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Hot Takes on Acute Management of ​Hereditary Angioedema
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Physician Assistants/Physician Associates: 0.25 AAPA Category 1 CME credit

Nurses: 0.25 Nursing contact hour

Physicians: maximum of 0.25 AMA PRA Category 1 Credit™

Released: December 03, 2024

Expiration: December 02, 2025

Marc Riedl
Marc Riedl, MD, MS

Dr. Marc Riedl (University of California): Hello, and welcome to this program entitled Hot Takes on Hereditary Angioedema: Clinical Care Options Independent Conference Coverage of the 2024 ACAAI Annual Scientific Meeting.  I am Dr.  Marc Riedl.  I am a professor of medicine in the Division of Allergy and Immunology at the University of California, San Diego.  It is my pleasure to briefly run you through some new data that was presented at the recent American College of Allergy, Asthma and Immunology meeting, specifically looking at hereditary angioedema. 

[00:00:41]

Updates on Acute Management of Hereditary Angioedema

In this segment, we are going to focus on updates in acute management of hereditary angioedema. 

[00:00:49]

KONFIDENT: Correlating HAE Attack Duration With Time to Treatment When Using Sebetralstat

We will begin with some data from the KONFIDENT trial.  This was a data correlating HAE attack duration with the time to treatment when using an investigational medication, sebetralstat, for on-demand therapy of HAE. 

[00:01:07]

KONFIDENT: Background 

By way of brief background, this is a data from the KONFIDENT study program.  We know that on-demand treatment is a very important strategy and in fact required strategy for every patient with HAE, so that they can treat these debilitating and dangerous angioedema attacks when they occur. 

There have been numerous studies showing that earlier treatment of HAE attacks with effective on-demand medication reduces attack duration, and in fact, this is the reason that international treatment guidelines unanimously recommend early treatment of HAE symptoms as soon as the symptom onset is recognized. 

However, there have also been data sets to show that there are challenges for rapid treatment of HAE attacks due to a number of factors.  A recent survey demonstrated that the average time to treatment was between two and three hours, and this can relate to the available medications being injections or infusions, difficulty with the portability of those treatments, or fear about side effects or technical aspects related to giving these treatments. 

Because of that, there has been considerable interest in developing oral on-demand HAE medications.  One of those is sebetralstat, which is an oral plasma kallikrein inhibitor that is given by mouth, and therefore may avoid some of the barriers to early treatment of HAE attacks that we encounter with injected or infused medications. 

[00:02:42]

          KONFIDENT: Study Design  

The KONFIDENT study was a randomized, double blind, placebo-controlled, three-way crossover study.  The results of this study, the pivotal trial have been published in the New England Journal of Medicine, showing the safety and efficacy of sebetralstat in treating HAE attacks on-demand at the time they occur. 

You can see the study was designed in a fashion where people were randomized into one of six sequences where they received different doses of sebetralstat or placebo for subsequent attacks.  And this crossover design allowed the study to show that this did work effectively to stop HAE attacks. 

What we are looking at here is the primary outcome of the beginning of symptom relief by the patient global impression of change, the PGI-C score within 12 hours of administration.  And specifically, this data that was presented looked to see the time of treatment and whether it had an effect on the time to improvement and time to resolution of the HAE attack. 

[00:03:54]

          KONFIDENT: Defining Time from Attack Onset to Treatment Administration

These investigators actually took the data set and segmented it in terms of time of treatment.  You can see here on median in this trial, patients took the oral medication about 41 minutes after the onset of their HAE symptoms. 

This group of researchers segmented these times to treatment into quartiles, and they defined the earlier treatment as that first quartile.  So these were 79 attacks that were treated within six minutes of symptom onset. 

And then also a later group, and you can see those were 66 attacks that were treated, 140 minutes or later after the symptom onset.  They use this earlier and later treatment groups to look at how that affected time to improvement or time to resolution of attacks. 

[00:04:44]

          KONFIDENT: Baseline Characteristics of Early vs Late Attack Treatment Participants

These are the characteristics of that early and late groups.  You can see there are no major differences in terms of the age, the gender, the ethnicity, the type of HAE or really the strategies that were used, again with about 23% on long term prophylaxis in the earlier group and about 13% in the later group. 

[00:05:07]

          KONFIDENT: Characteristics of Attacks Treated With Sebetralstat 

If you look at the characteristics of attacks, what is interesting here is that there is a difference in the mild or moderate with most of the attacks in the earlier treatment group being rated as mild, and most of the attacks in the later group being rated as moderate. 

So some difference in severity, perhaps due to the fact that patients waited longer to treat that attack and it progressed.  There were no major differences in the types of attacks with fairly equivalent of either mucosal or subcutaneous types of attacks, including laryngeal attacks in both earlier and later treatment groups. 

[00:05:40]

          KONFIDENT: Probability for Faster Complete Attack Resolution  

The upshot here was that there was a strong correlation between treating early and getting resolution quicker of those HAE symptoms.  So you can see here the hazard ratio strongly favored the early treatment group with a 2.72 hazard ratio or odds ratio of having faster resolution for patients that treated in that earlier cohort or earlier group. 

And that relationship between time to treatment and time to complete attack resolution was very strong at 0.88. 

