Intellia Therapeutics, Inc. (NTLA) Earnings Call Transcript & Summary

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. [Operator Instructions] This conference is being recorded at the company's request and will be available on the company's website following the end of the call. [Operator Instructions] I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics 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 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 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 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.

Thank you, Ian, and thank you all for joining us this morning. At Intellia, we're 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 2 in vivo clinical candidates, NTLA-2001 and NTLA-2002, we're now 2 for 2. Notably, we've dosed more than 50 patients with our in vivo CRISPR-based therapies in ongoing clinical studies with durability and safety data now out 2 years in the earliest 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're pleased to share today that we initiated the Phase II 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're 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're poised to submit an IND application for a pivotal trial for the cardiomyopathy manifestation of ATTR amyloidosis mid-year 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 medicines. With that introduction, I'll hand the call over to our Chief Medical Officer, David Lebwohl, who will review NTLA-2001 and NTLA-2002's progress in greater detail and outline updates across our clinical pipeline. David?

Thanks, John, and welcome, everyone. I'll begin with a review of 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 I clinical trial of 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 2001. The deep reductions were sustained with patient follow-up ranging from 4 to 6 months as of the data cutoff date. 2001 was generally well tolerated in all 12 patients. 2 of the 12 patients reported transient infusion reactions, which resolved quickly and which 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 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 dose expansion portion of the cardiomyopathy and polyneuropathy arms. 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 mid-year 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 III study, including discussions with regulatory authorities, and look forward to presenting additional clinical data from the ongoing Phase I study. I'll turn now to our second in vivo program, 2002, our investigational therapy for the treatment of hereditary angioedema, or HAE. We shared additional positive results from the ongoing Phase I/II 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 2002 led to robust reductions in plasma kallikrein and HAE attack rates. For the 25 milligram and 75 milligram cohorts, these deep reductions in plasma kallikrein were sustained in all patients through data cutoff, which range from Week 16 to Week 32. Importantly, all patients dosed in these 2 cohorts who completed the prespecified 16-week observation period have maintained an attack-free status as of the data cutoff date. Patients in the 50-milligram cohort have not yet completed the primary 16-week conservation period before the presentation cutoff date, and so we look forward to presenting attack rate data on this cohort later this year. At all 3 dose levels, 2002 is generally well tolerated, and the majority of adverse events were mild in severity. The most frequent adverse events were infusion-related reactions, which were mostly Grade 1 and resolved within 1 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 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 I portion of the study in 2023, including longer-term safety, durability and attack rate data across all 3 cohorts. As John mentioned, it's been a very productive first 2 months of the year, especially for the 2002 program. In January, Intellia was awarded the Innovation Passport in the United Kingdom for 2002, which provides entry to U.K.'s Innovative Licensing and Access Pathway. We were pleased to receive the ILAP 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 II portion of the study in New Zealand. The Phase II portion, a randomized, placebo-controlled expansion study, is evaluating 2 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's review. As 2001 and 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 CFO, who'll provide updates on our R&D efforts and platform advancements.

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 insertion, 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 knockout 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 program 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 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. I'll now hand over the call to Glenn, our CFO, who will provide an overview of our fourth quarter and full year 2022 financial results.

Thank you, Laura. Good morning, everyone. Intellia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform. 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.

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 forward new platform capabilities. This year, we look forward to advancing the Phase II 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 of NTLA-2001 for patients with the 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 Instructions] The first question comes from Maury Raycroft with Jefferies.

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

Maury, thanks for your question. It's pretty standard application and aligns with some of the comments we've made in prior communications of what FDA is looking for. I think where this IND may differ from other INDs is that we're 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, of course, careful to provide a very, very careful and complete update of that information. But otherwise, I would say it's pretty standard stuff.

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

So David, do you want to address that?

Yes. So the Phase II, we've shown it publicly. It's in our slides. But basically, it's 3 arms. There'll be an arm at 25 milligrams, an arm at 50 milligrams and a placebo arm. And the size, it's 10, 10 and 5 patients. And the idea here is to select the dose for the pivotal study. We have obviously some very good information already from the Phase I, seeing really excellent results at all 3 doses. 50 and 70 looked very much the same in terms of pharmacokinetics, so we did choose the lower dose, possibly being a safer dose. And the 25-milligram dose as well was quite good, but did look a little different in terms of pharmacokinetics. So that's really the trial. It will be informing our Phase III, which we are already thinking about the design and getting ready for. It will contribute to the eventual BLA by additional information about patients. But that's the main use of the trial.

