Activity Transcript

Timothy Craig, FAACAI, FAAAAI, FACP, FACOI: Hello, I'm Timothy Craig. I'm a professor of medicine, pediatrics, and biomedical sciences from Penn State University. I'm pleased to be here with you today, and I'll be talking about the early actors in hereditary angioedema (HAE) as a review, to level the playing field. Then talk about pathophysiology, and then really try to focus on therapeutic targets that are on the horizon in phase 2, and phase 3, because that's where I think a lot of the exciting information lies.

My objectives today are basically to review the basics of HAE, show you the drugs that are now approved, are in that process of the pathophysiology. Then have you understand the new medications that have been recently approved, and those that are actually in research at this time. Obviously, the main outcome we want from presentations like this is to improve the care, and outcomes of the patients you treat with HAE.

So, before I start anything, I did want to split up mast cell, and bradykinin. So, most of the angioedema you'll see, is actually mast cell. Less would be bradykinin, with the exception of angiotensin-converting enzyme (ACE) inhibitor, which is relatively common. About 40% of people presented to the emergency department (ED) each year from bradykinin induced disease, from ACE inhibitors.

So, you have to remember mast cell is secondary to histamine. Most people will have angioedema with hives, some just angioedema, some just hives. These people tend to be itchy, they have erythema. The histamine for some reason, prefers the face, where abdominal pain is usually not the case, unless someone has profound anaphylaxis, and mast cell induced angioedema is not hereditary.

In turn, bradykinin is hereditary. These people don't get redness and itching. They don't have hives. If they have hives, you can actually exclude the diagnosis. And here, instead of just the skin, it also affects the upper airway, less so with histamine induced disease. Also, though, in bradykinin, it really affects the abdominal, and about half the attacks in HAE will be abdominal, and it'll get obstruction with nausea, vomiting, and severe pain. So, that kind of sets the stage, so just separating those that are histamine, or mast cell induced, vs bradykinin.

So, the different bradykinin disease, there's hereditary, we call type 1. Type 2, those that have normal C1 inhibitor induced HAE, and then there's ACE inhibitor induced angioedema, and finally acquired angioedema, of low C1 inhibitor.

I am going to be focusing on these two today. That is type 1 HAE, where the protein is not secreted because of protein abnormalities, which don't allow the protein to fold correctly. So here, the protein will be low. The function because of that will be low, and C4 would be consumed. In type 2, here the enzymatic head is defective, but the protein folds correctly, and is secreted. So here, the protein could actually be normal, or high, but the function's low. And again, C4 is consumed.

In HAE, we've got normal C1 inhibitor. All the tests are normal. An ACE inhibitor induced angioedema, this is the C1 Esterase inhibitor is not metabolized. So here, all these tests will be normal, but bradykinin will be high. Then in acquired angioedema, with low C1 inhibitor, that usually occurs in older age. It can look just like type 1, or type 2 HAE, but instead, usually occurs later in life. Here the test that distinguishes HAE from acquired angioedema with low C1 inhibitors is actually C1Q. But not 100% of times that'll be the case, but it's usually what's asked for test purposes, at least.

There is this other, which is HAE, with normal C1 inhibitor. Unfortunately, most of these people don't have a firm diagnosis. It's supposed to be extremely rare compared to type 1, and type 2. But some databases like the French, has like 30% of their patients have normal C1 inhibitor HAE for some reason. Since most of these people can't be diagnosed except with genetic testing I'm not going to talk about this at all. But, I will be spending the time from now on, on both HAE 1 and 2.

So, I want to say before anything else, most of our therapies in the past really focused on on-demand therapy, that is a person has symptoms, they take their medication, and they get better. Since about mid 2000 teens, like 2017, now we've really focused on prophylaxis. That's what is really exciting.

And so, in the past, it was this woman having swelling, and getting to this point where she was normalized, to now, in this day and age, and especially a lot of the new therapies, we are looking for this lady to worry as much about swelling. She can go to camp, she can go to soccer tournaments. She can go to school, hoping not to worry about her angioedema. She'll always have to carry rescue, but I'm hoping with the new drugs, as well as those that have been recently approved, they work so well that I've had people who had no attacks at all for 4 or 5 years, on both lanadelumab, and sub-QC1 inhibitor. And I think the new drugs on the horizon are actually giving even better efficacy.

