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

Good morning, and welcome to the Intellia Therapeutics Investor Event. My name is Alan and I will be your conference operator today. Please be advised that this call is being recorded at the company's request. [Operator Instructions] I will now turn the conference over to Lina Li, Senior Director of Investor Relations and Corporate Communications at Intellia. Please proceed.

Thank you, operator, and good morning, everyone. I'm pleased to welcome you to Intellia's conference call to discuss the results from the NTLA-2002 Phase II study. Earlier today, Intellia issued a press release detailing these data which were published in the New England Journal of Medicine and will be presented at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting or ACAAI. This release, along with the accompanying presentation and slides from today's webcast, can be found in 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. Before we get started, I would like to take a minute to remind listeners that during this call, Intellia Management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for discussions of potential risks and uncertainties. All information presented on this call is current as of today and Intellia undertakes no duty to update this information unless required by law. Please note that NTLA-2002 has not been approved by any health authority. Joining me on today's webcast are Dr. John Leonard, our Chief Executive Officer; Dr. David Lebwohl, our Chief Medical Officer; and Dr. Danny Cohn, Internist in the Department of Vascular Medicine at Amsterdam University Medical Center and the lead principal investigator of our NTLA-2002 Phase II trial. Also on the call and available For Q&A are Dr. Paula Busse, Professor of Medicine in Clinical Immunology at the Icahn School of Medicine at Mount Sinai; and Dr. Jim Butler, our General Manager of the NTLA-2002 program. As outlined on this slide, we will begin with introductory remarks From John. Then Dr. Cohn will review the NTLA-2002 Phase II data, followed by David, who will provide an update on our Hereditary Angioedema program, including a review of the recently initiated Phase III study before opening the call for questions. With that, I'll now turn the call over to John.

Thank you, Lina. Welcome, everyone, and thank you for joining the call today. At Intellia, a relentless focus on advancing our proprietary CRISPR-based gene editing platform and clinical execution has positioned us at the forefront of a new era in medicine. With 3 active Phase III studies expected by year-end, we are on track to bring forth the world's first ever in vivo CRISPR therapies to patients. Back in August, we shared positive top line results from the Phase II study of NTLA-2002. Today, we will be reviewing the full data set that we believe clearly demonstrates NTLA-2002's potential to be a functional cure by eliminating HAE attacks after one-time treatment and removing the need for further treatment. With this potential product profile, NTLA-2002 could represent a total paradigm shift for how HAE is treated, addressing the desire of patients to live a life free from attacks and the ongoing treatment burden of chronic therapies. Before Dr. Cohn reviews these data in greater detail, I want to take a moment to reflect on the key learnings from the Phase II study. Both a single 25-milligram and 50-milligram dose led to deep reductions in attacks. The safety and tolerability profile observed continued to be highly encouraging and was consistent with its Phase I profile. As we anticipated, the 50-milligram dose led to a greater response compared to the 25-milligram dose across all measures of efficacy. An impressive 8 out of 11 patients achieved a complete elimination of attacks, an unprecedented result for this disease after one-time treatment. Overall, it's clear when looking at the totality of Phase I/II data that the 50-milligram dose is the optimal dose to advance into the Phase III study. As previously announced, we recently initiated HAELO, the global pivotal Phase III trial and expect to submit a BLA in 2026. We are full steam ahead in our efforts to bring what could be the world's first approved in vivo CRISPR gene editing treatment and a truly transformative one-time treatment for people living with HAE. With that, I am honored to turn the call over to Dr. Cohn, our lead principal investigator for the Phase II study and a global leader in the research, diagnosis and treatment of HAE.

