Intellia Therapeutics Inc (NTLA) 2022 Q3 法說會逐字稿

Good morning, and welcome to the Intellia Therapeutics Third Quarter 2022 Financial Results Conference Call. My name is Andrew, and I will be your conference operator today. (Operator Instructions) This conference is being recorded at the company's request and will be available at 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 third 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, and tell you 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 program. Laura will then recap the company's R&D progress, and Glenn will review Intellia's financial results for the third quarter. John will then offer some concluding remarks before we open up the call for Q&A.

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 by deploying the broadest and deepest toolbox. For pioneering novel editing and delivered 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 third quarter and more recently, we've continued to execute against our strategic priorities as we advance our full spectrum pipeline and modular platform. This includes achieving significant clinical milestones across our landmark first-in-human studies of NTLA-2001 and NTLA-2002. In September, we were delighted to share positive interim data from both clinical trials, which David will recap shortly. Both data sets demonstrate the potential for investigational therapies to be transformative onetime treatments for people living with either ATTR amyloidosis or hereditary angioedema.

By successfully editing a disease-causing gene, we showed for the first time that we can not only significantly reduce levels of the offending protein, but also in doing so, can elicit a clinically meaningful impact Further, these data provide powerful evidence of the modularity of our platform and highlight the strong foundation on which we will move forward a pipeline of CRISPR-based therapies. We're looking forward to sharing additional interim data from these ongoing studies with NTLA-2001 and NTLA-2002 in the coming weeks.

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 recently shared positive interim results from the cardiomyopathy arm of the ongoing Phase I clinical trial. These interim data were from 12 adult patients with ATTR amyloidosis with cardiomyopathy with New York Heart Association Class 1 to 3 heart failure. These data showed mean serum TTR reduction of 93% and 92% at the 0.7 and 1.0 milligram per kilogram doses, respectively, at day 28. At both dose levels, there were remarkably consistent levels of protein reduction achieved, ranging from 90% to 97%.

21 was generally well tolerated. 2 of 12 patients reported transient infusion reactions, which resolved quickly and was the only observed treatment-related adverse event. No clinically significant laboratory abnormalities were observed at either dose level. We continue to believe these deep, durable and consistent levels of protein reduction support NTLA-2001's potential to be the best TTR-lowering agent. We look forward to presenting for the first time these interim data, including extended follow-up at the AHA Scientific session to an audience of leading cardiologists. The selection of our abstract for a late-breaking oral presentation underscores the excitement the cardiology community has for a novel investigative approach.

We announced today that we initiated dosing at a 55 milligram fixed dose, which corresponds to the 0.7 milligram per kilogram dose in Part 2 of the study. Part 2, which is a dose expansion portion will include a minimum of 8 patients in the polyneuropathy arm and 12 patients in the cardiomyopathy arm. As previously guided, we expect to complete [prime] enrollment of both arms of the Phase I study by the end of this year. This will inform our dose selection decision for subsequent pivotal studies, which we expect will include U.S. clinical sites. We look forward to sharing additional details on next steps in early 2023.

Turning now to our second in vivo program, NTLA-2002, our investigational therapy for the treatment of hereditary angioedema or HAE. Here, we shared positive inter results from the ongoing Phase I/II clinical study at the 2022 Bradykinin Symposium in Berlin. We were thrilled to report that NTLA-2002 resulted in robust ad reductions in plasma kallikrein levels and the rate of swelling attacks in patients with HAE.

A single dose led to dose-dependent reduction in plasma kallikrein, with mean reductions of 65% and 92% in the 25-milligram and 75-milligram dose cohort by week 8, respectively. In addition to plasma kallikrein levels, HAE attack rates are also being measured in the study with the first analysis occurring at the end of the prespecified 16-week primary observation period.

A single 25-milligram dose of 2002 resulted in a mean reduction in HAE attacks of 91% through the 16-week observation period. Additionally, 2 of the 3 patients have not had a single HAE attack in treatment, and all 3 patients have been attack-free since week 10 through the presented follow-up.

These early data underscore the potential for a single dose of NTLA-2002 to permanently prevent the debilitating and potentially fatal dwelling attacks that characterize this chronic lifelong genetic disease. And importantly, marked the second time in history clinical data has been generated for a systemic in vivo CRISPR-based therapy.

