Two siRNA Therapies Show Promise for Hereditary Angioedema Prevention

Late-breaking data presented at the 2026 Annual Meeting of the American Academy of Allergy, Asthma & Immunology showed that BW-20805 reduced hereditary angioedema attacks by up to 100% with dosing intervals of up to 6 months in a phase 2 trial. An investigator from Charité-Universitätsmedizin Berlin stated the data is comparable or even superior to existing therapies.

BW-20805 consists of a small interfering RNA conjugated with N-acetylgalactosamine, enabling targeted delivery to hepatocytes via the asialoglycoprotein receptor. Once inside liver cells, the molecule inhibits messenger RNA responsible for producing prekallikrein, the inactive precursor of plasma kallikrein.

The ongoing open-label, international, multicenter phase 2 trial enrolled adults with HAE type 1 or type 2 and evaluated 3 dosing regimens of the investigational therapy: 600 mg every 24 weeks, 300 mg every 24 weeks, and 300 mg every 12 weeks. At the time of the interim analysis, 14 participants had been dosed, and 10 had post-dose efficacy data beyond day 29. Among those patients, 80% remained completely attack-free during the observation period.

Across dosing groups, the therapy demonstrated substantial reductions in attack frequency. The highest dose cohort experienced a 100% reduction in time-normalized HAE attack rate, while reductions of 89% and 87% were observed in the 300-mg every-24-week and every-12-week groups, respectively.

Within the first month after administration, prekallikrein levels declined by approximately 90% to 97%, depending on the dosing regimen. These reductions remained stable throughout follow-up in participants who continued in the study.

The therapy also demonstrated a favorable safety profile in early analyses. Most reported adverse events were mild and transient, primarily consisting of injection-site reactions. The interim analysis observed no treatment-related serious adverse events.

Unlike other prophylactic therapies, which often require monthly injections, BW-20805 has an extended dosing interval of every 3 to 6 months. The current findings come from a relatively small phase 2 cohort. Additional data will be needed to confirm the durability of efficacy and further characterize long-term safety. Future analyses will focus on longer follow-up periods, potential delayed adverse events, and whether pharmacokinetic data support even longer dosing intervals.

Separately, onvuzosiran (also known as ADX-324), another investigational small interfering RNA therapeutic candidate, is being evaluated in a Phase 3 clinical trial for the treatment of hereditary angioedema. Phase 1/2 clinical data and Phase 3 design for the program were presented at the 2026 AAAAI Annual Meeting in a poster titled "ADX-324, A Semi-Annual SC Investigational siRNA Targeting Prekallikrein for HAE Attack Prevention."

HAE is a rare genetic disorder characterized by recurrent, unpredictable attacks of swelling that can be painful, disabling, and life-threatening. These attacks result from dysregulation of the kallikrein-kinin system, which regulates blood pressure, inflammation, coagulation and pain. Prekallikrein is a critical protein in the plasma kallikrein pathway that activates a second protein called kallikrein, which, if present, produces bradykinin, a potent vasodilator. A dysfunctional kallikrein-kinin system leads to excessive release of bradykinin which causes the swelling attacks in HAE.

Onvuzosiran is an investigational siRNA therapy designed to inhibit prekallikrein generation at the mRNA level and reduce the production of plasma prekallikrein, thereby averting bradykinin generation and potentially preventing HAE attacks. Compared to currently approved prophylactic treatments, onvuzosiran is expected to decrease prekallikrein to a greater degree, offering the potential for greater and more durable control of kallikrein activity, which is expected to result in a higher proportion of patients remaining attack-free with a less frequent dosing regimen. Onvuzosiran is currently being evaluated in the Phase 3 STOP-HAE clinical trial and has received Orphan Drug Designation for the treatment of patients with HAE from the U.S. Food and Drug Administration.