Worry Free in HAE: Coffee Talks With the Experts on Leveraging Advances in Long-term Prophylaxis

Dr Marc Riedl (University of California San Diego): We are going to move along to the content, and we will start. The theme is of course the coffee chat. You see we have our coffee props up here.

[00:37:23]

Panel Discussion #1

I am going to start by pitching to my colleagues here just for a brief discussion. You guys see a lot of patients with HAE. What do patients express as far as the burden of living with this condition? What are you hearing most often from the patients and families?

Dr Aleena Banerji (Massachusetts General Hospital): Thanks for bringing that up. I actually think that Dr Lumry and I spend a lot of time thinking about this, trying to answer this question, and it is actually multifaceted. I think that there is many aspects to this. I think we often talk about treatment and burden of treatment, and side effects of treatment. That is just one part of the burden of disease for patients. I think that there are a lot of emotional factors.

We do not know when the next attack is going to occur. Access to treatment in terms of cost and insurance and calling and trying to get the refill, I think, has been a huge burden for patients. There is always the concern of having a child with hereditary angioedema. What is that going to mean? There is a lot of impact on missed work and missed school and travel, and all the things that we take for granted. I think all of those are just minor parts of what adds up to this being such a big impact on their burden of disease.

Dr Riedl: Bill, feel free to add to that. The next question here, which is really important, what are the unmet needs? We have seen a lot of progress in HAE, but where do you still hear we are not meeting expectations?

Dr William R. Lumry (University of Texas Southwestern Medical School): The theme that Aleena pointed out is all about unpredictability. Unpredictability of when the next attack is going to be, unpredictability about whether you are going to have your medicine, unpredictability about whether you are going to pass this disease on to your children, unpredictability about whether you are going to be able to go to school, go to work, and do life. That unpredictable piece about HAE, I think, really adds or characterizes the burden.

As far as unmet needs, you are right. We have made a lot of progress. When you think about the last 15, 16 years, we have gone from basically no HAE‑specific medications to now 11 that we can apply to treat this disease, but there are still gaps. We have filled a little bit of the biggest gap, which was the pediatric‑adolescent gap, both in on‑demand and LTP in the recent years, but there is still a needs gap in that age group, as well as in the older individuals that as far as their access to medication, their ability to be adherent to their medication, to be able to follow up with their physicians and get appropriate advice from their physicians. We still have room, I think, to improve, but we have come a long, long way, Marc.

Dr Riedl: I think while we have come a long way, if you really sit and talk with patients, there still is also a burden of treatment. I think for most patients, we can find something that improves their lives, helps to control the condition. There are still a few patients where efficacy is an issue, we do not have everybody free of attacks at this point. But also remembering that this is still a chronic, lifelong condition, and that taking medicine on a regular basis or having to keep your medicine available if you are using on‑demand treatment can be burdensome. Not overlooking that.

Then I think, as you pointed out, children and adolescents, that has been a real issue. It will be interesting to see – we have not proven this – but if we can diagnose and treat patients early in their lives, and they do not have to go through these traumatic, sometimes near‑death experiences with HAE, do we address some of the anxiety, some of the depression that unfortunately has been such a huge part of this condition?

Dr Lumry: Another unmet need is obviously diagnosis of the patients that have HAE with normal C1 inhibitor. We have made advances with that group. We are learning, but we still do not have a way to really nail down that diagnosis and provide appropriate treatment for that group.

Dr Riedl: For sure. All right. Excellent. I am going to hand the baton to Dr Banerji here. Just a reminder, as she goes into her presentation, you can ask questions through the iPad. I am sure you could raise your hand at the end of the program also, the old‑school way, but feel free to send along any questions that pop up as we are going through this.

[00:42:04]

Assessing Barriers and Unmet Needs in Patients With HAE

Dr Banerji: Thanks, Marc. Good morning, everybody. It is great to see a room packed at 6:45 in the morning around a topic that I think is so important. This next brief section is titled Assessing Barriers and Unmet Needs in Patients with Hereditary Angioedema.

[00:42:25]

Poll 3

We will start this with another question. How frequently do you assess potential barriers to long‑term prophylaxis in patients with hereditary angioedema?

1. Never;
2. Rarely;
3. Sometimes; and
4. Frequently.

We will come back to some of these. We do have answers. Sorry. It is working. A little bit of variability. 20% rarely, 20% sometimes, and the majority of you frequently. It is great to see.

[00:43:21]

Clinical Features of Hereditary Angioedema

All right, so just to set the stage, I am going to spend a few minutes talking about the clinical features of hereditary angioedema. We are talking about angioedema that is bradykinin‑mediated. These are individuals that have symptoms of swelling because of an increase in vascular permeability. This is in sharp contrast to individuals that have mast cell‑mediated angioedema. So these are individuals that have swelling, there is no urticaria, and there is no itching, which is one of the ways that we think about this when we see patients presenting to the office and really thinking about their clinical history.

