CE / CME
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
Nurse Practitioners/Nurses: 0.50 Nursing contact hour
Physicians: maximum of 0.50 AMA PRA Category 1 Credit™
Released: March 25, 2025
Expiration: March 24, 2026
The Road to Long-term Prophylaxis
There has been a lot of activity with approved medications as well as those in clinical development as we shift toward the prevention of life-threatening and debilitating HAE attacks. Of note, it is recommended that all patients on long-term prophylaxis continue to carry on-demand treatment just in case they have breakthrough symptoms.
The reason that research and practice have moved toward long-term prophylaxis is the recognized goal of trying to control HAE and normalize patients’ quality of life. HCPs should strongly consider long-term prophylactic therapy in patients with more frequent or severe attacks.1,2 However, long-term prophylaxis should be discussed with all patients as HCPs may not recognize some of the disruptions or issues that HAE attacks cause even if they are not severe or frequent. Treatment also must be tailored to each patient's preferences and goals.
In addition, HAE is a condition that changes over time. A patient initially may not elect to use long-term prophylaxis, but their symptoms may change over the next week, month, or year and a long-term strategy may become highly beneficial to them.
Long-term prophylactic therapies are effective in reducing attack frequency and improving quality of life, including helping with work and school productivity. However, there are patients who have not seen maximal benefit and continue to experience breakthrough attacks despite using these therapies.9
The final thing HCPs need to understand is that these treatments come with a burden. A recent survey found that more than 50% of patients using long-term prophylaxis reported this treatment as burdensome, even with the currently available and effective options. Research and development continue to look for more efficacious treatments that are safe and less burdensome.
HAE Therapeutic Targets for Long-term Prophylaxis
Here is a figure illustrating the therapeutic targets in HAE. As a reminder, HAE is caused by excessive bradykinin production. The dysregulation of the contact system occurs when the C1-INH protein production or function is insufficient. Factor XIIa, plasma kallikrein, and bradykinin receptors are targets that have been established as ways to better regulate the contact system and reduce either the overproduction or the effects of bradykinin via the B2 receptor.
There are both approved and investigational agents highlighted in this figure. Some of these agents look to replace C1-INH to restore the balance to this system, others seek to reduce prekallikrein or kallikrein to reduce the production of bradykinin. At that level, agents also may target Factor XIIa to stop contact system initiation and bradykinin overproduction or the B2 receptor to halt the effects of bradykinin.10,11
C1-Esterase Inhibitors for Long-term Prophylaxis of HAE Attacks
There are ways to replace C1-INH to address its deficiency, which is at the root of most HAE types. First, there is an intravenous C1-INH for HAE long-term prophylaxis. The FDA first approved this agent in 2008.12 Then it approved a subcutaneous version in 2017.13
The dosing and most common AEs are listed on the slide. Although C1-INH replacement has been an effective strategy for preventing attacks, it is particularly effective with the subcutaneous route of administration. The COMPACT study of the subcutaneous C1-INH showed an 84% reduction in the mean attack rate. For the intravenous administration agent, the CHANGE study showed only a 50% reduction in the mean HAE attack rate. Therefore, there is a marked effect in preventing attacks with the replacement of C1-INH via a twice weekly subcutaneous injection.14
Lanadelumab: Plasma Kallikrein Inhibitor and mAb
Another strategy that is currently FDA approved for HAE is lanadelumab. This is a monoclonal antibody (mAb) that targets plasma kallikrein and is given subcutaneously. The HELP study evaluated 3 different doses of lanadelumab, with the approved starting dose being 300 mg administered every 2 weeks.15 At that dose, there was approximately an 87% reduction in the mean attack rate with lanadelumab compared with placebo.16
This agent is highly effective at preventing attacks. It is typically started every 2 weeks but can be adjusted to every 4 weeks if patients are seeing very good efficacy and benefit with it.15
Lanadelumab: Safety Outcomes From HELP
The primary AEs reported with lanadelumab were injection-site pain, injection-site reaction, and viral upper respiratory tract infection compared with placebo. In general, lanadelumab is a safe medication and no serious AEs were considered treatment-related.17
Lanadelumab Efficacy in Pediatric Patients: SPRING Study
Lanadelumab also has been studied in children with HAE, leading to an FDA approval for use in patients aged 2 years or older.15 This is important because the pediatric population has historically been underserved because effective and safe prophylactic treatment has been limited. Of note, the dosing of lanadelumab is slightly different in pediatrics. For patients aged 6 years to younger than 12 years, lanadelumab is administered at 150 mg every 2 weeks, with 4-week dosing consideration for certain patients. Landelumab is then administered at 150 mg every 4 weeks for patients aged 2 to younger than 6 years.
