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. If you require operator assistance, please press star then zero. At this time, all participants are in a listen-only mode. 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 and 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 would 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 express or implied statements, and ask that you refer to our SEC filings available at sec.gov for 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 NTLA-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 Centre and physician at the Royal Free Hospital in the UK, and the National Coordinating Investigator for the clinical trial in the UK, 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-phase 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 Chief Executive Officer. 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're 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 and 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 the 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. 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. Julian Gillmore, a leading physician specializing in treatment of ATTR amyloidosis, to review the interim results. Dr. Julian Gillmore?
Thank you, John. Transthyretin amyloidosis, also known as ATTR amyloidosis, is a progressive and fatal disease. It's caused by the accumulation of amyloid deposits composed of misfolded transthyretin or TTR protein. Transthyretin amyloidosis may be acquired, known as wild type, or hereditary, known as variant or ATTRv. 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 people-500,000 people worldwide, but continues to be underdiagnosed. The clinical presentation is primarily with a cardiac phenotype. The amyloid deposits cause cardiomyopathy, resulting in heart failure with impaired diastolic and systolic function and conduction disorders.
Without treatment, amyloid deposits continue to accumulate in the heart, and the condition is fatal within three years to 10 years. Due to these factors, there's a high unmet medical need in ATTR amyloid cardiomyopathy. Progressive heart failure leads to impaired quality of life, considerable morbidity, and is universally fatal. The current standard of care treatment only slows disease progression, requires lifelong administration. 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 ever 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, amyloid 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 a 100% knockdown. Please see this graph showing the relationship between patient survival and degree of knockdown. 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 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 halt and potentially reverse this disease. Are the conviction behind my involvement with this study. NTLA-2001 is being studied as a two-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 one in the cardiomyopathy arm. Patients enrolled have either hereditary or wild type ATTR amyloidosis with cardiomyopathy and an NYHA classification between one and three.
Part 1 is a single ascending dose design with a minimum of three patients in each cohort of NYHA class I/class II administered 0.7 mg/ /kg, NYHA class III administered 0.7 mg/kg and NYHA class 1/class II administered 1.0 mg/kg. Based on safety and PD profile at 0.7 mg/kg, further dose escalation to 1.0 mg/kg in NYHA 3, class III patients was not undertaken. Part 2 entails administration of the dose selected from phase I data. The primary objective of this first-in-human study are to evaluate safety, tolerability, PK, and PD, the latter by serial measurement of serum TTR levels. I will report data on all 12 patients enrolled in the three cohorts included in part 1. This table summarizes the demographics of the 12 study participants.
Median age was 75 years, with range 68 years-86 years. All participants were male and had a median weight of 85 kg, with a range 63 kg-106 kg. 10 of the 12 patients were wild type. 50% of patients had NYHA class III heart failure, with another 42% being NYHA class II. The median NT-proBNP was around 2,000-2,400 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 two patients. Three 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 remain on study. A single Grade 3 infusion-related reaction was reported at the 0.7 mg/kg dose in an NYHA Class III patient and resolved without any clinical sequelae. The NYHA Class III 0.7 mg/kg cohort was expanded per protocol to six patients to further characterize safety and PD. No additional patients in this cohort reported treatment-related AE higher than grade 1. No clinically significant laboratory findings were observed. This table summarizes the most common adverse events occurring in more than 2 patients. These adverse events were predominantly transient, reversible, and most frequently grade 1. No clinically significant laboratory findings were observed. Transient grade 1 liver enzyme excursions were not considered clinically significant and resolved in all patients. The next two slides summarize the pharmacodynamic effects from part 1 of this first-in-human study.
The first figure depicts the mean TTR reduction from baseline at 28 days post-treatment for each of the three cohorts. Mean reductions in serum TTR were greater than 90% across all cohorts at day 28. Notably, these reductions were highly consistent across patients in both dose cohorts and in patients with either 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 mg/kg cohort have now reached six months of follow-up, achieving a consistent, sustained response with a mean 93% reduction.
In the NYHA Class III 0.7 mg/kg and NYHA Class I, II 1.0 mg/kg cohorts, mean reductions of 94% and 92% respectively can be observed at two 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 mg/kg doses. Mean TTR reduction of greater than 90% was observed across both doses by day 28 and sustained to last follow-up at between two months and six months. NTLA-2001 was 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 early 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 the cardiomyopathy and polyneuropathy arm of the study, we have filed a protocol amendment to evaluate a fixed dose equivalent of 0.7 mgs /kg 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 two doses tested. Second, the comparability of performance at the 0.7 mg and 1.0 mg/kg doses in the dose escalation portion of the polyneuropathy arm.