While it is rare, it is out there with an estimated global prevalence of 1 in 50,000, with a little bit of variability depending on which country we are talking about. When we are thinking about hereditary angioedema with C1 inhibitor deficiency, we know that it is an autosomal dominant condition, and that about 80% to 85% of individuals will have a family history. While it is autosomal dominant, we do see that in about 15% or 20% of individuals, it is a de novo mutation. They do not necessarily have a family history, but they have a 50% chance of passing it on because it is autosomal dominant.

With hereditary angioedema with C1 inhibitor deficiency, there are really 2 main types. There is type 1, where you have a dysfunctional protein, so you have a low protein level as well as functional level; whereas hereditary angioedema type 2, which is in about 20% of individuals, they are producing the protein, but the protein does not work. Ultimately, you still have a C1 inhibitor protein dysfunction.

What we talked about briefly about an unmet need is individuals who have hereditary angioedema with normal labs. Their C1 inhibitor level and function is normal, so it is very hard to diagnose, and we have certainly seen some work in the last few years and identified mutations. The majority of those mutations are autosomal dominant. One of the criteria that we have come up with is that you do have to have a family history to be diagnosed with hereditary angioedema with C1 inhibitor deficiency. The genetic tests are hard to test for, and so this still remains an area of unmet need.

Across all of these individuals with hereditary angioedema that is bradykinin mediated their symptoms of swelling last for 3 to 5 days, especially when it is untreated. And it is bradykinin‑mediated, so there is no response to antihistamines, corticosteroids, and epinephrine. We know that exogenous estrogens aggravate symptoms, and there are some identifiable triggers such as trauma, stress, surgeries, but there is also more than half the time where these attacks will occur without any known trigger. That certainly adds a lot to the emotional burden of having hereditary angioedema.

[00:46:16]

HAE's Spectrum of Symptoms

In terms of the spectrum of symptoms, we broadly categorize patients as having peripheral swelling, which is hand and foot swelling. We think about abdominal swelling, and then we think about airway swelling, which is laryngeal or facial swelling. These laryngeal episodes, especially when they are untreated, are life‑threatening. People can have asphyxiation, and in the last few years, we have seen patients with hereditary angioedema that are diagnosed, have an airway attack, and unfortunately pass away. This is a real‑life‑threatening condition even when the diagnosis is made.

[00:46:57]

HAE Impact on Health‑Related Quality of Life

As we were talking about in the coffee chat, the burden of disease for patients with hereditary angioedema is high. We know that this impacts their health status, their wellbeing, their work productivity. The data that we are showing on this slide is a specific EQ‑5D‑5L index. Simply what it is, it looks at 5 different domains that look at well‑being and quality of life. What you can see, and what is evident, is when you look at the score today, when somebody is not having an attack, it is relatively normal, which is actually surprising to me because in general, we see that the quality of life and burden of disease is much worse than the normal population. At least in this survey on a specific day, it was relatively similar to the general population.

When they had an attack, as you can see in orange, and certainly as the attack severity got worse, not surprisingly, the quality of life, the burden of disease, the impairment is much, much worse. There is still a lot of work to do for our patients because they continue to have attacks. On average, when you look at the data across a year, patients are still having about 2 attacks a year, and this is even despite the fact that we have 11 different treatments available in the United States.

[00:48:17]

HAE Impact on Psychological and Financial Health

Similarly, we know and what we already mentioned a little bit is that there is such a significant psychosocial and financial impact. Why is this? We talked about the fact that the majority of patients continue to have attacks, and these attacks are unpredictable. We do not often understand the trigger, and they can wake up this morning feeling perfectly fine and as they go through the day, suddenly have an attack, and that attack can be life‑threatening.

On average, what we are seeing is that patients, when they have an attack, will miss 3 to 4 days of work. That could be school, it could be work, it could be a missed trip. That has financial implications, and what the data on this slide also shows is that when you look at the mean anxiety severity over approximately 6 months, it is also worse as the attack severity is higher. Similarly, the score for depression over 6 months, again not surprisingly, is worse as you think about more severe attacks.

[00:49:20]

Managing the Burden of HAE Treatment

How should we thinking about managing the disease? I think we still have a lot of work to do. Despite the availability of multiple different prophylactic treatments in addition to the 2 that are approved this year, in a survey of patients that are treated with on‑demand and long‑term prophylaxis, so they have treatments available, the majority, over 96%, alter their plans the day after an attack. It is not only the day that they have the attack and they are able to use on‑demand, but it continues to impact their life the next day. They also do not feel like themselves. Almost all patients unanimously said they do not feel like themselves. Again, that is not something that is surprising to hear.

Then, when you ask what are their top 3 affected activities? Travel, work, social activities. What else is there? That is a lot of what we enjoy doing.

