Plasma Prekallikrein Inhibition by Antisense Oligonucleotide Reduces Hereditary Angioedema Disease Burden

An investigational antisense oligo-nucleotide (donidalorsen) that acts by degrading plasma prekallikrein messenger RNA was evaluated in patients with hereditary angioedema (HAE) and C1 inhibitor deficiency to assess whether this agent can reduce the frequency of angioedema attacks and the burden of disease.

In this Phase II trial, 20 HAE patients were randomized in a 2:1 ratio to receive four subcutaneous 80 mg doses of either donidalorsen or placebo, with one dose administered every four weeks. The primary endpoint was the time-normalized number of investigator-confirmed angioedema attacks per month between week 1 (baseline) and week 17.

From baseline, prekallikrein activity in the donidalorsen group decreased by 61 percent by the end of the study. The mean monthly angioedema attack rate was 0.23 (95% confidence interval [CI] 0.08 to 0.39), compared to 2.21 in those receiving placebo (95% CI 0.58 to 3.85), a mean difference of 90 percent. This closely corresponded with a 95 percent reduction in the number of attacks per month that required on-demand therapy between week 5 and week 17 (95% CI -99% to -52%). Beyond week 5, just one of 14 patients in the donidalorsen group experienced an attack, versus all six subjects in the placebo group.

The mean change in the 100- point Angioedema Quality of Life Questionnaire was -26.8 points in the donidalorsen group and -6.2 points in the placebo group. No serious adverse events were reported in either group. The investigators concluded that, in this small Phase II trial, donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo. [Study funded by Ionis Pharmaceuticals.]