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

Good morning, and welcome to Intellia Therapeutics' investor event to discuss interim clinical updates across the company's in vivo pipeline. My name is Andrew, and I will be your conference operator today. Please be advised that this call is being recorded at the company's request. [Operator Instructions] Following the formal remarks, we will open the call up for your questions. 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's investor webcast to discuss recent advances for our ongoing first-in-human studies of NTLA-2001 and NTLA-2002. Earlier today, we issued two press releases, detailing interim data from these clinical trials. The releases, along with an accompanying presentation for today's call can be found on the Investors & Media section of Intellia's website at intelliatx.com. As a reminder, this call is being broadcast live and a replay of the event will be archived on the company's website. At this time, I'd like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including expressed or implied statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Please note that NTLA-2001 and 2002 have not been approved by any health authority. Before we begin, allow me to introduce our speakers and share an outline for today's call. First, Dr. John Leonard, our Chief Executive Officer, will begin with some introductory remarks. Next, Dr. Julian Gillmore, Professor of Medicine at the National Amyloidosis Center and physician at the Royal Free Hospital in the U.K. and the National coordinating investigator for the clinical trial in the U.K. will review the interim results from the cardiomyopathy arm of the ongoing Phase I study of NTLA-2001 for the treatment of ATTR amyloidosis. Then Dr. David Lebwohl, our Chief Medical Officer, will highlight the next steps for the program, followed by an overview of the interim data presented at the Bradykinin symposium from the ongoing Phase I/II study of NTLA-2002 for the treatment of hereditary angioedema. John will then return to put today's announcements in broader context for Intellia and discuss where we might next deploy our industry-leading genome editing platform. We will conclude with a Q&A session, where Laura Sepp-Lorenzino, our Chief Scientific Officer, will also be available. With that, I'll now turn the call over to our CEO. John?

Thank you, Ian, and welcome, everyone. Last year with NTLA-2001, Intellia opened a new era of medicine. Today, with NTLA-2002, we build upon our success with powerful evidence of the modularity of our in vivo platform. At Intellia, we're building a full spectrum genome editing company by deploying the industry's broadest and deepest toolbox. We are pioneering novel editing and delivery solutions to harness the immense power of CRISPR-based technologies for in vivo and ex vivo therapeutic applications. Fueled by this limitless potential, our strategy is aimed at developing modular solutions that we can leverage to expand the horizons of both what CRISPR can do and serve as a springboard for success from one program to the next. The data we will share today from the ongoing studies of NTLA-2001 and NTLA-2002, represent a major milestone for people affected by ATTR amyloidosis in hereditary angioedema. It's also an important day for Intellia. And for the many other patients we hope to one day serve because these data strongly reinforce the promise of our clinically validated modular in vivo CRISPR-based platform. This clinical validation supports rapid expansion of our pipeline, instilling confidence in our ability to address a range of both rare and prevalent genetic diseases. In a moment, you'll hear results from the cardiomyopathy arm of the ongoing Phase I trial of NTLA-2001. We're honored to have Dr. Julian Gillmore join us in presenting those initial results, which support our belief that NTLA-2001 has the potential to halt and even reverse underlying cause of ATTR amyloidosis regardless of how it may manifest in an individual patient. We will also share a first look at interim clinical data on NTLA-2002, which were presented earlier today by Dr. Hilary Longhurst at the 2022 Bradykinin Symposium held in Berlin, Germany. These data continue to bolster our belief that NTLA-2002 has the potential to permanently prevent the debilitating swelling attacks associated with hereditary angioedema, following a single-dose treatment. Further, these data are yet another compelling demonstration that we've unlocked the liver. By changing only a small number of nucleotides of the guide RNA from one program to the next we're able to precisely edit a different disease associated gene with similarly remarkable results. And because angioedema attacks can be readily recognized, we have already observed within only weeks of dosing, just how profoundly genome editing can impact the disease itself. With that, I'll now ask Dr. Gillmore, a leading physician specializing in treatment of ATTR amyloidosis to review the interim results. Dr. Gillmore?