Third, while 21 has generally been well-tolerated, as previously reported, there was a patient who had a significant elevation in liver enzymes at the 1.0 mg/kg 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 amendments. We are also actively designing what we hope to be a future global pivotal trial.
With our review of the NTLA-2001 data now complete, I am delighted to provide a summary of the interim data from our second in vivo genome editing candidate, NTLA-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 data validate the modularity of Intellia's industry-leading genome editing platform and its potential to target a multitude of genetic diseases. Finally, we're 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 in that it's 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 1 in 50,000 people. Current treatment options often include 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 chronic 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/phase II study is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2002 in adults with type 1 HAE or type 2 HAE. The phase I portion of the 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 six initial patients in the ongoing dose escalation study. Single doses of 25 mg and 75 mg 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 pre-specified 16-week primary observation period. To date, all three patients in the 25 mg cohort have reached the end of this initial observation period. Patients in the 75 mg 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 a 50 mg dose. We expect to report interim findings 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 were required to have at least three 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 years. 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, NTLA-2002 was 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 1 and resolved within 1 day. There have been no dose-limiting toxicities, no serious adverse events, and no adverse events of grade 3 or higher observed to date.
In addition, no clinically significant laboratory abnormalities were observed, including any significant elevation in liver enzymes. 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 NTLA-2002 resulted in rapid dose-dependent reductions in plasma kallikrein and achieved maximum reductions by week eight, with mean reductions of 65% and 92% respectively among the three patients in each cohort. The dotted line at the 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 needs. Patient number one is a 30-year-old male who was diagnosed with HAE type 2, has a family history of the disease. Prior to enrollment, his HAE attacks were typically moderate in severity. Patient number two is a 52-year-old male diagnosed with HAE type 1, who also has a family history of the disease.
Like many HAE patients, he 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 number three, a 26-year-old male diagnosed with HAE type one, 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 three patients in the 25 mg cohort who have 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 attacks-7.2 attacks per month. A single 25 mg 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's plot of the three patients in the 25 mg cohort. The colored lines indicate any HAE attacks that occurred in either the screening period or in the subsequent observation period following administration with 2002.
Across all these patients, we now have attack data compiled through a range of weeks 24 through 32 weeks, making these results particularly robust. As you can see, the colored lines dramatically decrease after administration of 2002. You'll see that the second patient, who had the most frequent number of attacks prior to administration, is now also attack-free since week 10. One additional noteworthy detail that I'd like to highlight. Recall that the study allows for patients to continue their concomitant prophylactic therapy. The protocol then allows for investigators to withdraw this therapy if deemed appropriate after the initial 16-week period. In this cohort, there were two patients receiving prophylactic therapy, yet still having breakthrough attacks. One was on danazol and the other berotralstat. Both patients had those therapies withdrawn after week 16, and notably continued to remain attack-free through the latest follow-up available.
Finally, since patients in the 75 mg cohort 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 & Immunology Annual Scientific Meeting. We are heartened by these promising early data, which we believe support NTLA-2002's potential to address the significant treatment burden faced by patients living with HAE. These data reinforce our belief that NTLA-2002 holds a possibility for permanently preventing the debilitating swelling 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. With that, I'll turn the call back to John for closing remarks.
Thank you, David. 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, 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 the debilitating swelling attacks with a single dose treatment.
As we highlighted today, we're already beginning to see in the first three 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 hemophilia 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. We believe this is just the beginning for Intellia. These results from NTLA-2002, coupled with NTLA-2001's, demonstrate 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 remain 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.
We will now begin the question-and-answer session. To ask a question, you may press star then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you'd like to withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Good morning. Thanks for taking my question, 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. You know, 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 you know, 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'll give us a good sense of what we can achieve for protein reduction. With that, you know, as we expand the number of patients, I think we'll get a better sense of exactly where we are.
David, if you have any other comments that you want to add, be my guest.
I think part of the way we're gonna learn more is the randomized phase II that's listed there. 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.
Thank you.
The next question comes from Dae Gon Ha with Stifel. Please go ahead.
Yeah, great. Thank you very much for taking our questions, and let me add my congrats on this very robust sets of data that you presented today. Maybe a question on the 50-mg dose decision for the HAE trial. I guess specifically, can you speak to sort of the modeling or any other projection work as to why 50- mg 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 the target 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?
