Preventive Therapy in HAE: Barriers and Unmet Needs

Dr. Marc Riedl (University of California): Let us jump into a little content here. Again, we are going to ultimately focus mostly on preventative therapy, but let us first talk about HAE in general to provide some context.

[00:05:39]

Clinical Features of Hereditary Angioedema

Many of you are familiar with this condition, but just to level set the conversation. This is a very rare, genetic medical condition that causes angioedema without urticaria. Of course, in allergy practices, we see a lot of hives. This is angioedema without hives. We do not know the exact prevalence of HAE, but most of the epidemiologic studies suggest it is right around 1 in 50,000. We know, of course, that it affects the skin, the GI tract and the airway.

Now, as I mentioned, this is a genetic condition, and it often, but not always, has a positive family history. It is autosomal dominant. That is important, because if you identify a patient, there is a 50-50 chance that their offspring will inherit this genetic trait. Most patients that inherit the gene will be symptomatic. There are rare exceptions of asymptomatic patients.

There is a couple of subtypes of HAE, as you know. HAE type 1 and 2 are most common and result from either deficient levels of C1 inhibitor or a C1 inhibitor protein that is dysfunctional because it is not folded correctly due to the mutation. Do not forget there is this very rare condition called HAE with normal C1 inhibitor, where the complement labs will all be normal, but the patient has all the signs and symptoms of HAE that we will talk about.

We do not understand HAE with normal C1 inhibitor very well. It is a tough diagnosis to make, because we generally lack biomarkers, although there have been some progress in the genetics of HAE normal C1 inhibitor.

Now HAE causes these very severe and typically prolonged angioedema symptoms. They take generally 12 to 24 hours to hit their peak, and they last up to 5 days if they are not effectively treated. HAE, of course, does not respond to allergy medicines like antihistamines, corticosteroids or epinephrine, which is pretty much the reason we are here talking about this. HAE requires a very different set of therapeutics, a different treatment plan from the much more common mast cell-mediated swelling that we may see.

HAE is terribly unpredictable. This is one of the major burdens, because patients cannot predict when and where these attacks will occur. There are some known triggers. Estrogen can trigger HAE attacks. ACE inhibitors, of course, are contraindicated. We know that trauma, either physical or psychological trauma or stress, can be strong triggers in some patients.

But most attacks do not have a clear trigger. They appear to be random. They are unpredictable. This is really a huge burden on patients and their families.

[00:08:23]

HAE’s Spectrum of Symptoms

The other issue with HAE is, of course, the variability and that can relate to the frequency of the attacks, the types of attacks that occur. We know that the majority of attacks are either skin or GI, and skin attacks can hit anywhere but the face, the extremities are very common sites. You see genital attacks here. These are actually pretty common. Patients would not talk about this because it is embarrassing to them. But if you ask patients, many of them have urogenital involvement when they swell.

GI attacks, of course, are very painful, disabling and disruptive. Before we had treatments or even imaging, many patients historically were taken to the operating room because the abdominal pain was so severe that the surgeons did exploratory laparotomies, due to the severity of the pain.

Airway attacks, fortunately, are much less common than these other types, but are very serious. The mortality rate for untreated HAE attacks historically has been as high as 30%. This is something we worry about. We counsel patients about the threat and the unpredictability of airway events.

There are some prodromal symptoms that can precede the actual swelling. You see them listed here. Erythema marginatum is probably the most specific, the sort of lacy, serpiginous red rash that occurs often a few hours before the actual angioedema. Some patients will mistake this for hives. They will tell you they have hives, but if you saw it as a clinician, you would say that looks different than urticaria. But at any rate, that can be quite specific for HAE attacks.

These others tend to be a little more non-specific and vague and maybe not as good of predictors. But some patients have very reliable prodromes, which can be useful in anticipation of needing their acute treatment.

[00:10:12]

HAE Impact on Health-Related Quality of Life

Now, not surprisingly to any of you, HAE has a huge impact on health-related quality of life. There are many studies showing this. This is just a single study of 90-some patients using a validated tool, the EQ-5D-5L, which is, of course, a health-related quality of life, a snapshot in time of their health, quality of life.

You can see between attacks, this population was pretty comparable to the normal population in the US. But if you look at when they have swelling, you see this dramatic decrease, not surprisingly, due to the pain and disability of these episodes. Of course, the more severe the attack is, the more it impacts their quality of life. This just shows that these attacks do have a huge impact on people.

In fact, there is some association with poorer outcomes if you delay that on-demand therapy, which is why there is a huge emphasis in the guidelines to treat attacks early with an effective, HAE specific medication.

[00:11:14]

HAE Impact on Psychosocial and Financial Health

Lots of data and studies showing that HAE, at least historically, has been associated with anxiety and depression. We are hoping this changes as we manage it better, but this is, in fact, reality up until this point that these constant threat of unpredictable symptoms really weigh on people. It is a huge emotional burden. It affects their work. It causes social isolation. People, in fact, miss work. They miss school. And it has been shown to have a negative impact on their career trajectory, on their educational attainment.

These studies here, you can see look at anxiety, severity or depression severity. What I will point out is that, of course, the more severe your anxiety or depression, the more impaired you are when it comes to work productivity and activity impairment. But it is not just missing work. You can see absenteeism is affected a little bit, but the other domains, activity, work productivity, presenteeism. You can show up to your job or your school, but you do not get much done and you are not very productive. Again, even outside of the attacks, this is a chronic issue that HAE patients have dealt with. It, of course, affects their ability to travel and do other things, other activities, with their family as well.

