Earnings Call Transcript - NTLA Q4 2022

Operator, Operator

Good morning and welcome to the Intellia Therapeutics' Fourth Quarter and Full Year 2022 Financial Results Conference Call. My name is Drew 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. 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, Senior Vice President of Investor Relations and Corporate Communications

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics fourth quarter and full year 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 recap the Company's R&D progress across our pipeline. And Glenn will then review Intellia's financial results for the fourth quarter and full year 2022. 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 are advancing our leadership position as the industry's most innovative genome editing company, with the broadest and deepest toolbox of novel editing and delivery solutions. 2022 proved to be another outstanding year for Intellia, with several significant clinical milestones achieved across our pipeline. Having demonstrated human proof-of-concept for our first two in vivo clinical candidates, NTLA-2001 and NTLA-2002, we are now two for two. Notably, we have dosed more than 50 patients with our in vivo CRISPR-based therapies in ongoing clinical studies, with durability and safety data now out two years from our initial patients. These accomplishments reflect steady execution against our core strategy to harness the immense power of CRISPR-based technologies, both for in vivo and ex vivo applications. Building on last year's strong momentum, we have already hit the ground running this year. We are pleased to share today that we initiated the Phase 2 portion of the NTLA-2002 study outside of the U.S. Recently, we also submitted an IND application to the FDA to enable U.S. patient enrollment in this trial. We are highly encouraged by the rapid progress we have made in just the past few months and expect to hear back from the FDA in the coming weeks. Looking ahead for NTLA-2001, we are poised to submit an IND application for a pivotal trial for the cardiomyopathy manifestation of ATTR amyloidosis by midyear, with a trial initiation anticipated by the end of the year, subject of course to regulatory feedback. Importantly, we look forward to presenting new interim clinical updates from both ongoing NTLA-2001 and NTLA-2002 first-in-human studies this year. Turning to our research pipeline, we are advancing new platform capabilities to the clinic. This includes our CRISPR-based in vivo targeted gene insertion technology and a first-of-its-kind allogeneic cell engineering solution designed to avoid both T-cell and NK-cell mediated rejection. Additionally, we're leading the development of new gene editing and delivery modalities, which will drive further pipeline growth and allow us to reach a greater number of patients with our genetic medicine. With that introduction, I'll hand the call over to our Chief Medical Officer, David Lebwohl, who will review NTLA-2001 and NTLA-2002 progress in greater detail and outline updates across our clinical pipeline.

David Lebwohl, Chief Medical Officer

Thanks, John, and welcome everyone. I'll begin with a review of NTLA-2001, a potential single-dose treatment that may halt and reverse the disease for people living with ATTR amyloidosis. In November, we shared additional positive interim results from the cardiomyopathy arm of the ongoing Phase 1 clinical trial of NTLA-2001. These data, which were presented in a late-breaking oral presentation at the American Heart Association Scientific Sessions, demonstrated consistent greater than 90% serum TTR reduction following a single dose of NTLA-2001. The deep reductions were sustained with patient follow-up ranges from four to six months as of the data cutoff date. NTLA-2001 was generally well tolerated in all 12 patients. Two of the 12 patients reported transient infusion reactions, which resolved quickly, and these were the only observed treatment-related adverse events. 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 a best-in-class TTR lowering agent regardless of disease manifestation. In the last few months, we completed the planned enrollment for the dosing expansion portion of the cardiomyopathy and polyneuropathy arm. Data from these cohorts will be used to inform our dose selection decision for subsequent pivotal studies. For ATTR CM, we plan to submit an IND application midyear and plan to initiate a global pivotal study by year-end, subject to regulatory feedback. Additionally, we plan to present new and important interim clinical data later this year, including longer-term safety and durability data, as well as emerging clinical endpoints. For hereditary ATTR amyloidosis with polyneuropathy, we are continuing to prepare for a Phase 3 study, including discussions with regulatory authorities, and we look forward to presenting additional clinical data from the ongoing Phase 1 study. I'll turn now to our second in vivo program, NTLA-2002, our investigational therapy for the treatment of hereditary angioedema or HAE. We shared additional positive results from the ongoing Phase 1/2 clinical study at the American College of Allergy, Asthma and Immunology 2022 Annual Scientific Meeting this past November. The data presented demonstrated that a single dose of NTLA-2002 led to robust reductions in plasma kallikrein and HAE attack rates. With a 25 milligram and 75 milligram cohort, these deep reductions in plasma kallikrein were sustained in all patients through data cut-off, which ranged from week 16 to week 32. Importantly, all patients dosed in these two cohorts, who completed the pre-specified 16-week observation period, have maintained an attack risk status as of the data cutoff date. Patients in the 50 milligram cohort have not yet completed the primary 16-week observation period before the presentation cutoff date, and so we look forward to presenting attack rate data on this cohort later this year. At all three dose levels, NTLA-2002 was generally well tolerated and the majority of adverse events were mild to moderate severity. The most frequent adverse events were infusion-related reactions, which were mostly Grade 1 and resolved within one day. No dose-limiting toxicities, no serious adverse events, no adverse events of Grade 3 or higher, and no clinically significant laboratory abnormalities were observed. We believe these data speak to NTLA-2002's potential to address the significant disease burden faced by people living with HAE by permanently preventing the debilitating swelling attacks with a single dose. We look forward to presenting additional data from the Phase 1 portion of the study in 2023, including longer-term safety, durability, and attack rate data across all three cohorts. As John mentioned, it's been a very productive first two months of the year, especially for the NTLA-2002 program. In January, Intellia was awarded the innovation passport in the United Kingdom for NTLA-2002, which provides entry to UK's innovative licensing and access pathway. We're pleased to receive the ILF designation, which aims to accelerate time to market and facilitate patient access to innovative medicines. Today, we announced that Intellia has initiated patient screening in the Phase 2 portion of the study in New Zealand. The Phase 2 portion is a randomized placebo-controlled expansion study evaluating two doses, 25 milligrams and 50 milligrams. We anticipate expanding country and site participation in the coming months. To support inclusion of patients in the United States, Intellia recently submitted an IND application to the FDA, and we look forward to providing you with an update on the status of that application review. As NTLA-2001 and NTLA-2002 continue to progress, we believe we are moving closer to setting a new standard of care for people living with these serious diseases. I'll now hand over the call to Laura, our Chief Scientific Officer, who will provide updates on our R&D efforts and platform advancements.