[00:50:15]

Patient‑Reported Challenges With Prophylaxis Therapy

Then when you ask patients what are the challenges with prophylactic therapy, the things to focus on are in the dark orange, which in the survey is what they most strongly agreed with. This was things like, I prefer to administer my treatment when and where I need it. 69% of patients strongly agreed with that. Going to the hospital or infusion center for infusions is inconvenient. Again, not surprising, 59% strongly agreed. Then over a quarter to a third of patients saying that injections and infusions are difficult because my veins are bad, I am tired of injections and infusions, needles are unpleasant, and injections or infusions are unpleasant. Again, nothing is surprising here, but clearly suggests that we have a lot of work to do.

[00:51:03]

Goals for Prophylactic HAE Therapy

We know that we want a drug for long‑term prophylaxis that is safe, tolerable, and effective. No questions there, but certainly something that has less frequent administration, easier to administer, and requires less time to administer. I think still some goals that we have for our patients to make long‑term prophylaxis much easier, impact that burden of disease, improve their quality of life, and hopefully we will be able to continue to do that.

[00:51:33]

Posttest 1

Posttest Question. You saw this before. Which of the following correctly summarizes the impact of HAE on patients' quality of life?

1. HAE impacts a patient's work productivity, but is not strongly associated with economic burdens;
2. Patients taking prophylactic treatments are able to participate in social activities and travel without fear of attacks;
3. Patients with HAE experience higher levels of anxiety due to fear and future attacks; and
4. Patients with HAE taking prophylactic treatments report feeling like themselves again.

Clearly, the data I showed you, patients with HAE experience higher levels of anxiety due to the fear of HAE attacks. Great. All right, I will pass it along. Again, there we go. Coffee Chat.

[00:52:47]

Dr Riedl: Thank you, Aleena. Well done. A very quick but excellent summary of a very complex topic that I think, as you said, we continue to learn from our patients and families of how this affects them.

[00:53:02]

Panel Discussion #2

Just to chat for a few minutes until we turn it over to Bill. I will ask either one of you. We have guidelines, how do those inform your discussions with patients? As a caveat to that, what are the guidelines say about individualized therapy? Bill, I will let you start.

Dr Lumry: Okay.

Dr Riedl: Aleena just spent a whole bunch of time talking.

Dr Lumry: I know.

Dr Banerji: They do not want to hear more from me. They want to hear from you.

Dr Lumry: I think with all therapies in medicine, we have to find something that works for the patient, that the patient accepts, and the patient then will be adherent to and use. HAE medications are no different than that. Obviously, we need to, in the case of HAE prophylaxis, identify the patients that would be candidates for prophylaxis. One could argue if one of the guideline goals is complete control of the disease, then maybe everybody should be on prophylaxis and not just treating on demand when attacks occur.

Those guidelines may be modified a little bit going forward, as we understand that complete control is defined differently by different patients, what they are satisfied with, and is not necessarily what we might be satisfied with. We need to select patients and the therapies for patients that, again, work for them, that are safe, that fit into their lifestyle, if you will, from a standpoint of, also, what their preferences are. I think that those kinds of questions, and now that Danny Sotiris is here, we can say shared decision making. Danny, toast. Discussion about, here is what is available, what are your goals? Then, try to put what is available and the patient's goals together to come up with a plan for the patient.

Dr Riedl: The guidelines obviously have a lot to say, a lot of data. To your point, Bill, the goal is complete control, or one of the guidelines uses the word “normalize”, “normalization”, which I always put in quotes because I do not know what normal is exactly. That is the point, is that it is up to our patients to sort of, do they feel normal? Can they do everything that they would like to pursue? Aleena, then the last question here is about strategies to support this adherence that Bill mentioned that is so important. Any ideas there?

Dr Banerji: I think it is tricky because, as we have talked about, this is a shared decision‑making process, and not necessarily what I think is best for the patient is really going to be what they want. I think the guidelines, as you are hearing, is that every patient is eligible for long‑term prophylaxis and that we should be having a conversation about long‑term prophylaxis at every single visit.

In terms of adherence, I think there is 2 sides to this. As they have been available, the patients have also been doing better. The downside of that is that they are not necessarily coming for follow‑up. When they need their PA or they need their authorization, and it has been a long time since they saw me, that prompts them to come see me. I think there is some work to do that even when they are doing well, for them to make sure that they come back to see me.

Separately, it is making sure that I truly understand what is the impact on their day‑to‑day. Ask about missed work. Ask about missed school. Ask about the factors of anxiety and depression that you heard about, that we know is really part of the challenges. And not just about treatment. Is it working for you? Do you have side effects? Really thinking beyond that and trying to help them understand that those are important aspects of taking care of them that we want to focus on. It is not just, is it hurting? Are you tired of using these, etc.? Then focusing on those things I think will help with adherence, and I think actually having regular visits and regular communication.

Dr Riedl: These conversations are just so important, that qualitative information. Of course, we have the angioedema control test. There is the AE‑QoL. There are tools. I will put in a plug for the USHEA that has a shared decision‑making tool which is online. This can really help patients organize their thoughts, what is most important to them, before we have these conversations. At the end of the day, you have to learn from the patient these important facts. How is either the condition or the treatment still interfering with their life? We really have to initiate those.

