Hereditary angioedema attacks fall 62% with switch to donidalorsen

Key takeaways:

• Mean attack rates fell by 71% for patients with poorly controlled disease.
• Angioedema Control Test Scores rose from 11.3 to 13.9.
• The percentage of patients with well-controlled disease rose from 67% to 93%.

SAN DIEGO — Patients with hereditary angioedema who switched from other drugs to donidalorsen for long-term prophylaxis experienced fewer attacks and improved disease control, according to a poster presented here.

The safety and tolerability profile for the switch was acceptable as well, Marc A. Riedl, MD, said at the 2025 American Academy of Allergy, Asthma & Immunology/World Allergy Organization Joint Congress.

“Generally, people did well with the switch,” Riedl, clinical director of the U.S. HAEA Angioedema Center at University of California, San Diego, told Healio.

Donidalorsen (Ionis Pharmaceuticals) is an investigational drug that reduces the liver’s prekallikrein production, according to Riedl and colleagues.

The study enrolled 65 patients aged 12 years and older (mean age, 42 years; 59% female; 89% white) with HAE who used lanadelumab (Takhzyro, Takeda), berotralstat (Orladeyo, BioCryst Pharmaceuticals) or a C1 inhibitor for 12 weeks or more.

These patients then switched from these drugs to subcutaneous doses of 80 mg of donidalorsen every 4 weeks.

“This drug targets plasma prekallikrein,” Riedl said. “Lanadelumab and berotralstat also target kallikrein, so it’s a very similar mechanism of action.”

Riedl noted that donidalorsen specifically targets RNA, whereas lanadelumab and berotralstat target antibodies, and C1 inhibitors replace missing proteins.

“There are some nuances to them, but also some similarities,” he said.

Mean HAE attack rates fell by 62% for the full cohort and by 71% for patients with poorly controlled disease by week 16 of donidalorsen treatment. Mean Hereditary Angioedema Control Test (AECT) scores improved from 11.3 to 13.9, and the percentage of patients with well-controlled disease increased from 67% to 93%, also by week 16.

“They did see a reduction in their attacks after switching,” Riedl said.

Specifically, the lanadelumab group (n = 32; mean age, 40 years; 55% male; 84% white) had a mean HAE attack rate of 0.69 that fell 65% to 0.24.

In the berotralstat group (n = 11; mean age, 46 years; 73% female; 100% white), the mean HAE attack rate fell 73% from 1.8 to 0.48.

The mean attack rate fell 41% for the C1 inhibitor group (n = 22; mean age, 41 years; 73% female; 91% white), from 0.61 to 0.36.

Among patients with poorly controlled disease, mean attack rates fell from 1.68 to 0.45 (–73%) for the lanadelumab group (n = 8), from 2.54 to 0.62 (–76%) for the berotralstat group (n = 6) and from 1.19 to 0.47 (–60%) for the C1 inhibitor group (n = 8).

“We see a little bit deeper or greater improvement,” Riedl said.

Mean AECT total scores improved by 2.1 points for the lanadelumab group (n = 27), 4.5 points for the berotralstat group (n = 10) and 2.6 points for the C1 inhibitor group (n = 20).

Percentages of patients with well-controlled disease increased from 74% to 93% in the lanadelumab group (n = 27), from 50% to 90% in the berotralstat group (n = 10) and from 65% to 95% in the C1 inhibitor group (n = 20).

The researchers also recorded treatment-emergent adverse events in 45 (70%) of 64 patients, including 17 (27%) related to donidalorsen. One (2%) event led to discontinuation, and another (2%) was considered serious, but neither was related to the drug.

Also, 12 (19%) of the treatment-emergent adverse events related to the drug were mild, four (6%) were moderate and one (2%) was severe.

“Essentially, it was very safe,” Riedl said. “No major side effect issues.”

Based on these findings, the researchers concluded that patients experienced improvements in disease control after switching to donidalorsen, adding that the switch was safe and tolerable.

“It’s a very effective medication,” Riedl said.

“All these medicines are effective, but for an individual, one medication may work better than another,” he said. “This is reassuring that if people do make a switch, they seem to do well overall.”

Riedl said that the researchers will continue to follow this cohort as they continue to take donidalorsen in the open-label extension.

“The medication has finished phase 3, and it’s with the FDA right now,” he said.