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NEW YORK (Reuters Health) – Treatment with the experimental drug donidalorsen cut the number of attacks over 17 weeks by 90% in people with hereditary angioedema, according to the results from a 20-patient randomized phase-2 trial.

The six placebo recipients had an average of 2.21 attacks per month compared with 0.23 per month among the 14 volunteers who received four doses of donidalorsen, one every four weeks (P<0.001), zolpidem sleep researchers report in the New England Journal of Medicine.

The rate of mild-to-moderate adverse events was highest in the placebo group.

“Patients were very satisfied with this treatment,” senior author Dr. Danny Cohn of the University of Amsterdam told Reuters Health by email. “It seems very promising that we may meet the ultimate treatment goal for these patients, i.e. total control of the disease with an unimpaired quality of life.”

“Besides a dramatic decrease in angioedema attacks, patients also reported an impressive improvement of quality of life,” he said.

Developer Ionis Pharmaceuticals paid for the study of the antisense oligonucleotide.

The result “is very good news for persons with hereditary angioedema,” said Drs. Hilary Longhurst and Rohan Ameratunga of the University of Auckland, New Zealand, in a linked editorial. But a phase-3 study remains to be done.

The rare genetic disorder affects about 20,000 people in the United States and Europe. Attacks are unpredictable, causing pain and disfigurement. The swelling can be deadly; without specialized treatment, mortality can be as high as 40%.

The condition is caused by too much bradykinin, which causes blood vessels to widen and become leaky. Donidalorsen works by binding to – and inactivating – a molecule needed to guide production of a protein known as prekallikrein, which the body uses to create bradykinin.

Of the plasma kallikrein-suppressors approved for hereditary angioedema, Takeda’s Takhzyro (lanadelumab) is given subcutaneously twice a month, and BioCryst Pharmaceuticals’ Orladeyo (berotralstat) is a daily oral drug.

The new test was done on adults at seven U.S. sites and one in the Netherlands. During the run-in period of the study, the mean attack rate was 2.7 per month.

The researchers also looked at attacks that occurred between weeks 5 and 17, discovering that the monthly rate was 0.07 with the drug versus 2.06 with placebo.

“After the second administration, only one patient (patient 14) had three more attacks. The other 13 patients were free of attacks. The three attacks of patient 14 included 1 mild, 1 moderate and 1 severe attack,” said Dr. Cohn.

Meanwhile, “none of the 6 patients receiving placebo” were attack-free, the researchers report.

The scope of the attacks ranged from mild, which were mostly isolated swelling of a hand or a foot, to severe, which included upper airway obstruction or severe abdominal attacks with cramps and vomiting.

When the team used a 100-point scale, with higher scores reflecting poorer quality of life, the volunteers in the placebo group saw an improvement of 6.2 points versus 26.8 points with donidalorsen, a significant difference.

Two of the 14 donidalorsen recipients experienced headache and one reported nausea.

“The incidence of mild-to-moderate adverse events was higher among the patients receiving placebo than among those receiving donidalorsen (83% vs. 71%),” the researchers write. “All the adverse events that occurred during the treatment period resolved by the end of the trial.”

“I believe that doctors and patients will be enthusiastic to see the therapeutic options expanded,” Dr. Cohn said, “especially since this drug seems very effective with only a single, small, subcutaneous injection per month.”

The results were originally released November 7 during the American College of Asthma, Allergy & Immunology Annual Scientific Meeting in New Orleans.

An open-label extension of the trial, which will cover 156 weeks, is ongoing, as is a phase-3 study of the treatment that is expected to involve up to 84 participants and produce results in October of next year.

SOURCE: https://bit.ly/3t5aKSH and https://bit.ly/3tN93It The New England Journal of Medicine, online March 16, 2022.

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