I do not know if it is in this slide deck, but there is an interesting study from a few years ago. They surveyed patients and they surveyed doctors that take care of patients, and ask them “Who initiates these conversations about your therapy? How well are you doing, and whether there are changes that should be made.” Not surprisingly, about 80% of the doctors said they did it, and about 75% of the patients said they did it. There is a mismatch here somewhere. I think the point is that conversation needs to happen on a regular basis, regardless of who drives it.

Dr Lumry: To Aleena's point, if you do not ask, they will not tell. Patients want to please you. They want to let you know that you are doing a good job taking care of them. If you just ask simple questions like, have you had any attacks, or simply how are you doing, that is really not even scratching the surface. You really have to drill down and ask these questions directly to the patients. It is amazing how much information they will then provide to you that they may not have volunteered on their own.

Dr Riedl: Yep. Absolutely. All right, Dr Lumry.

[00:58:49]

Practical, Patient‑centered Strategies for Long‑Term Prophylaxis in HAE

Dr Lumry: Thank you. Good morning. I am glad to see everyone here this morning, and thank you to Ionis for supporting this and providing a forum to talk about these things. I am going to talk about, hopefully, some practical things, patient‑centered strategies to implement long‑term prophylaxis in individuals that have hereditary angioedema.

[00:59:15]

Poll 4

Let us start with another polling question if you will. Number 4 is how frequently do you evaluate the quality of life – we just discussed that – in patients with HAE?

1. Is it something that you discuss at every visit;
2. Is it something that you just discuss at the first visit that you see the patient in; or
3. Do you discuss it if the patient happens to bring it up.

If you would vote A, B, or C, let us see how this goes. Good. Thank you. The majority discuss at every visit, and some of us, maybe just when we are busy, when the patients bring it up, so good.

[01:00:25]

General Treatment Strategies for HAE‑C1INH

I think we all know in this room, those of us who take care of HAE patients or work in the HAE space, there are basically 3 pillars of therapy for hereditary angioedema. The first, and the one that we focused on years and years ago in the guidelines, was just to stop attacks and keep people alive. On‑demand therapy is obviously an important piece of this therapeutic paradigm, if you will, for patients, that they have to have availability of some type of an agent to stop an attack when it occurs. On‑demand treatment is for everybody with this diagnosis.

Sometimes I get questions, how many patients do you have on LTP and on‑demand? I said, well, 100% of my patients on LTP are on on‑demand as well. We want to have something that rapidly stops attacks, that is something that the patient can hopefully easily carry around and have with them, so they can treat an attack early. The guidelines suggest that patients have enough therapy to treat at least 2 and maybe more attacks.

It is interesting as you watch the posters through this meeting, the question of treat early. Treat early, treat early. It is on all the signs and the billboards here. When we ask patients in a survey what they treated early, the majority said, “Of course, we treat our attacks early.” The second question was, “How early do you treat?” They said, “Usually within 2 hours,” which at least in my opinion is not particularly early. We actually did a Delphi consensus between 19 individuals that treat HAE across the world and asked them what they felt early was. Finally, we have got a definition of early at least that might show up in the guidelines, being at 60 minutes or less.

The second pillar that we are going to talk about is long‑term prophylaxis, which is the topic of this symposium this morning. Can we actually prevent patients from having attacks and obviously not needing their on‑demand therapy? Hopefully lowering the burden of the disease and also lowering the anxiety and depression that goes along with the unpredictability of the disease. The points here are we want to reduce the burden. We want to decrease not only the severity but also the frequency of attacks. As we will discuss, long‑term prophylaxis needs to be individualized, with a patient basically buying in so that they can be adherent to the therapy. Again, in a discussion‑type mode, using a shared decision‑making or some other type of communication tool.

In the middle is short‑term prophylaxis. We know that we sometimes do things to patients, or things happen to patients that will trigger an attack: a medical procedure, a dental procedure, a stressful event. During those periods of times, if patients are just being managed on an on‑demand therapy, they may need supplemental short‑term prophylactic therapy to prevent attacks during those events.

Those 3 are the pillars that we look at and think about when we are treating patients with this disorder. Obviously, all of those have to be individualized in order to achieve the best outcome.

[01:03:39]

Considerations for Therapy Initiation

These are some things that you might think about if you are discussing long‑term prophylaxis or any type of therapeutic program with a patient. It is not just simply how many attacks do you have or how bad are your attacks, or what kind of attacks do you have? There is a whole host of other things that we need to consider when we are having these discussions. How old are they? What drugs are available for that particular age group to use? What is the data around that? What is the access that they have to urgent care or medical care if they need to access that? What is the availability through their payer or through their country for their particular type of therapy that we might want to prescribe? Then lastly, and probably as important, is what is the patient's preference? All of that has to come into it.

Unfortunately, as you know, the treaters in the room know, we go to insurance companies requesting approval for prophylactic therapy, often the question is, how many attacks are they having a month? Or how many times have they been to the ED or the hospital? That is not the point anymore. We are well beyond that with our situations now.

