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. 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 at the company's website following the end of the call. As a reminder, all participants are currently in a 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. 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 & 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. Laura will then recap the company's R&D progress. And Glenn will then 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. We're pioneering 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 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 datasets demonstrate the potential for investigational therapies to be transformative, one-time 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 2001 for the treatment of transthyretin amyloidosis or ATTR amyloidosis, we recently shared positive interim results from the cardiomyopathy arm of the ongoing Phase 1 clinical trial. These interim data were from 12 adult patients with ATTR amyloidosis, with cardiomyopathy with New York Heart Association class I to III heart failure. These data show mean serum TTR reduction of 93% and 92% at the 0.7 and 1.1 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%. 2001 was generally well tolerated. Two 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 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 that 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 two of the study. Part two, which is the dose expansion portion, will include a minimum of eight patients in the polyneuropathy arm and 12 patients in the cardiomyopathy arm. As previously guided, we expect to complete planned enrollment of both arms of the Phase 1 study by the end of this year. This will inform our dose selection decision for subsequent pivotal studies, which we expect will…

Thank you, David. Looking beyond NTLA-2001 and NTLA-2002, we continue to progress two wholly owned development candidates for the treatment of alpha-1 antitrypsin deficiency. This includes NTLA-3001, our gene insertion candidate for the lung manifestation of the disease, and NTLA-2003, a knock-out candidate for the liver manifestation. We're conducting IND-enabling activities for both candidates. Shifting now to our ex vivo efforts. At Intellia, we have developed a proprietary allogeneic platform which is designed to overcome rejection by the host [indiscernible] to the durability of current allogeneic investigational therapies. By implementing our LN-based cell engineering and novel matching approach, we create allogeneic T cells with high anti-tumor activity, which may be uniquely capable of persisting in the patient to maintain durable responses. Last month, at ESGCT, we shared for the first time the edits involved in our novel allogeneic genetic approach, which includes the knockout of HLA Class II and HLA-A, while retaining HLA-B and C proteins. The resulting cells, when tested in preclinical models, were able to avoid destruction by host T cells, and importantly, by host NK cells, a previously [indiscernible]. Further by only matching healthy donor to patient T cells for HLA-B and HLA-C, we can create an off-the-shelf therapy that addresses the majority of the patient population with only a small set of donors. Class I innovations such as these continue to propel our robust research engine and a 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, an allo CAR-T candidate in development for the treatment of CD30 expressing hematologic answers. We're also applying this technology to a TCR targeting WT1 as we transition our former clinical candidate, NTLA-5001 to an allogeneic person. 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 revolution. And now, I'll 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 of $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 advancements 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 the 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 and engaging with regulatory agencies, including in the US as we move closer to a pivotal trial. For HAE, we believe these preliminary data speak to NTLA-2002'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 2 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 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 2001 program, you mentioned moving into an additional dose escalation cohort at 55 milligrams. Can you discuss your priorities for dose selection decisions for subsequent pivotal studies?

David, do you want to speak to how we think about dose selection?

As we're designing the pivotal study, at the same time, we are 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 that the doses of 0.7 and 1.0 milligram gave 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. In looking at those two doses, we chose 0.7, the lower dose, as you always would, in terms of getting the best safety and translated that into a 55 milligram dose. Now, this is still in Phase 1. This part is a Phase 1 confirming that dose. But everything is looking quite good. And we do now anticipate that it's likely to be the Phase 3 dose. Of course, in Phase 1, you keep learning things and we do have to confirm that.

The next question comes from Joseph Thome with Cowen and 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 10 weeks 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.

It's what we're seeing with prior prophylaxis, obviously, as patients having breakthrough attacks, so that the therapies are getting – isn't getting them to their attacks. There isn't 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 treatments. 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 that 90%. So we think what will be a significant advance is first getting to – it's starting with a 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 2, looking at two doses, and using that to decide what is the best dose, obviously, looking at both the safety picture and the attack rates in Phase 2. We think the significant advances 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 one patient, or if that occurs right from the get-go when they first get the treatment.

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 is 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 J.P. Morgan.

It's great to see the progress. It seems like you're pretty confident to start at pivotal for ATTR and the Phase 2 for HAE with sites in the US. We're wondering if you can elaborate on where you stand in terms of lining things up to start trials in the US. Any insights from your interaction with the FDA will be super helpful.

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

We have had interactions with the FDA around both programs. So, we do feel we have a very good idea of what they are looking for in the IND. As stated for HAE, we've already said that that's going to happen in the first half, that we are going through Phase 2 and the US will be part of those Phase 2 trials. We haven't given the guidance. We'll be giving more guidance on TTR. In that case, we're clearly going to a more advanced study, likely a Phase 3 study in that case, so that it is a more extensive application for Phase 3, as you can imagine. 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 top 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 2 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.

