Intellia Therapeutics - Q3 2022
November 3, 2022
Transcript
Operator (participant)
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 listen-only mode. If you require operator assistance, please press star then zero on your telephone keypad. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.
Ian Karp (SVP of Investor Relations and Corporate Communications)
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, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law.
Joining me from 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.
John Leonard (CEO)
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 data sets 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 of NTLA-2001 and NTLA-2002 in the coming weeks. I'll now turn it over to David.
David Lebwohl (Chief Medical Officer)
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 I-III heart failure. These data showed mean serum TTR reduction of 93% and 92% at the 0.7 and 1.0 mg per kilogram doses, respectively, at day 28. At both dose levels, there were remarkably consistent levels of protein reduction achieved, ranging from 90%-97%. NTLA-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 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 Sessions 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 mg fixed dose, which corresponds to the 0.7 mg per kilogram dose in part two of the study. part two, which is a 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 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 interim results from the ongoing phase I/2 clinical study at the 2022 Bradykinin Symposium in Berlin. We were thrilled to report that NTLA-2002 resulted in robust reductions in plasma kallikrein levels and the rate of swelling attacks in patients with HAE.
A single dose led to dose-dependent reductions in plasma kallikrein, with mean reductions of 65% and 92% in the 25 mg and 75 mg dose cohorts by week eight, 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 pre-specified 16-week primary observation period. A single 25 mg dose of NTLA-2002 resulted in a mean reduction in HAE attacks of 91% through the 16-week observation period. Additionally, two of the three patients have not had a single HAE attack since treatment, and all three 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 swelling attacks that characterize this chronic, lifelong genetic disease, and importantly, mark the second time in history clinical data has been generated for 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-mg dose cohort and additional safety kallikrein reduction and attack rate data from the 25 mg and 75 mg dose cohorts. 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 CSO, who will provide updates on our platform and R&D efforts.
Laura Sepp-Lorenzino (Chief Scientific Officer)
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 knockout 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, a key limitation to the durability of current allogeneic investigational therapies. By implementing our LNP-based cell engineering and novel matching approach, we 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 edits involved in our novel allogeneic approach, which includes the knockout of HLA class II and HLA-A while retaining HLA-B and HLA-C products. 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 untold liability. 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.
Platform 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 alloCAR-T 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-5001, 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 revolution. I'll now hand over the call to Glenn, our CFO, who will provide an overview of our second quarter financial results.
Glenn Goddard (CFO)
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 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 continued 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-$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-$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-$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.
John Leonard (CEO)
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 U.S., 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 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 and 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 (participant)
We will now begin the question-and-answer session. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Greg Harrison with Bank of America. Please go ahead.
Mary Kate (Research Analyst)
Good morning. This is Mary Kate on for Greg. Thanks for taking our question. For the NTLA-2001 program, you've mentioned moving into an additional dose expansion cohort at 55 mg. Could you discuss your priorities for dose selection decisions for subsequent pivotal studies? Thank you.
John Leonard (CEO)
David, do you wanna speak to how we think about dose selection?
David Lebwohl (Chief Medical Officer)
Yeah, thank you. Yeah, 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 mg dose. What we saw in the patients with cardiomyopathy is that the doses of 0.7 mg and 1.0 mg 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 gonna eventually see. Looking at those two doses, we chose 0.7 mg, the lower dose, as you always would in terms of giving the best safety, and translated that into a 55 mg dose. Now, this is still in phase I.
This part two is a phase I confirming that dose, but everything is looking quite good, and we do now anticipate that is likely to be the phase III dose. Of course, in phase I, you keep learning things and we do have to confirm that.
Mary Kate (Research Analyst)
Great. Thank you.
Operator (participant)
The next question comes from Joseph Thome with Cowen and Company. Please go ahead.
Joseph Thome (Managing Director)
Hi there. Good morning, and thank you for taking our question. 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? Thank you.
John Leonard (CEO)
David, we'll turn to you one more time. How do you think about what we're shooting for with respect to attack rates?
David Lebwohl (Chief Medical Officer)
Yes. What we're seeing with prior prophylaxis, obviously, is patients having breakthrough attacks so that the therapies they're getting isn't getting them to zero 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. As you can see with these patients with breakthrough, that's not working for everybody, even at 90%. We think what will be a significant advance is first getting to, you know, it's starting with the pharmacodynamic endpoint of getting prekallikrein down.
Right now, we see we can get to 92% with the 75 mg 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 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 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 one patient or if that occurs right from the get-go when they first get the treatment.
Joseph Thome (Managing Director)
Perfect. Thank you very much.
John Leonard (CEO)
Yeah, 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. 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 of these patients need to take is a relative barrier to their success.
In addition to achieving those very, very, deep reductions in attack rates, which we're very excited about, we think we're gonna 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.
Joseph Thome (Managing Director)
Perfect. Thank you very much.
