FDA approves first RNA-targeted therapy for hereditary angioedema

FDA approves first RNA-targeted therapy for hereditary angioedema | Image credit: Contemporary Pediatrics.

The US Food and Drug Administration (FDA) has approved donidalorsen (DAWNZERA; Ionis Pharmaceuticals) for prophylaxis to prevent hereditary angioedema (HAE) attacks in adult and pediatric patients aged 12 years and older. Donidalorsen is the first RNA-targeted therapy approved for HAE and is designed to inhibit plasma prekallikrein, a protein involved in activating inflammatory mediators associated with acute attacks, according to the company.¹

Donidalorsen is administered via subcutaneous autoinjector, with available dosing once every 4 weeks (Q4W) or every 8 weeks (Q8W). HAE is a rare genetic condition characterized by recurrent and potentially life-threatening angioedema. Approximately 7000 individuals in the United States are estimated to have the disorder.¹

“DAWNZERA represents a significant advance for people living with HAE who need improved treatment options. With strong and durable efficacy, convenient administration and the longest dosing option available, we believe DAWNZERA will be the prophylactic treatment of choice for many people living with HAE,” said Brett P. Monia, PhD, CEO of Ionis.

Phase 3 trial data

The FDA approval was supported by results from the Phase 3 OASIS-HAE trial, a randomized, double-blind, placebo-controlled study (NCT05139810). A total of 90 patients were assigned to receive donidalorsen 80 mg subcutaneously every 4 weeks (n=45), every 8 weeks (n=23), or placebo (n=22).²

The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27-0.73) in the Q4W group, 1.02 (95% CI, 0.65-1.59) in the Q8W group, and 2.26 (95% CI, 1.66-3.09) in the placebo group. Donidalorsen Q4W reduced the mean attack rate from week 1 to week 25 by 81% compared with placebo (95% CI, 65-89; P<.001), while the Q8W regimen reduced attack rate by 55% compared with placebo (95% CI, 22-74; P=.004). Median reduction in attack rate from baseline was 90% in the Q4W group, 83% in the Q8W group, and 16% in the placebo group.²

During weeks 5 through 25, the Q4W regimen achieved an 87% lower mean attack rate than placebo (95% CI, 72-94; P<.001), while the Q8W regimen achieved a 60% reduction compared with placebo (95% CI, 25-79). Patients receiving donidalorsen Q4W also demonstrated improvement in health-related quality of life. The least-squares mean total score change on the Angioedema Quality-of-Life Questionnaire at week 25 was 18.6 points (95% CI, 9.5-27.7) better than with placebo (P<.001), with higher scores indicating worse quality of life.²

Extension study and switch data

Findings from the OASISplus open-label extension supported the durability of donidalorsen efficacy. Both Q4W and Q8W regimens achieved a 94% reduction in mean attack rate from baseline after 1 year. In a switch cohort, patients previously treated with lanadelumab, C1-esterase inhibitor, or berotralstat demonstrated a 62% reduction in mean HAE attack rate after switching to donidalorsen, with no increase in breakthrough attacks. A total of 84% of patients reported preferring donidalorsen over prior prophylaxis.

Safety profile

The most common adverse reactions reported in clinical studies were injection site reactions, upper respiratory tract infection, urinary tract infection, and abdominal discomfort. In the pivotal trial, injection site erythema, headache, and nasopharyngitis were most frequent, with 98% of adverse events rated as mild or moderate.

Expert perspective

“As the first FDA-approved RNA-targeted therapy for HAE, DAWNZERA represents a welcome advance in therapeutic options for preventing attacks. Today’s approval gives people living with HAE and their physicians another important choice for aligning treatment with individual needs,” said Anthony J. Castaldo, CEO and board chairman of the US Hereditary Angioedema Association and Hereditary Angioedema International.

Marc Riedl, MD, MS, clinical director, US HAEA Angioedema Center, University of California, San Diego, and trial investigator, stated, “People living with HAE manage this condition for all their lives, and many continue to face unpredictable, painful, and dangerous breakthrough attacks even with current treatments. Durable efficacy is essential in maintaining long-term disease control. DAWNZERA is positioned to help meet patient needs, providing substantial and sustained reduction of HAE attacks, continued improvement over time, and reduced burden of treatment.”

References:

1. DAWNZERA™ (donidalorsen) approved in the U.S. as first and only RNA-targeted prophylactic treatment for hereditary angioedema. Ionis Pharmaceuticals. August 21, 2025. Accessed August 22, 2025.
2. Riedl MA, Tachdjian R, Lumry WR, et al. Efficacy and Safety of Donidalorsen for Hereditary Angioedema. N Engl J Med. 2024;391(1):21-31. doi:10.1056/NEJMoa2402478