Thank you, John. Transthyretin amyloidosis, also known as ATTR amyloidosis is a progressive and fatal disease, it's caused by the accumulation of any deposits composed of misfolded transthyretin or TTR protein. Transthyretin amyloidosis may be acquired, known as wild-type or hereditary known as variant or ATTR B. Hereditary ATTR amyloidosis is estimated to affect approximately 50,000 individuals worldwide. It can present as either peripheral and autonomic neuropathy or cardiomyopathy with some patients having a mixed phenotype with both the autonomic and cardiomyopathy. Wild type ATTR amyloidosis is estimated to affect 200,000 to 500,000 people worldwide, but continues to be underdiagnosed. The clinical presentation is primarily with the cardiac phenotype. The amyloid deposits cause cardiomyopathy, resulting in heart failure with impaired diastolic and systolic function and conduction disorders. With our treatment amyloid deposits continue to accumulate in the heart and the condition is fatal within 3 to 10 years. Due to these factors, there's a high unmet medical need in ATTR amyloid cardiomyopathy. Progressive heart failure leads to the impaired quality of life, considerable morbidity and is universally fatal. The current standard of care treatment only slows disease progression, requires lifelong administration and in many regions, access to treatment is limited. Intellia's Phase I study is evaluating NTLA-2001 for all manifestations of ATTR amyloidosis. The focus of today's update will be on the cardiomyopathy arm. This is the population in whom knockdown of TTR protein has recently been shown to be of clinical benefit with the expectation that deeper TTR reductions will result in improved clinical outcomes. Let me explain why. In every type of amyloid that's never been treated, there's been a very strong correlation between the degree of knockdown of the relevant protein and clinical outcomes. The explanation is very simple. The turnover of amyloid deposits depends on the equilibrium between the rate of amyloid production and the rate of amyloid removal. The rate of removal is, by definition, very slow such that in an untreated patient, the rate of amyloid production exceeds the rate of removal and when it accumulates and results in clinical progression and death. The more one knocks down the concentration of the relevant protein, in other words, the rate of amyloid production, the greater the equilibrium in favor of amyloid removal. Initially, when we started treating AL amyloidosis, we thought a greater than 50% reduction in the light chain or the amyloid forming protein was sufficient because outcomes were better than in patients with no knockdown. Now having gathered sufficient data, we know to aim for what hematologists call a complete response equivalent to 100% knockdown. Please see this graph showing the relationship of patient survival and degree of knockdown. And here in ATTR amyloidosis, we see the same trend emerging, although the data at this point are less mature since TTR knockdown has only been possible in the last few years. This shows the relationship between the degree of TTR knockdown and change in neuropathy score. We see that lower serum TTR has been observed to be associated with better subsequent control of neuropathy symptoms. There is also emerging evidence that deep TTR reductions are clinically beneficial for patients with ATTR amyloid cardiomyopathy. Taken together, these data form a basis for the hypothesis that knockout of the TTR gene to achieve deep TTR reduction may hot and potentially reverse this disease. -- and the conviction behind my involvement with this study. NTLA-2001 is being studied as a 2-part open-label, multicenter study in adults with hereditary ATTR amyloidosis with polyneuropathy or ATTR amyloidosis with cardiomyopathy. Earlier this year, Intellia presented interim clinical trial results for the polyneuropathy arm at the European Association for the Study of the Liver International Liver Congress. Today, we report the first results of Part I in the cardiomyopathy arm, patients enrolled with either hereditary or wild-type ATTR amyloidosis with cardiomyopathy and an NYHA classification between 1 and 3. Part I is a single ascending dose design with a minimum of 3 patients in each cohort of NYHA class I or II administered 0.7 milligram per kilogram, NYHA Class III administered 0.7 milligram per kilogram and NYHA Class I/II administered 1.0 milligram per kilogram. Based on safety and PD profile of 0.7 milligram per kilogram, further dose escalation to 1.0 milligram per kilogram in NYHA III -- Class III patients was not undertaken. Part II, in terms of administration of the dose selected from Phase I data. The primary objectives of this first-in-human study are to evaluate safety, tolerability, PK and PD and latter by serial measurement serum TTR levels. I will report data on all 12 patients enrolled in the 3 cohorts included in Part I. This table summarizes the demographics of the 12 study participants. Median age was 75 with range 68 to 86 years. All participants were male and had a median weight of 85 kilogram of the range of 63 to 106 kilogram. 10 of the 12 patients were wild-type, 50% patients had were NYHA Class III heart failure with another 42% being NYHA Class II. The median NT-proBNP was around 2,000 and 2,400 in all cohorts. The next three slides summarize the safety data from this study. NTLA-2001 was generally well-tolerated across all cohorts through the follow-up period. Adverse events regardless of relationship are listed here. The majority of adverse events were mild in severity. The most commonly observed adverse event was infusion-related reaction in 2 patients. 3 of 12 patients, in other words 25% reported no AEs and 58% reported mild AEs. All patients completed their infusions, receiving their full doses and remained on study. A single grade 3 infusion-related reaction was reported at the 0.7 milligram per kilogram dose in an NYHA Class III patient and resolved without any clinical screening. The NYHA class 3.7 milligram per kilogram cohort was expanded per protocol to 6 patients to further characterize safety in PD. No additional patients in this cohort reported treatment-related AE higher than Grade I. Lastly, no clinically significant laboratory findings were observed. This table summarizes the most common adverse events occurring in more than two patients. These adverse events were predominantly transient, reversible and most frequently Grade I. No clinically significant laboratory findings were observed. Transient Grade I liver enzyme excursions were not considered clinically significant and resolved in all patients. The next two slides summarize the pharmacodynamic effects from Part I of this first-in-human study. The first figure depicts the mean TTR reduction from baseline of 28 days post treatment, for each of the three cohorts. Mean reductions in serum TTR were greater than 90% across all cohorts on day 28. Notably, these reductions were highly consistent across patients in both dose cohorts and in patients with either a Class I, II or Class III heart failure. This figure demonstrates the durability of effect of NTLA-2001, the mean percentage reduction for each cohort is depicted from baseline to the latest measurement. Patients in the NYHA Class I/II 0.7 milligram per kilogram cohort have now reached 6 months of follow-up, achieving a consistent sustained response with a mean 93% reduction. In the NYHA Class III 0.7 milligram per kilogram and NYHA Class I/II 1.0 milligram per kilogram cohorts, mean reductions of 94% and 92%, respectively, can be observed at 2 months of follow-up. Notably, all 12 patients achieved greater than 90% TTR reduction by day 28. In conclusion, deep consistent and durable TTR reductions were achieved at both 0.7 and 1.0 milligram per kilogram doses. Mean TTR reduction of greater than 90% was observed across both doses by day 28 and sustained till last follow-up between 2 and 6 months. NTLA-2001 is generally well-tolerated. The majority of adverse effects were mild with similar results across both dose levels and across both NYHA heart failure class cohorts. No clinically significant laboratory findings were observed. The data presented here are consistent with previously reported data from the polyneuropathy arm of this trial. These data further support and extend the earning findings from this pioneering trial demonstrating the promise of CRISPR-based in vivo gene editing in humans. More specifically, the deep and sustained TTR reductions observed in this study among patients with ATTR amyloid cardiomyopathy has the potential to bring about not only clinical stability, but also genuine clinical improvement in a disease that has hitherto been universally progressive and ultimately fatal. With that, I'll turn you over to the next part of the presentation to Intellia's Chief Medical Officer, David Lebwohl. Thank you.