[01:04:55]

Clinical Assessment Tools for Angioedema

As Marc mentioned, there are several tools to assess not only quality of life, but also activity of hereditary angioedema, looking primarily at attacks, and the impact of attacks. Two are shown here, and it is an eye chart. I apologize for that, but the angioedema activity score and the angioedema control test are 2 fairly simple tools that could be applied in your waiting room, waiting for the patient to be seen, they can fill these out and give you a nice idea of how the patient is at that particular time or how they have been over the last 4 to 8 weeks, depending on what tool that you use.

These are a couple of others. We can look at the angioedema quality of life score, and then there is actually another specific HAE PRO that patients can use. These are available online, free to use if you choose to. We use them quite frequently in our clinical trial work, but they do give you somewhat of a quantitative look at actually how the patient is doing, and that can be compared over time.

[01:06:04]

On‑Demand Therapy and Short‑Term Prophylaxis

What do we have available now? As I mentioned at the outset, we have now 11 drugs approved in the United States and in many countries around the world. We have a variety of on‑demand therapies. IV C1 inhibitor, both plasma‑derived as well as recombinant C1 inhibitor, the mainstay of on‑demand therapy for many years. We have icatibant, a plasma kallikrein inhibitor delivered subcutaneously in the United States. It is approved age 18 and above.

There was a gap, if you will, below age 18, where patients either had to use a drug that could deliver subcutaneously, but they could not self‑administer, ecallantide, or go to the challenge, if you will, of giving themselves or getting an IV therapy with C1 inhibitor. We now have a new oral drug approved earlier this summer, approved age 12 and up for treatment of attacks, which I think may turn out to be a real game changer, particularly for early treatment and for treatment of more attacks than what we are seeing now. We know that about 60% of patients say they do not treat all their attacks, and there are a variety of reasons for that. About 70% of attacks are treated, 30% of attacks are not treated with previously available medications. I think we can do better there.

There are second‑line therapies. Fresh frozen plasma. Third line therapies, again just fresh frozen plasma that is not solvent treated to remove potential pathogens. Again, we have already talked about 2 doses available, preferably to treat attacks.

As far as short‑term prophylaxis, we are still looking primarily at using C1 inhibitor products prior to a procedure, particularly a medical or dental procedure. There are other ways to raise C1 inhibitor levels using androgens a few days before and a few days after treatment. If those are not available as far as C1 inhibitor, then we can use other products to raise the level and hopefully protect the patient.

[01:08:13]

The Road to Long‑term Prophylaxis

The road to long‑term prophylaxis. Again, disease control. That may be defined by you or it may be defined by the patient but there has to be some agreement to what that looks like between the 2 of you. Hopefully, that then leads to an improved quality of life for the patients. Again, the considerations that we have already talked about; who should get it, what things should we be focusing on? It should not just be on the frequency or the type or the severity of the attacks that the patient is having. Obviously, those are all very subjective reports by patients.

We now have great therapy for long‑term prophylaxis. As time has gone along, we have lowered the burden of treatment from frequent IV therapy to frequent subcutaneous therapy, to less frequent subcutaneous therapy, to oral therapy. With that, I think we have done really a good justice, if you will, to the patients.

Interestingly, though, despite all the progress that we made, even 4 years ago more than half of the patients reported that they thought the treatment with their long‑term prophylaxis was somewhat burdensome. We have got some room to work there.

[01:09:24]

Adherence Among Patients With HAE Receiving Long‑term Prophylaxis

This is a look at adherence to the therapies that we have. This is a study that actually was published by Dr Zuraw and his colleagues earlier this year. This is an insurance claims database looking at adherence to prescribed medications, and the point was to say, are people going to be more adherent to an oral agent, or are they going to be more adherent to a frequently administered subcutaneous agent, or more adherent to a less frequently administered subcutaneous agent? You can see there is really no difference between the 3 different products. If you look over time, the adherence rates are north of 60%. They are not 100% by any manner of means. The longer you go from the initial 3‑month period, the lower the adherence rates are, but they are still north of 50% for all 3 of these drugs.

[01:10:20]

Shared Decision‑making 3D Model in HAE Management

We have talked a lot about shared decision‑making. I think all of you incorporate that in your discussions with patients in some manner. What are your goals? Here are the options. What do you want to do?

[01:10:31]

Posttest 2

With that we will go to the last posttest, if you will. A 45‑year‑old man with HAE controlled with lanadelumab given every 2 weeks reports misdosing due to injection fatigue. You have seen this question earlier. He also has IBS with baseline GI discomfort. Which of the following is the most appropriate next step to improve the patient's acceptance adherence to the long‑term prophylactic program?

1. Encouraged him to remain on his current treatment because it is working and it is safe;
2. Consider a subcutaneous long‑term prophylactic treatment with maybe a longer dosing interval;
3. Consider an oral long‑term treatment option; or
4. Discontinue prophylactic therapy and just treat with on demand.