So, let me first just go through the pathophysiology. So, this is C1 inhibitor, that's defective in type 1, and type 2. C1 inhibitor has a variety of roles. C1, the first component in the complement turns over all the time. If you don't have C1 inhibitor there, C4 is consumed. And that is a good kind of screening marker for HAE in some low and mid income countries, who really have nothing else available, except for C4. Between attacks, it's not 100%, it's about 90%. During attacks, it's almost 100% accurate.

It also affects the coagulation pathway too, a little bit, not much. It does affect the fibrinolytic pathway, and these people often have elevated D-dimers during attack, and in severe cases all the time. But the main role is to shut down the contact pathway. So, very important contact pathway is initiated with factor XII, and we'll talk about the new drug that's in research right now, that inhibits factor XII in a little bit.

So, factor XII turns over all the time, similar to the first component in the complement. If you don't have C1 inhibitor there, it becomes activated. It then goes back, and activates more factor XII, so it's a cascade, or a vicious cycle. Once it's activated, it turns prekallikrein into kallikrein. Kallikrein itself also can activate factor XII. So again, you get this double cascade. Finally, kallikrein splits, high-molecular-weight kininogen into 2 pieces. One goes off, the other becomes bradykinin, which brings us to this next slide.

Bradykinin is produced, binds to the B2 receptor on endothelial cells, generates cyclic guanosine monophosphate (GMP), prostacyclin, nitric oxide, and that's what happens in this next slide.

So, here you can see these are endothelial cells, right? You can see the green is a tight junction. Pink is the nucleus. These are not stimulated with bradykinin. Here you can see the same cells, still not stimulated. You barely see any microtubules of actin in them. Then you put bradykinin on there, and look at that tight junction, it just dissolves. If you look here inside the cell, those microtubules of actin are pulling that cell inward, away from its buddies, and colleagues around it. So, you can see how fluid shifts from the blood, or the blood space, into interstitial space, causing the angioedema we see in people with HAE, leading to bowel wall swelling, leading to upper airway swelling, and leading to skin swelling.

So I'm going to use this right here, as we talk about the drugs that are in process already, or approved, and those that are in research right now, as I go through my slide deck. So, let's first look at what drugs are on demand. Now, I'm not going to spend a lot of time, but I think it puts it in perspective of what's changed over the years. So, you could see, C1 inhibitors available. And in some cases, you can use that fresh frozen plasma (FFP), all work by increasing that pool of C1 inhibitor, which shuts down the contact pathway.

We also have ecallantide, that works by shutting down the activation of kallikrein. Then we have icatibant, that binds to that B2 receptor in a competitive fashion, to prevent bradykinin from binding to it. So that's what we have available for acute therapy. So ecallantide is available for 12 years and up. It does have the adverse effect of about 3 to 4% risk of allergic, or anaphylaxis from it. There's icatibant, which is available for up to 18 years and above. In Europe, it is approved to down to the age 2. About 97% of people who use icatibant will have some skin changes, either pain, or burning, or itchiness at the site of injection.

Then we have plasma derived, which is intravenous (IV) for rescue, and that's available for children, adults. It does everything you want a C1 inhibitor to do. It inhibits the contact pathway, plus the others. Then we have recombinant C1 inhibitor. It's available for adults, and adolescents. Has similar action as plasma derived. Its half-life is much shorter though because the polysaccharide that the rabbits accidentally add to the protein shorten the plasma half-life of the drug.

So, the important thing from this slide is that all these medications, none of them are 100% effective. They have varying effect, but in about 10% of cases, people will need a second dose. The importance of that is, you always have to make sure people have 2 doses available.

So, let's quickly look at short term prophylaxis, and that's important for people going under medical procedures, surgery, dental work, or even say, if they're getting married, right? Or having a final exam, or an important interview. So here are the drugs that work, a plasma derived C1 inhibitor, maybe recombinant derived C1 inhibitor, an FFP. Again, they all add to that pool of efficient C1 inhibitor. Some people in low income countries do use tranexamic acid. The data is not as good. The guidelines say probably it is not adequate. And that's what really, basically we have for short term prophylaxis.