Thank you, Dr. Gillmore for your continued leadership in this trial. Based on the totality of data from both to cardiomyopathy and polyneuropathy arm of the study, we have filed a protocol amendment to evaluate a fixed dose equivalent of 0.7 milligrams per kilogram in the expansion portion of the study. As shown on this slide, the key safety and PD data that informed our decision include: first, the data from the dose escalation portion of the cardiomyopathy arm, which indicated serum TTR reduction of greater than 90% is indistinguishable at the 2 doses tested. Second, the comparability of performance 0.7 and 1.0 milligram per kilogram doses in the dose escalation portion of the polyneuropathy arm. And third, while 2001 has generally been well-tolerated, as previously reported, there was a patient who had a significant elevation in liver enzymes at the 1.0 milligram per kilogram fixed dose equivalent. While the patient was asymptomatic and his liver enzymes returned to normal levels without any medical treatment, this finding partly informed our decision. Overall, it was a straightforward decision to move forward with a dose that we believe will deliver the maximum amount of benefit to patients at the lowest dose possible. We look forward to completing enrollment in the Phase I study by the end of this year, subject to regulatory feedback on the recent protocol amendment. We are also actively designing what we hope to be a future global pivotal trial. With our review of the 2001 data now complete, I am delighted to provide a summary of the interim data from our second in vivo genome editing candidate 2002 for the treatment of hereditary angioedema or HAE. As John mentioned earlier, this marks the second time clinical data has been generated, demonstrating that we can precisely edit target cells within the human body to treat genetic diseases with a CRISPR-based therapy. In addition, these standards validate the modularity of Intellia's industry-leading genome editing platform and its potential to target a multitude of genetic diseases. Finally, we are especially pleased that these data provide us with preliminary evidence that not only can we successfully edit a disease-causing gene. But in doing so, we can elicit a clinically meaningful impact for the patient. As a brief reminder, by targeting the KLKB1 gene 2002 is designed to reduce the production of kallikrein protein, which is a clinically validated approach for the treatment and prevention of HAE attacks. On this slide, you can see a summary of 2002's mechanism of action. You will notice that 2002 is engineered similarly to 2001 and that it is comprised of a lipid nanoparticle containing a guide RNA and a messenger RNA. The only difference is that 2002 has a different target site portion of the guide RNA. HAE is a rare genetic disease estimated to occur in one in 50,000 people. Current treatment options often includes lifelong therapies which may require intravenous or subcutaneous administration as often as twice per week or daily oral administration to ensure constant pathway suppression for disease control. Unfortunately, despite product administration, breakthrough attacks often occur and the burden of treatment for patients can be especially challenging, particularly as many patients are diagnosed in their adolescence. Intellia's ongoing Phase I/II study is evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of 2002 in adults with type 1 or type 2 HAE. Phase I portion of study is an open-label, single-ascending dose design used to identify up to two dose levels that will be further evaluated in the randomized, placebo-controlled Phase II portion of the study. The data presented today are from 6 initial patients in the ongoing dose escalation study. Single doses of 25 milligrams and 75 milligrams were administered and changes from baseline values of plasma kallikrein protein were measured for each patient. In addition to plasma kallikrein levels, HAE attack rate data is also being measured for all patients in the study with the first analysis occurring at the end of the prespecified 16-week primary observation period. Today, all 3 patients in the 25-milligram cohort have reached the end of this initial observation period. Patients in the 75-milligram cohort have not all completed the primary observation period and attack rate data for this cohort will be presented at an upcoming scientific meeting. Additionally, we have recently completed dosing in a third dose cohort to test the 50-milligram dose. We expect to report interim filings at the same upcoming scientific meeting. Here you can see the inclusion and exclusion criteria for the Phase I portion of the study. Notably, patients required to have at least 3 HAE attacks within 90 days prior to screening and were allowed to enter the study even if they were currently receiving prophylactic therapy. Here, you can see the patient demographics. The majority of the patients were male and the median age was 38. On this slide, you can see patients had a mean monthly HAE attack rate of 6.8 per month. Let's now review the results we have seen so far from the trial. Starting with safety. 2002 is generally well-tolerated at both dose levels with the majority of adverse events being mild in severity. The most frequent adverse events were infusion-related reactions which were generally Grade I and resolved within one day. There have been no dose-limiting toxicities, no serious adverse events and no adverse events of Grade III or higher observed to date. In addition, no clinically significant laboratory abnormalities are observed, including any significant elevation in liver enzyme. In summary, the safety and tolerability data reported to date is extremely encouraging at both doses. Now let's look at the activity data that begins on this slide. A single dose of 2002 resulted in rapid, dose-dependent reductions in plasma kallikrein and achieved maximum reductions by week 8 with mean reductions of 65% and 92%, respectively, among the three patients in each cohort. The dotted line is a 60% mark on this slide highlights the level of kallikrein inhibition, which has been associated with a therapeutically meaningful benefit to patients. This is based on other clinical trials investigating either monoclonal antibodies or antisense oligonucleotide therapies that also target kallikrein reduction. As you can see, we have already achieved our goal of greater than 60% kallikrein reduction at the first dose level. We take a closer look at the backgrounds of the first three patients in the study here. While there have been advances for patients living with HAE, you can see from each of their experiences that there is still significant unmet need. Patient #1 is a 30-year-old male who is diagnosed with HAE type II and has a family history of the disease. Prior to enrollment his HAE attacks are typically moderate in severity. Patient #2 is a 50-year-old male diagnosed of HAE type I, who also has a family history of the disease. Like many HAE patients has been on danazol for prophylaxis for years, but still suffered frequent breakthrough attacks in various parts of his body. When these would occur, he would frequently require C1 esterase inhibitor infusion and pain medication to manage his symptoms. During the screening period, this individual had an attack rate of 7.2 per month. For patient #3, a 26-year-old male diagnosed with HAE type I, he would oftentimes experience breakthrough attacks despite taking the recently approved oral kallikrein inhibitor, berotralstat. These breakthrough attacks would lead to swelling in different parts of his body, including his airway, which is particularly dangerous. Now we are pleased to report the HAE attack rate data for the 3 patients in the 25-milligram cohort with all reached the end of the 16-week primary observation period. In the screening period, prior to administration, patients had an investigator-confirmed HAE attack rate of 1.1 to 7.2 attacks per month. A single 25-milligram dose of 2002 resulted in a mean reduction in HAE attacks of 91% at the end of the 16-week period, when compared to the baseline attack rate from the initial screening period. Importantly, two of the three patients have not had a single angioedema attack post administration with 2002, and we'll learn more about the third patient in a moment. On this slide, you can see a swimmer plot of the three patients in the 25-milligram cohort. The colored lines indicate any HAE attack that occurred during the screening period or in the subsequent observation period following administration with 2002. Across all these patients, we now have a test data compiled through a range of weeks 24 through 32, making these results particularly robust. As you can see, the colored lines dramatically decreased after administration of 2002. You'll see that the second patient who had the most frequent number of attacks provider administration is now also attack-free since week 10. One additional noteworthy details that I'd like to highlight. Recall that the study allows for patients to continue their concomitant prophylactic therapy. The protocol then allowed for investigator to withdraw this therapy, if deemed appropriate after the initial 16-week period. In this cohort, there were two patients receiving prophylactic therapy and still having breakthrough attacks. One was on Danazol and the other, Berotralstat. Both patients had those therapies withdrawn after week 16 and notably continue to remain attack-free to the latest follow-up available. Finally, in patients in the 75-milligram cohorts have not all completed the primary 16-week observation period, we plan to present the attack rate data for this cohort in November at the American College of Allergy, Asthma and Immunology Annual Scientific Meeting. We are heartened by these promising early data, which we believe support 2002's potential to address the significant treatment burden faced by patients living with HAE. These data reinforce our belief that 2002 was a possibility for permanently preventing the debilitating slowing attacks associated with the disease following a single-dose treatment. We expect to select up to two doses to be further evaluated in the Phase II dose expansion study and to begin the study in the first half of next year. As part of the subsequent global placebo-controlled Phase II study, we plan to file an investigational new drug application or IND to the FDA to allow for the inclusion of U.S. clinical sites. And with that, I'll turn the call back to John for closing remarks.