If you will address that question, that will be great. I think the keyword in the question was needle fatigue. The choice of maybe less frequent injection routine is probably appropriate for this gentleman.

[01:11:51]

Thank you very much.

[01:12:00]

Panel Discussion #3

Dr Riedl: Thank you, Bill. Let us just chat for a few minutes about some of the topics you discussed. There are new therapies. I am going to talk about those in a second, but before I do, an entrée; how have these impacted your conversations with patients?

Dr Banerji: I will take this one first. I think that the new treatment options that are available certainly address the idea of needle fatigue. The biggest change with the 2 new treatment options that are available for long‑term prophylaxis in the last few months is that they are going to be less frequent. I think there are a lot of patients similar to what you saw in that case, that are really excited about the opportunity to have treatment options that are less frequent. They did not necessarily complain about it before because they did not have anything else to do, and they just put up with it unless you actually ask them. I think what we are thinking about now is that making sure that we have these conversations and help them understand that there are other treatment options and maybe even less injection site reactions. Maybe less pain, less burning, with some of those treatment options. Really, it is just a conversation with the patients at every visit to help them understand that there are more options available to them.

Dr Riedl: I am going to call a little bit of an audible here because there is a great question from someone in the audience. Maybe, Bill, you can take this. What do you hear from patients who have used a therapy for a long time? Are they really looking for other things or are they just accepting of what their life is now since it is better than before?

Dr Lumry: Marc, over the years, we have seen a progression from, again, very burdensome treatments to much less burdensome treatments. With each step, going from IV to subcutaneous to oral, there has been an increased number of patients that have accepted long‑term prophylaxis as their primary care treatment, going from maybe 25% when we did IV C1 every 3 days to now 60%, 70% with the options that we have.

To Aleena's point, patients, if you ask them, do they like their therapies, they would say, “They work well for me. I feel like that they are safe. Since you ask, they are somewhat burdensome.”

Again, before there was any options, they put up with that. I think we are going to see potentially a shift because patients are asking about what else can I do now? What might work as well but be less burdensome? We will see how this moves forward now that there are other options available.

Dr Riedl: In 2 minutes or less, how do you pick? Do you have all, what did you say, 11 therapies now? How do you choose.

Dr Banerji: I think you saw a slide from Bill, it is shared decision making. I think the core principles are safety and efficacy and they all are safe and efficacious. It is really just the nuances to it. There are patients who do not ever want to change. There are people who have been on something for a really long time and they do not want to change. They want to wait to “See how my friends do” or “How my family does.”

But if you really spend the time asking the questions, some of them are afraid to say it is not working because they are worried that they will not have access to that treatment. You can reassure them and really ask the questions about do you have needle fatigue? Is the frequent dosing just too burdensome for you? Use those to move the needle for them and to help them understand that this is not a one point in time decision. Whatever we decide today is not something that you are set in stone with. We can connect in a month, we can connect in 3 months. We can talk. You can send me a patient gateway message if it is not working.

I think giving them that flexibility and giving them all of the information. And then their life might change. It might be somebody that next year is going off to college or their job changes, and there is frequent travel, and making sure that you understand all of those aspects. That is my very short answer.

Dr Riedl: Very well put, but also not easy. It is that options are great, but the conversations become more complex if we are going to do them justice.

[01:16:21]

Advances in New and Emerging Therapies for Long‑term Prophylaxis

All right. Good. That being said, let me finish with a brief presentation, and my charge was just to walk you quickly through what are these new and emerging therapies for long‑term prophylaxis. I am going to move quickly to try to get you all out of here on time.

[01:16:35]

Poll 5

I am not sure if we saw this question, but I will ask it now. How confident are you about integrating new therapies for long‑term prophylaxis into your practice?

1. Not at all confident;
2. Somewhat not confident;
3. Somewhat confident;
4. Confident; or
5. Extremely confident.

How are you feeling about your mastery of these medicines?

All right. Decent, but we could be better, so somewhat confident and confident for most.

[01:17:25]

FDA‑Approved Long‑term Prophylactic Therapies

Very briefly, this is the lay of the land for our approved therapies, and again, I am not going to go through this whole table. You will recognize we have had C1 inhibitor either IV or subcutaneous. We have had lanadelumab and we have had berotralstat for a number of years now. Of course, C1 inhibitor is a replacement therapy. As you probably know, usually we are using the subcutaneous route of administration. Lanadelumab as a monoclonal antibody given subcutaneously every 2 to 4 weeks, which targets plasma kallikrein, and berotralstat as a targeted oral medicine, also a plasma kallikrein inhibitor.

As Aleena mentioned, we have 2 new entries just this year in garadacimab, which is a once monthly subcutaneous factor XIIa inhibitor, and then donidalorsen, which is an antisense oligonucleotide that targets prekallikrein and is dosed subcutaneously every 4 or every 8 weeks. Again, I will not go through all these, but of course, all these medicines have potential side effects. The good news is, in large part, our HAE therapies have been very safe in terms of any serious adverse effects.