Later this month at ACAAI, we look forward to presenting additional data that will include initial safety and kallikrein reduction data from the 50-milligram dose cohort and additional safety, palace reduction and attack rate data from the 25-milligram and 75-milligram dose cohort. As we've shared previously, we expect to begin the Phase II placebo-controlled dose expansion portion of the study in the first half of next year and anticipate including U.S. clinical sites as part of this trial.

I'll now hand over to Laura, our CFO, who will provide updates on our platform and R&D efforts.

Thank you, David. Looking beyond NTLA-2001 and NTLA-2002, we continue to progress 2 wholly owned development candidates for the treatment of Alpha-1 antitrypsin efficiency. This includes NTLA-31, our gene insertion candidate for the lung manifestation of the disease and NTLA-2003 and in (inaudible) candidate for the liver manifestations. We're conducting IND-enabling activities for both candidates.

Shifting now to our ex vivo efforts. At Intellia, we have developed a proprietary allogenic platform, which is designed to overcome rejection by the host, [acutely] patient to the durability of current allogeneic investigational therapies. By implementing our M&P based cell engineering and novel matching approach, which create allogeneic T cells with high antitumor activity, which may be uniquely capable of persisting in the patients to maintain durable responses.

Last month at ESGCT, we shared for the first time the [Edit] involved in our novel allogeneic approach, which includes the knockout of HLA Class II and HLAA while retaining HLA-B and C proteins. The resulting cells when tested in preclinical models were able to avoid distraction by host T cells and importantly, by host NK cells at previously untold liability.

Further, by only making healthy donor to patient T cells for HLA-B and HLA-C, which can create an off-the-shelf therapy that addresses the majority of the patient population with only a small set of dollars. Platform innovations such as these continue to propel our robust research engine and the host of wholly owned and partner programs.

Our allogeneic platform already underpins collaborations with AvenCell and Kyverna. For our wholly owned efforts, IND-enabling activities are currently ongoing for NTLA 6001 and allocate candidate in development for the treatment of CD30 expressing hematologic cancers. We're also applying this technology to a TCR targeting WT1 as we transition our former clinical candidate, NTLA-51, to an allogeneic version.

With the breadth and depth of our CRISPR-based toolbox, we're driving forward platform innovation to maintain our leadership position at the forefront of the genome editing evolution.

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, and good morning, everyone. Intellia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform. Our cash, cash equivalents and marketable securities were approximately $849 million as of September 30, 2022 compared to $1.1 billion as of December 31, 2021.

The decrease was driven by cash used to fund operations of approximately $276 million as well as the acquisition of Rewrite Therapeutics for $45 million. The decrease was offset in part by $62.1 million in net equity proceeds raised from the company's at-the-market agreement and $15.1 million in proceeds from employee-based stock plans.

Subsequent to Q3, through the period ended October 27, 2022, we continue to increase our cash position by raising an additional $115 million in net equity proceeds from our at-the-market agreement.

Our collaboration revenue increased by $6.1 million to $13.3 million during the third quarter of 2022 compared to $7.2 million during the third quarter of 2021. The increase was driven by our collaborations with AvenCell and Kyverna. Our R&D expenses increased by $36.2 million to $96.7 million during the third quarter of 2022 compared to $60.5 million during the third quarter of 2021. This increase was mainly driven by the advancement of our lead programs and personnel growth to support these programs.

Our G&A expenses increased by $3.4 million to $22.1 million during the third quarter of 2022 compared to $18.7 million during the third quarter of 2021. This increase was primarily related to employee-related expenses, including stock-based compensation of $2.4 million. Finally, we expect our cash balance to fund 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. As you can see, this quarter marked major milestones for Intellia and the patients we aim to serve. For ATTR amyloidosis, interim results from the cardiomyopathy arm of the study underscore the potential of NTLA-2001 to set a new standard for treating patients with this life-threatening disease regardless of manifestation. We're rapidly completing the dose expansion portion of the study in engaging with regulatory agencies, including in the U.S. as we move closer to a pivotal trial.