Laura Sepp-Lorenzino, Chief Scientific Officer

Thank you, David. We're entering the next stage of growth at Intellia as we advance new platform capabilities to the clinic, such as in vivo gene insertions, our allogeneic technology, and base editing. For targeted in vivo gene insertion, we're progressing both wholly-owned and partner programs leveraging our modular insertion platform. This includes NTLA-3001, our wholly-owned candidate for the treatment of AATD-associated lung disease, for which we plan to submit an IND or IND equivalent application in the second half of this year. In parallel, we're advancing IND enabling activities for NTLA-2003, our third in vivo local candidate as a treatment for the liver manifestation of AATD. In collaboration with Regeneron, we're also making important progress advancing our Factor IX insertion programs for people with hemophilia B. Turning to our ex vivo pipeline, we're advancing multiple programs, ours and those shared with partners, utilizing our proprietary allogeneic platform. These platform capabilities demonstrate the already broad opportunity of our robust research engine, but there is still more untapped potential and so we're further pushing the boundaries of what therapeutic gene editing can do. We have made rapid and significant headway with the development of our proprietary DNA writing technology. Since the acquisition of Rewrite Therapeutics, we have implemented and expanded the platform leveraging Intellia's genome editing toolbox and expertise and demonstrated robust performance and versatility. We're excited by the potential of our newest platform capability, offering us the potential to target diseases beyond those currently being explored in our pipeline. And now I’ll hand over the call to Glenn, our CFO, who will provide an overview of our fourth quarter and full year 2022 financial results.

Glenn Goddard, CFO

Thank you, Laura. 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 $1.3 billion as of December 31, 2022, compared to $1.1 billion as of December 31, 2021. The increase was driven by $337.9 million from our December follow-on offering, $227.9 million of net proceeds from the company's at-the-market program, and $17.2 million in proceeds from employee-based stock plans. The increase was offset in part by cash used to fund operations of approximately $372.8 million and the acquisition of Rewrite Therapeutics for $45 million. Our collaboration revenue increased by $0.7 million to $13.6 million during the fourth quarter of 2022 compared to $12.9 million during the fourth quarter of 2021. Our R&D expenses increased by $28.9 million to $100 million during the fourth quarter of 2022 compared to $71.2 million during the fourth 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 $1.5 million to $23.6 million during the fourth quarter of 2022, compared to $22.1 million during the fourth quarter of 2021. This increase was primarily related to employee-related expenses. Finally, we expect our cash balance to fund our operating plans beyond the next 24 months. With that, I will now turn the call back over to John for closing remarks.