Thank you, John, and good morning, everyone. Here are my disclosures. Hereditary angioedema, or HAE, is a rare, genetic disease leading to frequent, severe and unpredictable swelling attacks. NTLA-2002 is an investigational therapy designed to selectively target the KLKB1 gene with the goal of lifelong control of hereditary angioedema attacks after a single dose. Today I will share results from the Phase II portion of the first-in-human study. The primary efficacy endpoint was the number of angioedema attacks per month during the 16-week primary observation period. Key secondary endpoints included safety, the number of angioedema attacks per month during weeks 5 to 16 and the change from baseline in the total plasma kallikrein protein level. Before I walk through the results, we thought it would be helpful to highlight the key differences in trial dynamics between the Phase I and Phase II portions of the study. For the Phase I, this was a small open-label study with the goal of evaluating safety, tolerability as well as initial efficacy. Concurrent use of other long-term prophylaxis was allowed and because there was no placebo-control, attack reduction was measured relative to patient's baseline. In contrast, the Phase II was a double-blinded, randomized, placebo-controlled study which enrolled a total of 27 patients. One notable difference was patients were required to wash out their chronic prophylaxis therapy prior to receiving NTLA-2002 or placebo. Following the 16-week primary observation period, patients were then allowed to resume prior therapy at the discretion of the investigator. Patients randomized to placebo are now being offered the option to receive 2002. The second key difference was the attack rate calculation. Unlike the Phase I study where the rate reduction is relative to each patient's baseline rate, the Phase II attack rate reduction is the difference in attack rate between patients who received NTLA-2002 and those who received the placebo. The objective of Phase II was to further study the efficacy and safety of the 25- and 50-milligram doses and determine which dose to move forward into the pivotal Phase III trial. The Data cutoff date for this update is April 4, 2024 when 25 out of 27 participants completed the 16-week primary observation period. Here, you can see the patient demographics, which include both male and female patients across a wide range of ages from 18 to 76 years old. The enrolled patients had a range of baseline disease severity that is representative of the broader patient population. 17 of the 27 patients were previously on long-term prophylaxis therapies. Notably, 5 patients washed out of lanadelumab to enroll in the Phase II study and 4 patients washed out of berotralstat. The mean baseline monthly attack rate was 3.6 in both the 25- and 50-milligram arms and 3.7 in the placebo arm. Starting with safety, we are very pleased to share that NTLA-2002 continued to be well tolerated. The most frequent adverse events were headache, fatigue and nasopharyngitis. There have been no serious adverse events and all adverse events were either Grade 1 or 2. There were also no clinically significant laboratory findings observed. Moving on to the first measurement of activity, kallikrein reduction, a single administration led to dose-dependent and durable reductions from baseline measures of plasma kallikrein. The dotted line at the 60% mark on this slide represents our minimum target level of kallikrein inhibition based on the leading approved chronic HAE therapy. While this level often results in clinically meaningful reductions in attacks, many patients on current treatments continue to experience breakthrough attacks and all must contend with significant treatment burden. As shown here, the 50-milligram dose exceeded this target protein reduction, resulting in a mean plasma kallikrein protein reduction of 86% at week 16. Importantly, the deep reductions were sustained through the latest follow up and highly consistent across all patients treated, as indicated by the very narrow arrow bars seen on this graph. Turning now to the attack rate reductions, a single 25- or 50-milligram dose of NTLA-2002 led to deep reductions in attacks for patients with hereditary angioedema. The mean monthly attack rates relative to placebo were reduced by 75% and 77% for the 25- and 50-milligram arms during weeks 1 to 16 and by 80% and 81% during weeks 5 to 16, respectively. NTLA-2002 led to reduced levels of attack rate reduction at both doses, with the 50-milligram once again outperforming the 25-milligram dose. Similar to the Phase I study, we expect these attack rate reduction percentages will continue to increase with longer follow up. Next, let's look at the patient by patient view. Here you can see HAE attacks for each patient during screening, primary observation and the post primary observation periods through the latest follow up. The colored lines indicate any HAE attacks that occurred in either the screening period or in the subsequent observation period following administration with NTLA-2002. Each line portrays the incidence, duration and severity of attacks experienced by the respective patient. On the left you see the attack rate reduction from a patient's baseline during weeks 1 to 16. On the right you see the change in plasma kallikrein through the latest follow up. Now let's zoom in on the patients who received the 50-milligram dose. As you can see, 10 of the 11 patients achieved a clinically meaningful reduction in attacks during the primary observation period. Remarkably, and the key differentiator for NTLA-2002, 8 of the 11 patients ceased to have any attacks after receiving 2002 despite a mean attack rate of 3.6 attacks per month prior to treatment. All 8 patients continued to be free of all attacks through the latest follow up and did not require any further treatment. Further, only 11 patients in the 50-milligram cohort achieved clinically meaningful reductions in attacks in the post primary observation period. The 3 patients who did not achieve a complete response in the 50-milligram arm reported frequent breakthrough attacks prior to enrolling in the study and while taking other standard of care prophylactic therapies including Berotralstat, Cinryze and Lanadelumab. While these patients did experience a clinically meaningful benefit from NTLA-2002, it is unclear at this time why these 3 patients did not have a complete absence of attacks or if these patients will ultimately achieve complete attack control after a longer period of time as we observed in the Phase I portion of the study. Given the absence of a biomarker to confirm that symptoms experienced by participants are all true angioedema attacks, we rely on patients reporting their symptoms and use of acute treatments. Notably, patients may take some symptoms for early signs of an internal angioedema attack, such as throat irritation or abdominal discomfort, which may or may not be angioedema attacks. In the 25-milligram arm, we saw 4 of the 10 patients or 40% of patients experienced a complete response. In the 50-milligram arm, 8 of 11 patients or 73% of patients experienced a complete response with no attacks at all during the 16-week period and beyond and no subsequent treatment required after a single dose of 2002. This high complete response rate led to the selection of the 50-milligram dose level for further investigation in Phase III. In summary, results of the Phase II study continue to demonstrate that a single dose of NTLA-2002 has the potential to be a functional cure for patients with HAE. We are proud to have our groundbreaking clinical data published in the New England Journal of Medicine, which is now available online. Finally, I would like to thank the patients.