The next question comes from Greg Harrison with Bank of America.

I wanted to ask how you're 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?

Yes, thanks for the question. It's an important one and one that we certainly thought about even from the early stage of the company. I think what we've seen is that sickle cell is curable. I mean, 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 that -- where we believe we can make significant progress. So we've been focused really since the outset as we thought about that disease, doing it in an in vivo setting where one can avoid a bone marrow transplant and the morbidity and occasional mortality that comes with that. That's a more general solution for patients. And in fact, I think it's a very, 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've seen, that space is wide open, and we intend to get there first.

The next question comes from Joon Lee with Truist Securities.

This is Mahdi on for Joon. So I will follow up on the previous question and asking like what is your strategy now? Is 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 question.

Well, thanks again. Our strategy hasn't changed for some years now. And 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 and one that has been followed by them and others in the space. For us, we've always focused on the in vivo setting. From an editing point of view, we think there's any number of potential edits that can be successful. And our particular approach is not one that we've disclosed. But what I think we've learned is that the disease is curable. So it's really a matter of delivery and making sure that that's done in a way that is robust and works well for patients.

Awesome. And could you please provide some color on your in writing system? Any idea, is it similar to existing techniques out there like PASTE and PE, or is it more similar to homologous recombination? Any color in that domain would be appreciated.

Yes. We're not disclosing the specifics. We think about it in terms of capabilities, which is the resulting gene edit. 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 to develop. So we're excited about our ability to introduce the intended changes and do that with great fidelity and great specificity and great activity, frankly. So as we go on and the results mirror it, 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're very, very excited about where we are and where we're headed.

The next question comes from Swapnil Malekar with Piper Sandler.

So you had previously mentioned the likelihood of having an interim readout for the pivotal trial in ATTR cardiomyopathy. So I was just wondering like 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.

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

Sorry. I meant just in terms of clinical trial design, if there will be an interim analysis.

Okay. Yes. So for the Phase III, as you know, we're designing that now. We're not talking about the exact details. So we have said that we think the important endpoints are cardiovascular events and mortality. And we've seen some of the other trials out there. It does have to be a large trial to study these questions. We'll have a big advantage as we start to do our trial, and that 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, we also expect to have the best efficacy in that trial. And because of that, the trial could be positive in interim analysis, and we're looking carefully at that possibility.

Got it. And one follow-up I had is, so you mentioned that there have been like more than 50 patients dosed across 2 programs with some of the patients reaching 2-year mark. So I was just wondering if there were any relapses in KTR or kallikrein in any of the patients that required redosing.

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

The next question comes from Gena Wang with Barclays.

This is Harshita on for Gena. Can you hear me okay?

We can.

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

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. So stay tuned, and hopefully we'll have some favorable results to report.

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

David, what lies in store?

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

The next question comes from Terence Flynn with Morgan Stanley.

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 one kind of second question, which again, not sure if it's applicable or not. But yesterday, a CRO announced some supply chain issues with non-human primates, and I was just wondering if that might impact any of your preclinical work or timelines.

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 BD, we think about it 2 ways, I guess. You asked about it in terms of tools. An important part of our strategy is to have a toolbox that is complete. And we think about that in terms of the capabilities, in terms of those different changes that we want to be able to introduce into DNA. We think we've got a great toolbox. We watch what's happening on the outside. We have our own scientific efforts internally and look for new capabilities that we think would augment the toolbox. At this point, we're pretty satisfied with the things that we want to do, but of course, we'll keep our eyes open. I think the broader approach to BD for us is just thinking about deploying that toolbox, not bringing things into it. What we're seeing is all kinds of wonderful opportunities, some of which we're advancing ourselves, some of which we're advancing with collaborators. And in the last 18 months, we've had 4 different collaborators that -- for different collaborations that we've struck to augment the work that we do in our own pipeline. So whether it's ophthalmology with sparing vision, autoimmune disease with Kyverna, our spinout with AvenCell, or work in NK cells with ONK, these are really exciting applications of the capabilities already in hand, and we expect to do more. And I think if you step back and look at our pipeline, and bear in mind the clinical rights that we have, commercial rights that we have from, each of those different collaborations, you'll see that this is, especially for a company like ours, of this size, a wonderful pipeline that's replete with opportunities. So BD, yes. Toolbox good with a lot of internal work going to make sure that it remains unsurpassed.

