Mauro Cancian, MD, PhD, head of the allergy division at the University of Padua.

Mauro Cancian, MD, PhD

HAE in 2026: New Therapies, Updated Guidelines, the Case for Early Treatment

The treatment landscape for hereditary angioedema is undergoing one of its most significant evolutions in years. Updated international guidelines, pivotal phase 3 data, and promising early-phase results are collectively reshaping how clinicians approach both prophylaxis and acute management of this rare, potentially life-threatening condition.

 about where the field stands and where it is headed.

Guidelines Put Early Treatment Front and Center

have placed renewed emphasis on early, on-demand intervention, formally recommending sebetralstat (Ekterly) as a first-line option for acute treatment of attacks in patients aged ≥ 12 years.

 The oral plasma kallikrein inhibitor was approved by the US Food and Drug Administration (FDA) in July 2025.

Mauro Cancian, MD, PhD, head of the allergy division at the University of Padua and a KONFIDENT trial investigator, said the shift toward an oral agent has meaningfully changed how quickly patients are able to treat attacks.

"What we are emphasizing with our patients, and obviously as a result of the guideline, is that to make treatment more effective, you have to treat the attacks as early as possible," Cancian said. "That means treating at the onset of the attack, because we know that if there is a delay between attack onset and treatment, the drug will be less effective in reducing both the severity and the duration of the attacks."

Data from the phase 3 KONFIDENT study support this urgency. As of January 31, 2025, the median time from attack onset to treatment was just 4 minutes, with a median time to the beginning of symptom relief of 1.79 hours. In the open-label extension, treatment delays shortened further, to under 10 minutes, a figure Cancian attributed to the portability and ease of oral administration.

Cancian cautioned that even patients on long-term prophylaxis require reliable on-demand treatment, as no prophylactic therapy fully eliminates breakthrough attacks. That reality makes the availability of an effective, easy-to-administer acute option all the more critical.

BW-20805: A Long-Acting RNA Interference Approach

Among the investigational therapies attracting attention is 

, a small interfering RNA conjugated with N-acetylgalactosamine that targets hepatocytes via the asialoglycoprotein receptor. Once inside liver cells, it inhibits messenger RNA responsible for producing prekallikrein: the inactive precursor of plasma kallikrein and a central driver of the bradykinin cascade underlying HAE attacks.

Late-breaking phase 2 data presented at the 2026 American Academy of Allergy, Asthma & Immunology annual meeting in Philadelphia showed that BW-20805 achieved high rates of attack-free outcomes at dosing intervals of up to 6 months. Among 10 patients with post-dose efficacy data beyond day 29, 80% remained completely attack-free during the observation period. The highest dose cohort (600 mg every 24 weeks) achieved a 100% reduction in time-normalized HAE attack rate.

Within the first month after administration, prekallikrein levels declined by approximately 90% to 97% depending on the dosing regimen, with reductions remaining stable throughout follow-up.

"The drug BW-20805 is doing what we expect it to do, educing plasma kallikrein activity by more than 90% in a very stable way," said investigator Markus Magerl, MD, of Charité-Universitätsmedizin Berlin.

The therapy's safety profile has been favorable in early analyses, with most adverse events mild and transient, primarily injection-site reactions , and no treatment-related serious adverse events reported. Magerl noted the current findings come from a relatively small phase 2 cohort, and additional data from the completed phase 2 study and an eventual phase 3 trial will be needed to confirm durability and characterize long-term safety.

Lonvoguran Ziclumeran: One-Time CRISPR Therapy Shows 87% Attack Reduction

Perhaps the most headline-generating data came from the 

phase 3 HAELO trial of lonvoguran ziclumeran (lonvo-z)

, an in vivo CRISPR/Cas9 gene editing therapy that targets and inactivates the KLKB1 gene in hepatocytes, reducing kallikrein production and downstream bradykinin generation. Intellia Therapeutics reported top-line results in April 2026.

Patients receiving lonvo-z achieved a mean monthly attack rate of 0.26 compared with 2.10 in the placebo arm — an 87% reduction. More than half (62%) of patients in the treatment arm became both attack-free and free from long-term prophylaxis, compared with 11% on placebo.

Lead investigator Aleena Banerji, MD, professor at Harvard Medical School and director of clinical care at the Center for Drug and Vaccine Allergy at Massachusetts General Hospital, highlighted the significance of those findings, particularly the one-time dosing.