John Leonard, CEO

Thank you, Glenn. As you can see, we're making steady progress towards executing against our strategic priorities, which are focused on late-stage development of our CRISPR-based therapies while continuing to innovate and bring forth new platform capabilities. This year, we look forward to advancing the Phase 2 portion of the NTLA-2002 study and expect to add U.S. clinical sites. We're also focused on preparing for the initiation of a global pivotal trial NTLA-2001 for patients with a cardiomyopathy manifestation of ATTR amyloidosis. For both programs, we plan to provide further updates in the coming months. As we continue to deliver on the promise of gene editing, we maintain our broader vision for Intellia by rapidly expanding the reach of our platform to accelerate the impact on patients. With that, we'd be happy to answer any questions. Operator, you may now open the call for Q&A.

Operator, Operator

We will now begin the question-and-answer session. The first question comes from Maury Raycroft with Jeffries. Please go ahead.

Maury Raycroft, Analyst

Congrats on the progress and thanks for taking my question. I was going to ask about the HAE IND. Wondering if you're commenting anymore on what exactly FDA requested to be in the IND and what you included in the IND for the Phase 2? And do you expect a typical IND acceptance timeline for that program?

John Leonard, CEO

Maury, good morning, thanks for your question. It's a pretty standard application and aligns with some of the comments we've made in prior communications regarding what the FDA is looking for. I think where this IND may differ from other INDs is that we are pretty far along from a clinical point of view and we were able to supply clinical information from the ongoing study done outside the United States. So we were careful to provide a very thorough and complete update of that information. But otherwise, it’s pretty standard.

Maury Raycroft, Analyst

Okay. And maybe one follow-up. Just if you could talk a little bit more about the Phase 2 design and types of patients and how you can leverage the data for a potential streamlined pivotal study in HAE?

David Lebwohl, Chief Medical Officer

Yes, the Phase 2 study has been publicly presented and is included in our slides. It consists of three arms: one at 25 milligrams, another at 50 milligrams, and a placebo arm with sample sizes of 10, 10, and 5 patients, respectively. The goal is to determine the appropriate dose for the pivotal study. We have already obtained valuable information from the Phase 1 study, showing impressive results at all three doses. The pharmacokinetics for the 50 and 75 milligram doses were quite similar, leading us to select a lower, potentially safer dose. The 25 milligram dose also performed well but exhibited some differences in pharmacokinetics. This trial will inform our Phase 3 study, for which we are currently developing the design. It will also provide additional patient data to support the eventual Biologics License Application.

Greg Harrison, Analyst

Hey, good morning, and thanks for taking the question. I wanted to ask how you are thinking about the future of the curative sickle cell landscape. Now that some competitors have discontinued investment in the space, what do you think will be the next step beyond the CRISPR Vertex approach? And how do you win there?

John Leonard, CEO

Yes. Thanks for the question. It's an important one and one that we have certainly thought about even from the early stages of the Company. I think what we have seen is that sickle cell is curable. That question, in our judgment, has been answered, and I think that's great news for patients. The challenge for those patients, however, is the nature of that cure. The editing, I think, is in hand; it's the application of that editing where we believe we can make significant progress. We have been focused really since the outset on doing it in an in vivo setting, where one can avoid a bone marrow transplant from the morbidity and potential mortality that comes with that. That’s a more general solution for patients, and in fact, I think it’s a very broad-based solution even for patients outside the standard Western markets, where most patients with sickle cell reside. So that’s where we focused our efforts. And from our perspective, based on what we have seen so far, that space is wide open, and we intend to get there first.

Unidentified Analyst, Analyst

Hi. Good morning. This is Mehdi on for Joon. So, I will follow up on the previous question and ask what is your strategy now that you're following the same type of edits for sickle cell? And what would be your delivery mechanism? And I have a quick follow-up.

John Leonard, CEO

Our strategy hasn't changed for some years now. We've always been focused on the in vivo setting. Just to be clear with respect to the Novartis news, that was an ex vivo-only application. For us, we've always focused on the in vivo setting. From an editing point of view, we believe there are a number of potential edits that can be successful. Our particular approach is not one that we’ve disclosed yet, but what I think we've learned is that the disease is quite challenging. So, it's really a matter of delivery and ensuring that’s done in a robust way that works well for patients.

Unidentified Analyst, Analyst

Could you please give us some insights into your underwriting system? Is it similar to existing techniques or more aligned with homologous recombination? Any information you can provide in that area would be greatly appreciated.