The next question comes from Luca Issi with RBC.

Congrats on all the progress. This is Lisa on for Luca. Just one on the cardiomyopathy pivotal trial. Just wondering if we should expect 2 trials here, maybe one with the 6-minute walk test as the primary endpoint and another with cardiovascular-based outcome study. And maybe on sickle cell disease, can you expand further on why Novartis decided to discontinue the program? And if there's any clinical data available, will you be in a position to share it?

Yes. I can't speak to Novartis' decision, other than they've 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've not directly participated in. We provided reagents to them some years ago. We've always believed that the future lies with the in vivo approaches, and that's been a focus of the work that we do. I'm sure they looked at the ex vivo space and may have had some of the same realizations that we had some years ago. So I think it's apparent where that space will ultimately go. But David, maybe you can answer the question about pivotal trials. How many do you actually want to do?

Right. We're -- again, we're not telling the exact program, but we don't think that dividing those things into 2 trials is a great idea going forward. The 6-minute walk test, there's been more questions about how valuable it is to understanding how patients are doing, and you've seen that in some of the recent trials in amyloidosis. But again, we think the important endpoint's the cardiovascular events and mortality. And that's what the patients are interested in, the doctors are interested in, the payers are interested in. So it's really what we're most interested. The regulators, of course, are very interested in those factors.

The next question comes from Yanan Zhu with Wells Fargo.

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

David, what role does placebo play, and what's the aspiration?

Sure. So the placebos are -- having placebo-controlled trials are the gold standard in randomized trials. Of course, you don't expect them to benefit in the placebo arm, but of course, you've also seen there can be a strong placebo effect in many trials. And that's the risk of not having that arm to -- not to compare. It's not a comparative trial. It's a Phase II. But it's a reference arm to see that what we expect is to have a very strong effect in both of the doses, 25 and 50, and to have little or no effect on the attack rate in the placebo arm. And that will help, again, inform and help us design the pivotal trial and choose the dose. I should mention that the patients in placebo arm will be offered to cross over and get the active drug once their evaluation is completed. And of course, we do this because of the contribution they're making to our study and their desire to get this type of therapy as part of their potential cure going to the second part of this. This idea of a functional cure is what the idea that you could get to zero attacks in patients with this single treatment. And whether we can achieve that, it's too early to say. We're very encouraged by the early results. We are getting deeper reductions in kallikrein that's achieved with the best agents that are out there, so it is possible that this will also lead to better efficacy. And again, this aspiration to have a functional cure or to patients to have no attacks after receiving our drug.

Great. If I could 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 the cardiac amyloid will be resolving? Or is the expectation that it is just stabilizing and no more additional amyloid addition?

Yes. This hasn't been well established. Of course, there aren't therapies that get to the very low levels of TTR that we're able to achieve. But the idea we have, and we hear from the key investigators in this area, is that if you do get to low enough TTR levels, the rate of amyloid deposition into organs will be so reduced that the equilibrium will be the other way. In other words, the removal of amyloid from the heart is greater than the addition of amyloid due to the small amount of TTR that would be in the blood at that point. So that's what we're hoping to. The idea then is a possible reversal of the heart disease by getting rid of that amyloid, and that is our aspiration for that trial.

Next question comes from Salveen Richter with Goldman Sachs.

This is Shrunatra on for Salveen. Could you provide some color on the nature of discussions that you're having with regulators regarding the global pivotal study for NTLA-2001 in both ATTR-CM and PN? And also regarding NTLA-2002, how confident are you regarding the IND acceptance? And do you have any timelines in mind about when we'll get this information?