[00:06:17]

          KONFIDENT: Conclusions  

So this analysis shows us that the earlier treatment with sebetralstat of these HAE attacks resulted in attacks that were more likely to be mild, attacks that were reached symptom resolution faster compared to a group that treated later in the course of their symptoms.  And it really, again, reinforces this important recommendation of early treatment.  We are hopeful that oral on-demand medicines will facilitate or allow this earlier treatment. 

But we also have to recognize we do not have direct comparisons or head-to-head comparisons between the oral medications and the parenteral medications for HAE treatment.  So more research to come on that I would expect. 

[00:07:03]

RAPIDe-2 Extension Study Results: Oral Deucrictibant for Long-Term Treatment of Hereditary Angioedema

The second data set I would like to show you from ACAAI is on the RAPIDe-2 extension study results.  This is a trial of another oral on-demand medication, deucrictibant, for the long-term treatment of HAE attacks. 

[00:07:20]

          RAPIDe-2 Extension Study: Background

Now, again, we have talked about the importance of treating attacks early recommended in the international guidelines, and the fact that oral medication may allow patients to treat earlier and make them more likely to take medication without delay. 

Deucrictibant is an oral on-demand medication.  it is a mechanism of action.  Is a bradykinin B2 receptor antagonist.  This is actually being studied both for on-demand treatment and prophylactic treatment of HAE attacks. 

What I will show you here is data on the RAPIDe-2 phase II trial.  This is an on-demand treatment study using deucrictibant immediate release, again, taken orally at the time of HAE symptoms for on-demand therapy. 

[00:08:10]

          RAPIDe-2 Extension Study: Part A Study Design

The data that was presented was from Part A of this RAPIDe-2 extension study.  You can see these patients after a randomized portion of the study rolled into an open-label extension, where they were assigned to one of three different doses of deucrictibant to be taken at the time of onset of an attack. 

This data looked at pooled data from all three of these doses.  Again, open-label trial, we look primarily at safety and tolerability, but will also look closely at the outcomes of efficacy. 

[00:08:45]

          RAPIDe-2 Extension Study: Baseline Characteristics

These are the baseline characteristics.  You can see a relatively small group of patients, phase II open-label extension, 19 subjects.  But a relatively high number of attacks, over 330 attacks that were in this analysis, mostly white patients, and again, primarily a type 1 HAE that was studied. 

[00:09:06]

          RAPIDe-2 Extension Study: Primary Endpoint, Safety

The primary endpoint of safety was very reassuring.  There was actually only one serious treatment-emergent adverse event, that was not believed to be due to the medication.  This was actually some dental caries or cavities that occurred in a subject in the study.  And importantly, no treatment-emergent adverse events that led to discontinuation of the trial, withdrawal or death. 

[00:09:30]

          RAPIDe-2 Extension Study: Secondary Endpoints, Time to Onset of Symptom Relief 

Then if we look at a secondary endpoint of onset of symptom relief, again, this is initial symptom relief as measured by an improvement in PGI-C.  You can see this very rapid onset of relief.  The median time to onset of symptom relief was 1.1 hours.  You can see by a couple of hours, up to nearly 90% of patients had onset of symptom relief. 

[00:09:58]

          RAPIDe-2 Extension Study: Secondary Endpoints, Efficacy

Looking at some other efficacy endpoints, again, the PGI-C or patient global impression of change is in the top couple of pie charts.  By 12 hours, over 98% of the patients had onset of symptom relief, and over 96% of patients had achieved what they called substantial symptom relief.  This means, on the PGIC, they said they were better as opposed to a little better, which was the initial onset of symptom relief.  So very encouraging efficacy endpoints there. 

Then if you look at PGI-S, which is the patient global impression of severity, so a change in the severity of their symptoms.  At 12 hours, over 97% had achieved a reduction in severity.  So this would be from severe to moderate, moderate to mild or mild to none.  And if you look at complete attack resolution, which is the highest bar, symptoms are entirely gone.  Over 85% of patients had complete attack resolution by a 24-hour time point after treatment. 

[00:11:05]

          RAPIDe-2 Extension Study: Part A Conclusions

The conclusions here from this additional data, first, the deucrictibant treatment was well tolerated at all three doses studied.  No concern for treatment-emergent adverse events.  And the efficacy showed importantly the median time to substantial symptom relief.  So at least better was 2.7 hours.  The median time to the reduction in severity was 2.6 hours, and the median time to complete attack resolution was 11.5 hours. 

And so these results in the open-label trial were quite consistent with what was seen in the phase II randomized study, again supporting long-term efficacy and safety of this on-demand oral treatment, deucrictibant, for treating HAE attacks and, I think, push us ahead to a planned phase III that will continue to look at this as a promising option for managing HAE attacks. 

[00:12:01]

          Key Takeaways

The key takeaways from this new data at the ACAAI meeting, include the fact that sebetralstat in the clinical trials allowed for earlier treatment of HAE attacks, and in fact, that earlier treatment resulted not only in attacks that were more likely to be mild when they were treated, but also to earlier symptom relief as well as quicker resolution of symptoms in this early treated group compared to those that treated later. 

And also with deucrictibant, the oral on-demand medication, promising data from their phase II open-label extension study, showing reassuring safety data, well-tolerated treatment, but also impressive treatment in terms of the onset of symptom relief with this oral on-demand therapy. 

With that, thanks very much for your attention.  I hope you enjoyed the presentation.  And do not forget to claim your CME credit by clicking on the link.

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