[00:12:37]

Managing the Burden of HAE Treatment

So recognizing there is this burden, a lot of focus with our therapies has been can we reduce the burden of HAE? We have made progress. Some of these measures have been built into clinical trials, and we are extremely grateful for the progress that has been made.

This is some data presented by Stephen Betschel at the European Academy of Allergy meeting showing that as recently as a couple of years ago, patients still had issues. They still had burden on their daily activities despite having HAE on-demand and prophylactic therapy. You can see here over 90% of patients alter their plans after an attack. Over 90% do not feel like themselves due to their HAE. And over half had their travel, work and social activities affected by the condition.

While there has been a huge amount of progress, we are not quite there yet. We have not truly normalized people's lives, even with the advances we currently have in our toolbox to manage the condition.

[00:13:44]

          Posttest 1

Let us revisit one of our questions. Which patient-reported concern is most commonly cited as a primary contributor to decreased quality of life in individuals with HAE? Same answers as before. Is it:

1. Concern over the genetic transmission of disease;
2. Fear of spontaneous attacks interfering with activities;
3. Dissatisfaction with prophylactic medication adverse effects; or
4. The financial burden of diagnostic testing.

Would you answer this the same or differently from your previous response? We will have a look at the answers. Great. I do think this is the best answer. I think most of you answered this to begin with. Of these concerns, this is the one we hear over and over in the research looking at patient concerns.

[00:14:38]

          Posttest 1: Rationale  

If we just look at these answers quickly, again, as I have said a couple of times now, it is this unpredictability that really drives the anxiety, the depression, the interference with work, school and other activities.

Now, A is absolutely true. Patients are worried about transmitting this to their kids. It is one of the things we have not been able to fix, even with our therapeutic advances. It is still a genetic condition that can be passed on.

The dissatisfaction with prophylactic medicines. Fortunately, these medicines have been quite safe in general. There are some side effects that we will see when we go through the clinical trials. Some patients may be dissatisfied with that, but that has not been probably the major concern.

Then financial burden is always a concern, probably not so much related to diagnostic testing, but certainly when we talk about management, the cost of medications and so forth. That does become a major issue for many patients. So probably not so much in the testing. Could be, but more with the therapies that we are using to manage HAE.

[00:15:43]

Implementing Long-term Prophylaxis in HAE: Practical, Patient-Centered Strategies

Let us talk a little bit about now the treatment strategies. Of course, we will try to keep this patient-centered because we have to work with our patients to develop the best plan for each of them.

[00:15:55]

General Treatment Strategies for HAE-C1INH

As you will recall, we have these 3 strategies that we use to manage hereditary angioedema. First and foremost, on-demand therapy. This is medication, of course, used to stop an attack at the time it occurs. This is necessary for all patients. We have a rule at our center. No one that has a new diagnosis leaves the office without a plan and a prescription for a rescue medicine, because, again, you just do not know when and where these attacks will hit and they can be life-threatening.

The guidelines recommend that patients have enough medication to treat at least 2 HAE attacks. So on-demand therapy for everyone.

We would not spend a lot of time on short-term prophylaxis, but recognize this is important to mention to patients because this is short-term treatment used before an event or a time span where we might expect a high risk of attacks. Most commonly, we talk about surgical procedures, intubation, dental procedures because we know that can trigger HAE symptoms.

Sometimes, though, we are talking about situational prophylaxis, which kind of refers more to life events. This could be, you are getting married, you have a big final exam, you have a vacation that you do not want to have screwed up by an attack. There may be short periods where we use prophylaxis, but not necessarily for medical procedures. So that is important to recognize.

But we need our patients to know about this, so they inform us about these important either procedures or events, and we can help them get through that hopefully minimizing the risk of HAE.

Then long-term prophylaxis, which is just what it sounds like. This is medicine, of course, taken regularly to decrease the frequency and the severity of these attacks. Ideally prevent them entirely, although that is certainly not true for all treatments and all patients. But a lot of our efforts in recent years have been in this long-term prophylactic domain, because it can potentially get the patient closest to normalizing their life, to putting HAE in the background.

May not be used in every patient, but increasingly, we are seeing patients migrate to preventative treatment. I think that makes sense. That is the evolution of medicine. Why wait to get sick if you can prevent the condition from making you ill in the first place?

As we walk through this, just remember, we have some choices now. So individualization has become a buzzword, like it is for a lot of the things we treat, trying to tailor the treatment plan for each individual patient.

[00:18:32]

Considerations for Therapy Initiation

Now, as we choose therapies and make decisions with our patients and their families, there is a lot of factors to consider. You see attack data on here a lot, attack frequency, location severity. And absolutely, that is important. It is what we have always focused on because that is the major symptoms of the condition, these attacks that we are trying to navigate or prevent.

But recognize as we have evolved, there are other factors. It is not just about attacks. It is about quality of life, as we have talked about. It is about the patient preference and what is going to work best for their goals and their life. It is about resource availability. While attacks are important, I would say we do not want to exclusively focus on that. Do not forget about these other important considerations as we put together management plans.