Thank you, Dr. Cohn. We appreciate your leadership on this trial and your conviction in the potential of 2002 to be a transformative treatment for patients with HAE. As Dr. Cohn mentioned, we have selected the 50-milligram dose to advance into the global Phase III trial. The 50-milligram dose led to greater kallikrein reduction and importantly, a higher number of patients who achieved complete elimination of attacks compared to the 25-milligram dose cohort consistent with prior Phase I results. In our view, these results speak directly to the strong potential of 2002 to reset the standard of care for HAE. We have now advanced 2002 into the final stage of clinical development where we hope to further demonstrate what we've observed in the Phase I/II study. We are actively screening patients in the HAELO pivotal trial, a global, randomized, double-blind, placebo controlled study. 60 patients will be randomized 2 to 1 to receive a single 50-milligram infusion of 2002 or placebo. Patients randomized to the placebo arm will be eligible for optional crossover to 2002 at week 28. The primary endpoint is the number of HAE attacks from week 5 through 28. A key secondary endpoint will be the percent of patients who achieve attack free status during the same time period. Importantly, the data from the primary analysis will support our planned BLA submission in 2026. Ultimately, our goal for 2002 is to functionally cure people with HAE. As such, we're evaluating complete responder status in the Phase III trial, that is a treatment outcome in which patients are both free from attacks and untethered from requirements of chronic therapy following our one-time treatment. Looking ahead, we believe that if approved, there will be a strong demand for 2002. We recently conducted market research to get a better understanding of how 2002 could fit into the treatment landscape and the results were loud and clear. Despite available treatments, HAE patients are seeking improved efficacy and convenience. In a survey with patients and caregivers, there were 3 key themes reported. First, many patients continue to have attacks even when taking existing therapies and therefore are seeking a further reduction in the frequency of their HAE attacks. Second, patients expressed a strong desire for treatments that are less burdensome, offer more freedom and ultimately a better daily life. Third, access related challenges such as health insurance renewals, delays and denials of chronic treatments have a significant negative impact on the quality of life for HAE patients. Across all 3 of these factors, we believe 2002 has the opportunity to reset the treatment paradigm for people living with HAE. What was previously an unimaginable potential to be free of chronic therapy and free of attacks is one step closer to becoming a reality for the HAE community. In both the patient and physician surveys, there was high interest for 2002's product profile. In a survey of over 190 physicians who treat HAE patients, we found that over 75% of these U.S. prescribers would offer a product with 2002's target profile to all patients within 3 years of launch. And over time, we anticipate this percentage will continue to grow. For HAE patients who are typically diagnosed in their adolescence, they must contend with many decades of treatments. Their current options are limited to chronic, long-term prophylaxis treatments, either regular IV infusions or injections or a daily pill in exchange for lower efficacy or on demand therapies once an attack has already begun. As such, patients need to plan their lives around the limitations of existing treatment options. When you walk in the shoes of a patient, we believe the option of a one-time treatment that could eliminate all attacks will be a compelling choice. We are now focused on rapidly enrolling the Phase III study, which we believe will demonstrate what we've seen thus far. 2002 can be a one-time treatment that offers the potential of a complete response for people living with HAE. We are grateful to the patients and their families who participated in our clinical study and thank our investigators and Intellia colleagues for their continued efforts to advance 2002 to patients. With that, we'd be happy to answer any questions. In addition to Dr. Cohn, we are pleased to have Dr. Busse here with us today to share her insights as an expert physician in the HAE space. Operator, you may now open the call for Q&A.