Maybe David, you can address how we think about the pivotal and when we'll be in a position to share information. I just -- with respect to the IND, I would say it this way. We've had a variety of interactions with various regulators, including the FDA, in the runup to this. We believe that we're addressing the questions that they wanted us to address. It's not just the list of those questions, but it's the extent of the data that we've tried to provide that actually goes to making sure that we're not just checking boxes, but we're really answering questions and helping them to evaluate the product. Additionally, as I said at the outset, we've supplied clinical information, which I think is unique with respect to some of the other INDs that have played out over the last few years in the space. And we think that that's a helpful bit of information for the FDA to consider as they do their evaluation. So we look forward to the outcome. Obviously, it'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 the information in terms of the outcome of that review, we will share it, and everybody will know at the same time. David, you just want to say a few words about how we approach the pivotal and when we'll be in a position to share that information?

Yes. So just what John said about all aspects of our, say, the IND submission, another piece of that are clinical discussions that have gone on both in the pre-IND setting with regulators around the world, in Europe. And with that, we have -- we're coming forward with a trial design. We have the leading investigators in this area, supporting us in designing this trial. And the point at which we'll have an agreed trial, we'll have to do around the time of the IND. We've said that's the middle of the year for the IND for 2001 and as well in Europe with the CTA applications that go on for that Phase III as well. So that will be -- and the other thing we've said is that the trial will start by the end of the year. So that's sort of the time frames you have. As we have more details, we will share those with you.

I might add one important distinction for the listeners to keep in mind. With respect to 2001, which differs from the 2002 IND application, we're talking about an IND that would pursue a pivotal trial. So in some respects, it's not just an IND with all the preclinical work. It's also supplying the information that would typify an end of Phase II meeting with the FDA. So we expect the 2001 application to be a very, very substantial filing when we in fact do it, which is different from 2002, and it's certainly different from most of the other INDs in the space that have been for first-in-human applications. So as the year goes on, well, I'm sure we'll be talking more about this.

The next question comes from Rick Bienkowski with Cantor Fitzgerald.

Congrats on all the progress. For the 2002 program, the worldwide Phase II trial initiation looks to be a bit staggered with sites outside 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?

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

Yes. I should say that when you're submitting a trial around the world, different regulators will often have different ideas about details of the trial, usually; not the big picture. So it is very possible that there can be amendments to the trial that occur related to feedback either in the U.S. or from outside the U.S. And sometimes it's very helpful. We think they're good ideas. Sometimes we just have to follow their direction for various reasons. But the -- yes, that certainly could happen, but there is a good mechanism for doing that, which is the amendment process for the trial.

Great. Got it. And a quick follow-up. So there's a few novel technologies in the early pipeline now -- gene writing, base editing and proprietary LNPs. 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. So are there any timelines for when we may get some more substantial updates for the progress of these earlier stage technologies?

We haven't guided to any particular products or pipelines. We've spoken generally in prior presentations about useful applications of base editing where we think it makes the most sense. That tends to fall primarily in the ex vivo setting where one is hoping to introduce many simultaneous knockouts, and we have very, very advanced work in that space. We've talked a little bit about our allogeneic platform that we're very, very excited about. And so I would encourage you to stay tuned with respect to future updates in that, and where base editing may fit in in that space, we'll see. With the gene writing approach, it's earlier days, but we're making really excellent progress in terms of getting very high levels of specificity, and we're able to introduce the intended changes that we're looking to do. So as that moves along, we'll find what we think are the appropriate applications and talk more about that. But in the meanwhile, we're focused on progressing 2001 and 2002 and making sure that we continue to demonstrate that any of these technologies really matter for patients in a meaningful way. And that's where we think we are with the current progress. So more to come, and we'll share those updates as appropriate.

[Operator Instructions] The next question comes from Raju Prasad with William Blair.

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

It's really unrelated to what you're saying. It's -- 2002 is at the proper point to begin Phase II. 2001 will be at the point to begin Phase III work. And to have the information necessary to support that 2001 IND, which again, I liken to an end of Phase II meeting, a far more substantial filing than a typical first-in-human IND. Getting the full complement of clinical information, which is not just the acute exposure and the short-term editing results, but actually following these patients for some period of time, is an important part of that application. It's just the way the timelines work out. David, if you have anything to add to that? I mean, that's the essence of it.

No, those are the important features of the timing.