Operator (participant)
The next question comes from Brian Cheng with J.P. Morgan. Please go ahead.
Brian Cheng (Senior Biotech Analyst)
Hey, guys. It's great to see the progress, and thanks for taking my question. 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, you know, 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. Thank you.
John Leonard (CEO)
Again, David, do you wanna speak to that?
David Lebwohl (Chief Medical Officer)
Yeah. We have had interactions with the FDA around both programs. We do feel we have a very good idea of what they're looking for in the IND. As stated for HAE, we've already said that that's gonna happen in the first half, that we are going to phase II and the US 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're, you know, 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. Again, we've had those interactions, and we have a good idea of what they want.
We'll be talking about it more. We do wanna get agreement. You know, we don't wanna 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.
Brian Cheng (Senior Biotech Analyst)
Thank you.
Operator (participant)
The next question comes from Richard Law with Credit Suisse. Please go ahead.
Richard Law (Analyst)
Hey, guys. Good morning. Based on the positive data so far in HAE, is there any possibility that the phase II could become pivotal? If not, what type of data would you need to collect before proceeding to a pivotal study? Thank you.
John Leonard (CEO)
David, here we go again.
David Lebwohl (Chief Medical Officer)
Thank you. Yeah. The phase II is a small study right now. It's a total of 25 patients, including two different doses where we have 10 patients, five patients with placebo. We do believe that is too small to be a pivotal study. However, 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. We will be obviously using the phase II data to support the future BLA, but we will design a pivotal study to support that as well.
Operator (participant)
The next question comes from Swapnil Malekar with Piper Sandler. Please go ahead.
Swapnil Malekar (Research Analyst)
Hey, good morning. Thanks for taking my question. Two-part question. One is, what additional data can we expect at the AHA meeting in the upcoming weekend?
The second part is like, now that you have collected a lot of data and experience from NTLA-2001 and NTLA-2002, is there a possibility to initiate the first in human trial for the AATD program in U.S.? Thanks for taking my questions.
John Leonard (CEO)
David, I'm not sure we can run too far ahead of information that's gonna be presented literally in just a couple of days. I would encourage you to wait to get the fuller picture. Do you wanna speak a little bit more about what lies ahead for some of the other programs?
David Lebwohl (Chief Medical Officer)
Yeah. What is, you know, important, we think, going to AHA is we will be in front of the largest cardiology study in the world, I guess. It is an important setting where we have this late-breaking aspect, late-breaking abstract. It does reflect the high interest of cardiologists in our program and we will. You know, 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. Extended data. Yeah, we do. As I said, we are preparing. It's always been in the plan to have the U.S. as part of the Alpha-1 antitrypsin. Yeah, no, you know, we haven't said exactly where it's gonna start.
What we have said is in the second half of the year we will have a CTA or IND or both for NTLA-3001. That's our first knock-in program, so very excited about that. That is in 2023. We haven't given guidance yet on NTLA-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. We are, we do plan to give some more guidance to that in the new year.
Swapnil Malekar (Research Analyst)
Thank you.
Operator (participant)
The next question comes from Gena Wang with Barclays. Please go ahead.
Speaker 17
Hi. Good morning. This is Rashida 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 NTLA-2001 and NTLA-2002? Any color here would be appreciated. Thank you.
John Leonard (CEO)
I think I can speak to that pretty quickly. Any LNP given in sufficient 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. 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, as does everybody else in the industry as well. Yes, you can see LFT elevations. The goal is to have a therapeutic index that's wide so that you can administer these LNP to patients successfully with little to no increases, which has in fact characterized the clinical program thus far.
Operator (participant)
The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Speaker 18
Hi. Thanks for taking our question, and congrats on the progress. This is Tommy 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? Thank you.
John Leonard (CEO)
Yeah. Thanks for the question. The way we think about our work in general is a set of filters that we apply to, you know, 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. As we look at TTR and HAE, these were very clear examples where a straightforward 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. 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. 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? Can we do this in a way that we can be competitive and ideally reset the therapeutic bar?
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 our work is far from done in vivo targets, and we're excited about where we're able to take it.
Speaker 18
Thank you.
Operator (participant)
The next question comes from Dae Gon Ha with Stifel. Please go ahead.
Dae Gon Ha (Director and Equity Research Analyst)
Good morning, guys. Thanks for taking our question. Wanted to ask you about the NTLA-2002 timeline. The goal here is to start the phase II in first half 2023, two doses being explored with a placebo arm. Given the proximity to ACAAI, where we'll probably have relatively less of a follow-up on the 50 mg cohort, and given what we know about TTR where, you know, 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 mg fixed in the dose expansion. 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. Thank you.
John Leonard (CEO)
I think I can set the foundation for that. You know, 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. 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, you know, 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. We have the added advantage of seeing within, you know, a few weeks of follow-up, 16 in the cases of studies to give us a really good sense of where these patients settle out. We think we're in a good position to meet that guidance. David's team is well on its way to moving that forward. Stay tuned as we give you more details.