The reason why C1 inhibitor is the most important, you can see, it has about a 30 hour half-life. Now, granted that half-life varies by who you study it in. If you have a severe person with C1 inhibitor deficiency, vs mild, vs normal, that half-life is going to change when remarkably. But the human derived are about 30 hours, plus minus.

You can see ecallantide and icatibant are 2 short acting. Recombinant C1 inhibitor may be effective, but it is those polysaccharides cause the drug to have a much shorter half-life. Subcutaneous (subq) C1 inhibitor has a delayed onset. Lanadelumab has a delayed onset, so you can't use them. Same with berotralstat. Danazol does work, but it induces the protein, so they have to start 5 days before, and the toxicity associated with using danazol long term, for long term prophylaxis, really just is not of importance when you use it for short term. Then you have the tranexamic acid, which has minimal data, but if you don't have anything else available, it's probably worth trying. And that's true in most low, and medium income countries.

Now, one of the important things are what dose should you use? And this is a study done by Bork. He showed using C1 inhibitor with no use of any therapy, about 22% of people have an attack after dental work, and extraction. If you give them 500 units of C1 inhibitor, you reduce that down to 17. If you give them 1000, you reduce it down to about 7. My feeling, if you give 20 units per kg, that puts the normal weight person, right about at 1500 units, then hopefully there will be a decreased risk. That also allows you to titrate the dose for a very small child, vs a very large man.

So, who needs prophylaxis? Well, the guidelines really are not too definitive on who needs it. Actually, they say there's a lot of soft areas that are important to consider. So, obviously the burden of disease, if someone has a lot of attacks, if someone can't go to work, if someone is overwhelmed by anxiety, or a posttraumatic stress syndrome, that's important to take into consideration.

How often they have attacks is important, because remember anxiety changes at the time of an attack, and that time after, the anxiety's high, and then slowly between attacks, it goes back towards normal. If people have severe attacks, especially if they're intubated, that can really interfere with their anxiety, and post-traumatic stress syndrome. So, that has to be kept in mind. Urgent care is important. If you live in northern Canada, and you have to take a dog sled to the hospital, I mean, obviously you might want to use prophylaxis.

Then we have all those soft attributes as well. So, is someone going to work? Are they being productive? Is the disease interfering with that? Are they able to go on vacation with their family? Are they able to go on a plane without worrying about dying? Are they able to sleep at night without waking up, or worrying about waking up with airways swollen? So all that is taken into account, in who should, and who should not be on prophylaxis.

So, what drugs are available right now for Long-term prophylaxis? Well, there's plasma derived C1 inhibitor, IV, and there's also subq. You could use FFP, but the problem with that is there's risks of allosensitization, and other risks of viruses. You can use androgens, but you have start them 5 days before, and a couple days after. They do work, there's no doubt about it, except toxicity limits their use. You could use tranexamic acid but the data are minimal. The guidelines, which mainly represent what we do in high income countries, say it's not adequate to use. But for low, and medium, I really do feel that if there's nothing else, it's worthwhile to try it. Then we had the kallikrein inhibitors, berotralstat, and lanadelumab. Berotralstat just approved a year ago, December. Lanadelumab, I think 3 or 4 years old. So that's where we are right now in therapy. So, let's just quickly look at them, and then I'll talk about what's on the horizon.

So, C1 inhibitor, plasma derived IV, approved for 6 years and older. The problem here is the drug burden from the IV needs. It was approved for 1000, but the FDA has approved the dose to 2500. But please remember when you increase that dose, you also increase the cost. There's plasma derived subq, which causes a depo effect. It's also available for 6 years and older. The dose is 60 units per kilogram, and it's tolerated well.

And then we have lanadelumab, which is approved for 12 years and older, and it's 300 milligrams every 2 weeks. It's also approved for 300 milligrams once a month, and it's also works at that, the efficacy decreases. Then we have berotralstat, which is approved for 12 years and older, at 150 milligram. They do have 110, in case you need it because of liver, or kidney dysfunction. Then there's danazol, which I won't spend much time on. It is 200 milligrams, for once a day or less. And then you have tranexamic acid, again, which is not recommended by guidelines.