John Leonard, CEO

Yes, we're not disclosing the specifics. We think about it in terms of capabilities, which is the resulting gene edits. In our case, we're most interested in what the resulting change in the DNA is, and the specifics of how you get there, the particular enzyme system is proprietary and one that we've worked hard to develop. So, we're excited about our ability to introduce the intended changes and do that with great fidelity and specificity, and frankly with great activity. So, as we go on and the results mirror this, we will be in a position to share more about the progress we're making. But needless to say, as Laura made clear in her remarks, we are very excited about where we are and where we're headed.

Swapnil Malekar, Analyst

So you had previously mentioned the likelihood of having an interim readout for the pivotal trial in ATTR cardiomyopathy. So just wondering how the new emerging data and the new emerging clinical endpoints that you mentioned in the press release are informing this decision of an interim analysis?

John Leonard, CEO

David, do you want to address that? I just want to clarify, we're not talking about sharing interim results of a pivotal trial. Maybe David, you could just clarify what their plans are with data disclosure for the ongoing study?

David Lebwohl, Chief Medical Officer

I mean, just in terms of clinical trial design, if there will be an interim analysis, yes. Okay, yes. So for the Phase 3, as you know, we're designing that now, but we have said before that we think the important endpoints are cardiovascular events and mortality. As you’ve seen in some of the other trials out there, it doesn't have to be a large trial to study these questions. We will have a significant advantage as we start to do our trial since we may see early results from the other trials, which will help inform how we design this trial. But we are considering whether an interim analysis would be valuable here because we have the best reduction in TTR, and we expect to have the best efficacy in that trial. Because of that, the trial could be positive and could yield an interim analysis, and we are looking carefully at that possibility.

Swapnil Malekar, Analyst

And one follow-up I had is, so you mentioned that there have been more than 50 patients dosed across two programs, with some of the patients reaching the two-year mark. So just wondering if there were any relapses in TTR or kallikrein in any of the patients that required three dosing? Thanks for taking my questions.

John Leonard, CEO

I think what you've seen in our studies is this effect seems to be permanent. We see consistent reductions across time with these drugs. So based on the mechanism and based on what we're seeing clinically, we do expect the effects to be permanent.

Unidentified Analyst, Analyst

Hi, good morning. This is Rashida on behalf of Gina. Thank you for taking our questions. Can you hear me okay?

John Leonard, CEO

We can.

Unidentified Analyst, Analyst

Awesome. Thank you. For NTLA-2002, are you able to disclose how recently you've submitted the IND? And how will you communicate to the investor community the outcome? Can we expect a press release?

John Leonard, CEO

We're not sharing when we submitted the IND. We're giving a broad update today. And so that's part of that process, but we will of course share the results of the FDA review when we have that information. Just as we promised from the outset here, stay tuned, and hopefully we'll have some favorable results to report.

Unidentified Analyst, Analyst

And I had a very quick follow-up. On NTLA-2001, in the prepared remarks, I think David mentioned to expect new emerging data on other endpoints later in 2023. Can you elaborate on what other endpoints that we can expect it on? That would be great. Thank you so much.

John Leonard, CEO

David, what lies in store?

David Lebwohl, Chief Medical Officer

Yes, so what we're looking at, the patients who have been longer from the trial where we would possibly have the most information with the patients would probably be the neuropathy cohort. Some things we've looked at include the NIS score, which is slightly different from the NIS plus 7, but gives similar information on the neuropathy symptoms. Another thing we're looking at is cardiac amyloid, which is present in both polyneuropathy patients and in the cardiomyopathy patients. So, those are the types of things that we may have enough information on later this year.

Terence Flynn, Analyst

I was just wondering, as you think broadly about the pipeline. I know you did the Rewrite Therapeutics deal, but just thinking more broadly, do you think there's a need for any additional business development, or do you think you have all the tools you need at this point, John? And then on another kind of second question, which again, I'm not sure if it's applicable or not, but yesterday, a CRO announced some supply chain issues with non-human primates. I was just wondering if that might impact any of your preclinical work or timelines? Thank you.

John Leonard, CEO

Yes, thanks for the question. Yes, we read the same news and have inquired. We're not aware today that there's any impact on the work that we're doing. And we hope that that doesn’t change, but that’s the current situation. With respect to business development, we think about it two ways. You asked about it in terms of tools. An important part of our strategy is to have a complete toolbox, and we think about that in terms of the capabilities needed to introduce different changes that we want to make in DNA. We believe we have a great toolbox. We watch what's happening on the outside, we have our own scientific efforts internally, and we are always looking for new capabilities that we think would augment the toolbox. At this point, we are satisfied with the things that we want to do. But of course, we will keep our eyes open. The broader approach to business development for us is just thinking about deploying that toolbox, rather than bringing new things into it. We are seeing wonderful opportunities, some of which we are advancing ourselves, and some of which we are advancing with collaborators. In the last 18 months, we have had four different collaborations that we have struck to augment the work we do in our own pipeline. So, whether it's ophthalmology, sparing vision, autoimmune disease with Kyverna, our spin-out with AvenCell, or work in NK cells with O&K, these are really exciting applications of the capabilities already in hand, and we expect to do more. If you look at our pipeline including the clinical rights and commercial rights from each of those different collaborations, you will see that for a company of our size, we have a wonderful pipeline that’s replete with opportunities. So, we are good with our toolbox and focused on internal work to ensure that it remains a strong asset.