[Operator Instructions] Our first question comes from Luca Issi of RBC.

Congrats on the data. I have a quick one. Maybe, David, how should we think about the data today versus the last time that it was presented? I think the European Academy of Allergy, which was just a few weeks ago, I think you showed reduction attacks in the low 90s versus today you're showing reduction attack, I think in the low 80s or even upper 70s. What's the best way to rationalize why those numbers have come down just in a few weeks? Any thoughts there, much appreciated?

[Technical Difficulty] that the patients in Phase I were compared to their baseline rates while in [Technical Difficulty] arm changes in the placebo arm rates.

David, can you just repeat that? I think you were -- there was a little bit of audio cutoff there.

Okay. Thanks, Luca. Yes, to talk about some of the difference which Dr. Cohn started to talk about is that in the Phase I, patients being compared to their baseline rate, while in Phase II, they're being compared to the placebo. So this comes out differently. The patients in Phase I came in were able to be on prophylaxis, while in the case of the other study of the Phase II, we did withdraw the prophylaxis prior to the patients coming on to the study. And part of being on a placebo-controlled trial is the patients don't know that they received the therapy. And in fact, in the data you've seen, they haven't -- they haven't at all been informed about what's going on. What we saw in the Phase I and the reason -- one big reason it went to the higher, somewhat higher numbers, is that the numbers of attacks went down over time as the patients realized that some of the things they were experiencing were not, maybe not HAE attacks. And Dr. Cohn mentioned some things like throat irritation would sometimes be interpreted as an attack. And the patients were taught to immediately treat those before they even knew fully that it was an attack. And that's very smart for patients, but it does make it more difficult to interpret these attacks.

Maybe one other thought to add would be with the 98% reduction that was with very extended follow-up. So the denominator of time grew is we expect this pattern to play out again with this study as well as we've seen all of the patients with continued follow-up to continue to have attack reductions.

That's right. The most exciting thing about the data is the number of patients who had no attacks. 8 out of the 11 patients have no attacks. Adding that to the Phase I, it's really 12 out of 15 now. So this is what we think patients are really looking for a treatment, a one-time treatment with no additional burden of disease in which they will be attack free for their entire life without additional therapy. And that's what we're looking to get for all patients and the goal of our treatment.

Our next question comes from Maury Raycroft from Jefferies.

Congrats on the update. I kind of have a follow-up to the last one based on the placebo response. The New England Journal of Medicine editorial mentioned that the intra-individual reduction of 16% attack rate occurred in the placebo group. How does that compare to historical Phase III placebo arms? And was this accounted for in your Phase III design and patient selection criteria?

Cohn, do you want to address some of the particulars?

Yes, it's not unusual to have a decrease in the attack rate compared to baseline, also in patients allocated to placebo. This was about 25% in the Phase III trial assessing lanadelumab. And we have seen comparable decreased numbers of angioedema attack rates also for garadacimab and donidalorsen.

The next question comes from Mani Foroohar of Leerink Partners.

Congrats on the data. So I guess the first question that I have, I guess, a 2-part question. Question 1 is can you clarify the difference in how an attack will be define and adjudicated in the Phase III versus what we've seen in the Phase I and Phase II to get to sort of apples and apples and apples? And then I have like a quick follow-up.

The answer to your first question is simple, it's the same.

Great. And I'm looking at the patient response chart on Page 17. You mentioned that obviously as the -- normally if time goes up, the attack-free patients have more and more follow ups to attack rates. So attack reduction rate evolves upward. Are there specific characteristics of non-complete responders, especially patient 1, that we should keep in mind? There's a little bit of incongruity between the depth of plasma kallikrein reduction and the attack rate for that patient. And I'm trying to understand if that's sort of something we can keep in mind for baseline characteristics or that's just the variation in response that happens in relatively small patient populations?