[00:19:20]

Clinical Assessment Tools for Angioedema

We have gotten better at measuring some of these other factors. There is actually a slew of tools now that have been validated. You see some of them here, and of course, you are not expected to read this fine print. But some of these look at the activity of the angioedema attacks. Many of them incorporate quality of life measures. I just draw your attention to that third panel over. That is the angioedema control test. It is 4 questions. It is very quick and easy for patients to fill out before they see you, while they are waiting to see you.

It is analogous to the asthma control test that many of us are familiar with. But it has been validated. If you score 10 or higher, that is considered to be well controlled. If it is lower than that, we have some work to do. So it provides another angle, another snapshot that we can look at and use as we have visits with our patients, do we need to make changes or are we accomplishing our goal in terms of controlling the angioedema condition?

[00:20:17]

On-Demand Therapy and Short-term Prophylaxis

Just a few words about on-demand therapy and short-term prophylaxis, and then we are going to turn to long-term prophylaxis.

Again, on-demand therapy can never overlook this because we do not have perfect preventative measures yet. The recommended effective HAE meds are listed here:

• Icatibant;
• Ecallantide;
• IV C1 inhibitor;
• Many of you know there was an oral on-demand HAE medicine, FDA-approved a few months ago, sebetralstat.

If you do not have access to those or patients do not have access to those, you can consider some of these second and third-line therapies, recognizing they have not been proven to be as effective or as safe as those first-line treatments.

Just a reminder, again, ideally, patients have enough medicine to treat at least 2 attacks because these are unpredictable and because they may have a second attack before they get their medicine refilled after treating an attack.

Short-term prophylaxis I mentioned. Again, mostly we need to hear from our patients when they are going to have procedures that can trigger attacks.

IV plasma-derived C1 inhibitor is considered first-line. This is based on retrospective data. We do not have rigorous prospective data, but the retrospective data we have points to IV C1 inhibitor being the most protective or the most effective for short-term prophylaxis.

Again, you see some second-line agents there, recombinant C1 inhibitor, FFP, androgens, which could also be used and are likely to be beneficial in terms of preventing attacks during procedures or other events that may trigger HAE.

[00:21:56]

The Road to Long-term Prophylaxis

Let us turn to long-term prophylaxis, or LTP now. As I mentioned, there has been a lot of action in this area in recent years, primarily because it is best suited to reach this goal that is listed in pretty much every evidence-based guideline. That goal of disease control and aiming to normalize patient quality of life.

As I noted, perhaps not every patient needs or elects to go on long-term prophylaxis, but we are seeing more and more patients move in that direction. Certainly, the more frequently patients swell, the more severe attacks they have, the more complications they have, that is a patient where we need to strongly be considering prophylactic therapy, but we have to tailor it to our individual patients.

As I already mentioned, we have got effective options. I am going to show you the data on our current options for LTP. But there continues to be work going on in this area, because, as we already talked about, there are even very recent studies showing that patients are still not quite meeting their goals or the treatment that they are on is burdensome. There is a burden of treatment that is actually interfering with their life or their quality of life. So I think we will continue to see some evolution and advances in the coming years. And I will show you a little bit of data on what is in the pipeline that might help us to better reach these goals, reduce the burden of HAE, but also hopefully reduce the burden of treatment.

[00:23:27]

C1-Esterase Inhibitors for LTP of HAE Attacks

It is going to be a whirlwind, but let us talk about some of our options for long-term prophylaxis. This is data on C1 inhibitor for LTP of HAE attacks. As you know, C1 inhibitor has been around for many years, approved in 2008 as an IV prophylactic treatment and then a significant advance in 2017 with subcutaneous C1 inhibitor approved for long-term prophylaxis.

As you can imagine, we have really moved towards the subcutaneous route, not only because of the advantages of how it is administered, but the efficacy data looks better for subcutaneous  C1 inhibitor. You see these studies. I will draw your attention to this box in the middle of the chart, which shows the mean reduction in HAE attack rate 84% compared to placebo for the subcutaneous C1 inhibitor, 50% in the pivotal trial for IV C1 inhibitor.

These are effective therapies, have generally been very safe. You can see there are some AEs listed there. These are generally infrequent. This is a very effective and has historically been a very safe option for patients.

[00:24:39]

Lanadelumab: Plasma Kallikrein Inhibitor and mAb

A significant advance in 2018, when lanadelumab as a monoclonal antibody that targets plasma kallikrein was approved in the United States. This is, as you know, administered subcutaneously, generally started at 300 milligrams every 2 weeks, but can be shifted to 300 milligrams every 4 weeks if patients have an excellent response to the treatment.

I will just point your attention here to the right column in the orange. This is the starting dose, the highest dose of 300 milligrams every 2 weeks. You do not have the percentage here, but this was about an 87% reduction in mean reduction in attack rate compared to the placebo. Again, a highly effective medication now given every 2 to 4 weeks.

[00:25:32]

Lanadelumab: Safety Outcomes From HELP

These are the safety data from the pivotal trial. Again, this is generally been a very safe medication, no serious AEs. You can see the most common adverse effects were injection site pain or reactions, somewhat higher compared to the placebo. But otherwise a very favorable safety profile for lanadelumab.