So, here's IV C1 inhibitor, at a 1000 units twice a week. This is birds on a wire. This is the placebo treated people. You can see how dense this is. Each of these slashes, if you want to call them that, is the severity, the rescue use of a medication, as well as the duration. So, you can see, you move into those people on treatment, and look at the difference. You can see really a radical difference in density. But this decrease was only a 50% reduction of attacks. And when we talk about the next few drugs, you'll see that there is an improvement from this. This was, I think, approved in 2008. So, in the mid 2000 teens, you'll see the other drugs that were approved, that have much greater efficacy.

This is looking at subq C1 inhibitor. Now that study was done with 40 units per kilogram, and 60 units per kilogram. The FDA approved a 60, and I'm glad they did, because quality of life's greater with the 60 than the 40. But let's look at their birds on a wire. So, you can see here, this is the placebo. You can see how dense it is. You look at those on therapy. You can see a remarkable difference in densities, showing that there's decreased number of attacks, decreased severity, decreased rescue use. If you look at median, it's about 95% reduction of attacks, if you look at mean it's about 85 plus or minus a point.

If you look at the compact study in a different way, I think it is relatively remarkable, and when you look at that 60 units. So here people coming into this study, this is with subq C1 inhibitor. The people who had over 4 attacks per month, so really severe people. On that 60 units per kilogram, you can see their attack rate decreased significantly, to 0.52, showing that there was a drastic reduction in these very severe people, to less than an attack per month, which I think is very remarkable. Again, I've had people on this drug now for many years, some for 4 or 5 years between studies, and so on, who have been attack free.

If we look at instead at lanadelumab, which targets kallikrein, you can see here, birds on a wire, again, the placebo group. And then you look at the reduction, 80% reduction of attacks. And the adverse effects are really minimal. Mainly site reactions, very similar to the subq C1 inhibitor I just talked about, which the major side effect was actually site reactions as well.

If you look at the HELP study, this is again, lanadelumab. This is looking at their placebo group, much milder group than those who are on the C1 inhibitor subq trials. But you can see they were also very good at reducing it to less than an attack a month, where they would normally almost have 2 attacks per month. So again, very effective therapy.

This is the data on berotralstat. Now here, I don't have a bird on the wire as such, but you can see here, people coming in on the drug, on berotralstat 150 milligrams, can see their attack rate was about 3.2, if I'm not mistaken. Then with therapy, they went down to about 1.7. So you can see it was about a 50% reduction. I think the exact was a 47% reduction of attacks, with the oral medication berotralstat. And that's what makes it unique, is that it's an oral medication, first oral medication on the market.

If you look at it a different way, you can see that, just focus on here, the 150 milligrams, you can see, this is the attack level before coming onto the study drug. Here, you can see the reduction on study drug, and as they continue on study drug, there's increase in improvement. So, again, shown very effective, but not quite as effective as lanadelumab, or subq C1 inhibitor.

So what more would we want for therapies? We have 4 long-term prophylactic drugs. Two of them have exceptional safety, and exceptional efficacy. The other two, the IV C1 inhibitor, the doses can be pushed higher and higher to get the efficacy. It does have safety. Berotralstat works, not quite as good as these other drugs, but it is oral, so it has a lower drug burden.

So what could we want for newer therapies in the future? So, when you think about it, you would want to improve therapies of HAE by increasing the efficacy, and I'll show you that at least by phase 2 studies, there does seem to be an increased efficacy. Now, you'll always want to wait until the final phase 3 are published before saying that, but I think the data are pretty promising.

Increased safety, well, I think the drugs that are approved already are very safe, but there's always room for increase in safety. Reduction of treatment burden. That's key, right? So if you have to give a drug twice a week, verse twice a month, verse once a month verse, maybe even every other month, that decreases the drug burden. Also, IV to subq, to oral (PO), also reduces the drug burden. So there's room there.

Improved accessibility, and I think that's very important when we think about HAE as a global disease, it's not just a disease of high income countries. In fact, most of these drugs are not available at all in most low or medium. So, increase accessibility. Hopefully I know everybody says, you'd never talk about cost when you're talking about a disease that is devastating to a person, but if we can get the same efficacy, and the same safety with reduced cost, I think that's important, especially for low, and medium income countries' accessibility.