The Phase 1 is a small study right now. It's a total of 25 patients including three different doses where we have 10 patients, 5 patients in placebo. So, we do believe that is too small to do a pivotal study. For the pivotal study, we'll 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 same Phase 2 data to support the future BLA, but we will design a pivotal study to support that as well.

The next question comes from what Swapnil Malekar with Piper Sandler.

Two part question. One is what additional data can we expect at 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 on 2001 and 2002, is there a possibility to initiate the first-in-human trial for the AATD program in US?

David, do you want to? I'm not sure we can run too far ahead of information that's going to be presented 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?

What is important, we think, going to AHA is we will be in front of the largest cardiologist setting in the world, I guess. So, it is an important setting where we have this late breaking abstract. It does reflect the high interest of cardiologists in our program. It hasn't been very long, as you know, since we gave some of the initial data. So we will extend that a bit in this presentation of extended data. It's always been in the plan to have the US as part of the alpha-1 antitrypsin. 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 CTA or IND or both. For 3001, that's our first knock-in program. So very excited about that. And so, that is in 2023. We haven't given guidance yet on 2003, which is the knockout of the mutants, alpha-1. So, don't take that as meaning that it's very far behind the other one or even behind it. But we did plan to give some more guidance for that in the new year.

The next question comes from Gena Wang with Barclays.

Hi, good morning. This is Rashida [ph] on for Gena. We were wondering, could you remind us if you saw any LFT elevations in preclinical models, I guess specifically non-human primates for both 2001 and 2002. Any color here would be appreciated.

I think I can speak to that pretty quickly. Any LNP, given in sufficient quantities, will lead to LFP 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, as part of preclinical work, one goes to determine the therapeutic index by getting to actual levels of toxicity, which is an FDA regulation that we follow us as everybody else in the industry as well. So, yes, you can see LFP elevations. The goal is to have a therapeutic index that's wide, so that you can administer the LNPs to patients successfully with little to no increases, which does, in fact, characterize the clinical program thus far.

The next question comes from Salveen Richter with Goldman Sachs.

Congrats on the progress. This is Tomi [ph] 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?

The way we think about our work, in general, let's say, set of filters that we apply to considering particular programs to advance, we think about the nature of the edit, 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 if 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 and clinical results that would be relatively straightforward to manage in 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 insertions. This is reconstituting a gene that may be deficient or otherwise non-functional. 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 rules apply, is there unmet medical need? Do we believe that we can advance the therapeutics for 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 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. Our work is far from done in in vivo targets and we're excited about where we're able to take it.

The next question comes from Dae Gon Ha with Stifel.

Wanted to ask you about the 2002 timeline. The goal here is to start the Phase 2 in first half 2023, two 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 2? 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 two days or in rare instances within the first four 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 settle out within the first four weeks. There's other agents out there that we can extrapolate from, which have been guideposts 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 sounds like you're having additional conversations with regulators. So just wonder if you can share any color there.

Well, so work in progress in, 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 extensive?

Yeah, 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 design our pivotal study. But the most important endpoints, as John was saying, are the those clinical benefits, the reduction in cardiovascular events, 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 HAE experience so far, does it help narrow the type of patient you want to enroll into the Phase 2 portion, including based on a baseline attack severity? And at this point, do you know what the Phase 2 study duration will be? Could it be a three or four 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 2 study?

The standard follow-up for these studies is in the 16 week to 24-week period. The studies go quickly based on that, as you know, and we should get our answer fairly quickly once the Phase 2 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 shared development and commercialization risk?

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 in 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, we 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 two 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 tectonic 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.

Congrats on all the progress. 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, in day 28. I think last time we spoke, you mentioned that a number of hypothesis 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 who appears to be very much an outlier [indiscernible] so far.

We don't have anything new in terms of viruses. We haven't identified the virus. So, 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. The TTR has a perfect reduction, very good 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 polymerization of the mutant alpha-1 – the AAT and deliver. Any thoughts on that. And with the metric for success being 11 micromoles 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.

We have two candidates. 2003 allows us to knock out the mutant form. And 3001 inserts a healthy copy. And those two can be used separately or in combination, in any order. So, the other thing to keep in mind is that patients who are heterozygous Z allele, right, they have no liver manifestation and no lung manifestation. So, if the expression of your normal allele is high enough, you may – and just using conditional language, right – may be able to phenocopy heterozygous phenotype. So, that's to keep in mind. And yes, our goal is to achieve normal levels of alpha-1 antitrypsin. So it would not be 11 micromolar. It would be normal levels.

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.