Thank you, David, and thank you, Dr. Gillmore. Altogether, Intellia is leading the genome editing revolution as we expand the horizons of what CRISPR can do and where in the body it can do it. In the near term, we look forward to sharing more from NTLA-2001 and NTLA-2002 and our broader pipeline as we continue to work toward fully realizing the promise of genomic medicines. While our initial work is focused on diseases that originate in the liver, we're advancing our technology in a broader set of tissue types as well. For individuals with ATTR amyloidosis, we believe these interim results underscore the potential of NTLA-2001 to halt and possibly reverse the disease after a single-dose treatment. For people with HAE, we believe these early data speak to NTLA-2002's potential to permanently prevent debilitating swelling attacks with a single-dose treatment. And as we highlighted today, we're already beginning to see in the first 3 patients how our investigational genome editing therapy can impact their lives. Beyond these two programs, we're pursuing investigational therapies in a variety of additional genetic diseases, including alpha-1 antitrypsin deficiency and also in collaboration with Regeneron, hemophilia A and B. We've selected these initial indications based on the unmet medical need, the size of the patient population and the technical feasibility of leveraging our editing and delivery tools to specifically address these conditions, but we believe this is just the beginning for Intellia. These results from NTLA-2002, coupled with NTLA-2001's demonstrates the strong foundation on which we will advance our pipeline. Our next series of programs includes knockout as well as insertion approaches. There are a wide range of diseases that could benefit from our genome editing approach beyond the liver. We're also excited about the opportunity for targeting diseases in additional tissues such as the bone marrow and CNS, utilizing our deep expertise in developing novel delivery and editing technologies. As we progress our pipeline, we will develop selected programs on our own, advance others with Regeneron and may pursue new collaborations with future partners. I would like to close today's formal remarks with an image of our mission statement that you can find on Intellia's website and on the walls throughout our offices and laboratories here in Cambridge, Massachusetts. It says change life stories with genome editing therapies. While the data we have shared today are truly remarkable, it is what these data represent that has me most excited. I believe we have taken another important step forward towards actually changing life stories. Before we move to the Q&A, I would like to convey my thanks to the patients and their families who have participated in these groundbreaking trials, and of course, to the investigators, our collaborators at Regeneron and the amazing team we have here at Intellia, who have all contributed and remained committed to advancing genomic medicines. 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 Salveen Richter with Goldman Sachs.

