 6-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...

Yes, it's pretreatment regimen for 2001, any change?

Yes, 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, do you want to give any insights into how you think about the toolkit?

Yes, 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 yes, we will be sharing more data when available. But we are really leveraging a very deep experienced team and working very collaboratively with our take-ups colleagues to ensure that tools we develop in research, they have the robust and deployable. So we can (inaudible).

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 cast biology, either from a homing point of view or for engineered proteins. 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 in 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, investment, some of the manufacturing infrastructure, the region 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, can you comment a little bit on that?

Yes, 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 and 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 spend, I don't think there's going to be much 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 be making this pivot in the future. So I think we're well established from an externalized relationship perspective on the tech op side.

That's helpful. And then one follow-up, I feel like I was missing the party if I didn't ask something about TTR. Obviously, we -- obviously, the scale of a clinical trial that's likely to perform for a genome editing approach, it's unlikely to look like something on the scale of attract. But whatever you 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 passive regarding to do an outcome study? Is that implausible for genome editing approach? Or should we expect that whatever pivotal path and TTR cardiomyopathy pursue is going to be some kind of sort of a clinical endpoint, 6-minute walk, et cetera.

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. I mean, obviously, inputs that are coming for the additional information we'll 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 is not formally recognized as would be, say, cholesterol or viral load and different disease condition.

So there's no doubt that would certainly speed the process because TTR is so readily measured. But thus far, the stances of regulators has been to look for those actual clinical outcomes irrespective of the TTR effect. I don't know David, anything...

I think those are the main points. We're seeing the Alnylam study sort of as a win 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 outcome study. And again, we have this advantage that by getting a deeper reduction, 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.

Thank you for the update. 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 there 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 in pursuing a program that targets broader indications such as liver disease or cardiovascular disease related to protective mutations?

About 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.

Yes, I mean, 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 respective 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, et cetera, we certainly look to that space as informative for relevant targets to go after. But what we would ask how 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 authorities around comparator?

David, do you want to address that?

Yes, what we see, all the studies that are being done currently, of course, don't have an active comparator. And if a fire answer is approved, our study will likely be running before any approval come certainly in Europe. as well as the U.S. 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 we mentioned, there's 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 onetime treatment for patient as well and those things, I think will drive a lot of interest in our trial.

Thanks for that information and one follow-up. The body weight 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, I mean, which -- it's sort of an open question at this point and we don't think it's related to the direct LNP infusion. Remember, we said this is a patient who did extremely well with the infusion, it's 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, it starts with the substantial efficacy that we have, which, again, as David has pointed out, when you look at 0.71 as we've accumulate 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 and if possible to kindly limit yourself to one question only if possible.

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 2 are probably unrelated? Thank you.

David, any thoughts?

Yes, 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...

Yes, yes, so we think.

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

Yes, 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 is, I think, the average 86. If you can inform us on that percentage without outlier, that would be great. And then for the ALT elevation around day-28, have you ruled out immune response, i.e., a T-cell, 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 rule that out.

David, do you want to address that?

Yes, so the percentage without the outlier would be greater than 90%, yes. So there will be more details on that. Yes, we can't -- if we can't -- we don't rule out a T-cell. There are a lot of pauses, 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.

Not much to add, I mean, at this point, we don't know. Again, the patient asymptomatic, it was laboratory finding that disappeared quickly and just bear that in mind as we go. As we learn more, I mean, we'll report on any insights that we have is 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. We 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.