Unidentified Analyst, Analyst

Thanks for taking our questions and congrats on all the progress. This is Lisa on for Luca. Just one on the cardiomyopathy pivotal trial. Just wondering if we should expect two trials here, maybe one with the six-minute walk test as the primary endpoint, and another with a cardiovascular-based outcomes study? And on sickle cell disease, can you expand further on why Novartis decided to discontinue the program? And if there is any clinical data available, will you be in a position to share it? Thank you.

John Leonard, CEO

Yes, I can't speak to Novartis's decision other than they have been going through what appears to be a broad review of their pipeline and their different approaches to it. I would just remind you that, for us, that has been a Novartis-only program, one that we have not directly participated in; we have provided reagents to them some years ago. We have always believed that the future lies with in vivo approaches and have focused on that work. I’m sure they looked at the ex vivo space and may have had some of the same realizations that we had years ago. So it’s apparent where that space will ultimately go. But David, maybe you can answer the question about pivotal trials. How many do you want to do?

David Lebwohl, Chief Medical Officer

Again, we are not discussing the exact program, but we don’t think that dividing those things into two trials is ideal going forward. The six-minute walk test is in more questions about how valuable it is to understand how patients are doing. You've seen that in some recent trials in amyloidosis. However, we believe the important endpoints are cardiovascular events and mortality. That is what patients are interested in, doctors are interested in, and payers are interested in. So, these are the most important factors for regulators.

Yanan Zhu, Analyst

On the HAE program, I was wondering, what's the reason or rationale for having this placebo arm in this Phase 2 study? And also in terms of the goal of the treatment for this kind of one-time treatment approach? Do you think complete cure is the expected outcome for this type of approach? Or could there be a different outcome and still be appropriate for this approach?

John Leonard, CEO

David, what role does placebo play? And what’s the aspiration?

David Lebwohl, Chief Medical Officer

Sure. Having placebo-controlled trials is the gold standard in randomized trials. We don't expect any benefits in the placebo arm, but of course, we've seen there can be a strong placebo effect in many trials, and that is the risk of not having that arm. It's not a comparative trial to Phase 2, but it's a reference arm to see that, what we expect is to have a very strong effect at both the 25 and 50 milligram doses and little or no effect on the attack rate in the placebo arm. This will help, again, inform and help us design the pivotal trial and choose the dose. It should be mentioned that the patients with the placebo arm will be offered to cross over and receive the active drug once their evaluation is completed. We do this out of respect for the patients’ contribution to our study, and their desire to access this type of therapy as part of their potential cure going into the second part of that. So, this idea of a functional cure is that you could get to zero attacks for patients with this single treatment. Whether we can achieve that is still too early to say. We are very encouraged by the early results. We are achieving deeper reductions in kallikrein than seen with the best agents currently available. Therefore, it is possible that this will also lead to better efficacy. The aspiration is to have a functional cure where patients experience no attacks after receiving our drug.

Yanan Zhu, Analyst

If I have a quick follow-up on the cardiac amyloid you mentioned that might be a readout for the 2001 program. Just wondering, is the expectation that cardiac amyloid will be resolving or is there an expectation that it will just stabilize and no more additional amyloid deposition?

John Leonard, CEO

The system is well established. Of course, there aren't therapies that get to very low levels of TTR that we're able to achieve. However, we have been advised by key investigators that if you reach low enough TTR levels, you will slow the rate of amyloid deposition into organs so that the equilibrium favors removal. In other words, the removal of amyloid from the heart would exceed the addition of amyloid due to the small amount of TTR that would remain in the blood. That’s what we’re aiming for, with the expectation that our approach could facilitate a reversal of heart disease by clearing that amyloid. That is our aspiration for that trial.

Unidentified Analyst, Analyst

Hi, this is on behalf of Salveen. Thank you for the update. Could you share more details about the discussions you are having with regulators regarding the global pivotal study for NTLA-2001, specifically for ATTR CM and ATTR PN? Also, concerning NTLA-2002, how confident are you about the acceptance of the IND? Do you have any timelines for when we might receive this information?

