Novel Hereditary Angioedema Treatments on the Horizon

Novel hereditary angioedema (HAE) drugs aim to push treatment and prevention toward more convenient, long-acting agents and gene-editing cures by targeting plasma kallikrein and the contact activation cascade to prevent uncontrolled bradykinin production.

Recently approved drugs have moved toward extended-interval dosing, such as the anti-factor XIIa biologic garadacimab (Andembry) approved in 2025 for subcutaneous injection once monthly and the RNA-targeted therapy donidalorsen (Dawnzera) approved in 2025 for subcutaneous injection every 4 or 8 weeks.

The slate of therapeutics in the pipeline offers potential for further progress, according to a review in Advances in Therapy.

“Emerging therapeutics are being rationally designed to address persistent gaps in HAE management, including treatment burden,” authors wrote. “Together, these innovations represent a shift from reactive symptom management to mechanism-based, individualized prophylaxis that aligns with patient preferences and evolving standards of care.”

Monoclonal Antibody

Navenibart (formerly STAR-0215) is a long-acting monoclonal antibody targeting plasma kallikrein in development for long-term prophylaxis with a dosing interval of 3 to 6 months.

In phase II ALPHA-SOLAR trial data presented at the American Academy of Allergy, Asthma & Immunology (AAAAI) meeting in February, navenibart reduced monthly attack rate by a median 97% with both every 3-month and every 6-month prophylaxis.

The phase III ALPHA-ORBIT trial is underway testing both the 3- and 6-month navenibart prophylactic dosing schedules in adults and adolescents.

Small Molecule Agents

The novel oral small-molecule bradykinin B2 receptor antagonist deucrictibant is undergoing evaluation for both acute treatment and long-term prophylaxis.

In the phase II CHAPTER-1 trial and long-term extension phase, HAE attack rate remained low on prophylactic 40-mg daily deucrictibant, with an overall on-study attack rate more than 92% lower during the open-label extension out to a maximum 33.8 months of exposure compared with baseline.

For acute treatment with deucrictibant, researchers presented phase III RAPIDe-3 trial data at the AAAAI meeting showing significantly faster relief from and resolution of acute HAE attacks compared with placebo.

Another investigational oral, small-molecule protease inhibitor, dubbed KV998086, is in early development both as an on-demand acute treatment and for chronic prevention. Studies have pointed to its potential to suppresses factor XIIa and single chain factor XII enzymatic activation of the kallikrein-kinin system.

Other small molecule agents being investigated for long-term prophylaxis include ATN-249, VE-4062, and VE-4666, all plasma kallikrein inhibitors.

RNA-based Therapies

An investigational small interfering RNA oligonucleotide, onvuzosiran (or ADX-324), that cleaves prekallikrein mRNA to prevent HAE attacks is given once every 6 months. In findings presented at the AAAAI meeting, a small phase II study showed that patients who had at least 80% reduction in plasma prekallikrein with the drug experienced no HAE attacks. That’s the dosing target for a phase III prophylaxis trial now underway.

Another novel agent, BW-20805, designed to silence the gene responsible for producing prekallikrein in the liver, has also shown promise for long-lasting prophylaxis. In phase II results also presented at AAAAI, 80% of patients (eight of 10) given the subcutaneous injection with data past day 29 remained attack free, and two remained so to 169 days. In those given the drug every 6 months, the time-normalized HAE attack rate dropped by 89-100%.

Gene Therapy

If less-frequent dosing is a goal, then in vivo CRISPR-based therapy lonvoguran ziclumeran (lonvo-z) would be a winner.

Lonvo-z is administered as a one-time, outpatient IV infusion over 2 to 4 hours. It involves a lipid nanoparticle to deliver CRISPR gene editing to the liver where it inactivates the KLKB1 gene that leads to overproduction of bradykinin via kallikrein.

In newly published data in the phase III HAELO trial, lonvo-z lowered HAE attack frequency by a relative 87% after the single infusion, with 0.26 average monthly attacks from weeks 5 through 28 compared with 2.10 in the placebo group (P<0.001) while off long-term HAE prophylaxis.

Over that same period, 62% of the patients who received lonvo-z were considered by the investigator to be HAE attack-free without the use of long-term prophylaxis, as compared with 11% in the placebo group and 40-60% with prophylactic medication in their pivotal trials.

Developer Intellia Therapeutics announced plans to file for FDA approval in the latter half of the year. If approved, lonvo-z would be the first in vivo CRISPR-cas gene editing therapy for any indication, according to the company.

“In sum,” the Advances in Therapy review concluded, “the field stands at a pivotal moment: if emerging therapies fulfill their clinical promise and guideline frameworks adapt with sufficient agility, HAE could transition from an unpredictable and burdensome disease to one that is controllable — and potentially curable — for all individuals living with the condition.”