I guess, is there a reason for you to try and avoid that for the time being? Thanks.
David, maybe you could say a few words about how we think about the dose-response curve.
Yeah. Think back to TTR, where we've just shown you that, going to this intermediate dose of 0.7 mg, we found that we could get the same level of reduction at a lower dose. Of course, that is the goal, to get the lowest dose and getting the best possible result. You'll also see that these doses are quite corresponding to what we saw with TTR, 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 mg dose. Again, that would be desirable. Now, of course, the first dose level in three patients, we've eliminated all attacks, so you could say, you know, this could declare a 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 or null for this gene, for KLKB1, and those patients apparently live a normal life. Of course, we're not getting rid of it completely as those people do with that Fletcher trait. We do think this is quite safe from everything we know both genetically and from our experience so far. 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.
Sounds good. I'll hop back to you. Thank you.
The next question comes from Luca Issi with RBC. Please go ahead.
Oh, great. Thanks so much for taking my question. Maybe a quick one on the TTR polyneuropathy. Obviously, you have this ALT elevation, which was grade four. Can you just give us some additional color on why it was adjudicated as grade four here? Thanks so much.
David, that one's for you.
Sure. Grade four is having a greater than 20x the upper limit of normal. That's a high level, but you have to remember with a liver enzyme, it doesn't mean much in terms of the patient's effect on the patient. 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. That's what it means. Whether it is possibly related, but we don't know that it's related to the drug. Of course, we'll be further exploring this with additional patients being treated in the trial. So far, you know, we have now 32 patients in the trial.
This is the only patient with this, with a high elevation.
Of course, the additional patients from HE. 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.
Thanks so much. Hop back in the queue. Thanks so much.
The next question comes from Joon Lee with Truist. Please go ahead.
Hey, thanks for taking our questions and congrats on the impressive data. You say that, you have not seen any dose-limiting tox, but isn't 1 mg per kilo really the limit to LNP-based dosing? Seems like the 2 out of the 2 liver signals both came from the 1 mg per kilo dose. Based on our conversations with experts in the field, the LNP may be the limiting factor here. You know, along this line, with this limitation, how do you plan to target non-liver organs? I mean, Cas9 is a little big for AAV, as I understand it. Thank you.
Well, there's really two questions in there. I think with respect to how we think about 1 mg per kg, it's, there's not those limiting toxicities. We just talked about, you know, the 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, you know, flattening of the response curve, whereas we move to 1 mg from 0.7 mg, we're just not getting any incremental efficacy. From that standpoint, we think the right decision and certainly conforms with FDA guidance to choose that dose that gives you know, the maximal 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 re-reported earlier last year some of our work with taking in vivo approaches with LNPs to go after the bone marrow, where I think, you know, 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. But what remains to be addressed is the bone marrow transplant, which brings with it significant morbidity, mortality even, and obviously cost. 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, you know, I think there's particular uses for AAV that relate, for example, to our insertion program with alpha-1, and so you'll see some utility there, but that's not to deliver a Cas9 system. As we take our platform forward, we'll look for the proper role of AAV, if any, as we explore other delivery approaches. I'd stay tuned as we make headway in the various endeavors here.
Thank you.
The next question comes from Gena Wang with Barclays. Please go ahead.
Thank you for taking my questions. Also congrats on the great data on both datasets. I have one quick clarification question and one very quick question for Dr. Julian Gillmore. First clarification question is.
On Slide 29, we do have a historical monthly attack rate, and that's a 6.7 attack rate and 6.8 attack rate. On Slide 32, you have a 1.1 attack rate, 7.22.9 attack rate. I know this is during the screening period. 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? Compare that to the historical monthly attack, and they were both based on prophy therapy. Then a quick question for Dr. Gilmore. 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, if you wanna speak to Gena's question, and then we'll turn to David, and he can talk about the attack rates and how they're calculated. Dr. Gillmore?
Yeah. Thank you for the question. You know, 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. Obviously we need to take the fact that we're seeing different patients to what were being seen at the time of ATTR-ACT, which was the trial testing tafamidis, a TTR stabilizer some years ago. This is going to have to be a phase III trial with hard endpoints, including hospitalizations and mortality. The precise design is.
Numbers, et cetera, is still, you know, in being worked out, as it were.