[00:25:53]

EMPOWER: Real-World Efficacy and Safety for Lanadelumab in Patients With HAE

Here is some real-world efficacy data. This is a phase IV trial data, where patients were treated for up to 36 months, just to show that this efficacy is maintained. You can see this 85% mean reduction in HAE attack rate over this very prolonged treatment period of about 3 years. About half of the patients reported some AEs, but most were mild or moderate. So evidence of a durable efficacy for this treatment in preventing attacks.

[00:26:26]

Berotralstat: Plasma Kallikrein Inhibitor

The next advance came along in 2020, and this was berotralstat, which was an oral targeted drug, an oral plasma kallikrein inhibitor. There has been considerable interest in specific oral medications in HAE. This pivotal trial on the left showed the highest dose of 150 milligrams once a day, a 44% reduction in the mean attack rate.

In the population not quite as high as we are seeing with the subcutaneous drugs, but much more variability. If you look at the subset of the responder analysis, there are patients where this drug is very effective. That was also seen in a significant reduction in HAE attacks that required treatment with this once-daily oral medicine.

[00:27:17]

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

Again, this has been a very safe medicine. We had long-term efficacy and safety data from this open-label study. Again, you can see here, out to 96 weeks, this significant reduction in HAE attack rates. This study over 96 weeks also demonstrated the safety of the medication with no major safety concerns.

I will point out, there was diarrhea in about 15% of patients. This has been something we discussed with patients, because a subset of them will develop some GI side effects. These are usually mild to moderate and manageable. It has been fairly rare for people to discontinue due to that, and generally decreases over time. But this is a little bit of a unique adverse effect in a subset of patients with the oral medications that we should certainly be discussing and helping our patients manage through, if they elect this as their long-term prophylactic therapy.

[00:28:16]

Garadacimab: Activated Factor XIIa Inhibitor (mAb)

Now we are up to the present year, 2025, and we have seen a couple of additional long-term prophylactic options, approved by the FDA. One of those being garadacimab. This is a monoclonal antibody targeted at Factor XIIa. Recall, Factor XIIa sits up top of the contact system, the kallikrein bradykinin system. This has been a useful target for HAE prophylaxis.

You can see in this phase III study of garadacimab given subcutaneously now once a month, that there is this significant 87% mean reduction in the mean monthly attack rate. So very strong efficacy.

On the right, you see a responder analysis. I will point out here at the far right, the orange bar, 62% of the patients receiving the active treatment were attack-free during this 6-month study, where only 8% of the placebo were attack-free. This attack-free status is something we are thinking about more often. Again, can we completely prevent attacks? It is not attainable in all patients, but increasingly being looked at in studies as an outcome. So that was interesting to see in this particular trial.

[00:29:39]

Garadacimab Safety: VANGUARD Study

Again, if we turn to safety, garadacimab has been quite safe and tolerable. You can see some of the side effects here in low numbers of patients. In fact, the injection site reactions were quite low in this particular trial.

You see over here AEs of special interest. Because Factor XII has a role in the coagulation system, there has been a very close eye on things like bleeding or clotting. Fortunately, there have not been any signal or events of concern for these areas of special interest. So that has been reassuring both in the pivotal trial and now in open-label extension studies.

[00:30:21]

VANGUARD OLE: Long-term Efficacy and Safety of Garadacimab in Patients With HAE

Here is some of that open-label efficacy and safety data. Again, for patients that were on 12 months of treatment, you can see this consistent efficacy, responder analysis showing somewhere between 50% and 63% of patients were attack-free during this open-label trial.

Again, the safety data set is fairly reassuring. You can see the injection site reactions are a bit higher, though, we do not have a comparator group in this open-label trial. Then low levels of things like headache and nasopharyngitis.

[00:30:57]

VANGUARD OLE: Mean Improvement in AE-QoL Scores

This is some quality of life data. Again, as you probably know, this has been integrated into most of the clinical development programs now because we want to measure that. We want to know that these medications not just prevent attacks but improve quality of life.

What is interesting about this, as you can see, in these cohorts, so attack-free, and 1 or more attack during the study period in groups that were either naive to garadacimab or had previously been on garadacimab. What I will point out is lower is better here for AE-QoL scores. You can see the significant difference from baseline to treatment.

The minimally clinically important difference here is 6 points. You can see it far exceeds that from baseline to treatment. But there is also a difference in patients who were attack-free compared to just even having 1 attack, so 23 down to 8. That is far more than 6. And same over here, 19 down to 8.

Again, this idea that being attack-free does have benefits when you measure quality of life even to having a rare attack here and there. That is something we continue to look at in trials.

[00:32:11]

Donidalorsen: Prekallikrein-Targeted Antisense Oligonucleotide

The other major advance this year has been the approval of donidalorsen. Donidalorsen has a unique mechanism of action. It is not unique in medicine. It has been used in other areas, but it is unique to our field. This is an antisense oligonucleotide. It is actually very precisely targeted at messenger RNA, in this case in hepatocytes. This is a medication that hones into hepatocytes very precisely degrades mRNA for a very specific protein. In this case, it is plasma prekallikrein.

If you reduce the amount of plasma prekallikrein coming out of the liver, you do not have substrate to make bradykinin. This is the strategy for preventing attacks.

You can see in this phase III study that looked at either every 4-week subcutaneous dosing or every 8-week subcutaneous dosing. There is this significant reduction in attack rates, if we jump over to the table with the every 8-week, it was an 81% reduction in mean attack rate and 55% for every 8-week dosing.