And congratulations on this data. Just a question here on your knockdown target. You're already sitting at greater than 90% reduction in HAE attacks. And really nice reductions in knockdown here. What is that kind of target level you're going to? And maybe help us understand how comfortable you are with the dose-finding work, particularly as you look at the safety profile?

Thanks for the question. As you pointed out, we're still finding exactly where we are with respect to dose responses. We've talked a little bit about the initial dose and the activity we're seeing there, our expectation would be with greater degrees of reduction in the protein, we may further improve on activity, but time will help us make that assessment. As David mentioned in his comments, we're trying to probe the dose response curve. We've gone high, low and somewhere in the middle. And I think that will give us a good sense of what we can achieve for protein reduction. And then with that, as we expand up the number of patients I think we'll get a better sense of exactly where we are. But David, if you have any other comments that you want to add, be my guest.

I think part of the way we're going to learn more is the randomized Phase II that's listed there. So we'll be looking at two doses and really have a robust decision about the dose before we go forward to pivotal studies.

Of course, our objective would be to eliminate all attacks and that's certainly what we're shooting for.

The next question comes from Dae Gon Ha with Stifel.

Let me add my congrats on this very robust set of data that you presented today. Maybe a question on the 50-milligram dose decision for HAE trial. I guess specifically, can you speak to sort of the modeling or the -- any other projection work as to why 50-milligram is something that you're trying to thread the needle here? And in that regard, is there anything you can speak to in terms of a thorough reduction of plasma kallikrein, since we're getting 65% and 92% with already robust attack rate reduction rates from the 65% what could potentially be a safety question that you have on, say, 80%, 90% durable reduction in kallikrein? And is there a way for you to, I guess, is there a reason for you to try and avoid that for the time being?

David, maybe you can say if you were how we think about the dose response curve?

Yes. So -- and I think back to TTR where we've just shown you that going to this intermediate dose of 0.7, we found that we could get the same level of reduction at a lower dose. And of course, that is the goal to give the lowest dose and given -- have the best possible result. You'll also see that these doses are site corresponding to what we saw at CTR, showing sort of the value of the modularity of the platform that we do believe both based on modeling and what we're seeing so far, that we could achieve similar reductions in kallikrein using the 50-milligram dose. Again, that would be desirable. Now of course, the first dose level in three patients, we eliminated all attacks. So you could say this play our success. However, we know from other experiences there can be breakthrough attacks when you get to 60% reduction, and we really want to get as best possible to try to achieve a complete reduction. Now on the safety question, we do know there are patients who have now for this gene for KLKB1, and those patients apparently live a normal life. And of course, we're not getting rid of it completely as those people do with that Berotralstat. So we do think this is quite safe from everything you know, both genetically and from our experience so far. And we'll -- so we will make a decision to go in probably a range greater than 60%, but we'll be obviously looking at the data carefully before making that decision.

The next question comes from Luca Issi with RBC.

Maybe a quick one on the TTR polyneuropathy. Obviously, you have this ALT elevation, which was Grade IV. Can you just give us some additional color on why it was adjudicated as Grade IV here?

David, that one is for you.

Sure. So Grade IV is having a greater than 20-fold times the upper limit of normal. So that's -- it's a high level. But you have to remember with a liver enzymes, it doesn't meet much in terms of the patient's effect on the patient. So a patient who has a normal bilirubin, a patient who in this case, of course, is asymptomatic as well. It's a biochemical event, but not something that adversely affected the patient in any long-term effect. It's just a transient increase. So that's what it means. I think it is possibly related, but we don't know that it's related to the drug. And of course, we'll be further exploring this with additional patients being treated in the trial. So far, we have now 32 patients in the trial. This is the only patient with a high elevation.

And of course, the additional patients from HAE. So this one patient is an outlier and as yet, we don't have an explanation for whether or not it's even related to the drug.

The next question comes from Joon Lee with Truist.

