New Genetic Clues and Oral Therapies Reshape Hereditary Angioedema Care

Hereditary angioedema is one of those rare diseases that most people have never heard of and yet, for the families who carry it, it can dominate every aspect of daily life. The condition, most often caused by pathogenic variants in the SERPING1 gene that encodes C1-esterase inhibitor, produces recurrent episodes of swelling in the skin, the gut and, most dangerously, the airway. A new collection of meeting abstracts from the 14th C1-inhibitor Deficiency and Angioedema Workshop, published in the journal Allergy, Asthma & Clinical Immunology as part 2 of the workshop proceedings, offers a snapshot of where the field now stands: on one side, genetics is revealing surprises in individual families; on the other, a wave of oral drugs is being tested and followed over years, changing what long-term control of the disease can look like.

Among the most striking contributions is a case series from a monocentric Italian cohort at the ITACA Reference Center in Rome, presented by Paola Triggianese and colleagues from the University of Rome Tor Vergata and the University Hospital of Padua. The team reported four patients with C1-inhibitor-deficient hereditary angioedema in whom genetic work-up uncovered not one but two rare inherited diseases. In three of the four cases, the second diagnosis emerged from clinically driven investigation after the angioedema diagnosis had already been made; in one sporadic case it was an incidental finding. Three of the four concurrent conditions were rare neurological disorders, a concentration the authors describe as the moment when a rare disease becomes an ultra-rare one.

The individual stories illustrate why the combination of careful clinical phenotyping and genomic testing matters. One male patient who inherited his SERPING1 variant from his affected mother also developed progressive loss of coordination and balance along with hypertrophic cardiomyopathy, leading to a pediatric diagnosis of autosomal recessive Friedreich ataxia caused by compound heterozygous GAA expansions in the FXN gene. A female patient who inherited her variant from her father developed drug-resistant myoclonic epilepsy at Tanner stage II and was diagnosed with Myoclonic Epilepsy of Lafora 2 due to compound heterozygous NHLRC1 pathogenic variants. A third patient, diagnosed with hereditary angioedema only at age 55, carried a very rare deletion of the entire SERPING1 gene and, incidentally, the canonical PMP22 deletion that causes hereditary neuropathy with liability to pressure palsies. The fourth patient, born with congenital cardiopathy and mild dysmorphisms, had Noonan syndrome from a de novo PTPN11 variant before an inherited SERPING1 variant was documented when she presented with abdominal attacks at Tanner stage I. The authors argue that clinicians should suspect a second inherited condition whenever a patient’s phenotype seems incoherent with the primary diagnosis.

Genetic complexity also surfaced in a cosegregation study from Southern Spain. Krasimira Baynova and colleagues at Virgen del Rocío University Hospital in Seville examined eight unrelated families with hereditary angioedema due to C1-inhibitor deficiency, covering 39 patients of whom 16 were male. Because disease severity varies enormously even among relatives carrying the same SERPING1 variant, the team used next-generation sequencing to look at 45 genes belonging to the kallikrein-kinin system, the biochemical pathway that generates bradykinin, the mediator responsible for angioedema attacks. Seven families had type 1 disease and one had type 2, and each family carried a different heterozygous SERPING1 variant.

The Spanish results were largely sobering, with one notable exception. In two of the eight families, the CPN1 variant c.533G>A appeared to behave protectively: in family 1 it was present in heterozygosity in all patients with a mild phenotype and absent in those with moderate or severe disease, and in family 7 it was found in one of the mildest patients but not in the two most severely affected relatives. Every other variant detected, in genes including SERPINF1, MASP2, PLG, KRT1, TLR4, MME, IL5, ANGPT1, ELANE, XPNPEP2, MASP1, ACE and C1R, showed no correlation with clinical phenotype. The authors themselves conclude that more studies of genotype-phenotype association in hereditary angioedema are needed, a reminder that modifier genetics in this disease remains largely unmapped.

A Mexican case report pushed the genetic frontier in a different direction. Sandra Nieto and Rolando Laurel Laurel of the Mexican Association of Hereditary Angioedema described a 63-year-old man with recurrent facial swelling, prodromal sensations of impending attacks, and episodes triggered by lack of sleep and fatigue, occurring two to four times a month since 2020. His complement and C1-inhibitor levels were normal, placing him in the category of hereditary angioedema with normal C1-inhibitor activity. Genetic testing in July 2023 revealed a novel hemizygous variant in XPNPEP2, NM_003399.5:c.373A>T p.(Met125Leu), and he was the first case of hereditary angioedema in his family. The authors suggest the finding expands the molecular understanding of angioedema with normal C1-inhibitor, while stressing that further research into the variant’s role in the disease is warranted. Their report also notes that in Mexico the estimated diagnostic delay for hereditary angioedema extends to age 22, and that the condition has historically been potentially fatal in 25 to 40 percent of cases.