Yeah. Gena, I'd say that certainly, we take the input from Dr. Gilmore, as clearly he's, you know, a world expert in the area and is well experienced in these sorts of trials. As David said in his comments, we're thinking 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. David, you wanna say a word about how these attack rates are calculated?
Yeah. As you see in the swim plot slide, we did two things. Prior to screening, before the patients were screened, we wanted to make sure they had enough attacks to come onto the trial. They did keep a diary or a paper diary of how many attacks they saw in that period. That's where you see patient one about two attacks, patient two about 14 attacks, patient three about two attacks. Recall for patient two and patient 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 plots, 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. There you see that again, the patients had a different number. You know, this is gonna be variable over time. These were adjudicated very carefully by the investigators, part of the trial process. All these things do affect that number. Clearly these patients were suffering two of them despite having prophylaxis.
In the interest of time, please limit yourself to one question to help us get to as many questioners as possible. The next questioner comes from Liisa Bayko with Evercore ISI. Please go ahead.
Hi. Congrats on the data, and thanks for taking my question. I was curious, is there anything about reducing kallikrein, you know, to levels, you know, 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 nulls exist, where in fact they're completely devoid of the functioning protein. You know, there's a set of those individuals that come to attention for you know, inadvertent reasons, not because of clinical consequences. We know that, as a group, they tend to be otherwise entirely healthy. From the standpoint of reducing levels of kallikrein to you know, the levels we've already achieved or even beyond, we're quite confident that that's not gonna represent a safety issue for patients.
Just one other point is, you know, we're knocking out the kallikrein in the liver, but there is an important role for kallikrein in the tissues. We don't touch that kallikrein. In that, kallikrein luckily is not involved in angioedema. We have a very good as part of the safety profile, like you're not knocking down all of kallikrein.
Perfect. That was my next question, so I'm all done. Thanks a lot, guys.
Thanks.
Thanks, Liisa. The next question comes from Joseph Thome, excuse me, of TD Cowen. Please go ahead.
Hi there. Good morning. Thank you for taking my question, and congrats on the update. Maybe just a little to 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 can 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 in more regions, is there a way to standardize that can make you feel comfortable? Thank you.
David, do you wanna take that?
You know, the one thing we see here is the attacks going to zero. For a patient who has this for years and years, they clearly are recognizing the fact that the attacks going to zero. That's very reassuring. 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, you know, very objectively have some patients on treatment, some patients not getting treatment. They don't know what they've gotten. With that, we will measure the difference between the placebo arm and the active arm.
Okay, perfect. Thank you very much.
The next question comes from Mani Foroohar with SVB Securities. Please go ahead.
Thanks for taking the question, and congrats on the great data. A lot of nuances around efficacy have been discussed, so I just wanna clarify around this one high-grade ALT elevation that's been discussed. Is it correct to believe that this was an isolated ALT elevation that was not 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 Lebwohl, do you wanna take that?
Yeah, go ahead. Yeah, like all ALT elevation, there is a corresponding increase in AST. It's just part of what happens when you get elevations in the liver. That, you know, the ratio is interesting. ALT is being greater than AST is much more suggestive of a liver source, and that's what we're seeing for this patient. That was the only, you know, nothing that was clinically significant to the patient, and that's the 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.
Great. Thanks for that clarification.
The next question comes from Maury Raycroft with Jefferies. Please go ahead.
Hi. Good morning. 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 if you plan on filing the US NDA by the, or the US IND by the end of this year?
David, do you wanna speak to when we'll have data to?
Yeah, we will have data on NT-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.
We'll continue.
Got it. Got it.
To collect patients in the ongoing study.
Oh, yeah, we're continuing to treat patients to get more information as well, of course. Yeah.
Got it. Okay, thanks for taking my questions.
The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.
Hi, thanks, for taking my questions and congrats on the data. On patient two, 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 the kinetics? 'Cause all of a sudden the patient stopped to have attacks after week 8. Is that correlated with the PK, the kallikrein levels? Thanks.
David, maybe you could say a few words about the sort of apparent gliding effect to what appears to be no attacks in that particular patient.
Yeah. We, you know, don't completely understand why that happens. You know, this is a patient who's having attacks every other day, so it's really probably a challenge for that patient even to interpret what's happening to himself, you know, after being treated in some ways. I think, there's no strict correlation with kallikrein, which was down quite a bit by day 28, and he did taper off completely by about, you know, 8 weeks.
Including stopping his.
Yeah.