John Leonard, CEO

Maybe David can address how we think about the pivotal and when we'll be in a position to share information. I just want to say with respect to the IND, we have had a variety of interactions with various regulators, including the FDA leading up to this. We believe that we are addressing the questions that they wanted us to address. It's not just about the list of those questions, but it’s the extent of the data that we've tried to provide to ensure that we are not just checking boxes but really answering questions and helping them evaluate the product. Additionally, as I mentioned at the outset, we supplied clinical information, which I think is unique with respect to some of the other INDs that have been submitted in the last few years in the space. We believe that this information will be a helpful bit of evidence for the FDA to consider as they assess our IND application review. So, we are looking forward to the outcome. Obviously, that’s subject to their review, but we think we've done a good job of robustly supplying information. And as we’ve said, with respect to timelines, when we have that information regarding the outcome of that review, we will share that with everyone at the same time. David, do you want to say a few words about how we approach the pivotal and when we will be in a position to share that information?

David Lebwohl, Chief Medical Officer

What John said about all aspects of our IND submission is correct, and another piece of that is the clinical discussions that have gone on, both in pre-IND meetings with regulators and around the world in Europe. We are moving forward with a trial design that has support from leading investigators in this area. The point at which we will have an agreed-upon trial will align with the IND timeline; we’ve said that’s by mid-year for the IND for NTLA-2001, and that will also occur in Europe with the CTA applications for that Phase 3. The other thing we’ve mentioned is that the trial will start by year-end. Those are the timelines you can expect—we will share more details as they become available.

John Leonard, CEO

I might add one important distinction for the listeners to keep in mind with respect to NTLA-2001, which differs from the NTLA-2002 IND application. The IND for NTLA-2001 is aimed at pursuing a pivotal trial, meaning it isn't just an IND with all the preclinical work. We’re providing information that would typify an end-of-Phase 2 meeting with the FDA. Therefore, we expect the 2001 application to be a very substantial filing when we actually submit it, which is distinct from the 2002 IND and certainly different from most of the other INDs in the space that have been for first-in-human applications. As we progress throughout the year, we will talk more about this.

Rick Bienkowski, Analyst

Hi everyone. Good morning. Congratulations on all the progress and thanks for the questions. For the NTLA-2002 program, the worldwide Phase 2 trial initiation looks to be a bit staggered with the U.S. opening first while the IND application was submitted to the FDA. So my question is, if the FDA does have any feedback on either trial design or endpoints in the study after the IND review, are there any mechanisms to amend the trial protocol for sites outside the U.S. after the trial has already started?

John Leonard, CEO

David, do you want to speak to that? I mean, I'd remind everyone this is a Phase 2 study. It's not a pivotal trial; some of the details are less consequential. But David, do you want to speak to that?

David Lebwohl, Chief Medical Officer

Yes, when submitting a trial around the world, different regulators will often have different expectations regarding trial details. Therefore, it is very possible that there can be amendments to the trial stemming from feedback either in the U.S. or from outside the U.S. Sometimes smaller details may be subject to helpful suggestions for improvement, while other times we may have to adhere to specific guidelines for various reasons. But yes, that could certainly happen, and we have procedures in place, specifically amendment processes for the trial.

Rick Bienkowski, Analyst

Great, got it. Thank you. And a quick follow-up. So, there are a few novel technologies in the early pipeline now, including gene writing, base editing, and proprietary LMPs. I guess it's difficult to get a sense of how far away all these technologies are from getting into the clinic or what sort of indications these technologies might be able to address. Are there any timelines for when we may get some more substantial updates about the progress of these earlier-stage technologies?

John Leonard, CEO

We haven't guided to any specific products or pipelines. We’ve spoken generally in prior presentations about useful applications of base editing where we think it makes the most sense. It tends to fall primarily in the ex vivo setting, where one is hoping to introduce many simultaneous knockouts. We have very advanced work in that space, and we have talked about our allogeneic platform that we are very excited about. I would encourage you to stay tuned with respect to future updates in that regard, and where they sit or may fit into that space we will see. With the gene writing approach, it’s still early days, but we are seeing excellent progress in achieving very high levels of specificity, allowing us to introduce the intended changes we aim for. So as that progresses, we'll determine what we believe will be the appropriate applications and discuss these further. Meanwhile, our focus remains on advancing NTLA-2001 and NTLA-2002 while demonstrating the importance of these technologies in a meaningful way for patients. So, more to come and we will share those updates as appropriate.