For HAE, we believe these preliminary data speak to until a 202's potential to address the current treatment burden by permanently preventing the debilitating swelling attacks associated with HAE following a single-dose treatment. We plan to initiate the Phase II portion of the study in the first half of next year.

With the second clinical proof of concept in hand for systemic in vivo gene editing, we're continuing to lead the genome editing revolution by expanding the horizons of what CRISPR can do. We look forward to additional data presentations from both NTLA-2001 and NTLA-2002 in the coming weeks in the sharing of our 2023 strategic priorities for advancing our full spectrum pipeline and platform early next year.

With that, we'd be happy to answer any questions. Operator, you may now open the call for Q&A.

(Operator Instructions) The first question comes from Greg Harrison with Bank of America.

This is Mary Kate on for Greg. So for the 21 program, you mentioned moving into an additional drug expansion at 55 milligrams, could you discuss your priorities for dose selection decisions for subsequent pivotal studies?

David, do you want to speak to how we think about those selections.

Yes. Thank you. So as we're designing the pivotal study at the same time, we're collecting more information on dose and we did announce that we started to treat patients at the 55 milligram dose. What we saw in the patients with cardiomyopathy is that the doses of 0.7 and 1.0 milligram as really the same reduction in TTR, which is our main pharmacodynamic endpoint, and we think is very closely aligned to what efficacy we're going to eventually see.

So looking at those 2 doses, we chose 0.7, the lower dose, as you always would in terms of giving the best safety and translate that into a 55 milligram dose. Now this is still in Phase I is Part 2 is a Phase I confirming that dose, but everything is looking quite good, and we do now anticipate that it's likely to be the Phase III dose. Of course, in Phase I, you keep learning things, and we do have to confirm that.

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

In terms of the response for HAE and attack rates, I guess, what is sort of the bar here for patients that are on prior prophylaxis obviously taking everyone to zero after time is an amazing result. But as we start seeing longer-term follow-up, what represents sort of a significant advancement in the field versus prophylaxis if anyone has any breakthroughs.

David, we'll turn to you one more time. How do you think about what we're shooting for with respect to attack rates.

Yes, what we're seeing with prior prophylaxis, obviously, as patients having breakthrough attacks. So the therapies you're getting in getting them to zero attacks. There is an extensive work in this group. And as we move to more advanced studies, it's likely that most of the patients would not be on prior prophylactic treatment. However, the standard -- the current therapies often achieve about a 90% reduction overall.

But as you can see with these patients with breakthrough that's not working for everybody, even at 90%. So we think that will be a significant advantage for to getting to -- it's starting with the pharmacodynamic endpoint of getting pre-kallikrein down. Right now, we see we can get to 92% with the 75 milligram dose. So we know that we can get to lower levels that have been achieved with other therapies.

We'll be looking at the whole picture in Phase II, looking at 2 doses and using that to decide what is the best dose, obviously, looking at both the safety picture and the attack rates in Phase II. We think the significant advance is what we're trying to get to is that all patients or as many patients as possible do get to zero attacks, whether that occurs after 10 weeks as it did in 1 patient or if that occurs right from the get-go when they first get the treatment.

Yes, just to add one thought to that. One of the things that I think needs to be borne in mind is it's not just attack rates. Obviously, that's the primary manifestation of the disease. But one of the things that we think really brings additional value to patients would be freeing up what is a very significant burden of care. One of the things we've learned in talking to KOLs and patients themselves is that the very involved treatment that many patients need to take as a relative barrier to their success.

And so in addition to achieving those very, very deep reductions in attack rates, which we're very excited about, we think we're going to be in a position where we may be able to free up many of these patients from actually taking any therapy at all, which I think will really constitute a significant advance in the space.

The next question comes from Brian Cheng with JPMorgan.

It's great to see the progress. It seems like you're pretty confident to start a pivotal for ATTR and the Phase II for HAE with sites in the U.S. We're wondering if you can elaborate on where you stand in terms of lining things up to start trials in the U.S. Any insights from your interaction with the FDA would be super helpful.

Again, David, do you want to speak to that?