Great. And maybe just a quick follow-up. Just wondering the rationale behind the ATM in Q4 on top of the follow-on. Just wondering why.

Glenn, do you want to speak to our fundraising?

Sure. Yes. We thought the end of Q3 of last year and early Q4 was an opportune time to use the program, just based on how the stock was trading and volume. And then an opportunity opened up in late November/December to do the follow-on, we took advantage of that. So, wasn't preplanned to do it that way. It's just how things worked out.

The next question comes from Dae Gon Ha with Stifel.

Congrats on all the progress. I'll just stick with the IND question again. So with regards to the 2002, I guess, to what extent do you think you fully address some of the FDA concerns? And we're obviously very limited to what's publicly disclosed from one of your competitor programs or peer companies. And to what extent is the depth and the extensive nature of your submission, so in the case of how many pages you submit, will that be a limitation factor as it pertains to the review within that 30-day period?

I can't speak to the number of pages and how fast the various reviewers at the FDA read them. But -- and that's not the metric that we use. Although these applications tend to be very, very large, as you know, because there's a lot of information shared. But we try to address the questions as posed by the regulators. And I think an important thing to emphasize is it's not just data, but it's really testing the robustness of the system. And these are principles that apply not just to our space, but to drug development in general, whether you're doing small molecules, antibodies, whatever. We've tried to apply that kind of thinking, knowing from prior experience how the FDA thinks about this stuff. With respect to other people, I can't address that. I don't know the work, the nature of it, et cetera. We'll see. The FDA, as they review it, I'm sure will pose questions to us. We'll do our best to answer them. But we don't expect to have major deficiencies in the IND. If there's smaller questions that they want clarification on, we will answer them as quickly and as robustly as we possibly can, but we think we have the full complement of information available.

John, just a naive question. With regards 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?

My understanding is that it's 30 days, and you get a clearance or a hold. And then if there is a hold, there's additional information provided by the FDA in terms of what they're looking for in a very formal way. And then that's when you're in a position to best answer their follow-up. If it takes a little longer for them to go through this stuff, we'll see. But again, we believe that the full complement of information has been provided to them.

The next question comes from Debjit Chattopadhyay with Guggenheim.

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

I think we'll keep it at the high level. Collectively, over 50 patients have been treated. A lot of the information is already out there in terms of different groups and different studies, et cetera. So most of that information is fairly current. Obviously, we continue to dose patients in the second phase of the study. And later on this year, we'll give you the full complement of that information.

Next question comes from David Lebowitz with Citi.

This is [ Debanjana ] on for David. So we wanted to ask if you can provide us 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?

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

Yes. So we are collecting both kallikrein protein and activity. We said we'll be presenting more data towards the end of the year. The important piece of that data is a dose that we haven't reported on in terms of attacks, and that's the 50 milligram dose. So recall, we went 25 to 75 and then stepped back to 50 to sort of fill in our dose response. We found 50, as I said, is good as 70. And we expect, of course, to get a similar activity to 25 and 70 because they both were able to reduce attacks to zero. But we will be reporting that later this year.

The next question comes Rich Law with Credit Suisse.

HAE's Phase II studies such that the timeline is not dependent on U.S. sites? For example, if you receive a clinical hold on the IND, you can run the trial to completion in the ex-U.S.?

We can.

Mr. Law, can you please repeat your question?

Yes, sorry. So the question is that you designed HAE Phase II study such that the timeline is not dependent on the U.S. sites. So if you get a clinical hold from for the IND, you can run the entire Phase II study outside the U.S., and it wouldn't affect the overall development trial completion.

Yes. I mean the simplest answer to that question is, yes, we can. Of course, the priority is to have U.S. sites participating, and that's the expectation. And that's something we're going to work very, very hard to do.

And also, have you thought about what's the -- for ATTR-PN, will you use an external control group or an active control group for the pivotal?

David, are you in a position to talk about your polyneuropathy study designs?

Yes. Again, we're not giving the exact designs. We have been very interested in all the submissions -- or all the pivotal trials so far have not used an active comparative arm. And that has to do with the rarity of this disease and the reliability of some of the historical data about what's happening in these patients. And that's been used, as you've seen in, for example, the vutrisiran submission. So we're looking at all that, and we'll be coming forward with the design that we'll talk about when we have the details.