Prophylaxis.
Yeah. True. Stopping his prophylaxis. More to learn there, but I think, you know, the great result is that he has gone to zero attacks.
I think it's probably true to say we don't think there's a strict threshold. You know, we know from the pre-existing work that, you know, you when you get below 60%, or beyond a 60% reduction in activity, you across a population of patients, you see pretty good efficacy. The real question is. Can you get everybody, as you go further beyond that? What we've seen thus far with the levels of reduction is, you know, if that's the case, we're gonna learn that, because, you know, we've gotten to these very low levels of kallikrein, which I think is quite exciting.
Thanks. Very helpful.
The next question comes from Debjit Chattopadhyay with Guggenheim. Please go ahead.
Hey, good morning, and congrats on the data. Just two 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 in grade of TTR for a quick read? Thanks so much.
Julian Gillmore, maybe we can start with you. 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 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. What we really haven't seen is improvement in the disease. You know, in every other type of amyloid that has been treated, when we knock down you know very very deeply, as it were, what we actually see is amyloid regression and clinical improvement. 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. It's extremely exciting.
We would work in our clinical trial to demonstrate the, you know, 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, you know, test this hypothesis, which I think is well supported by other areas of amyloid. Thank you, Dr. Gillmore. David, is there anything special about an IND for HAE?
Yeah, 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 the U.S. in the phase II.
The next question comes from Greg Harrison with Bank of America. Please go ahead.
Hey, good morning. Congrats on the data. Thanks for taking our question. 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 de-risk these other types of edits?
Well, thanks for that question. Because we look at this work as absolutely foundational for everything that we're doing. What we are trying to do is learn the principles of how editing takes place within a cell. 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, you know, gene reconstruction or the insertion of genetic material. This work is foundational to that.
It all begins with taking an LNP, having, you know, 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. We present preclinical data, very much along the lines and derivative of the work that we've done on knockout 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. You know, we're also doing work in hemophilia with our colleagues at Regeneron, which we're quite excited about.
I think if you can step back further and say it really comes down to, you know, 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 gonna behave. 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. We're making headway there, and we'll continue to innovate with our own laboratories. As we make progress, we'll share that with you in the appropriate scientific venues.
Great. Thanks again for taking the question, and congrats again on the data.
Thank you.
The next question comes from Swapnil Malekar with Piper Sandler. Please go ahead.
Hey, thanks for taking my question, and let me add my congrats on the data as well. Just one question, with TAKHZYRO, we see like there are breakthrough attacks in the frequency of approximately 0.6 attack rate-1.7 attack rate every three months. Do you think, with 92% kallikrein reduction with NTLA-2002, you could get to zero attack rate, or would you still see some breakthrough attacks? Just trying to understand, like, pathophysiologically, 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 agent. One of the, I think, really important aspects of our work in this particular approach is that the variability within a patient.
Excuse me, Dr. Leonard. Go ahead.
The variability within a patient is quite limited. There is no pharmacokinetic variability, and we think that's gonna 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. Please go ahead.
Good morning. Thanks for taking the question. 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 if you'd be willing to comment now on if you're seeing stabilization or improvement across those clinical endpoints. Thank you.
David, when are we gonna have some clinical information?
These endpoints are taken, as you know, at the nine months to 12 months. 12 months is the first time. The patients who are at the higher doses are actually, as you saw from our last update, just reaching 12 months. In part one, 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. I think the most important information will come from the dose expansion. What we do know, and it's you know, coming from data with patisiran, is that the greater the reduction, the greater the benefit. You'll see some new reports coming from us that looks greater than proportional.
That as you go down in TTR, you actually get a greater than linear effect on improving, neuropathy. That's what we expect when we go, you know, that we may see in the phase I data. Of course, without a placebo control that's hard to look at. 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. Please go ahead.
Thanks for taking the question. 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? Regarding the potential for weaning 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? Thank you.
David, maybe you can refer, Raju to a particular slide.
Slide 12, it has the genotypes. 10 patients of the 12 patients that you heard about were wild-type patients. This is maybe a typical ratio now in studies for patients with cardiomyopathy. On the second one.
Quick. When would you withdraw prophylaxis? I'm not sure we've mandated that in these studies. That's been an investigator's decision.
Yeah. We did it 16 weeks. I don't know if you're also asking how long they were on therapy. They were on therapy for years, these patients. 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. Thank you everyone for joining us today and for your continued interest and support in 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 line.