Yes. So we have had interactions with the FDA around both programs. So we do feel we have a very good idea of what they're looking for in the IND. As stated for HAE, we probably said that that's going to happen in the first half that we're going to Phase II and the U.S. will be part of those Phase II trials. We haven't given the guidance, we'll be giving more guidance on TTR. In that case, we are clearly going to a more advanced study, likely a Phase III study in that case.

So that it is a more extensive application for Phase III, as you can imagine. But again, we've had those interactions, and we have a good idea of what they want. And we'll be talking about it more. We do want to get agreement. We don't want to come out prematurely with what that design is, but we do feel we have a very good design with experts consulting with us and supporting our approach.

The next question comes from Richard Law with Credit Suisse.

Based on the positive data so far in HAE, is there any possibility that the Phase II could become pivotal? And if not, what type of data would you need to collect before posting to a pivotal study?

David, here we go again.

Thank you. Yes. So the Phase II is a small study right now. It's a total of 25 patients, including 2 different doses where we have 10 patients, 5 patients with placebo. So we do believe that is too small to be a pivotal study. So the pivotal study will not be much larger than that. Often, you have a total of about 100 patients or even less that are needed to get an approval in this disease. So we will be obviously using the Phase II data to support the future PLA, but we'll design a pivotal study to support that as well.

The next question comes from Swapnil Malekar with Piper Sandler.

So 2-part question. One is what additional data can we expect that the AHA meeting at the upcoming weekend? And then the second part is like now that you have collected a lot of data and experience in 2001 and 2002, is there a possibility to initiate the first in-human trial for the AATD program in U.S.?

David, do you want to -- I'm not sure we can run too far ahead of information that's going to be presented in literally in just a couple of days. So I would encourage you to wait to get the fuller picture. But do you want to speak a little bit more about what lies ahead for some of the other programs?

Yes. So what is important, we think going to AHA is we will be in front of the largest cardiology study in the world, I guess. So it is an important setting where we have this late-breaking aspect breaking abstract. It does reflect the high interest of cardiologists in our program, and we will -- it hasn't been very long, as you know, since we gave some of the initial data, so we will expand that a bit in this presentation –expand the data. Yes. We do -- as I said, we are preparing -- we've always been in the plan to have the U.S. as part of the -- the -- sorry, the Alpha-1 (inaudible). Yes. No, we haven't said exactly where it's going to start. What we have said is in the second half of the year. We will have a CPA or IND or both for 3001. That's our first knock-in program. So very excited about that.

And so that is in '23. We haven't given guidance yet on 2003, which is the knockout of the mutant alpha-1 -- so don't take that as meaning that it's very far behind the other one or even behind it, but we are -- we do plan to give some more guidance to that in the new year.

Next question comes from Gena Wang with Barclays.

This is [Rashida] on for Gena. We are wondering, could you remind us if you saw any LFT elevations in preclinical models, I guess, specifically nonhuman primates for both 2001 and 2002. Any color here would be appreciated.

I think I can speak to that pretty quickly. Any LNP given insufficient quantities will lead to LFT increases. That is a class effect that's routinely seen across literally every single LNP that we're aware of that's ever been tested across the field from different companies, et cetera. And as I'm sure you know, is part of preclinical work, one dose to determine the therapeutic index by getting to actual levels of toxicity, which is an FDA regulation that we follow does everybody else in the industry as well. So yes, you can see LFT elevations. The goal is to have a therapeutic index that's wide so that you can administer these LNPs to patients successfully with little to no increases, which is, in fact, characterized the clinical program thus far.

The next question comes from Salveen Richter with Goldman Sachs.

Congrats on the progress. This is Tommie on for Salveen. How are you thinking about further in vivo programs beyond TTR and HAE and the decision-making for pursuing more in vivo programs versus ex vivo cell therapy programs.

Yes. Thanks for the question. The way we think about our work in general is a set of filters that we apply to considering particular programs to advance. We think about the nature of the edits we think about unmet medical need, we think about benefit risk. And we try to do all of this in a very deliberate fashion where we add information as we get it in the clinic. So as we look at TTR and HAE, these were very clear examples where the straight forward edit of knocking out of a well-established genetic target would lead to biochemical effects that we could monitor in clinical results that would be relatively straightforward to managing standard sort of clinical trial formats. And thus far, that approach has served us well.