[01:18:36]

EMPOWER: Real‑world Efficacy and Safety for Lanadelumab in Patients With HAE

I will very quickly show you data for a few of these. This is lanadelumab open‑label or real‑world efficacy data phase IV study, just to basically demonstrate that this has been generally a very durable, effective medication. These are patients treated for 3 years. You can see about half of them reported some adverse events. Most were mild or moderate in severity, and you see the reduction in this real‑world study of about 85% when you look at attack rate compared to baseline, and that persisted throughout the study period. You can see the attack rate remains quite stable and generally very low.

[01:19:15]

APeX‑S: Long‑term Efficacy and Safety of Berotralstat in Patients With HAE

Similarly, this is open‑label data for berotralstat. The APeX‑S study, which was actually an open‑label phase II trial. Again, these patients treated in the US for 96 weeks. Again, you can see this durable efficacy. The attack rate is not quite as low with this oral agent as compared with the subcutaneous drugs, but this has been a very attractive option to some patients, given what we heard about needles and injections, an oral agent that does clearly reduce attacks. I will point out that there is the 15% diarrhea there and under the AEs, and that also shows up in the pivotal trial that one of the more common side effects was some GI side effects that we do counsel patients about and can, once in a while, become an issue, usually is tolerated and wears off or wanes over time with treatment. But that is a bit of a unique adverse effect with the oral agent.

[01:20:13]

VANGUARD: Efficacy and Safety of Garadacimab in Patients with HAE

This is garadacimab, so just approved in 2025. Approved for ages 12 and older. As I mentioned, this is subcutaneously dosed once a month, and it targets factor XIIa. We have here a responder analysis. You can see the efficacy with 74% of patients getting at least a 90% reduction and 62% of the treated patients that were attack‑free in the randomized, placebo‑controlled study. The adverse events on the right, and you can see actually well‑tolerated overall. There is some low rate of injection site reactions, and then the usual things that we see in studies, including URIs and nasopharyngitis.

[01:20:56]

OASIS‑HAE: Efficacy and Safety of Donidalorsen in Patients With HAE

Then this is the pivotal trial data for donidalorsen. As I mentioned, an antisense oligonucleotide that reduces the expression or production of plasma prekallikrein. This is also dosed subcutaneously in patients 12 or older, is the approval. This is given either every 4 weeks or every 8 weeks. This is the change in attack rate for the placebo‑controlled study. Again, you see over the first 5 weeks this fairly significant reduction. If you look from Week 1 to Week 25, it was an 81% reduction in attacks. If you push it out from Week 5 to Week 25, which was the secondary endpoint, you get an 87% reduction in attacks.

What is a little bit interesting is you see, as you go out further in the weeks, that the Q8 dosing eventually seem to reach about the same prevention rate as the Q4 week dosing. Thus, the labeling gives us the option of every 4 or every 8 weeks. Adverse events here you can see again injection site reactions low, but about 20% in the every‑4‑week dosing had reported some injection site reactions.

[01:22:05]

CHAPTER‑1 OLE: Deucrictibant Long‑term Efficacy and Safety in Patients With HAE

Now these are investigational drugs from here on out. This is phase II study data. An oral bradykinin or B2 receptor antagonist called deucrictibant. You can see here on the left, initially the randomized portion in the gray shaded area, where you see a very rapid reduction in attack rate, this orally administered daily medication. And then of course rolling into open‑label, really, all patients have a very significant reduction in their attack rate. That does appear to be quite durable with low attack rates all the way out to at least month 21 in this particular open‑label data set. Again, the adverse event profile looks quite clean with really no major patterns or concerns about side effects, at least in this early phase II study.

[01:22:58]

Navenibart: Antiplasma Kallikrein mAb Phase Ib/II ALPHA‑STAR Trial Efficacy Outcomes

This is navenibart. Navenibart is a YTE‑modified monoclonal antibody targeting plasma kallikrein. This is a subcutaneous injection that could be given perhaps every 3 months or even every 6 months to prevent HAE attacks. Again, phase Ib/II study data, so fairly small numbers, but 3 different dosing cohorts studied here. You can see regardless of how it is dosed, either 450mg once, 600 followed by 300 at about 3 months, or 600 followed by 600 a month later, regardless, you get about this 90‑plus percent reduction in attack rate, so appears very effective, although very small numbers in this early study. Again, no real safety signals, the most common treatment‑related adverse event being a low rate of injection site reactions.

[01:23:54]

NTLA‑2002: CRISPR‑Based Gene‑Editing Therapy

Finally, this is the NTLA‑2002 phase II data. This is CRISPR‑Cas9 gene‑editing targeting, again, plasma prekallikrein in the liver. This was a single dose vs placebo, and you can see at the 2 doses that were studied, either 75% or 77% reduction in attack compared to placebo in this study out to Week 16. Of course, these patients continue to be followed for long‑term efficacy and safety. In the short term, the safety looks reasonably good with no major or severe safety concerns. I think with gene editing, of course, we are all interested in the long term and whether there is any safety concerns along those lines.