Raju Prasad, Analyst

Just kind of wondering the cadence of the IND submissions. Why is NTLA-2002 going to come ahead of NTLA-2001? Was it because, as you referred to earlier, the 2001 application is larger? I'm just wondering, because the durability and amount of data for the 2001 on the clinical side is much higher.

John Leonard, CEO

It's really unrelated to what you're saying. NTLA-2002 is at the appropriate point to begin Phase 2. NTLA-2001 will be at the point to begin Phase 3 work, with the information necessary to support that 2001 IND, which I liken to a Phase 2 meeting—a far more substantial filing than a typical first-in-human IND. The full complement of clinical information involves not just acute exposure but longitudinal follow-up with these patients. That's an important part of that application. It’s simply the way the timelines worked out. David, if you have anything to add to that, that’s essentially the essence of it.

Raju Prasad, Analyst

Maybe a quick follow-up. Just wondering the rationale behind the ATM in Q4 on top of the follow-on, just wondering why?

Glenn Goddard, CFO

Sure, yes. We thought at the end of Q3 last year and early Q4 were an opportune time to use the program, based on how the stock was trading and volume. An opportunity opened up in late November to December for executing the follow-on, so we took advantage of that. It wasn’t preplanned to do it that way; it’s just how things worked out.

Dae Gon Ha, Analyst

I'll just stick with the IND questions again. With regards to NTLA-2002, how confident do you feel you adequately address some of the FDA’s concerns? We're obviously very limited to what's publicly disclosed from one of your competitors’ programs or peer companies. To what extent is the depth and extensive nature of your submission a critical factor as it pertains to the review within that 30-day period?

John Leonard, CEO

I can't speak to the number of pages and how fast the various reviewers at the FDA read them. That’s not the metric we use, but these applications tend to be very large, as you know, since there’s a lot of information shared. We aim to address the questions as posed by the regulators. It’s important to emphasize that it’s not just about data. It’s really about testing the robustness of the system. These principles apply across drug development, whether you're working with small molecules or antibodies. We try to apply those principles, knowing how the FDA thinks about this space. Regarding others in our field, I can't address their work. It remains to be seen how FDA evaluates this data. If the FDA has follow-up questions during their review, we’ll do our best to answer them promptly. We don't expect major deficiencies in our IND, but if minor questions arise, we will respond as quickly and effectively as we can. We believe we've provided a comprehensive set of information to them.

Dae Gon Ha, Analyst

John, just a naive question with regard to the IND review. Is there something analogous to a PDUFA extension where they just need more time to review, or does it have to be a binary yes or clinical hold?

John Leonard, CEO

My understanding is that it's 30 days; you get either clearance or a hold. If there's a hold, then additional information will be communicated by the FDA regarding what they require, which then puts you in a position to respond to their follow-ups quickly. We will see, but again, we believe that the full complement of information has been provided.

Debjit Chattopadhyay, Analyst

Can you provide an update of how many patients have been treated across each clinical stage program, including the dose expansion cohorts?

John Leonard, CEO

At a high level, collectively over 50 patients have been treated. Much of this information is already available regarding the different groups and studies involved. We continue to treat those patients in the second phase of the study, and later this year we will provide more complete information.

Unidentified Analyst, Analyst

Hi, this is Debanjana on for David. We wanted to ask if you can provide any further color with respect to the timing of data in 2023? And also, are you collecting kallikrein activity data in addition to the reduction in protein levels?

John Leonard, CEO

David, do you want to speak to what we're actually collecting with NTLA-2002 with respect to kallikrein and what the anticipated flow of clinical data across the program this year looks like?

David Lebwohl, Chief Medical Officer

Yes, we are collecting both kallikrein protein and activity data. We expect to present more data towards the end of the year. The important piece of that data is on the dose level we haven’t reported on, specifically the 50 milligram dose. We've previously examined the 25 to 75 milligram doses; thus we wanted to fill in the dose-response relationship. We found the 50 milligram dose as effective as the 75 milligram dose and expect that it will yield similar activity as seen in the 25 and 75 milligram doses, because those doses have reduced attack rates to zero. We will report that data later this year.

Rich Law, Analyst

Thank you. HAE Phase 2 study’s timeline is not dependent on U.S. sites, for example, if you receive a clinical hold on the IND. Can you run the trial completion entirely outside the U.S., and would that affect the overall development and timeline of the trial?

John Leonard, CEO

Yes, that's the simplest answer to your question: yes, we can. Of course, it’s a priority to have U.S. sites participating, and we are working very diligently to make that happen.