Operator (participant)
The next question comes from Terence Flynn with Morgan Stanley. Please go ahead.
Terence Flynn (Biotech and Biopharma Analyst)
Hi. Thanks for taking the questions. On NTLA-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. Just wondering if you can share any color there. Thank you.
John Leonard (CEO)
Well, it's a work in progress. As David referred to earlier, you know, we wanna have a clinical study that's gonna 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, you know, 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. David, do you have anything you wanna add to that extends that?
David Lebwohl (Chief Medical Officer)
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. That's also part of what we're thinking as we define our pivotal study. The most important endpoints, as John is saying, are those clinical benefit, 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.
Operator (participant)
The next question comes from Maury Raycroft with Jefferies. Please go ahead.
Maury Raycroft (Senior Equity Research Analyst)
Hi, good morning, and thanks for taking my question. Based on the HAE 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? At this point, do you know what the phase II study duration will be? Could it be a three or a four-month study based on the amount of time where you can see efficacy?
John Leonard (CEO)
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 I or type II HAE. David, do you wanna share any thoughts with respect to the duration of the phase II study?
David Lebwohl (Chief Medical Officer)
Yeah. The standard follow-up for these studies is in the 16-week to 24-week period. You know, the studies go quickly based on that, as you know, and we should get our answer fairly quickly once the phase II is underway.
Maury Raycroft (Senior Equity Research Analyst)
Got it. Thanks for taking my question.
Operator (participant)
The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Jay Olson (Managing Director and Senior Analyst)
Oh, hey, thank you for taking the question. Can you talk about how you prioritize allocation of the $840 million of cash you have on your balance sheet? Any thoughts about partnering in order to extend your cash runway and share development and commercialization risk?
John Leonard (CEO)
Sure. I mean, it's something that we think a lot about because we wanna make sure that we're doing the best we can for our shareholders who are counting on 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, you know, 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. Critically important, this is a platform that's evolving rapidly, and we wanna be not only proficient, but leaders in all aspects of that.
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 this space. Thus far, we think that's certainly the case here. Clearly advancing the clinical programs is of primary importance for us. Our work in NTLA-2001 and NTLA-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, raise 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.
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.
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. If you look across those partnerships that we've done thus far, that's basically how all of them are set up. I would expect that as time goes on, we'll continue to take exactly that kind of approach. 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.
Jay Olson (Managing Director and Senior Analyst)
Super helpful. Thank you.
Operator (participant)
The next question comes from Luca Issi with RBC. Please go ahead.
Luca Issi (Senior Biotech Analyst)
Oh, great. Thanks so much for taking my question. 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, 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. Just wondering if at this point we have enough evidence to suggest whether that ALT was or was not drug-related. Thanks so much.
John Leonard (CEO)
David, do you wanna speak to that? That unusual patient who appears to be very much an outlier for our work so far.
David Lebwohl (Chief Medical Officer)
Yeah. We don't have anything new in terms of viruses. You know, we haven't identified the virus, so if it is, it's a virus we haven't been able to test for. You know, we don't know more about alcohol usage. It is, as John said, it's an outlier. Patient is doing great, by the way. The TTR had perfect reduction or a very good reduction like the others. That's where we are and obviously we don't expect much more to come in at this point.
Luca Issi (Senior Biotech Analyst)
Got it. Thanks so much, guys.
Operator (participant)
The last question today comes from Joon Lee with Truist. Please go ahead.
Joon Lee (Managing Director)
Hey, thanks for taking our questions. 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 and AAT in the liver. Any thoughts on that? And with the metric for success, the 11 micromolar of plasma AAT or something else when you do start the trial? Thank you.
John Leonard (CEO)
Laura, I'm gonna call on you. How do you think about producing normal protein in the presence of, the mutant form? I think it's important to remind people how we differentiate ourselves versus standard gene therapy.
Laura Sepp-Lorenzino (Chief Scientific Officer)
Yeah. Two thoughts, Joon, and thank you for the question, right? We have two candidates, NTLA-2003 allows us to knock out the mutant form, and NTLA-3001 inserts a healthy copy. Those two can be used separately or in combination in any order. You know, the other thing to keep in mind is that patients who are heterozygous, you know, for this allele, right? They have no liver manifestation and, you know, no lung manifestation. If the expression of your normal allele is high enough, you may be able to, and I'm just using conditional language, right? You know, phenocopy heterozygous phenotype. That's, you know, to keep in mind. Yes, our goal is to achieve normal levels of Alpha-1 antitrypsin.
It would not be 11 micromolar. It would be normal levels.
Operator (participant)
This concludes our question and answer session. I would like to turn the conference back over to Ian Karp for any closing remarks.
Ian Karp (SVP of Investor Relations and Corporate Communications)
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.
Operator (participant)
The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.