[01:24:42]

Posttest 3

That is a whirlwind tour of what is out there. Hard to do with justice in 10 minutes or less. As Bill said or Aleena said, there is a lot of data. It has been a lot of data at this meeting. I encourage you to get out there, look at the posters, hear the presentations, because all of these programs have been very forthcoming about their safety and efficacy data.

All right. Here is our posttest. Which of the following statements about new and emerging long‑term prophylactic therapies for HAE is most accurate based on the clinical trial data? This is the were you paying attention question to what I just said.

1. In a phase II trial, NTLA‑2002 displayed sustained kallikrein knockdown after multiple doses;
2. The CHAPTER-1 OLE of deucrictibant showed promising prophylactic efficacy that diminished over time;
3. In OASIS‑HAE, donidalorsen decreased monthly high attack rate, with injection site reactions being a common adverse event; or
4. In the VANGUARD study, garadacimab was effective in lowering HAE attack rates in patients aged 10 years or older.

Which one is correct? It does feel like the longest time standing up here. All right. Good. A little bit of improvement. And that is the correct answer, that donidalorsen did decrease the monthly attack rate with injection site reactions being a common adverse event. Why are the other ones incorrect? NTLA‑2002, of course, is a single dose, not multiple doses. Deucrictibant did show promising efficacy, and it did seem to be sustained over many months in open‑label trial. Garadacimab was effective in lowering HAE attack rate, but it is 12 and older, not 10 and older. A little bit of trick questions, but you guys did well. You were paying attention to the details.

[01:26:56]

Key Takeaways

Here is the wrap‑up and takeaways. We definitely have seen advances in long‑term prophylaxis, and we do believe based on all the evidence, that this is the best strategy to meet the treatment goals. Those being, of course, a reduction in HAE attack rates, but as importantly or even more focus now on improved quality of life; complete control is our goal.

The treatment choices should balance efficacy, safety, administration route, and patient‑related lifestyle factors. I think we have had some nice conversations about that, how we really have to dig in and tailor the treatment since we do have options, and we should take advantage of that.

We need to engage patients through education and discussions on their goals of treatment and treatment choices. As we have discussed, this includes aligning with the patient's values and their lifestyle and what they are willing to adhere to, which are key for really improving persistence and adherence. I think, as we have talked about, this requires some digging sometimes. It does resonate with me that sometimes patients are like, “I am good enough,” but they are not great, and they are still not doing the things they want to. I think we are at a point where we should not accept good enough as okay.

[01:28:14]

Question and Answer Session

I am going to wrap up. We have 2 to 3 minutes for questions. There was a question on here that I thought was important, well, a couple of questions. One was if a patient's HAE is suspected to be from estrogen therapy or hormone replacement therapy, do you consider that they stop the estrogen or hormone replacement therapy?

Dr Banerji: The simple answer is absolutely yes. We know that generally exogenous estrogens, in whatever form, are an aggravating factor and are generally contraindicated in patients with hereditary angioedema. Yes.

Dr Riedl: I agree with you. The right answer, the short answer is yes. It is interesting, as we have progressed with long‑term prophylactic therapy and have more effective drugs – we do not know the answer to this, I am speculating – but can we get away with more of these triggers that sometimes, I have women that it is really important to them that they would be able to consider at least some low‑dose estrogen for menopausal symptoms? As you said, we do not recommend it, we are very cautious, but we will have to look at that as we have better preventative therapies. Can they do some of that without getting into trouble?

Same for short‑term prophylaxis for procedures. You mentioned that, Bill, but I do not think we really know how well these new long‑term prophylactic drugs perform in that setting of a procedural trigger.

The last question from the audience, which is certainly reasonable, how is the performance of the new autoinjectors? Is there any perceived difference that you have heard or seen?

Dr Lumry: Patients like them. Obviously, autoinjectors have been around a long time now, and the ones that are used with the 2 newest prophylactic medications, garadacimab and donidalorsen, are very similar to what we are used to with other biologics in other spaces, rheumatology, etc. It takes a minute of training. For patients it is not completely obvious how to use these things or how to administer them. I am a big proponent of that training happening in your office, if at all possible, rather than the patient trying to read a piece of paper to tell them how to do it.

You basically take a cap off, inject it into subcutaneous tissue in the deltoid, in the thigh, in the belly, just like we used to do with the prefilled syringes. You will hear a click, and there is a little yellow monitor that goes down a window, and it goes all the way. Takes about 5 seconds to go down. Then, once you hear the second click, you ask the patient to count to 5 before pulling the needle out, rather than jabbing and pulling out. Because if they do that, it will just spray all over the room and they have wasted their drug.

Showing the patient how to do it and then having them demonstrate that they know how, I think, is key to using these autoinjectors. Then after that, as we mentioned earlier, these drugs, the new drugs do not have any spray as a stabilizer in them, and so they are much less painful than some of the older subcutaneous medications. It is not a problem with the autoinjector hurting with a rapid injection like that.