Congrats on the impressive data. You say that you have not seen any dose limiting tops, but isn't 1 milligram per kilo really the limit to LNP-based dosing? It seems like the 2 out of the 2 liver signals both came from the 1 milligram per kilo dose. And based on our conversations with experts in the field, the LNP may be the limiting factor here. And along this line, with this location, how do you plan to target nonliver organs. I mean Cas9 is a little big for AAV, as I understand it.

Well, there's really two questions in there. I think with respect to how we think about 1 mg per kg, it's not too many toxicities. We just talked about one patient we've seen, which we don't even know if it's truly related to the drug. What we're really seeing is flattening of the response curve whereas we move to 1 mg from 0.7, we're just not getting any incremental efficacy. So from that standpoint, we think the right decision and certainly conforms with FDA guidance to choose that dose that gives you the maximum effect of the lowest possible dose. And that's what we think we're doing. The second question about what is there after the liver? Well, we've reported earlier last year, some of our work with taking in vivo approaches with LNPs to go after the bone marrow, where I think there's exciting clinical data that indicates from a genetic point of view and a gene editing point of view, we've certainly shown that we can cure those patients. And I think that's exciting for CRISPR-based therapies in general. What remains to be addressed is the bone marrow transplant, which brings with it significant morbidity, mortality even and obviously, cost. And we think the correct final, definitive solution would be being able to treat those patients with an LNP-based in vivo approach that obviates the bone marrow transplant. Your comment about AAV. I think there's particular uses for AAV that relate, for example, to our insertion program with Alpha-1. So you'll see some utility there, but that's not to deliver Cas9 system. And as we take our platform forward, we'll look for the proper role of AAV, if any, as we explore other delivery approaches. So I'd stay tuned as we make headway in the various endeavors here.

The next question comes from Gena Wang with Barclays.

Also congrats on the great data on both data sets. So I have one quick clarification question and one very quick question for Dr. Gillmore. So first clarification question is on Slide 29, we do have a historical monthly attack rate and that's a 7.7 and 6.8. But on the Slide 32, you have 1.1, 7.2, 2.9. I know this is during the screening period or the other one is a historical monthly attack. Can you give a little bit more color on how long is the screening period for each patient and then compare that to the historical monthly attack and it were both based on protein therapy? And then a quick question for Dr. Gillmore, given the recent APOLLO-B data and you saw the 2001 data today so far, what could be the best Phase III trial design for 2001 in cardiomyopathy?

Maybe we could start with Julian. And if you want to speak to Gena's question, and then we'll turn to David, he can talk about the attack rates and how they're calculated. Dr. Gillmore?

Yes. Thank you for the question. So obviously, the APOLLO-B data is extraordinarily encouraging for TTR knockdown in amyloid cardiomyopathy. It was the first hard data showing clinical benefit with knockdown. Your question with respect to design of the best design of a Phase III trial at this stage, I think it's rather early to say that's in planning phase. And obviously, we need to cope the fact that we're seeing different patients to what were being seen at the time of attack, which was the trial testing tafamidis a TTR stabilizer some years ago. So this is going to have to be a Phase III trial with hard endpoints, including hospitalizations and mortality, but the precise design is -- and numbers, et cetera, is still being worked in opposite way.

Yes. Gena, I'd say that certainly, we take the input from Dr. Gillmore clearly, he's a world expert in the area and is well experienced in these sorts of trials. And as David said in his comments, we're think carefully about what would be the appropriate design to achieve all the necessary regulatory purposes that we're shooting for. Maybe we can turn to the other question. And David, do you want to say a word about how these attack rates are calculated?

Yes. So as you see in the swimmers plot slide, we did two things coming before the screen -- before the patients were screened, we wanted to make sure they had enough attacks to come on to the trial. So they did keep a diary or a refall diary of how many attacks they saw in that period. And that's where you see patient 1, about 2 attacks, patient 2, about 14 attacks, patient 3 about 2 attacks. Recall for patient 2 and 3, these are patients who are on prophylaxis, so they are breaking through their therapy to get these attacks. In the screening period, if you look further on the swim plot, there are actually variable amounts of recording with the goal of being at least one attack per month was really the goal in that screening period just before treatment. And there you see that, again, the patients had a different number, this is going to be variable over time. These were adjudicated very carefully by the investigator as part of the trial process. And all these things do affect that number, but clearly, these patients were suffering two of them despite having prophylaxis.

[Operator Instructions] The next question comes from Liisa Bayko with Evercore ISI.

Congrats on the data. I was curious is there anything about reducing kallikrein to levels into the like 80%, 90% range that would be concerning in any way? Or do you have pretty good safety with having low levels of kallikrein on a consistent basis?

One of the, I think, really very helpful aspects of this particular condition is that human -- knows exist where, in fact, they're completely devoid of the functioning protein. And there's a set of those individuals that come to attention for inadvertent reasons, not because of clinical consequences. And we know that as a group, they tend to be otherwise entirely healthy. So from the standpoint of reducing levels of kallikrein to the levels we've already achieved or even beyond we're quite confident that, that's not going to represent a safety issue for patients.