Then, also, improve patient outcomes, right? Longer lasting prophylactic treatments, thus lower dosing. Targeted oral medications, so there's less offsite binding, and thus less toxicity. Also have additional monoclonal antibodies, and I'll show you some of the data on that. In addition, we're looking at RNA interference, and that's pretty exciting, really similar to what we do with the COVID-19 vaccines. And then we're looking at gene therapies now, and also clustered regularly interspaced short palindromic repeats (CRISPR) technology. So, I'll kind of march you through these.

So this is what's in investigation right now. So, this is phase 3, and I'll show you the data on these. These are more phase 2 studies. I don't have much data on these to really show you, but we'll talk about them a little bit. So, this is a KVD900. It's pronounced sebetralstat, and it is a study for on demand. It's an oral medication used when people are having symptoms. There are some data I can show you on that, which are pretty exciting. This is garadacimab. This is a subq, a therapy, it's a monoclonal. It has actually some phase 3 data, showing that it's very effective. I can't talk about that phase 3 data yet, because we hopefully will publish that in a high priority journal very shortly. It is however available for greater than 12. I'll show you the phase 2 data, which are very promising though. Then there's another subq drug. This is the antisense molecule, donidalorsen, is the pronunciation, and it seems to be very promising. This may be able to be used every other month. We'll see.

The phase 2 that are in right now, is KVD824. This is similar to the 900, KVD900, which is for on demand. This instead is an oral medication, twice a day, that is for long term prophylaxis. PHA121, which is also an oral medication twice a day. They're looking at it both for acute treatment for on demand, as well as long term prophylaxis. And then NTLA-2002, which is CRISPR technology, where they're editing the gene prekallikrein, and hopefully shut down the kallikrein pathway, as I mentioned. Then there's gene therapy, replacing the defective C1 inhibitor gene, so that you would have better production, and hopefully less symptoms.

So, where did these drugs all take effect? So again, going back to my pathway, here's C1 inhibitor, here's the contact pathway. Gene therapy, is replacing that C1 inhibitor, that's deficient, or defective, and thus shutting down the contact pathway. We have garadacimab, which is inhibiting the factor XII, which seems to be a very vital, that's the start of the contact pathway, right? And it seems to be both very effective, and very safe, and we'll talk about that a little bit. There's also donidalorsen, that inhibits kallikrein. There's the drug, that works by inhibiting, or removing prekallikrein. Then we have the KVD824, which inhibits kallikrein. And then lastly, we have drug 121, that inhibits the bradykinin receptor.

So let's look at the data that's available. So this was published in the Lancet just recently. It's the phase 2 data on garadacimab. So, you had placebo people, they had a dose of 75. They had a dose of 600 milligrams, and the dose of 200 milligrams. In fact, the phase 3 now were mainly focusing on the dose of garadacimab 200 milligrams. Coming into this study, the phase 3, it was 4.6 attacks a month. You could see I'm focusing on the 200, that seems to be the better one. You can see, by median there's 100% reduction of attacks, which is very, very exciting to me. Now, nothing's 100% in life, but it seems to be close to it. When the phase 3 data are published, we'll see how close it looks compared to the phase 2.

This I like even better. This shows it a little different way. So, we have this column, those who had a reduction of 50% of attacks. This column had a reduction of those of 60% of attacks, this is 90% of attacks, and this is 100% of attack reduction. Now, these groups are small, because there's a phase 2, so take that into consideration, and that's why a phase 3 is necessary. But you could see, 100% of the people, on the 200 milligram dose, had a reduction of 50%. 100% had a reduction of 70%, 100% had a reduction of 90%, and 88% of people had a reduction of 100% of attacks, through an iteration of the study. So very, very exciting, and there's an open label study that was also done on this, that shows that this efficacy rate seems to be reflected there too.

Now, this is just looking at birds on a wire. So, a little different setup instead of lateral comparison. This is up and down. Here's the placebo group on top. This is the 75 milligram dose people. This is the 200 milligram dose people. These are the 600. And again, you can see, looking at the density here at the placebo, compared to the garadacimab of 200, what are remarkable difference. So, it does show efficacy.