On the therapeutic side, the abstracts chart the rise of orally administered drugs that spare patients injections. Timothy Craig and an international investigator group reported an analysis from the phase 3 KONFIDENT trial of sebetralstat, an oral on-demand therapy, focusing on the anxiety that surrounds attacks. Among 264 treated attacks, 250 included anxiety records on a Modified Generalized Anxiety Numeric Rating Scale from 0 to 10, with a median baseline score of 3.0. More than 40 percent of attacks were rated as moderate to extreme anxiety at the time of treatment. Baseline anxiety correlated with attack severity, shorter time since diagnosis, and female sex. Cumulative anxiety scores over 12 and 24 hours were significantly reduced with both sebetralstat 300 mg and 600 mg compared with placebo, and among participants with moderate-to-extreme anxiety the least squares mean reduction at 12 hours reached 3.5 points with 300 mg and 4.3 points with 600 mg, versus 1.7 points with placebo. Critically, participants whose attacks achieved the beginning of symptom relief within 12 hours had a better chance of reaching a meaningful anxiety reduction of at least 2 points, with a Cohen’s kappa of 0.47 linking the two outcomes.

Deucrictibant, a selective oral bradykinin B2 receptor antagonist developed by Pharvaris, appeared in two complementary extension studies. In the CHAPTER-1 open-label extension for long-term prophylaxis, 30 participants who had completed the placebo-controlled part of the phase 2 trial continued on 40 mg once daily, with a data snapshot at a mean treatment duration of 12.8 months and a maximum of about 20 months. Their mean baseline attack rate of 2.18 attacks fell to a least squares mean of 0.15 attacks per month during the extension, with monthly rates of moderate and severe attacks and of attacks requiring on-demand medication each at 0.07, and a median proportion of days with symptoms of 0.0 percent. No treatment-related serious adverse events or discontinuations were reported. In the parallel RAPIDe-2 extension for on-demand use, 17 participants treated 265 attacks with deucrictibant immediate-release capsules; the median time to onset of symptom relief was 1.1 hours, substantial symptom relief was reached within 12 hours in 96.2 percent of attacks, complete resolution occurred within 24 hours in 85.8 percent, and rescue medication was needed in only 1.5 percent of attacks, again with no treatment-related serious adverse events.

Even earlier in development, ADX-324 from ADARx Pharmaceuticals is an investigational small interfering RNA targeting prekallikrein, designed for subcutaneous injection every six months. In phase 1 dose-escalation work in healthy volunteers, a single 300 mg injection produced a mean reduction of prekallikrein-kallikrein levels of more than 90 percent at nadir, maintained above 80 percent out to day 169, and early phase 2a data in three patients with hereditary angioedema mirrored the pharmacodynamics seen in healthy subjects. The compound was well tolerated, with headache and injection-site reactions the most common adverse events, and a phase 3 program is being initiated. Meanwhile, an Amsterdam case series documented an unexpected hazard of the older era of therapy: four patients who had taken danazol for a median of 28 years developed transient, symptomless hepatitis within four weeks of stopping the drug, with peak alanine transaminase values up to 337 U/L, a liver biopsy in one patient showing dysfunctional hepatic microcirculation, and full normalization within 17 weeks without intervention.

Real-world experience with the established oral kallikrein inhibitor berotralstat rounded out the clinical picture. A Vienna case series of four patients treated since mid-2018 reported a mean attack reduction of roughly 90 percent over a follow-up of 66 months, the longest follow-up yet described for this drug, with attack-free periods ranging up to about 43 months and no treatment-emergent adverse events. Finally, a survey of Canadian physicians conducted in 2017 and 2024 by Natasha Correa and Stephen Betschel showed that while the proportion of patients on long-term prophylaxis stayed nearly stable, the drugs used changed dramatically: lanadelumab and berotralstat rose to the top of the list for type 1 and 2 disease, danazol use collapsed from 41.9 percent of physicians to 13.5 percent, and physicians cited route of administration, side effects and access as the decisive non-efficacy factors. Together, the workshop abstracts portray a field in transition, where deeper genetics and gentler, needle-free therapies are converging on a disease that has long demanded both scientific patience and daily vigilance from patients.

Subject of Research: Genetic findings and long-term treatment data in hereditary angioedema presented at the 14th C1-inhibitor Deficiency and Angioedema Workshop

Article Title: Abstracts of the 14th C1-inhibitor Deficiency and Angioedema Workshop: part 2

Article References: Abstracts of the 14th C1-inhibitor Deficiency and Angioedema Workshop: part 2. (2026). Allergy, Asthma & Clinical Immunology, 22(1), 57. https://doi.org/10.1186/s13223-026-01017-1 (Author names are not included in the publisher’s citation export.)

Image Credits: AI Generated

DOI: 10.1186/s13223-026-01017-1

Keywords: hereditary angioedema, C1-inhibitor deficiency, SERPING1, sebetralstat, deucrictibant, berotralstat, danazol, prekallikrein, bradykinin, genetics, clinical trials, angioedema workshop