And just one other point is we're knocking out the kallikrein in the liver, but there is an important role for kallikrein in the tissues, and we don't touch that kallikrein that -- and kallikrein is not involved in angiodema. So we have a very good -- that's part of the safety profile, you're not knocking down all of kallikrein.

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

Congrats on the update. Maybe just a little follow-up on the attack rate reporting process. I guess, how consistent is that between patients. I could see that maybe pain and abdominal swelling could be a little bit more subjective and we can watch within the patient itself. But between patients, is there any variability and as you look to go to more patients and more regions, is there a way to standardize that, that can make you feel comfortable?

David, do you want to take it?

Yes. One thing we see here is the attacks going to zero. So for a patient who has this for years and years, they clearly are recognizing the fact that the attack is going to zero. So that's very reassuring. But your point is very important. When we go to regulatory studies, the placebo control helps control for the factor that you're thinking about, that we will very objectively, have some patients on treatment, some patients not getting treatment. They don't know what they've gotten. And with that, we will measure the difference between the placebo arm and the active arm.

The next question comes from Mani Foroohar with SVB Securities.

Congrats on the great data. A lot of nuances around efficact have been discussed. So I just want to clarify around this one, high-grade ALT elevation that's been discussed. Is it correct to believe that this was an isolated ALT elevation, without a bilirubin increase, no clinical sequelae and no other notable increases in other liver function tests, i.e., an isolated single increase in one enzyme and not a broader clinical picture? And would that characterization apply to the other lower-grade ALT elevations seen elsewhere?

David, do you want to take that?

Yes, go ahead. Yes. Like all ALT elevation, there is a corresponding. There's an increase in ASP. It's just part of what happens when you get elevations in the liver. And that the ratio is interesting. ALT is being greater than ASP is much more suggestive of the liver source, and that's what we're seeing for this patient. But that was the only -- nothing that was clinically significant to the patient, and that's a really important part. When hepatologists rate, the effect of liver enzyme changes, if there's no bilirubin change, it's really good that they're asymptomatic as well. It's considered a mild event.

The next question comes from Maury Raycroft with Jefferies.

I'll add my congrats on the data as well. I was wondering for the cardiomyopathy patients. Alnylam saw a rapid response on NT-proBNP levels post dosing. Can you comment on what you're seeing on BNP? And can you clarify -- the other question is, do you plan -- can you clarify if you plan on filing the U.S. NDA by the -- or the U.S. IND by the end of this year?

David, do you want to speak to when we'll have data...

Yes, we will have data on proBNP. It's a little too early in terms of the follow-up at this point, but we are very much looking forward to presenting that at a future upcoming meeting. In terms of the IND, we haven't given guidance to the IND. Part of that is developing, as we talked about a pivotal study that will be working worldwide. And we're working actively with that obviously, data coming out of other studies like APOLLO-B is helping us with that design process.

And we'll continue to collect patients in the ongoing study.

Yes. And we're continuing to treat patients to gain more information as well, of course.

The next question comes from Yanan Zhu with Wells Fargo Securities.

And congrats on the data. So on patient 2, for the NTLA-2002 25 mg cohort, is there anything to be learned about the correlation between the clinical finding of attack rate and the knockdown in terms of kinetics because all of a sudden, the patients stopped to have attacks after week 8. Is that correlated with the kallikrein levels?

David, maybe you could say a few words about the sort of gliding -- apparent gliding effect to what appears to be no attacks in that particular patient.

Yes. We don't completely understand why that happens. This is a patient who's having a tech every other day. So it's really probably a challenge for that patient even to interpret what's happening to themselves after being treated in some ways. But I think there's no strict correlation with kallikrein which was down quite a bit by day 28, and you did taper off completely by about 8 weeks.

Including stopping at prophylaxis.

Yes, stopping at prophylaxis. So some more to learn there, but I think the great result is that he has gone to 0 attacks.

I think it's probably true to say we don't think there's a strict threshold. We know from the preexisting work that when you get below 60% or beyond a 60% reduction in activity across a population of patients, you see pretty good efficacy. The real question is, can you get everybody as you go further beyond that? And what we've seen thus far with the levels of reduction is if that's the case, we're going to learn that because we've gotten to these very, very low levels of kallikrein, which I think is quite exciting.

The next question comes from Debjit Chattopadhyay with Guggenheim.

Congrats on the data. So just 2 quick ones from us. On the HAE program, what does the FDA want you to demonstrate before approving an IND? And then if I may with Dr. Gillmore, given the depth of the TTR knockdown that you see here versus the APOLLO-B study, meaningfully, how can any of these programs differentiate versus stabilizers within a clinically relevant 36-month window or alternatively, would you start looking at improvements and grade of TTR for a quick read?

Julian, maybe we can start with you. And if you didn't hear the question, it's like how can these significant results that we have differentiate with other drugs that have gotten some level of TTR reduction.

I mean I think what is very clear is that the current drugs have all been associated with ongoing progression, albeit slower progression than compared to patients on placebo. But what we really haven't seen is improvement in the disease. And in every other type of amyloid that has been treated when we knock down very, very deeply as it were, what we actually see is amyloid regression and clinical improvement. So I think that what we can hope for and what we can perhaps even expect is that some of these patients might actually improve and their disease actually improve, which is not something that we've seen with any other treatment so far. So it's extremely exciting.