Now, I'm not going to go through the safety. The safety tended to be okay. The most common reaction was at the injection site. We looked at thrombosis, and bleeding, and a few other really important safety issues, and there was really wasn't any activity in those areas. So, it looks safe, especially in those ones that may have involved factor XII.

Now this is donidalorsen. This is a phase 2 study published in the New England Journal of Medicine. This is the antisense for pre-kallikrein, which is very exciting. Here you can see, these are monthly attacks. It's the mean change of monthly attacks. This is the placebo people, really not changed from the beginning to the end, except for one little spot. But you can see those who are given active therapy, tended to have a considerable decrease in their attack rate. So, it does look like it's very effective.

If you look at again, birds on a wire, these are the placebo people, here's those on active therapy. And again, really great reduction of symptoms. Again, just like garadacimab, I think the efficacy of this drug is going to be superb, and hopefully be a new addition to what we already have.

The third drug is KVD900. It's pronounced sebetralstat. I haven't heard any of the pharmaceutical company people yet say the name, but they're still mainly using KVD900. This was a phase 2 study, and this is for acute therapy, not for prophylaxis like the first 2 I just showed you. When you give the medication within 15 minutes, there's 80% reduction you can see of kallikrein, showing that inhibition of kallikrein very quickly. And then you can see as we go out to 4 hours, there's a greater than 95% reduction, showing that by pharmacokinetics, if you don't have activated kallikrein, you're going to shut down that pathway. So it seems to be very effective.

So it's kind of look at what data they showed. So this is the median time to symptom relief. This is percentage. So, 50% we're looking at. This is time. You can see the drug, the active drug. You can see it's about 1.6 hours to median time of symptom relief. That compares to placebo, which was 9 hours. So, a substantial difference between those two. So this is a tablet that's taken on demand when you have an attack. They're also, however, looking at a drug for prophylaxis.

So, what about those drugs in phase 2? So I just went through right, KVD900 for acute therapy. I went through garadacimab, that's for long term therapy. Donidalorsen for long term prophylaxis. And now, there's the KVD824, they're looking at long term prophylaxis, in contrast to their earlier drug, that already has a phase 2 done. This is PHA121. Again, they're looking at both acute therapy, and long term prophylaxis. And then we have the CRISPR technology, with excision of the gene. And this is very exciting, and that's just started. And then we have gene therapy, and that's also very exciting.

So in summary, in the past, we focused on treating attacks. We had one prophylactic agent really early on. We had androgens. We had tranexamic acid. But really, the drug that was new was in 2008 with the approval of IBC-1 inhibitor, but because IV had had a lot of burden. Then we had the newer drugs, subq C1 inhibitor, lanadelumab, which had much better efficacy. We had berotralstat. That was an oral, so it added a whole new line of therapies. These then allowed us to really focus on prevention instead of treating acute attacks. As I talked about with that young lady, having a drug where they could be free of attacks in most cases, and have a very high efficacy drug, and being able to be, quote, almost normalized is so important.

Now these newer drugs seem to have greater efficacy, and good safety, and again, lower drug burden. So, we're all very excited to see and as I mentioned, there was just a release on the early informational data for the phase 3 of garadacimab. So, we'll see how that turns out in the near future.

My suspicion is, that we're approaching a relative cure for HAE. That is, we're going to have people who feel very, very comfortable. So in other words, normal living. Now, they'll always have to carry their rescue, and it's going to be a task for us to ensure that people carry their rescue, because nothing's a 100% percent in life.

What we need though, is better guidelines, I think, really, to say, who should, and who should not be on prophylaxis. How do we get better drugs into low and medium income countries? How do we determine which drugs are better for specific populations? So, I think the new research is really exciting, and I'm really looking forward to the years coming, when all the data from the phase 2s, and phase 3s will be available.

So with that, I thank you for participating in this activity. Please take a moment to complete the program evaluation, to receive your CME credits. That's very important. Without the evaluation, you won't get your credits. So again, I'm Tim Craig from Penn State, and thank you for spending this half an hour with me.

This is a verbatim transcript and has not been copyedited.