If you look at attacks that were required treatment, it was 92% reduction for the every 4-week dosing. Again, we are seeing these dramatic reductions. What is interesting here, you see the every 8-week dosing, the further you go out, out to 25 weeks, these lines start to converge. Based on the labeling, this is a medicine that might make sense. You can decide with your patients, but it might make sense to start it every 4 weeks and then move out eventually to every 8 weeks if they are doing very well. So less frequent dosing, less burden of treatment.

[00:33:54]

Donidalorsen Safety: OASIS-HAE Study

This is the side effect profile or the safety data from the pivotal trial. Again, very reassuring overall. You can see again the most common adverse event reported was injection site reactions in a small subset of patients. Otherwise, AEs were mild or moderate and generally not much difference from placebo, overall, for both the every 4-week and every 8-week dosing.

[00:34:21]

OASIS-HAE: Donidalorsen Impact on Quality of Life in Patients With HAE

Again, quality of life. Important to have a look at this. You can see these significant improvements in quality of life if you look at the AE-QoL data, again, most prominent for things like functioning, which is very important compared to placebo, and work in productivity and activity impairment. Again, these very significant reductions, most prominent for the every 4-week dosing in this pivotal trial. So people getting back to work, getting back to school, compared to those that were on placebo.

[00:34:54]

Adherence Among Patients With HAE Receiving Long-term Prophylaxis

Now, having said all of that, we have really generally very effective tools. We have choices. How do we put together a plan for our patients? This was an interesting study looking at adherence for patients, because as it turns out, these medicines only work if our patients take them, if they only stick to the recommended schedule that has been shown effective.

PDC1 is product coverage. It basically is a measure of do you have enough medicine for the number of days that you are supposed to be treating? It looked at EMR or EHR claims data for prescriptions. They did 2 different analyses in this study, so that is the 1 and the 2. But generally people, at least most of them, fill enough medicine for the number of days that we are trying to treat them for.

You can see, depending on how you look at the data, it is either better than 90% or better than 60%. But what is interesting is it does not really matter if it is oral medicine or if it is subcutaneous medicine or how frequently it is dosed, which I think speaks to the fact that our patients have different preferences in what they are willing to do or would like to do for their treatment.

If you look at persistence here, and this is, did patients keep refilling their prophylactic medicine up to 12 months? We are not surprised, there is some fall off, around 70% or 80%. And by 12 months, we are 50% to 60%. But again, you do not see dramatic differences based on the actual medicine that is being prescribed. I think this speaks a little bit to the complexity of decision-making, matching a medicine to our patients preferences.

You can see here they also asked about patient factors, what was most important to them? No surprise that cost and insurance coverage is right at the top of that list. But things like convenience, administration, route and safety are very important to our patients. I think we need to be asking about these things because adherence is so critically important.

If we make good matches with our patients, we can get most of them to stick with their treatment and reap the benefits of that.

[00:37:08]

Shared Decision-making 3D Model in HAE Management

That brings up this concept of shared-decision making. Again, this is a new to those of you that are in clinical practice, but it is really applicable to HAE, because it is such a variable condition and because we have some choices now in the treatments that we may prescribe. This all starts, as you know, with discovery, listening to our patients, asking about their needs, their goals, making sure that they know that they have options.

Then I think where we, as specialists come in, is up here, discussion. We know the data. We know the efficacy. We know the side effects, the safety concerns. Making sure our patients have reliable evidence-based data to match up and make decisions with their specific goals and preferences. I say I am notoriously bad at predicting what a given patient will choose to do, and that is part of this conversation. I know the data, but I do not know exactly where they are coming from or how HAE may affect them.

Then, of course, we make decisions based on these conversations, and we go round and round. This is, of course, not a static condition. The symptoms may change, the attacks may change. Life changes with things like pregnancy and work and travel and family life. So we need to follow up with our patients and make sure that whatever plan is in place, it is actually working as designed. As treatments change, we may want to adapt or adjust the treatment plan as new options become available.

[00:38:38]

Rethinking HAE Management

This is just a conceptual wrap up slide of this section. I think we have continued to move the goalpost with HAE. When I started specializing in HAE, we just wanted to keep people alive. That was the goal. We put them in the hospital, in the ICU. That is still the goal, of course, and occasionally it comes to that putting someone in the hospital, reducing their pain, reducing the mortality or preventing the mortality. But we are aiming for much more than that, reducing the disability, and ultimately that goal of reaching a life without HAE interference.

On the right, these are just some questions I try to ask my patients:

• Do you feel in control of the condition;
• What are the concerns you have about your medicine;
• It may be working good enough, but can we improve on the efficacy, on the side effects, on the burden of treatment in some way; and
• Then, my favorite question is, what are you not doing or not doing well because of HAE?

I leave that open because I am always surprised at the responses. Of course, you hear about work and relationships and travel, but certain hobbies, certain family issues, what are they struggling with?

I think leaving that latitude for patients to fill in the blank and then working backwards from there, can we make a change in treatment that will allow them to pursue those goals without HAE perhaps getting in the way or being constantly on their mind?