Yes, thanks for the question, Mani. First of all, I'd say that there's an imperfect correlation between response and kallikrein reduction. That's not strictly one-for-one and we've looked very, very closely at that. The other aspect I think as mentioned by Dr. Cohn is really important to keep in mind, which is what patients experience and how they report what they're experiencing. What we found and are continuing to find in this study, especially with the extended follow-up, is that when patients know they've received a drug, they're in a position to think differently about what they're experiencing and report lower attack rates as time goes on. We've seen that uniformly in the Phase I study. And thus far as this study is playing out, we're seeing the same sort of pattern.

The next question comes from Terence Flynn from Morgan Stanley.

This is Chris Yu on for Terence Flynn. Just kind of follow-up the previous question, 2 parts for us. For those 3 patients that did not get complete response, any similarities between them? That's one. And then second, did any of them receive rescue medication as a result of the attack?

So first I'd like to remind everybody that, the 8 of 11 patients that had no attacks is something that I think we shouldn't look past as we see a handful of patients who are still probably equilibrating with respect to the therapy. But Dr. Cohn, if you want to speak to whether those patients received any therapy or differences in terms of how these patients responded.

So these patients were from 3 different sites, but I think what they have in common is they have all used prophylactic therapies in the past and still had angioedema attacks during that long-term prophylactic therapy. In the other end, there's no way that there are no other similarities amongst these patients except that they always had symptoms that could or could not have been angioedema attacks and were all treated early with on-demand treatments. And yes, the on-demand treatment, since we don't have any reliable biomarker, we won't know for sure if it was an angioedema attack. But all the symptoms resolved in the end whether or not this was due to the on-demand treatment.

The next question comes from Gena Wang from Barclays.

I wanted to say thank you very much for the complete transparency of the data. I think, Slide 17 really laid out all the important information that we are interested. So, for me, I think one puzzle is why certain patients -- when we look at the attack rate very high, we can debate, are these real attacks or not, but they still had some kind of attack. But when we look at the kallikrein knockdown level, we have a 91%, 89% and you have another one at about 78% and then the other 2, I look at all the 80%, pretty high level, maybe only 1 patient is at 46% knocked out. So can you help us understand why there is no clear correlation with this? And is that patient baseline characteristic, is that baseline kallikrein, the protein level, anything you can help us understand? And another very quick question, sorry you said 1 question but I do wanted to ask 2 doctors here. With 70% attack-free rate, this clinical profile, what kind of patient population you think will be best suitable for this modality of a therapy?

Maybe we can start with just the correlation of kallikrein. As you move to the higher dose, 50 milligrams, there is pretty similar reductions in kallikrein that we've seen at 25 milligrams. I think you pointed to a patient with -- in the 40s in terms of reduction of kallikrein. That's why we didn't choose that dose. So 50 milligrams we think is definitely the way to go. We know from prior studies that patients -- there's always a group that behaves a little bit differently. What we've seen in the Phase I study and what we're also seeing here is that remainder set of patients, once they have information about the therapy that they received, may perceive what they've been considering attacks differently. But Dr. Cohn, maybe you can speak to that again. And then, I think, Gina's question relates to this profile with 8 of 11 patients having no further attacks, what kind of patient would that appeal to?

Yes. First of all, let's not forget that until the end of the data that we are seeing now in the primary observation period, all patients had been blinded during the entire follow-up. So since we as physicians have always instructed patients to treat as early as possible, I assume that these patients treated these symptoms just like they did in the past. I know that almost all of these attacks that were reported were internal attacks or alleged internal attacks. So there were no, I mean -- no observations in these patients in which we can definitely conclude that these were truly angioedema attacks. And I'm pretty confident that after de-blinding, we will see that the number is -- that also these patients are likely to improve. But we will need to see that, of course, in the follow-up. Regarding the 73% complete response, I think that is unprecedented if we compare this to other trials, and also to my first comment, I'm sure that after de-blinding, as we observed also in Phase I, this percentage is likely to increase.