"The biggest benefit that we're seeing here is a one-time treatment that is leading to a significant reduction in attacks similar to the other long-term prophylactic treatments, except that this one does not require any ongoing long-term treatment," Banerji said.

Safety findings to date have been consistent with earlier studies, with no serious adverse events reported during the primary observation period. Common adverse events, all mild to moderate, included infusion-related reactions, headache, and fatigue. Banerji noted that continued follow-up will be essential to monitor for any delayed risks associated with in vivo gene editing.

Intellia has begun a rolling biologics license application submission, expected to be completed in the second half of 2026, with a potential US launch in 2027 pending approval.

These developments reflect a field moving with unusual speed. Patients with HAE now have access to 11 approved treatments in the United States — 6 of them for long-term prophylaxis — with potentially more on the horizon.

"This certainly adds another novel treatment option for prevention of attacks," Banerji said of lonvo-z. "It moves the needle quite a bit for our patients with hereditary angioedema as a one-time treatment with a significantly high rate of efficacy and very good safety data."

For clinicians, the evolving landscape underscores the importance of individualized decision-making, weighing treatment burden, patient preference, and the persistent need for effective on-demand options alongside any prophylactic strategy. As Cancian put it, the goal has not changed, even as the tools to achieve it multiply.

"The main goal [remains] to reduce the number of attacks and to improve the quality of life of patients,” Cancian said.

Check out other allergy news this year here: 

Farkas H, Martinez-Saguer I, Bork K, et al. International Guideline on the Diagnosis and Management of Pediatric Patients With Hereditary Angioedema. 

Zhi Y, Zhao X, Zhu R, et al. Significant HAE Attack Reduction with BW-20805, a Long-Acting Prophylactic Injection- An Ongoing Phase 2 Study in Adult with Hereditary Angioedema. Journal of Allergy and Clinical Immunology. 2026;157(2):AB426. 

doi:https://doi.org/10.1016/j.jaci.2025.12.948

Derman C. Single-Dose Lonvoguran Ziclumeran Cuts HAE Attacks by 87% in Phase 3 Trial. HCPLive. Published April 27, 2026. Accessed April 27, 2026. 

https://www.hcplive.com/view/single-dose-lonvoguran-ziclumeran-cuts-hae-attacks-87-phase-3-trial

Videos

Experts weigh in on a rapidly evolving treatment landscape, from a first-line oral option to a one-time CRISPR therapy showing 87% attack reduction.

Transitioning to Oral On-Demand HAE Therapy, With Mauro Cancian, MD, PhD

guidelines reinforce early, patient-controlled treatment, questions remain about how clinicians should approach transitioning patients from injectable on-demand therapies to oral options. In an interview with 

, Mauro Cancian, MD, PhD, head of the allergy division at the University of Padua, discussed practical considerations following results from the phase 3 KONFIDENT trial of oral sebetralstat.

The updated international guidance emphasizes treating attacks at symptom onset and ensuring all patients have reliable access to effective on-demand therapy.² Historically, acute treatment has relied on injectable agents such as plasma-derived or recombinant C1 inhibitor and the bradykinin B2 receptor antagonist icatibant. These therapies have demonstrated efficacy but may introduce logistical challenges that delay administration, particularly outside clinical settings.

According to Cancian, the primary consideration in transitioning to an oral option is treatment burden, eliminating pain and the need to carry around an injectable therapy. He noted that injectable therapies require preparation, storage, and administration that may complicate travel or daily activities. In contrast, oral tablets may reduce both practical and psychological barriers to early treatment.

“Obviously, patients usually prefer to take a pill because [it] is easier…having appeal reduces the burden of treatment,” Cancian said. “There is no special plan for transition. You [only] ask patients.”

He said that, typically, patients not used to HAE treatments prefer to start with oral, not injectable, drugs. However, for patients used to injectable drugs, he advised clinicians to inform their patients that the oral option is very effective and safe.

He acknowledged that some patients may perceive injectable therapies as inherently more potent, a belief shaped in part by emergency department practices where intravenous medications are common. Cancian emphasized that efficacy and safety data from KONFIDENT support the use of oral sebetralstat for acute treatment.¹ The trial demonstrated significantly shorter time to beginning of symptom relief compared with placebo in adolescents and adults with type I or II HAE.¹

Regarding limitations, Cancian noted that, as with most clinical trials, KONFIDENT enrolled selected patients with well-characterized disease, which may not fully reflect heterogeneous real-world populations. However, he pointed to findings from the open-label extension, which suggested sustained efficacy and shorter delays to treatment initiation as patients became more confident using the medication.