As we look ahead, we think about additional modalities, which builds on the work we've done so far, and that is to move to actual gene insertion. This is reconstituting a gene that may be deficient or otherwise nonfunctional. That speaks to our Alpha-1 program that we just shared a few thoughts on. We also think about targets that either move more into the rare disease space or into more prevalent sorts of conditions. But the same rule supply, is there unmet medical need? Do we believe that we can advance the therapeutics from those patients in a meaningful fashion. And can we do this in a way that we can be competitive and ideally reset the therapeutic bar.

And so there's several conditions that we've been working on. And as we've laid out, there will be some additional in vivo targets that we'll speak to as time goes on. And some of this guidance will be reset at the beginning of the year when we talk a little bit more about advances that we've made. But we -- our work is far from done in in vivo targets, and we're excited about what we're able to take it.

The next question comes from Dae Gon Ha with Stifel.

I wanted to ask you about the 2002 time line. The goal here is to start the Phase 2 and first half '23, 2 doses being explored with a placebo arm. But given the proximity to ACAAI where we'll probably have relatively less of a follow-up on the 50-milligram cohort. And given what we know about TTR, where, obviously, there were very profound effects, but some of the short-term follow-up didn't quite give you the full picture on the safety side as you progress the 80-milligram fixed in the dose expansion. So how do you think about sort of being confident around what you get before the end of the year and deciding the doses going forward in Phase II? Hope that makes sense.

I think I can set the foundation for that. One aspect of your question, I think, is not quite on target, which is what we can learn in the short term, particularly with respect to safety. Virtually everything that we've seen with respect to safety has taken place either within the first 2 days or in rare instances within the first 4 weeks. And that gives us a great deal of confidence to think about the safety aspects of any dose that we would ultimately pursue. With respect to HAE in both the knockdown and the clinical aspects we're able to see the knockdown activity very, very quickly, just exactly as we did in the TTR case, where things pretty much settled out within the first 4 weeks. There is other agents out there that we can extrapolate from which have been guidepost for us up to this point.

And we have the added advantage of seeing within a few weeks of follow up 16 in the case of these studies to give us a really good sense of where these patients settle out. So we think we're in a good position to meet that guidance. And David's team is well on its way to moving that forward. So stay tuned as we give you more details.

The next question comes from Terence Flynn with Morgan Stanley.

On 2001, I was wondering if you can share any more thoughts on the potential control arm. I know that's something you guys have alluded to in the past, but it sounds like you're having additional conversations with regulators. So just wondering if you can share any color there.

Well, it's a work in progress. And as David referred to earlier, we want to have a clinical study that's going to be meaningful with respect to patients and the doctors who treat them that will address the regulatory requirements and that speaks to the set of agents that are available currently. I think the bottom line is there's very good paradigms already out there, and I would look to them for guidance in terms of the general approach. But David, do you have anything you want to add to that, that extends that?

Yes. I think those are the main points. What we're very encouraged about, of course, is that we can get to deeper levels of TTR reduction, which we think will make a difference in terms of how effective the drug is relative to some of the other drugs that are being tested in this area. So that's also part of what we're thinking as we define our pivotal study. But the most important endpoint, as John is saying, are those clinical benefit, the reduction in cardiovascular reduction in mortality and those will be very important in our trials as we come forward, you'll hear more about that.

The next question comes from Maury Raycroft with Jefferies.

Based on the experience so far, does it help narrow the type of patient you want to enroll into the Phase II portion, including based on baseline attack severity? And at this point, do you know what the Phase II study duration will be. Could it be a 3- or 4-month study based on the amount of time where you can see efficacy?

Well, just to set some expectations with respect to patients. We believe that the approach will be generally applicable. And certainly, our objective as we develop the drug for the treatment of these patients would be to bring something that's therapeutically relevant to the broadest set of patients possible. We think ultimately that could be virtually anybody who suffers from type 1 or type 2 HAE. But David, do you want to share any thoughts with respect to the duration of the Phase II study.

Yes. So the standard follow-up for these studies is in the 16-week to 24-week period. So we'll be -- the studies go quickly based on that, as you know, and we should get our answer fairly quickly on the Phase II is underway.