Rich Law, Analyst

And also, have you thought about what you'll do for ATTR PN? Will you use an external control group or an active control group for the pivotal?

David Lebwohl, Chief Medical Officer

Yes, we are not providing exact designs. We have been very clear that all the submissions for pivotal trials thus far have not included an active comparative arm. This is due to the unique nature of ATTR disease and the reliability issues with historical data concerning these patients. The next submission has been made for the pivotal trials, as you have seen in the case of patisiran. We are analyzing all that now, and we will present the design when we have further details.

Jay Olson, Analyst

Thanks for the update and congrats on the progress. For NTLA-2002, can you explain the rationale for using the 25 and 50 milligram doses in the Phase 2 study? And is there any particular reason for not pursuing the highest 75 milligram dose? And are there any lessons learned or insights from the NTLA-2002 IND that you plan to apply to the NTLA-2001 IND? Thank you.

John Leonard, CEO

David will discuss the doses and our approach to them. Regarding the read-through, we will see. Clearly, NTLA-2002 is the priority at this time. If we receive any information or feedback, we will certainly apply that to NTLA-2001. The same fundamental philosophy has been utilized for both programs, particularly in our prior interactions with regulatory agencies and their requirements, which are consistent across programs. To clarify, NTLA-2001 is a more advanced clinical program regarding its progression and the nature of the IND as it moves toward pivotal programs, where selecting the right dose is crucial and designing the pivotal trial will be part of that discussion. We believe this will be a significantly extended undertaking. However, in terms of the essential pre-clinical data needed, we anticipate they will be quite similar. Perhaps you could elaborate on the dose selection for the Phase 2 study of NTLA-2002?

David Lebwohl, Chief Medical Officer

The Phase 2 was always planned to study two doses in addition to the placebo. This is a preferred method from regulatory agencies to really understand the best dose rather than picking it coming right out of Phase 1. In this case, all three dose levels were safe, leading to zero attacks, which makes it more challenging. However, we observed pharmacokinetics similarities when saturating around the 50 milligram dose. Therefore, we chose this dose as one of the trial doses for regulatory purposes, to demonstrate that higher doses could yield improved results for safety. Although we are not overly concerned about that aspect since safety is very strong. This is the rationale behind our dose selection.

Brian Cheng, Analyst

We're curious if you have any thoughts around the regulatory bar for IND clearance specifically in the U.S. for in vivo gene editing for some of the non-orphan larger disease indications compared to smaller orphan markets. What feedback can you provide on how regulators are handling the risk-benefit analysis, especially in indications with larger total addressable markets?

John Leonard, CEO

I can't speak to how the FDA is assessing benefit-risk analysis with respect to the application of an editing approach. We've been very careful to choose disease states in which it is clear that an editing approach will benefit every patient exposed to the treatment. Treating risk factors, for example, has its own challenges, though a compelling case can be made for that. When we think about the current evolution of these therapies, a benefit-risk analysis is most favorable when considering mortality-inducing illnesses or conditions posing grave risks to patients. We believe the FDA has indicated some understanding of this perspective through guidances they have released. Thus, as new indications arise, we anticipate these conversations will have to be tailored case-by-case before various sponsors.

Joseph Thome, Analyst

Maybe just the first. How come you didn’t have a formal pre-IND meeting before the HAE IND, or was one not appropriate at that time? And then just a follow-up on the CM trial: is the main gating factor for initiation just the clearance of the U.S. IND? Or is there a particular amount of follow-up you want to see from those extension cohorts?

John Leonard, CEO

Maybe David can speak to the nature of our conversations with the FDA concerning the NTLA-2002 IND. Regarding the NTLA-2001 pivotal trial, we intend for it to be a global program, which means having U.S sites involved. We will not commence a pivotal trial without those U.S. sites, at least as it stands now. We're focused on a very robust filing that includes extensive clinical information, similar to a Phase 2 filing. This ongoing work is crucial; data collection will be part of the application. In a pivotal program, we aim to have all final commercial material available for use in the clinical trial, and that’s certainly integral to this undertaking. The program is quite advanced and moving as we had hoped, so I suggest staying tuned. David, do you want to add anything to the NTLA-2002 context?

David Lebwohl, Chief Medical Officer

We did have a formal pre-IND meeting for this, and we addressed the questions raised in that process.

Ian Karp, Senior Vice President of Investor Relations and Corporate Communications

Great. Thanks so much, everyone for joining us today and for your continued interest. We look forward to providing additional updates as we progress throughout the year. So thanks and have a great day.

Operator, Operator

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