Antisense Drug Slashed Hereditary Angioedema Attacks in Small Study

Patients with hereditary angioedema who were treated with an antisense oligonucleotide treatment, donidalorsen, experienced significantly fewer attacks than patients who received placebo, a phase II trial showed.

Over 17 weeks, the mean number of investigator-confirmed angioedema attacks was 0.23 per month among the 14 patients treated with donidalorsen 80 mg every 4 weeks compared with 2.21 per month among the six patients in the placebo group (mean difference -90%, 95% CI -96% to -76%, P<0.001), reported Danny Cohn, MD, PhD, of the University of Amsterdam, and colleagues.

Additionally, the mean change in Angioedema Quality of Life Questionnaire score — in which scores range from 0 to 100, with higher scores indicating worse quality of life — from baseline to week 17 was -26.8 points in the donidalorsen group versus -6.2 points in the placebo group (mean difference -20.7 points, 95% CI -32.7 to -8.7), they wrote in the New England Journal of Medicine.

The number of attacks per month leading to on-demand therapy from week 5 to week 17 was reduced by 95% (95% CI -99 to -52) with donidalorsen, the authors noted. Beyond week 5, only one patient in the treatment group had an attack, while all patients in the placebo group had an attack.

Cohn and colleagues suggested that results from week 5 of treatment onwards may be more representative of the clinical effects of donidalorsen, to account for the effect of prekallikrein produced prior to donidalorsen injection.

Hereditary angioedema is a genetic disorder caused by decreased levels (type I) or reduced functionality (type II) of C1 esterase inhibitor, which blocks the activity of kallikrein, an enzyme whose overactivation plays a role in angioedema attacks resulting in painful, potentially fatal episodes of swelling in various parts of the body.

Donidalorsen acts by degrading the mRNA of plasma prekallikrein, a precursor to kallikrein. By the end of the 17-week study period, prekallikrein activity decreased by 61% from baseline in the donidalorsen group, Cohn and colleagues noted.

This phase II study, previously reported at last year’s American College of Allergy, Asthma and Immunology annual meeting, ran from January to October 2020 at seven U.S. sites and one site in the Netherlands.

Twenty adults (mean age 38, 65% women, 18 with type I hereditary angioedema) were randomized 2:1 to donidalorsen 80 mg or placebo every 4 weeks administered at a clinical site via subcutaneous injection into the abdomen, thigh, or upper arm. Patients were included if they had a diagnosis and clinical history of hereditary angioedema confirmed with testing. They were also required to have at least two investigator-confirmed angioedema attacks ≤8 weeks prior to the treatment period.

“An advantage of donidalorsen over [current] therapies is the lower frequency of administration,” Cohn and team wrote. For example, lanadelumab (Takhzyro), a current long-term treatment option for hereditary angioedema, requires injection every 2 weeks.

However, one patient in the donidalorsen group withdrew at week 13 due to long commute times; this patient was still included in the intention-to-treat and safety analyses, the authors said.

No deaths or serious adverse events occurred in either group. The most common adverse events in the treatment group were headache (14%) and nausea (7%), though both occurred at a higher incidence in the placebo group, Cohn and colleagues pointed out.

They noted that their study population did not reflect the racial and ethnic demographics of patients with hereditary angioedema in the U.S. or Europe, which was a limitation to the study.