Cancian said he would like to see longer-term real-world data confirming the durability of response across attack types, including laryngeal and gastrointestinal episodes, and continued evaluation for potential rebound phenomena observed with some injectable agents. He also highlighted the importance of pediatric studies in children < 12 years, a population with substantial treatment burden.

“The takeaway is…the opportunity to treat [HAE] attacks by oral tablets, which allow[s] [for treating] early,” he said. “Only early treatment allows patients to be adherent [and]…to normalize their life.”

Cancian M. HAE Guidelines Reinforce Early On-Demand Treatment, With Mauro Cancian, MD, PhD. HCPLive. Published on February 23, 2026. Accessed on February 24, 2026. 

https://www.hcplive.com/view/hae-guidelines-reinforce-early-demand-treatment-mauro-cancian-md-phd

Updated HAE guidelines support early self-treatment; Cancian discuss transitioning patients from injectable on-demand therapy to oral sebetralstat after KONFIDENT data.

 HAE Guidelines Reinforce Early On-Demand Treatment, With Mauro Cancian, MD, PhD

place renewed emphasis on early, on-demand treatment.

The guidelines recommend sebetralstat (Ekterly), an oral plasma kallikrein inhibitor approved by the 

 in July 2025, as a first-line option for the acute treatment of attacks in patients aged ≥ 12 years.

, Mauro Cancian, MD, PhD, head of the allergy division at the University of Padua, discussed how data from the phase 3 KONFIDENT study contributed to this guideline change.

“The result has been very interesting, because there has been a reduction in the interval between onset of symptoms and treatment compared with previous, available treatments that were only injectable,” Cancian said.

KONFIDENT, which assessed sebetralstat in adolescents and adults with HAE, showed that the drug is very quick at stopping disease progression and improving symptoms. As of January 31, 2025, investigators found that the median time from attack onset to treatment was 4 minutes, the median time to the beginning of symptom relief was 1.79 hours, to the reduction in severity was 3.53 hours, and to complete attack resolution was 15.09 hours.

 In the open-label extension, treatment delays were shorter, which Cancian attributed in part to the portability and ease of administration of sebetralstat.

“[The] main delay now is less than 10 minutes,” Cancian said. “That's not a delay. [It] is really every treatment because…10 minutes is the time you…recognize that an attack is happening.”

HAE due to C1 esterase inhibitor deficiency is characterized by recurrent, bradykinin-mediated swelling that can involve the extremities, gastrointestinal tract, and airway. Historically, acute treatment options have required intravenous or subcutaneous administration, including plasma-derived or recombinant C1 inhibitor and the bradykinin B2 receptor antagonist icatibant.

 These agents are effective but may introduce practical barriers that delay administration outside clinical settings.

Cancian cautioned that long-term prophylaxis, though increasingly effective, does not eliminate breakthrough attacks. Therefore, reliable on-demand treatment remains essential even for patients receiving preventive therapy.

Limitations remain, including the absence of head-to-head trials comparing oral and injectable agents and the need for additional real-world effectiveness data. Pediatric use is currently limited to patients aged ≥ 12 years.

Overall, the updated guidelines formalize a management strategy centered on early intervention, individualized care, and maintaining quality of life.

“What we are emphasizing with our patients, and obviously as a result of the guideline, is that to make [a] more effective treatment, you have to treat [the attacks] as early as possible,” Cancian said. “That means treating at the onset of the attack because we know that if there is a delay between attack onset and treatment, the drug will be less effective in reducing both the severity and the duration of the attacks.”

Johnson V. Sebetralstat FDA-Approved as First Oral, On-Demand for Hereditary Angioedema. HCPLive. Published on July 7, 2025. Accessed on February 23, 2026. 

https://www.hcplive.com/view/sebetralstat-fda-approved-as-first-oral-on-demand-for-hereditary-angioedema

KONFIDENT investigator Cancian discusses oral sebetralstat’s role in the updated HAE treatment guidelines.

Mauro Cancian, MD, PhD

Articles