[00:40:06]

          Posttest 2

We are moving towards the last section here. Here is a second post-test question. You recall our 45-year-old gentleman. He has got HAE. It is generally well-controlled on lanadelumab every 2 weeks. But he is honest with you that he is missing some doses. He is tired of doing these injections every 2 weeks. He does have some baseline GI symptoms due to IBS. He is asking you for your recommendations. What is the most appropriate next step to improve his acceptance and adherence to an LTP strategy? Our options are:

1. Encourage him to remain on his current treatment due to the favorable efficacy and safety;
2. Consider a subcutaneous long-term prophylactic treatment option with less frequent dosing like every 4 to 8 weeks;
3. Consider oral long-term treatment options; or
4. Discontinue LTP and just go with on-demand since his HAE episodes have decreased.

Which one do you think is the best advice? Let us see what you think. Okay, great. Again, I do not know that there is necessarily a right or wrong here. I would probably favor number 2 like most of you. I think he is obviously willing. He has done subcutaneous treatments. The frequency is what seems to be wearing on him.

I showed you a couple of options. One of them being donidalorsen, which could be dosed every 4 weeks, perhaps even every 8 weeks. There are other treatment options that are dosed less frequently. That might be the place to start.

[00:41:55]

          Posttest 2: Rationale

The oral treatment also would be a good consideration. The only concern about the oral treatment is that it does sometimes have these adverse GI side effects. He has already got some chronic GI issues, and so you would at least want to have that conversation. He might do fine on it, but that would be something you would have to navigate as a side effect with the oral medication that we have available currently.

Finally, I think discontinuing LTP might be a little misguided. You could try that. But he needed to be on LTP before. Generally, these people go back to their baseline frequency and severity. Just going with on-demand treatment might be a little bit anxiety provoking. However, the new oral on-demand treatment option might change the math for him somehow.

Anyway, I think B is the best answer, but this demonstrates we have got options. You have to walk through these options with individual patients.

[00:42:53]

Advances in New and Emerging Therapies for Long-term Prophylaxis in HAE

For the last few minutes before we move to some question and answer, let me show you what is happening in the pipeline, because I do not think we are done yet. I do not think we have quite arrived. We have come a long way.

[00:43:05]

          Goals for Prophylactic HAE Therapy

But a lot of efforts continue to see can we prevent attacks either more effectively or with less burden of treatment? You see some of the goals here:

• Less frequent administrations;
• Easier ways to administer medicine;
• Fewer side effects; or
• Just simply taking less time out of life to deal with your HAE treatment plan.

These are all goals of some of the emerging therapies or investigational therapies.

[00:43:32]

HAE Therapeutic Targets for Long-term Prophylaxis: Emerging Therapies

This is a map, again, of the contact system. Everything that we have been talking about is predicated on this understanding of prekallikrein, kallikrein producing bradykinin and bradykinin of course causing the symptoms, the swelling of HAE. We have gone over a number of these medicines that we already have approved for use.

What is emerging still are come in different categories and they are color coded here. There is a monoclonal antibody, navenibart, and it has a prolonged half-life that is being developed targeting kallikrein. We have other RNA-targeted therapies and specifically a program with siRNA. The advantage there being that you might be able to dose that once every 3 months, every 6 months, maybe even less than every 6 months and still prevent attacks by preventing prekallikrein production.

There are other oral medications. The one that is furthest along is deucrictabant, which is an oral B2 receptor antagonist that is being looked at for both prophylactic treatment but also to treat attacks.

Finally, there is a gene therapy program in human studies, CRISPR-Cas9 technology that basically reduces pre-kallikrein production from the liver by targeting the KLKB1 gene with a single dose, ideally having long-term preventative effects.

[00:44:54]

Deucrictibant: Bradykinin B2 Receptor Antagonist Phase II CHAPTER-1 Trial Efficacy Outcomes

Let me very quickly show you some of the data, so you know what is coming along. This is deucrictibant, the oral B2 receptor antagonist. This is the long-term preventative phase II study, the so-called CHAPTER-1 trial. This is an oral medicine that in the trial was given twice a day. They have now have a long-acting formulation. In the phase III study that is going on, it is dosed only once a day. But you can see this B2 receptor antagonism was very effective at preventing attacks when taken daily.

You can see an 85% reduction in the mean monthly attack rate compared to placebo. So right there in the ballpark for what we are seeing with the subcutaneous drugs, but this time with an oral medication.

Now it is a phase II study. It is a small group of people, and so we will have to wait and see if this holds up in the phase III trial. But the phase II study showed very favorable safety.

[00:45:51]

Deucrictibant Safety: CHAPTER-1 Study

You can see there is really not a lot to talk about as far as side effects. One patient with dizziness. A patient with transient liver enzyme increases. So far looks very favorable in terms of the side effect profile.

[00:46:11]

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

This is long-term safety data. Again, small numbers, you can see started with 30 patients. This is as they go along. But there is almost 10 patients now that have been out for about 19 months. Point being that there continue to be very strong efficacy, very strong preventative effects, and really not much to talk about in terms of adverse events.

The phase III data will come out hopefully in the coming year, and we will see if this is a viable option for preventative treatment.

[00:46:44]

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

This is navenibart. This is a YTE-modified monoclonal antibody. Remember, the YTE modification allows recycling of the antibody so that the half-life is much longer. The goal here is to have a kallikrein inhibitor that could be dosed every 3 months or maybe even every 6 months and still effectively prevent attacks. Three different dosing cohorts here, either 450 once, 600 followed by 300, or 600 which is repeated 28 days later.