The next question comes from Jay Olson with Oppenheimer.

Can you talk about how you prioritize allocation of the $840 million of cash you have on your balance sheet? And any thoughts about partnering in order to extend your cash runway and share development and commercialization risk?

Sure. I mean it's something that we think a lot about because we want to make sure that we're doing the best we can for our shareholders who are counting us to deliver a meaningful return. It's very much a balancing act across various priorities that we try to talk about not only that are reflected in our guidance. But as we think about how we design the company, as you know, we characterize ourselves as a full spectrum genome editing company because we think that there's very significant opportunities in both the in vivo and the ex vivo space. But critically important is this is a platform that's evolving rapidly, and we want to be not only proficient, but leaders in all aspects of that. So we will always focus on the platform and making sure that our ability to do genome editing of any type is unsurpassed by any company operating space. And thus far, we think that's certainly the case here.

Clearly, advancing the clinical programs is of primary importance for us. Our work in 2001 and 2002 validates the work that we do on the platform side. So I think it's very important to move forward programs that will give us clear signals about the nature of our work, but also programs that, as we said, reset the bar for the therapeutics that are available to these patients.

We're also very thoughtful about how we think about the ex vivo space. And here, you heard in Laura's comments about the work we've done to what we think significantly advances the allogeneic space, which is, again, sort of a platform capability that's broadly applicable, not only across programs that we wholly own ourselves, but that we think will serve as the basis for important collaborations across the industry. We've already established 2 of those. We referred to AvenCell and Kyverna.

As we think about partnering, it's less about funding the advance of the company because we think with the cash balance that we have, we're able to do those things that I've already referred to. But as we look to partnerships, we think of them in terms of the technology or biology that it can bring to us that advances what we're able to provide from a genome editing perspective. And if you look across those partnerships that we've done thus far, that's basically how all of them are set up. And I would expect that as time goes on, we'll continue to take exactly that kind of approach.

So there it is. It's a lot going on at the company, but we think that we have ample resources to carry out what we've set out as our top priorities.

The next question comes from Luca Issi with RBC.

Maybe a quick one for David. Any update on the etiology of the Grade 4 ALT you previously reported for TTR polyneuropathy that occurred, I think, at day 28. I think last time we spoke, you mentioned that a number of hypotheses were being explored, including alcohol or maybe viral in nature. So just wondering if at this point, we have enough evidence to suggest whether that ALT was or was not drug related.

David, do you want to speak to that? That unusual patient appears to be very much an outlier for our work so far.

Yes. So we don't have anything new in terms of viruses, if it -- we haven't identified the virus, though if it is, it's a virus we haven't been able to test for. And we don't know more about alcohol usage. So it is, as John said, it's an outlier. patient is doing great, by the way, that TTR has perfect reduction, a very big reduction like the others. So that's where we are. And obviously, we don't expect much more to come in at this point.

And the last question today comes from Joon Lee with Truist.

There's a view out there that gene therapy for alpha-1 antitrypsin failed because normal copy that gets produced gets caught up by the polinization of the mutant AAT in the liver. Any thoughts on that? And with the metric for success, the 11 micromolar plasma AAT or something else, when you do start the trial?

Laura, I'm going to call on you. How do you think about producing normal protein in the presence of the mutant form. And I think it's important to remind people how we differentiate ourselves versus standard gene therapy.

Yes. So 2 thoughts, John, thank you for the question, right? So we have to candidate 2003 allows us to knock out the mutant form and 31 inserts a healthy copy. And those 2 can be used separately or in combination in any order. So the other thing to keep in mind is that patients who are heterozygous for the (inaudible) right? They have no liver manifestation and no lung manifestations. So you -- if the expression of your normal allele is high enough, you may -- and I'm just using conditional language, right, may be able to phenocopy heterozygous phenotype. So that's to keep in mind. And yes, we are -- our goal is to achieve normal levels of alpha 1, so it would not be 11 micromolar. It would be normal level.

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

Great. Thanks so much, Andrew, and thank you all for joining us today and for your continued interest and support in Intellia. We look forward to updating you on our progress in the coming weeks and months ahead. Have a great day, everyone.

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