Dr. Busse, maybe you could say a word or 2 about patients in your clinic, patients you're familiar with in terms of the profile of the drug as it currently exists and how attractive that will be and to which patients?

Sure. So, I mean, in my opinion, all patients are eligible for prophylactic treatment. It's really a shared decision making. And the reason I'm saying patients are eligible is that there is a huge burden of -- burden of not only treatment, but of disease. Patients may be afraid to travel if they -- you know, they might have attacks. But I really think that peace of mind that you're not going to have attacks in the future is a huge component. So in my opinion all patients are going to be available for it. I wouldn't say based upon number of attacks per month or year. And in my population really there's -- and I think this is happening worldwide is that many patients are switching from -- or most patients are switching from on-demand to long-term prophylaxis. And the problems that we have with long-term prophylaxis is that people are not getting complete relief. There's a burden of treatment, frequent injections which may be painful, a daily pill which is a constant reminder of you having hereditary angioedema without complete relief. And I think, going into future, if we can get a therapy that's safe for kids as well and for women who are pregnant, I mean, this is a huge game changer in my opinion. And one thing I'd like to point out is that one of my patients who is going to -- some of them are so excited and they said they really have to change their mindset to living with a disease that they've had their whole life to then not having this disease. So it's really, I think this is a game changer, in my opinion.

Yes, this is Danny, again. I can -- I fully agree and based on the experiences of the patients that have participated in the trial, I have heard really these touching stories about this patient. Mother of a family that for the very first time went to an amusement park with the family, which she didn't there before because of the stress of angioedema attacks. Other patients now for the first time taking holiday trips where they are for the first time daring to leave the proximity of the hospital where they were receiving their on-demand treatments in the past is really a game changer for these patients.

Our next question comes from Dae Gon Ha from Stifel.

Great. And let me add my congrats to your data as well. Going back to Mani's question, just one quick clarification, so for patient 1, 2 and 7, I was wondering if you can comment on anybody that's in the adolescent age. Just curious if the hormonal imbalance may have been exacerbating the attacks here? And then my actual question is, when you look at placebo patients, for those that have now started prophylaxis, what agents were they going on? And I guess, what -- why wouldn't they go on Intellia 2002?

I can speak to the adolescent question. There were none. Patients need to be 18 years or above to participate in the trial. And the second question, do you want to speak to it, David?

Yes. So the placebo patients are being offered 2002 and we suspect that all of them had either placebo or many of the 25-milligram patients will receive the drug.

Our next question comes from Kostas Biliouris from BMO Capital Markets.

Congrats on the data. A 2-part question from us as well. Did you observe any correlation between safety and response? For example, you mentioned that in 2 cases you had a temporary interruption of study drug and 1 patient had a Grade 2 ALT response. Were those people responders or non-responders? And then I have a follow-up.

Dr. Cohn, is that something you can address? Patients who either interrupted or...

Yes, there were 2 patients overall in which the administration was just very briefly interrupted. One of these patients was my patient that reported back pain just very briefly. After we discontinued the infusion for no more than 15 minutes, the pain resolved spontaneously and we could continue the rest of the treatment. I don't recall about safety and efficacy. This was none of these patients that reported. I don't recall by heart.

No apparent correlation between...

No apparent correlation.

Between those patients and their response, so short answer. You had a follow up?

Yes, the follow-up which is relevant is we know it takes about 4 weeks for the kallikrein levels to go down, but we don't really see any attacks in the 4 weeks, which is great. But I'm wondering what helps patients during these 4 weeks that the kallikrein is still not low but the 8 patients that are still attack-free did not get any patients -- any attacks at all. Any thoughts around these 4 weeks? How can it be clean here?

Dr. Butler, do you want to speak?

Yes, sure. So I get the observation. I think in short, the steady state isn't reached or pseudo steady state isn't reached till about 4 weeks or 5 weeks. But the reality is if you look at the data, we probably get very good reduction within the first week. So after probably 7 days, you're seeing a significant effect that may have something to do with the -- what we're observing with respect to the clinical efficacy.

And I'm not sure if all the patients, but a few patients received just very prior to the administration of the drug on the study day, a dose of C1 inhibitor concentrate to avoid them having any attacks during the -- at the day of the infusion. So that may also account for the lack of angioedema attacks during the very first days after treatment.