You can see in all 3 of these cohorts, small numbers of patients, but very strong efficacy. So over 90% reduction compared to their baseline attack rate with this monoclonal antibody. This looks very encouraging.

[00:47:34]

Navenibart Safety: ALPHA-STAR Study

Again, the safety, really not much to talk about, the most common being these injection site reactions in small numbers of patients. Phase III study also going on with navenibart, and we look forward to seeing a larger data set to see if this is safe and effective.

[00:47:51]

Gene Editing for Treating HAE

The last thing I will mention is gene editing. This is just a quick diagram, a reminder of how gene editing works, in this case, CRISPR-Cas9 technology. Lipid nanoparticles that are loaded with this CRISPR technology, targets the hepatocytes. Once in there, it is very specific at targeting a gene, in this case, the KLKB1 gene. You insert an indel, you stop the transcription or translation of prekallikrein. So you reduce the amount of prekallikrein that makes it out into the circulation, thereby preventing or reducing the ability to make excessive bradykinin.

[00:48:31]

NTLA-2002: CRISPR-Based Gene-Editing Therapy

This is the data that was published this past year in The New England Journal. Again, a phase II study. So relatively small numbers of patients, 10 in this 25 milligram dose, 11 in this 50 milligram dose, but a 1-time IV treatment that you can see very effectively reduces plasma kallikrein levels. So at the higher dose, you get these fairly dramatic reductions, 80% or greater. At the lower dose, not as robust. But you get below this 60% line, you expect to see clinical preventative effects.

That was borne out in the clinical data, where there was a 75% reduction in attack rate compared to placebo, the mean number of attacks per month, and a 77% attack rate in the higher dose compared to placebo. They now have data that they have continued to report. Some of these patients have been out to close to 3 years and continue to see this significant reduction in attack rate from this single dose. So cannot say it is a cure. Do not know how long it will last for certain, but it does seem to accomplish a very durable preventative effect in this small phase II study.

The phase III is ongoing, and of course, we will look at that closely.

[00:49:46]

NTLA-2002 Safety: Phase II Study

The side effects here were mostly related to the actual infusion. You can see a number of side effects that were reported in less than half of the patients, headache, fatigue, nasopharyngitis. I think with gene editing, of course, we are going to look at the long term, what is that safety and efficacy look like? But so far, looks encouraging. Again, we will have to see what this larger phase III study data looks like over the coming year or 2.

[00:50:17]

Additional Therapeutics in Early Development

I am not going to have time to go into these other early developments in clinical therapeutics. But be aware, there is siRNA therapy that is now moved into, in fact, a phase III study that is revving up. RNA interference treatment that might be dosed subcutaneously every 3 months. Every 6 months, maybe even less often than that.

Oral therapies, including a Factor XIIa inhibitor that is very early on. There continue to be interest in some other types of gene therapy or gene editing, though none of those have made it into human studies at this point.

[00:50:54]

          Posttest 3

All that being said, I am going to re-ask you this question. How confident are you in your ability to appraise the safety and efficacy data for emerging long-term prophylactic treatments for HAE patients?

1. Not at all confident;
2. Slightly confident;
3. Neutral;
4. Somewhat confident; or
5. Now very confident.

We will see if anything changed here. Okay, good. Yes, it was a lot to cover. It is a lot to digest in a short time. But I am glad to see more confidence than when you started. That is the whole point, that we gain some familiarity with this data and can communicate that to our patients.

[00:51:44]

Key Takeaways

We are near the end. Just a few closing thoughts. I hope that I have communicated that long-term prophylaxis really is an important part of how we manage patients. We have seen advances. We have many more options than we did a decade ago to offer our patients. But we still see patients having attacks. We still see a reduction in quality of life. Along those lines, there is also a treatment burden that we have to be cognizant of.

So that is the whole point of talking about this and looking at what is new and what is emerging, that we still may be able to improve the lives of our patients by looking at their treatment plan and making adjustments.

There are a lot of factors to consider. Of course, as clinicians, we always hold safety and efficacy as the gold standard. If a drug is not safe or it is not effective, it is not going to be favored by us or our patients. But there are other factors that are becoming important, the administration route, the schedule, and how does a given therapy fit into our individual patient's lifestyle and preferences?

I know we are all aware of this, but increasingly we really have to engage patients. Education is important, listening to their preferences that we know they come in with all kinds of notions from outside factors, some of which are accurate and some of which are not. So having these discussions, making sure they have good quality information and evidence to make their choices, that is really an important role that we play.

But recognizing we also have to bend a little bit sometimes or at least recognize our patients values. Again, I probably mentioned this. I tell my patients, “Listen, I am an expert in HAE. It is part of my specialty. But you are the expert in how this condition affects you and what you are willing to do to manage your condition.”

So we have to meet in the middle to make sure that patients get benefit from all these advances that we are discussing.

[00:53:47]

Q&A

I appreciate your attention. I hope this was interesting. We do have a few minutes for question and answer, which I am always happy about, because that is perhaps the most valuable part of any of this. If you have questions, please put them in the question and answer section and I am happy to take those as they come in. There will also be a few polling questions as I go through that you can give some feedback, as we wrap up here.