There is robust efficacy reported from the SPRING study, where lanadelumab led to a 94% vs 98% reduction in mean attack rates from baseline for 150 mg every 2 weeks and 150 mg every 4 weeks, respectively. This trial found lanadelumab to be safe and well tolerated for pediatric patients. Injection-site reactions were the most common AEs reported, and they were mostly mild to moderate. There were no serious treatment-emergent AEs or discontinuations.18
Berotralstat: Plasma Kallikrein Inhibitor
Another long-term prophylaxis option is berotralstat, an oral plasma kallikrein inhibitor that is taken daily and was approved by the FDA in 2020.19 The approval of berotralstat has addressed the demand for oral long-term prophylactic options, which is helpful for patients who prefer to take an oral medicine.
Data from the APeX-2 trial showed that berotralstat 150 mg led to a 44% reduction in the mean attack rate among patients with HAE aged 12 years or older compared with placebo. This was statistically significant, although not quite at the level seen with the parenteral agents previously discussed. However, via a responder analysis, 50% of the population saw at least a 70% reduction in their attack rate with berotralstat 150 mg vs placebo.
Berotralstat works well for some patients and is an attractive treatment option given its oral route of administration. Although it is available in 2 doses, HCPs typically use the 150 mg dose in most patients.20
Berotralstat Safety: APeX-2 Study
In terms of safety, berotralstat appears to be quite safe and tolerable. The most frequent AEs reported were gastrointestinal related and grade 1 or 2 compared with placebo. A small percentage of patients had nausea, abdominal pain, vomiting, or diarrhea, which is perhaps the most unique and common safety concern that HCPs should counsel patients about.
Four patients discontinued berotralstat due to treatment-emergent AEs (1 patient in 150 mg group and 3 patients in 110 mg group) vs 1 patient in the placebo group, but most AEs were mild or moderate. Berotralstat is a safe agent as evidenced by this clinical study data.20
Antisense (RNA-Based) Therapy for HAE
A new treatment approach in HAE management is antisense or RNA-based targeted therapy.
This is a diagram illustrating how RNA-targeted therapies work: the PKK (plasma prekallikrein) antisense oligonucleotides approach or the small, interfering RNA (siRNA) approach. Both of which are targeted in the liver. You can see that they are taken into the hepatocytes by endocytosis, where they migrate and bind to degrade messenger RNA. This degradation prevents the production of protein, in this case plasma prekallikrein, which reduces the level produced by the liver; therefore, reducing circulating prekallikrein and the ability to make bradykinin.21
In terms of what is currently being studied, the most advanced approach is the PKK antisense oligonucleotides. But agents using the siRNA approach are proceeding in development to determine if this has a longer lasting, more durable preventative effect in HAE.
Donidalorsen: Prekallikrein-Targeted Antisense Oligonucleotide
Donidalorsen is an investigational prekallikrein-targeted antisense oligonucleotide. It is not yet FDA approved but it has completed a phase III study. The OASIS-HAE study evaluated subcutaneous donidalorsen 80 mg given either every 4 weeks or 8 weeks vs placebo.
The graph here highlights the significant reduction in mean attack rate observed with donidalorsen vs placebo. This reduction was a bit more robust with the 4-week dosing than the 8-week dosing schedule. As time goes on, you can see that the donidalorsen lines converge in terms of attack rate reduction. This trend also was reported in the OASISplus open-label extension study.22 It appears that the 8-week dosing efficacy is ultimately similar to the 4-week dosing efficacy, though it may take a little longer for the 8-week dosing to get to the same level of efficacy as the 4-week dosing.
The table also shows numerically the 81% mean attack reduction observed with donidalorsen every 4 weeks and a 55% reduction with donidalorsen every 8 weeks compared with placebo. Further, many patients were attack-free at Week 25: 53% in the 4-week dosing group and 35% in the 8-week dosing group.23
Donidalorsen Safety: OASIS-HAE Study
As far as safety, AEs were seen similarly in both donidalorsen groups and most were mild or moderate. The most common AEs were injection-site reaction or headache, which were seen in a small proportion of patients. In addition, headache appeared to be no different with donidalorsen than placebo. There were no serious treatment-related AEs and only 1 discontinuation due to a treatment-related AE in the donidalorsen 8-week group.23
Garadacimab: Activated Factor XIIa Inhibitor (mAb)
Another investigational agent is garadacimab, an mAb that targets Factor XIIa (FXIIa). If you recall from the contact system graphic, FXIIa sits at the top and is one of the initiating factors that leads to bradykinin production. It cleaves prekallikrein to kallikrein and kallikrein creates bradykinin from high molecular weight kininogen.10
In the VANGUARD study, garadacimab was given subcutaneously as two 200-mg loading doses and then once monthly thereafter. The data on this slide show robust efficacy, including an 87% reduction in the mean attack rate with garadacimab compared with placebo.