The next question comes from Jay Olson with Oppenheimer.

Congrats on the progress. For 2002, can you talk about the rationale for using the 25 and 50 milligram doses in the Phase II study and any particular reason not to pursue the highest 75 milligram dose? And then are there any lessons learned or read-across from the 2002 IND that you plan to apply to the 2001 IND?

David will speak to the doses and how we think about that. I think with respect to the read-through, we'll see. Obviously, 2002 is going in before 2001. And if there is information or feedback that we can apply, we would certainly do that. But the same basic philosophy has been applied to both of those programs with respect to prior engagement with regulatory agencies, the sorts of things that they're looking for which doesn't differ across the programs. Just again, to draw the distinction, 2001 is a far more advanced clinical program. And the nature of -- the progression of the program in that IND would be moving to pivotal programs where a dose, dose selection, CMC material, a pivotal trial, et cetera, will all be part of that review, which we think will be more substantial in nature. But in terms of the basic preclinical information, we expect them to be quite similar. David, do you want to speak to the dose selection in the 2002 Phase II?

Yes. So the Phase II has always planned to study 2 doses in addition to the placebo. This is the preferred method from regulatory agencies to really understand the best dose rather than picking it coming right out of Phase 1. And in this case, the 3 dose levels were all safe. They all led to zero attacks, so it made it a little more challenging. But what we did see is that the pharmacokinetics was very similar. We think we're saturating by the time we reach about 50 milligrams. So 75 milligrams looked very similar in terms of pharmacodynamics, the reduction in kallikrein reduction. And based on that, we chose the 2 -- 50 as one of the doses. This is sort of, we think, as high as you need to go to get optimal activity. We chose the 25 as a second dose. A little bit less in terms of pharmacodynamics, as you saw. Instead of reaching towards 90%, it was more like a 50% reduction in kallikrein. But we thought, again, for regulatory agencies to demonstrate that the higher dose might be better than the lower dose is important because you are going to a higher dose for the potential additional risk of going to a higher dose. All in all, the safety is so good, we're not really too concerned about that aspect of it, but that's why you do those things.

The next question comes from Brian Cheng with JPMorgan.

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

I can't speak to how the FDA is assessing benefit/risk in terms of the actual application of an editing approach. We've tried to be very, very careful about choosing disease states in which it's pretty clear that an editing approach should benefit every single patient that is exposed to the agent. Treating risk factors, for example, has its own challenges. I think a good case can be made to do that. But when we think about at this point in the evolution of these therapies, a benefit/risk backdrop where you're dealing with mortal illnesses, or illnesses that pose great risk to patients, is the right setting to apply the particular modalities. And the FDA has shared some sense of that, I think, in guidances that they've released. But I think the regulators, in my experience, try to take a considered view of what one can do for patients with different approaches. And so as they assess some of these other indications, those are conversations that I'm sure will play out as they're brought up one by one by the various sponsors who do that. So that would be our experience thus far.

That's helpful.

The last question today will come from Joseph Thome with Cowen and Company.

Maybe just a first housekeeping one. Did you have a pre-IND meeting formally before the HAE INDUSTRY, or maybe why wasn't one appropriate at this time? And then just a follow-up on the CM trial. In terms of timing of that initiation, is the main gating factor just clearance of the U.S. IND? Or is there a certain amount of follow-up that you want to see from those expansion cohorts?

Maybe David can speak to the nature of our conversations with FDA in 2002. Just with respect to 2001 pivotal trial, we intend for it to be a global program, which means U.S. sites. We wouldn't begin a pivotal trial, at least the way we think about it now, without those U.S. sites. As we've said previously, what we're looking for is a very robust filing that includes extensive clinical information, tantamount to an end of Phase II filing, and that work is underway. That data collection will certainly be a part of what the application is. When you do a pivotal program, you want to have your final commercial material available to be used in that clinical trial. That's certainly part of this as well. So the program is quite advanced and moving as we had hoped. So I would stay tuned. As we have more information, we'll share it. David, do you want to say anything about 2002?

Yes. So we did have a formal pre-IND meeting for this. And we, I think as we've said before, we have -- feel we've addressed the questions that they have raised in that process.

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

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

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