And we would work in our clinical trial to demonstrate the benefits that come with these TTR reductions. And that's something we're actively thinking through with Dr. Gillmore and our other investigators as we try to test this hypothesis, which I think is well-supported by other areas of amyloid. So thank you, Dr. Gillmore. David, is there anything special about an IND for HAE?

Yes. No, we have a very clear idea of what the FDA wants based on our discussions with them. We don't need to include them in the Phase I, but it is our plan to include U.S. in the Phase II.

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

Congrats on the data. So how do these results impact your confidence in other types of edits beyond knockouts? What additional challenges would you expect there? And what do you think is necessary to derisk these other types of edits?

Well, thanks for that question because we look at this part as absolutely foundational for everything that we're doing. And what we are trying to do is learn the principles of how editing takes place within the cell. And we think we've gotten to the point here where this notion of modularity applies in that -- from the standpoint of knockouts, we're in a pretty good position here to anticipate likely results for other knockout programs just based on what we've already seen. You may recall some of the comments earlier today and things that we presented elsewhere that we're also looking to move from not just gene inactivation but to gene reconstruction or the insertion of genetic material. And this work is foundational to that. It all begins with taking an LNP, having the cargo, RNA, both mRNA and the guide RNA. That target a site specifically so that a transgene when provided is able to be introduced. And we present preclinical data very much along the lines and derivative of the work that we've done on that out to support that work that will be headed towards clinical testing potentially as early as next year, where we expect to begin the regulatory process for alpha-1 antitrypsin deficiency program. So now, we're also doing work in hemophilia with our colleagues at Regeneron, which we're quite excited about. But I think if you can step back further and say it really comes down to the inside of a given cell or the outside of a given cell. And what we're learning is that pretty much independent of the particular cell type once you're in that cell and you've worked out these rules, you have a good likelihood of understanding how things are going to behave. So this work, this clinical work, we think, extends directly to our bone marrow work and some of the other tissues that Laura's team is working on, as we work to address that other issue, which is reaching those tissues via delivery. And we're making headway there, and we'll continue to innovate with our own laboratories. And as we make progress, we'll share that with you in the appropriate scientific menus.

The next question comes from Swapnil Malekar with Piper Sandler.

And let me add my congrats on the data as well. So just one question with attacks, we feel like there are breakthrough attacks in the frequency of approximately 0.6 to 1.7 every 3 months. So do you think with 92% kallikrein introduction with 2002, you could get to 0 attack rate? Or would you still see some breakthrough attacks, just trying to understand like pathologically what do you expect to see there?

Well, we believe we can improve on what's out there. I think an important aspect to bear in mind with literally every other therapy that's out there is not only compliance, which is the behavioral aspect of a patient, but also even with perfect compliance, the pharmacokinetic variability of any age. And one of the think really important aspects of our work in this particular approach is that the variability within a patient is quite limited. There is no pharmacokinetic variability. And we think that's going to translate into opportunities to improve beyond the levels of reduction that we've achieved and importantly, address what is a significant treatment burden that all of these patients face.

Okay. The next question comes from Steve Seedhouse with Raymond James.

It's on the TTR program. I was wondering if you were planning to share the polyneuropathy clinical efficacy endpoints that you're collecting in those PN cohorts near term or you'd be willing to comment now on if you're seeing stabilization improvement across those clinical endpoints?

David, when are we going to have some clinical information?

Yes. These endpoints are taken, as you know, at the 9 to 12 months. 12 months at the first time. And the patients who are at the higher doses are actually, as you saw from our last update just reaching 12 months. But in the Part I, we only had the NIS score, not as robust as the mNIS+7 which we'll be using in the dose expansion part of that trial. So I think the most important information will come from the dose expansion. But what we do know, and it's coming from a data with patisiran is that the greater the reduction, the greater the benefit. And you'll see some new reports coming for us, that looks greater than proportional and as you go down in TTR, you actually get a greater than linear effect on improving neuropathy. So that's what we expect when we go -- that we may see in the Phase I data, of course, without a placebo control, that's hard to look at. But as we go to future trials, we do think we'll be able to demonstrate a greater benefit to the patients with neuropathy.

The next question comes from Raju Prasad with William Blair.

You may have mentioned this in your prepared remarks, but can you just give a commentary on the percent of wild-type cardiomyopathy patients in the trial? And then regarding the potential for reading these patients off prophylactic therapy, can you just remind us how long the attack rates need to be kind of reduced for you to take patients off prophylaxis?

David, maybe you can refer the particular slide?

So Slide 12 has the genotype, and 10 of the 12 patients that you heard about were wild-type patients. And this is maybe a typical ratio now in studies for patients with cardiomyopathy. On the...

There was when where you withdraw prophylaxis? I'm not sure we've mandated that in these studies that's been an investigator's decision.

Yes. We did at 16 weeks. I don't know if you're also asking how long they were on therapy. They were on therapy for years in these patients. So we felt they had a stable breakthrough rate at that point.

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

Great. Thanks so much, Drew, and thank you, everyone, for joining us today and for your continued interest and support of Intellia, and we look forward to updating you as we continue to progress. Have a great rest of your day and a great weekend. Bye now.

The conference has now concluded. Thank you. You may now disconnect your lines.