The graphic on the right illustrates the responder analysis, showing that 74% of patients had at least a 90% reduction in their attack rate with garadacimab. Further, 62% of patients were attack free at Day 182.24
Garadacimab Safety: VANGUARD Study
The most common AEs were upper respiratory tract infections, headache, nasopharyngitis, and injection-site reactions with garadacimab vs placebo. There were no major differences between the 2 groups. No AEs led to discontinuation and there were no AEs of special interest (ie, bleeding or thrombosis).24
Deucrictibant: Bradykinin B2 Receptor Antagonist Phase II CHAPTER-1 Trial Efficacy Outcomes
Moving to phase II clinical trials, there are investigational agents that are earlier in development but are being studied in patients with HAE.
This slide shows data on deucrictibant, which is an oral bradykinin B2 receptor antagonist. Of interest, deucrictibant is currently being studied as both an on-demand treatment and a long-term prophylactic therapy option in HAE. The CHAPTER-1 study looked at the long-term prophylaxis setting, where 2 doses of deucrictibant—20 mg or 40 mg daily—were evaluated against placebo. Investigators reported an 85% reduction in the mean monthly attack rate with 40 mg deucrictibant vs placebo. There was also a large reduction (93%) seen with attacks requiring on-demand treatment with deucrictibant 40 mg compared with placebo.
This early data look very promising, and deucrictibant may become an effective oral treatment option to prevent HAE attacks.25
Deucrictibant Safety Outcomes in CHAPTER-1 Study
On this slide, you can see a small smattering of reported AEs: 1 patient with nausea and 1 patient with dizziness in the 20-mg deucrictibant group, 1 patient with transient increase in gamma-glutamyltransferase in the 40-mg deucrictibant group, and 1 patient with headache in the placebo group.
Further, all treatment-related AEs were mild; there were no serious treatment-emergent AEs; and no AEs led to discontinuation, patient withdrawal from the study, or death. Safety and tolerability will continue to be tracked in future and larger phase III studies of deucrictibant.25
Gene Editing for Treating HAE
Gene-editing clustered regularly interspaced short palindromic repeat (CRISPR)-associated 9 (Cas9) technology is being investigated as a prophylactic treatment for HAE attacks. This diagram outlines how the CRISPR/Cas9 technology works. It is encapsulated in lipid nanoparticles that migrate into the liver through the low-density lipoprotein receptor, where it then finds the specific location in the DNA—the KLKB1 gene.
This is the gene that encodes plasma prekallikrein. If you knock out that gene in numerous cells, you can prevent the production of plasma prekallikrein. This is the approach that early phase I/II studies of CRISPR technology are using for long-term prophylaxis in HAE.21
NTLA-2002: CRISPR-Based Gene-Editing Therapy
Here are data from the phase II study, conducted outside of the US, of the CRISPR-based gene-editing therapy NTLA-2002. Of importance, the right figure shows the reduction in plasma kallikrein protein in patients who received NTLA-2002 vs placebo. The trial looked at 2 doses of NTLA-2002, and the higher dose (50 mg) resulted in an 80% to 92% mean reduction in plasma kallikrein protein levels. That corresponds, looking at the left figure, to the significant reduction in mean attacks per month over 16 weeks. The highest dose of NTLA-2002 led to a 77% reduction in mean attacks per month compared with placebo.
These appear to be promising data both from a mechanistic and efficacy standpoint. While this must be confirmed in a larger study, there is now the potential for therapy that can achieve a significant durable reduction in plasma kallikrein protein levels with a single gene-editing treatment.26
NTLA-2002 Safety: Phase II Study
Regarding the safety of NTLA-2002, most AEs were mild or moderate. The most common AEs were headache, fatigue, and nasopharyngitis. The table shows the comparison between the active treatment groups vs the placebo group. Although there was 1 patient in the placebo group who had significant edema of the tongue, no serious AEs were observed in the NTLA-2022 treatment groups.
These are promising data for both efficacy and short-term safety. Of course, this treatment will need to be investigated in larger and longer phase III trials.26
Additional Therapeutics in Early Development
There are some other long-term prophylactic agents in development, but they are much earlier in the process. One is navenibart (STAR-0215), an mAb with a long circulating half-life. In phase I/II studies, this agent looks like it could be administered subcutaneously every 3 to 6 months and still show effective inhibition of plasma kallikrein.
ADX-324 is an siRNA administered as a subcutaneous injection. Like the data for donidalorsen, this siRNA aims to reduce plasma prekallikrein production by the liver. ADX-324 may also have long-acting effects, meaning that it might be able to be given every 3 to 6 months and still effectively prevent HAE attacks.
In the preclinical setting, there are other oral agents, including FXIIa inhibitors, and gene therapies being developed. It will take time to determine if any of these are going to be worth investigating.
There continues to be a lot of activity in the pipeline for HAE prophylaxis, to investigate strategies that are highly effective, safe, and greatly reduce the treatment burden of HAE. This is important given there is currently no cure for this disorder. Future HAE prophylaxis treatments have the potential to reduce the burden of therapy and still achieve excellent symptom control.21
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