Let me look at what we got. Here is a really interesting question. I get this often. What level of dental procedures would you recommend using short-term prophylaxis or not?

Really, a good question, and one we do not have a lot of study data on. I can tell you that most of the data that shows an increased risk of HAE attacks is for what I would call oral surgery. Really kind of invasive tissue trauma, things like root canals, wisdom teeth extraction or tooth extraction in general.

Routine dental cleanings tend to not be an issue. I also have not anecdotally seen problems with orthodontics for the most part. Invisalign, of course, is very popular these days. Generally have not run into issues with dental cleaning, Invisalign, orthodontics.

But I think anytime that there is a lot of anesthesia used, injections, trauma to the gums, certainly extractions, that is where we tend to get into trouble with oropharyngeal or throat swelling. So I recommend short-term prophylaxis for oral surgery, those things that are more invasive.

Let me see what else we have here. Can you comment on any considerations in selecting between plasma kallikrein inhibitors versus other LTP options in patients with comorbidities or unique risk profiles?

I think this is getting at mechanism of action, which I also get a lot of questions about. Is there a mechanism of action that is right for a specific patient or a specific type of HAE or a specific age? I would say generally no. When we are talking about C1 inhibitor deficiency, we have not really seen any predictors of response based on levels, based on genetics, based on phenotype, if you will.

So I think it really does come down to efficacy, safety and patient preference in terms of how a drug is given and the dosing schedule. I cannot really say, this is a plasma kallikrein inhibitor patient. This is a C1 inhibitor replacement patient. This is a Factor XII patient. This is an RNA interference patient.

I would say one thing to be aware of is that, with the oral medicines, there are a few drug interactions to be aware of. We have been maybe a little spoiled with protein therapeutics, monoclonal antibodies and C1 inhibitor, and even the RNA-targeted therapies that do not really have drug interactions.

Now, as we are getting more oral options, there are a few drug interactions you have to look at based on CYP inhibitors and so forth. So that is something to look at if you are prescribing oral medicines is make sure you look at the patient's medication list, because now that is a factor that you may have to navigate. They are not common drug interactions, but they are there.

But outside of that, I would say it is really mostly about the study data, how well does a drug work? What are the side effects? That is probably more critical for most of our decision-making than any known MoA, if you will.

We have time maybe for 1 or 2 more. Yes, here is another good one worth pointing out. Have you had difficulties getting hospital systems to stock C1 inhibitors for unexpected acute management needs?

Absolutely. This is still a little bit of a bane of our existence, particularly we take care of a pretty large population. It is still quite unusual for hospitals to have access to C1 inhibitors. And we are fortunate in our hospital system where some of our patients go, we can facilitate that. But most hospitals that we deal with for our patients that travel to see us do not have that. So, if there is a need for rescue treatment using a C1 inhibitor, if there is a need for short-term prophylaxis prior to an unplanned surgery or even a planned surgery, we often struggle to get that in a timely fashion.

We do often have better success, maybe not for rescue treatment because that needs to be there immediately. But if we have a little bit of lead time, we have some success getting C1 inhibitor to our patients, we have to expedite it through the payers. And as we all know, that not does not happen quickly sometimes.

But getting it to our patients for them to take it to the hospital and then getting the hospital understand. They need to bring that medicine in if their pharmacy would not provide it. That is why I say especially for short-term prophylaxis, making sure our patients know, “Hey, we need a little lead time. If it is a trauma or unexpected, there is nothing we can do about that. But if there is a planned procedure, we need some lead time to get this medicine set up, ideally in your hands as the patient and talk to the anesthesia or surgeon so they know to give this ahead of time.”

Because to this person's point, it is unusual that they are going to have that sitting in the hospital pharmacy. So we have to overcome that barrier.

I would just add to that, we have very little data to know if short-term prophylaxis is still absolutely necessary for patients that are on effective long-term prophylactic therapy. Almost no study data to show if the LTP therapies we just talked about will prevent attacks during these surgical procedures and so forth. We need that data. In the absence of it, we still err on the side of caution of trying to get short-term prophylaxis with C1 inhibitor.

Hopefully, there has been some efforts to collect that data. Hopefully, we will know the answer to whether we need to keep doing this short-term prophylactic measures. But in the absence of that, ideally we err on the side of safety, which is giving C1 inhibitor before procedures.

We are nearly out of time. Let me take 1 more. I know some people have to move on with their evening. The last question I wanted to address was LTP for younger children and adolescents.

Again, be aware that if you have children or adolescents you are taking care of, have a look at the PI, have a look at the FDA-approved indications, because there are some age differences. We have a couple of options, but not as many options in children under the age of 12. Adolescents in particular is a time when being a teenager is hard enough. Many patients in that age group, they do not want to have the condition, and they do not want to do the treatment because there is a stigma attached to that.

That is a time when they are exerting their independence, where I think we need to be particularly careful, have discussions not only with the parents, but ideally trying to talk with the adolescent as, well, what are they willing to do so that we can keep them safe, keep them in sports, keep them in hobbies, keep them off to college or that first job without HAE being a burden or a disruption?

So I think that is a really unique time. We need more data on adolescents to figure out how best to navigate that. But those are unique populations, where hopefully we will learn more in the coming years and be able to better apply and use long-term prophylaxis.